Life | Editor’s choice Articles

14 pages, 5268 KB

Open AccessEditor’s ChoiceArticle

CXCR3 Expression and Genome-Wide 3′ Splice Site Selection in the TCGA Breast Cancer Cohort

by Lauren A. Levesque, Scott Roy and Nicole Salazar

Life 2021, 11(8), 746; https://doi.org/10.3390/life11080746 - 26 Jul 2021

Cited by 5 | Viewed by 4116

CXCR3 is a chemokine receptor with two well-characterized isoforms that have unique, context-dependent roles: CXCR3-A and CXCR3-B, which are produced through alternative 3′ splice site selection (A3SS). RNA-seq data from The Cancer Genome Atlas (TCGA) were used to correlate CXCR3 expression with breast [...] Read more.

CXCR3 is a chemokine receptor with two well-characterized isoforms that have unique, context-dependent roles: CXCR3-A and CXCR3-B, which are produced through alternative 3′ splice site selection (A3SS). RNA-seq data from The Cancer Genome Atlas (TCGA) were used to correlate CXCR3 expression with breast cancer progression. This analysis revealed significant CXCR3 expression patterns associated with survival and differential expression between the tumor and adjacent normal tissue. TCGA data were used to estimate abundance of immune cells in breast cancer, which demonstrated the association of CXCR3 with immune infiltration, particularly in the triple-negative subtype. Given the importance of A3SS in CXCR3, genome-wide analysis of A3SS events was performed to identify events that were differentially spliced between breast cancer tissue and adjacent normal tissue. A total of 481 splicing events in 424 genes were found to be differentially spliced. The parent genes of differentially spliced events were enriched in RNA processing and splicing functions, indicating an underappreciated role of A3SS in the integrated splicing network of breast cancer. These results further validated the role of CXCR3 in immune infiltration of tumors, while raising questions about the role of A3SS splicing. Full article

(This article belongs to the Special Issue Chemokines and Their Receptors)

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13 pages, 1395 KB

Open AccessEditor’s ChoiceArticle

Multimodal Patient-Specific Registration for Breast Imaging Using Biomechanical Modeling with Reference to AI Evaluation of Breast Tumor Change

by Cheng Xue, Fuk-Hay Tang, Christopher W. K. Lai, Lars J. Grimm and Joseph Y. Lo

Life 2021, 11(8), 747; https://doi.org/10.3390/life11080747 - 26 Jul 2021

Cited by 8 | Viewed by 3213

Abstract

Background: The strategy to combat the problem associated with large deformations in the breast due to the difference in the medical imaging of patient posture plays a vital role in multimodal medical image registration with artificial intelligence (AI) initiatives. How to build a [...] Read more.

Background: The strategy to combat the problem associated with large deformations in the breast due to the difference in the medical imaging of patient posture plays a vital role in multimodal medical image registration with artificial intelligence (AI) initiatives. How to build a breast biomechanical model simulating the large-scale deformation of soft tissue remains a challenge but is highly desirable. Methods: This study proposed a hybrid individual-specific registration model of the breast combining finite element analysis, property optimization, and affine transformation to register breast images. During the registration process, the mechanical properties of the breast tissues were individually assigned using an optimization process, which allowed the model to become patient specific. Evaluation and results: The proposed method has been extensively tested on two datasets collected from two independent institutions, one from America and another from Hong Kong. Conclusions: Our method can accurately predict the deformation of breasts from the supine to prone position for both the Hong Kong and American samples, with a small target registration error of lesions. Full article

(This article belongs to the Special Issue A New Era of Multidisciplinary Radiology: Fast Growing of Medical Radiation/Imaging/Artificial Intelligence Research)

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15 pages, 2079 KB

Open AccessEditor’s ChoiceArticle

Does Needle Design Affect the Regenerative Potential of Bone Marrow Aspirate? An In Vitro Study

by Nadia Feddahi, Monika Herten, Tjark Tassemeier, Heike Rekasi, Alexander Hackel, Marcel Haversath and Marcus Jäger

Life 2021, 11(8), 748; https://doi.org/10.3390/life11080748 - 26 Jul 2021

Cited by 6 | Viewed by 3359

Abstract

While autologous bone is still the gold standard for treatment of bone defects, its availability is limited. Sufficient numbers of mesenchymal stroma cells (MSC) may be an alternative. Small volumes of bone marrow aspirate (BMA) were harvested with two different needle systems comparing [...] Read more.

While autologous bone is still the gold standard for treatment of bone defects, its availability is limited. Sufficient numbers of mesenchymal stroma cells (MSC) may be an alternative. Small volumes of bone marrow aspirate (BMA) were harvested with two different needle systems comparing the yield and regenerative potency of the MSCs. BMA (10 mL) was aspirated from the posterior iliac crest of 12 patients with degenerative spinal disc disease using both needle systems in each patient: the Jamshidi needle (JAM) and on the contralateral side the Marrow Cellution^® Needle (AMC). Number of mononuclear cells (MNCs) and regeneration capacity (colony-forming unit/CFU) were determined. MSCs were characterized for surface markers and their differentiation into trilineages. There was no significant difference between the two harvesting needles regarding the quantity of MNCs in BMA: 5.2 ± 1.8 × 10⁹ MNC/mL for AMC vs. 4.8 ± 2.5 × 10⁹ MNC/mL for JAM, p = 0.182. The quantity of CFUs per ml BMA was similar for both groups: 3717 ± 5556 for AMC and 4305 ± 5507 for JAM (p = 0.695). The potency of MSCs expressed as colony-forming potential per 10⁶ MNC resulted in 0.98 ± 1.51 for AMC and 1.00 ± 0.96 for JAM (p = 0.666). Regardless of the needle design, 10 mL bone marrow aspirate contains a sufficient number of about 40,000 MSCs that can be used to enhance bone healing. Full article

(This article belongs to the Special Issue Healing after Trauma)

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16 pages, 633 KB

Open AccessEditor’s ChoiceReview

Non-Coding RNAs and Splicing Activity in Testicular Germ Cell Tumors

by Marco Barchi, Pamela Bielli, Susanna Dolci, Pellegrino Rossi and Paola Grimaldi

Life 2021, 11(8), 736; https://doi.org/10.3390/life11080736 - 24 Jul 2021

Cited by 11 | Viewed by 4534

Abstract

Testicular germ cell tumors (TGCTs) are the most common tumors in adolescent and young men. Recently, genome-wide studies have made it possible to progress in understanding the molecular mechanisms underlying the development of tumors. It is becoming increasingly clear that aberrant regulation of [...] Read more.

Testicular germ cell tumors (TGCTs) are the most common tumors in adolescent and young men. Recently, genome-wide studies have made it possible to progress in understanding the molecular mechanisms underlying the development of tumors. It is becoming increasingly clear that aberrant regulation of RNA metabolism can drive tumorigenesis and influence chemotherapeutic response. Notably, the expression of non-coding RNAs as well as specific splice variants is deeply deregulated in human cancers. Since these cancer-related RNA species are considered promising diagnostic, prognostic and therapeutic targets, understanding their function in cancer development is becoming a major challenge. Here, we summarize how the different expression of RNA species repertoire, including non-coding RNAs and protein-coding splicing variants, impacts on TGCTs’ onset and progression and sustains therapeutic resistance. Finally, the role of transcription-associated R-loop misregulation in the maintenance of genomic stability in TGCTs is also discussed. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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13 pages, 544 KB

Open AccessEditor’s ChoiceReview

Role of Matrix Gla Protein in the Complex Network of Coronary Artery Disease: A Comprehensive Review

by Marko Kumric, Josip A. Borovac, Tina Ticinovic Kurir, Dinko Martinovic, Ivan Frka Separovic, Ljupka Baric and Josko Bozic

Life 2021, 11(8), 737; https://doi.org/10.3390/life11080737 - 24 Jul 2021

Cited by 8 | Viewed by 3978

Abstract

Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather [...] Read more.

Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather than passively, as previously regarded. Matrix Gla protein (MGP), a vitamin K-dependent protein, emerged as an important inhibitor of both intimal and medial vascular calcification. The functionality of MGP hinges on two post-translational modifications: phosphorylation and carboxylation. Depending on the above-noted modifications, various species of MGP may exist in circulation, each with their respective level of functionality. Emerging data suggest that dysfunctional species of MGP, markedly, dephosphorylated-uncarboxylated MGP, might find its application as biomarkers of microvascular health, and assist in clinical decision making with regard to initiation of vitamin K supplementation. Hence, in this review we summarized the current knowledge with respect to the role of MGP in the complex network of vascular calcification with concurrent inferences to CAD. In addition, we discussed the effects of warfarin use on MGP functionality, with concomitant implications to coronary plaque stability. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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21 pages, 815 KB

Open AccessEditor’s ChoiceSystematic Review

Neuroimaging Studies of Nonsuicidal Self-Injury in Youth: A Systematic Review

by Marcelo J. A. A. Brañas, Marcos S. Croci, Ana Beatriz Ravagnani Salto, Victoria F. Doretto, Eduardo Martinho, Jr., Marcos Macedo, Euripedes C. Miguel, Leonardo Roever and Pedro M. Pan

Life 2021, 11(8), 729; https://doi.org/10.3390/life11080729 - 22 Jul 2021

Cited by 20 | Viewed by 7547

Abstract

Nonsuicidal self-injury (NSSI) is prevalent and affects mainly the youth population. It is prospectively associated with suicide attempts, making it a target for suicide prevention. Recently, several studies have investigated neural pathways of NSSI using neuroimaging. However, there is a lack of systematized [...] Read more.

Nonsuicidal self-injury (NSSI) is prevalent and affects mainly the youth population. It is prospectively associated with suicide attempts, making it a target for suicide prevention. Recently, several studies have investigated neural pathways of NSSI using neuroimaging. However, there is a lack of systematized appraisal of these findings. This systematic review aims to identify and summarize the main neuroimaging findings of NSSI in youth. We followed PRISMA statement guidelines and searched MEDLINE, APA PsycInfo, and Google Scholar databases for neuroimaging studies, irrespective of imaging modality, specifically investigating NSSI in samples with a mean age of up to 25 years old. Quality assessment was made using the Newcastle–Ottawa and Joanna Briggs Institute scales. The initial search retrieved 3030 articles; 21 met inclusion criteria, with a total of 938 subjects. Eighteen studies employed functional neuroimaging techniques such as resting-state and task-based fMRI (emotional, interpersonal exposure/social exclusion, pain, reward, and cognitive processing paradigms). Three studies reported on structural MRI. An association of NSSI behavior and altered emotional processing in cortico-limbic neurocircuitry was commonly reported. Additionally, alterations in potential circuits involving pain, reward, interpersonal, self-processing, and executive function control processes were identified. NSSI has complex and diverse neural underpinnings. Future longitudinal studies are needed to understand its developmental aspects better. Full article

(This article belongs to the Special Issue Innovations in the Neurobiology of Neuropsychiatric Disorders)

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37 pages, 5057 KB

Open AccessEditor’s ChoiceReview

TCA Cycle Replenishing Pathways in Photosynthetic Purple Non-Sulfur Bacteria Growing with Acetate

by Ekaterina Petushkova, Ekaterina Mayorova and Anatoly Tsygankov

Life 2021, 11(7), 711; https://doi.org/10.3390/life11070711 - 19 Jul 2021

Cited by 20 | Viewed by 12856

Abstract

Purple non-sulfur bacteria (PNSB) are anoxygenic photosynthetic bacteria harnessing simple organic acids as electron donors. PNSB produce a-aminolevulinic acid, polyhydroxyalcanoates, bacteriochlorophylls a and b, ubiquinones, and other valuable compounds. They are highly promising producers of molecular hydrogen. PNSB can be cultivated [...] Read more.

Purple non-sulfur bacteria (PNSB) are anoxygenic photosynthetic bacteria harnessing simple organic acids as electron donors. PNSB produce a-aminolevulinic acid, polyhydroxyalcanoates, bacteriochlorophylls a and b, ubiquinones, and other valuable compounds. They are highly promising producers of molecular hydrogen. PNSB can be cultivated in organic waste waters, such as wastes after fermentation. In most cases, wastes mainly contain acetic acid. Therefore, understanding the anaplerotic pathways in PNSB is crucial for their potential application as producers of biofuels. The present review addresses the recent data on presence and diversity of anaplerotic pathways in PNSB and describes different classifications of these pathways. Full article

(This article belongs to the Special Issue Metabolism of Photosynthetic Organisms)

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25 pages, 2054 KB

Open AccessEditor’s ChoiceReview

Sorghum’s Whole-Plant Transcriptome and Proteome Responses to Drought Stress: A Review

by Rudo Ngara, Tatenda Goche, Dirk Z. H. Swanevelder and Stephen Chivasa

Life 2021, 11(7), 704; https://doi.org/10.3390/life11070704 - 17 Jul 2021

Cited by 29 | Viewed by 5800

Abstract

Sorghum is a cereal crop with key agronomic traits of drought and heat stress tolerance, making it an ideal food and industrial commodity for hotter and more arid climates. These stress tolerances also present a useful scientific resource for studying the molecular basis [...] Read more.

Sorghum is a cereal crop with key agronomic traits of drought and heat stress tolerance, making it an ideal food and industrial commodity for hotter and more arid climates. These stress tolerances also present a useful scientific resource for studying the molecular basis for environmental resilience. Here we provide an extensive review of current transcriptome and proteome works conducted with laboratory, greenhouse, or field-grown sorghum plants exposed to drought, osmotic stress, or treated with the drought stress-regulatory phytohormone, abscisic acid. Large datasets from these studies reveal changes in gene/protein expression across diverse signaling and metabolic pathways. Together, the emerging patterns from these datasets reveal that the overall functional classes of stress-responsive genes/proteins within sorghum are similar to those observed in equivalent studies of other drought-sensitive model species. This highlights a monumental challenge of distinguishing key regulatory genes/proteins, with a primary role in sorghum adaptation to drought, from genes/proteins that change in expression because of stress. Finally, we discuss possible options for taking the research forward. Successful exploitation of sorghum research for implementation in other crops may be critical in establishing climate-resilient agriculture for future food security. Full article

(This article belongs to the Special Issue Plant Proteomics)

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12 pages, 1206 KB

Open AccessEditor’s ChoiceReview

The Role of Protein S-Nitrosylation in Protein Misfolding-Associated Diseases

by Yun-Jin Ju, Hye-Won Lee, Ji-Woong Choi and Min-Sik Choi

Life 2021, 11(7), 705; https://doi.org/10.3390/life11070705 - 17 Jul 2021

Cited by 14 | Viewed by 4272

Abstract

Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, [...] Read more.

Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, the relationship between S-nitrosylated proteins and the accumulation of misfolded proteins was reviewed. We particularly focused on the S-nitrosylation of E3-ubiquitin-protein ligase, parkin, and endoplasmic reticulum chaperone, PDI, which contribute to the accumulation of misfolded proteins. In addition to the target proteins being S-nitrosylated, NOS, which produces NO, and GSNOR, which inhibits S-nitrosylation, were also suggested as potential therapeutic targets for protein misfolding-associated diseases. Full article

(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)

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12 pages, 3240 KB

Open AccessEditor’s ChoiceArticle

Bone Morphogenetic Protein 7 Effect on Human Glioblastoma Cell Transmigration and Migration

by Ting-Chung Wang, Sheng-Jie Luo and Shun-Fu Chang

Life 2021, 11(7), 708; https://doi.org/10.3390/life11070708 - 17 Jul 2021

Cited by 4 | Viewed by 3023

Abstract

Glioblastoma, World Health Organization—grade IV, is the most malignant glioma type and it is still an incurable tumor due to the high level of heterogeneity and uncontrolled metastatic nature. In addition to the tumorigenicity-suppressing activity, bone morphogenetic protein 7 (BMP7) has recently been [...] Read more.

Glioblastoma, World Health Organization—grade IV, is the most malignant glioma type and it is still an incurable tumor due to the high level of heterogeneity and uncontrolled metastatic nature. In addition to the tumorigenicity-suppressing activity, bone morphogenetic protein 7 (BMP7) has recently been found for its invasion-promoting role in glioblastoma. However, the detailed and precise mechanism in this issue should have more elucidation. Thus, in this study, we determined the BMP7 effect on glioblastoma transmigration and migration regulations and the underlying mechanisms. Human LN18/LN229 glioblastoma cells were used in this study. Our results showed a higher BMP7/pSmad5 level in human malignant glioma tissues compared to healthy brain tissues. In addition, it was demonstrated that endogenous and exogenous BMP7 stimulation could increase the transmigration and migration capabilities of human LN18/LN229 glioblastoma cells. Moreover, this event is regulated by Smad5 and p75 neurotrophin receptor (p75NTR) signaling. Furthermore, unexpected data are that the Smad1 gene knockdown could lead to the cell death of human LN18 glioblastoma cells. Overall, the present study finds that the invasion-promoting activity of BMP7 might be an autocrine stimulation of glioblastoma and this effect could be regulated by Smad5-p75NTR signaling. Full article

(This article belongs to the Section Physiology and Pathology)

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15 pages, 3968 KB

Open AccessEditor’s ChoiceReview

Structure, Activity and Function of the Suv39h1 and Suv39h2 Protein Lysine Methyltransferases

by Sara Weirich, Mina S. Khella and Albert Jeltsch

Life 2021, 11(7), 703; https://doi.org/10.3390/life11070703 - 16 Jul 2021

Cited by 32 | Viewed by 7910

Abstract

SUV39H1 and SUV39H2 were the first protein lysine methyltransferases that were identified more than 20 years ago. Both enzymes introduce di- and trimethylation at histone H3 lysine 9 (H3K9) and have important roles in the maintenance of heterochromatin and gene repression. They consist [...] Read more.

SUV39H1 and SUV39H2 were the first protein lysine methyltransferases that were identified more than 20 years ago. Both enzymes introduce di- and trimethylation at histone H3 lysine 9 (H3K9) and have important roles in the maintenance of heterochromatin and gene repression. They consist of a catalytically active SET domain and a chromodomain, which binds H3K9me2/3 and has roles in enzyme targeting and regulation. The heterochromatic targeting of SUV39H enzymes is further enhanced by the interaction with HP1 proteins and repeat-associated RNA. SUV39H1 and SUV39H2 recognize an RKST motif with additional residues on both sides, mainly K4 in the case of SUV39H1 and G12 in the case of SUV39H2. Both SUV39H enzymes methylate different non-histone proteins including RAG2, DOT1L, SET8 and HupB in the case of SUV39H1 and LSD1 in the case of SUV39H2. Both enzymes are expressed in embryonic cells and have broad expression profiles in the adult body. SUV39H1 shows little tissue preference except thymus, while SUV39H2 is more highly expressed in the brain, testis and thymus. Both enzymes are connected to cancer, having oncogenic or tumor-suppressive roles depending on the tumor type. In addition, SUV39H2 has roles in the brain during early neurodevelopment. Full article

(This article belongs to the Special Issue Structure, Activity, and Function of Protein Methyltransferases)

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16 pages, 5103 KB

Open AccessEditor’s ChoiceArticle

Mitogenomics, Phylogeny and Morphology Reveal Ophiocordyceps pingbianensis Sp. Nov., an Entomopathogenic Fungus from China

by Siqi Chen, Yuanbing Wang, Kongfu Zhu and Hong Yu

Life 2021, 11(7), 686; https://doi.org/10.3390/life11070686 - 14 Jul 2021

Cited by 11 | Viewed by 3725

Abstract

The new entomopathogenic fungus Ophiocordyceps pingbianensis, collected from Southeast China, was described by mitogenomic, morphological, and phylogenetic evidence. The systematic position of O. pingbianensis was determined by phylogenetic analyses based on six nuclear gene (ITS, tef1-α, nrSSU, nrLSU, rpb1 [...] Read more.

The new entomopathogenic fungus Ophiocordyceps pingbianensis, collected from Southeast China, was described by mitogenomic, morphological, and phylogenetic evidence. The systematic position of O. pingbianensis was determined by phylogenetic analyses based on six nuclear gene (ITS, tef1-α, nrSSU, nrLSU, rpb1 and rpb2) and 14 mitochondrial protein-coding gene (PCGs) (cox1, cox2, cox3, atp6, atp8, atp9, cob, nad1, nad2, nad3, nad4, nad5, nad6 and nad4L) data. Phylogenetic analyses reveal that O. pingbianensis was belonged to the Hirsutella nodulosa clade in the genus Ophiocordyceps of Ophiocordycipiaceae. This fungus exhibits distinctive characteristics which differed from other related Ophiocordyceps species with slender and geminate stromata, monophialidic conidiogenous cells with an inflated awl-shaped base, a twisty and warty phialide neck and a fusiform or oval conidia, as well as being found on a tiger beetle of Coleoptera buried in moss at the cave. The complete mitochondrial genome of O. pingbianensis was a circular DNA molecule 80,359 bp in length, containing 15 PCGs, 24 open reading frames genes (ORFs), 25 transfer RNA genes (tRNAs) and 27 introns. Ophiocordyceps pingbianensis, containing 27 introns, has the second largest mitogenome in Ophiocordycipiaceae and was next to O. sinensis. To our knowledge, this is the first report of the mitogenome from a new entomopathogenic fungus, and thus provides an important foundation for future studies on taxonomy, genetics and evolutionary biology of Ophiocordycipiaceae. Full article

(This article belongs to the Special Issue Biodiversity and Ecology of Fungi in Terrestrial and Marine Ecosystems)

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26 pages, 2065 KB

Open AccessEditor’s ChoiceReview

‘Whole Organism’, Systems Biology, and Top-Down Criteria for Evaluating Scenarios for the Origin of Life

by Clifford F. Brunk and Charles R. Marshall

Life 2021, 11(7), 690; https://doi.org/10.3390/life11070690 - 14 Jul 2021

Cited by 18 | Viewed by 7080

Abstract

While most advances in the study of the origin of life on Earth (OoLoE) are piecemeal, tested against the laws of chemistry and physics, ultimately the goal is to develop an overall scenario for life’s origin(s). However, the dimensionality of non-equilibrium chemical systems, [...] Read more.

While most advances in the study of the origin of life on Earth (OoLoE) are piecemeal, tested against the laws of chemistry and physics, ultimately the goal is to develop an overall scenario for life’s origin(s). However, the dimensionality of non-equilibrium chemical systems, from the range of possible boundary conditions and chemical interactions, renders the application of chemical and physical laws difficult. Here we outline a set of simple criteria for evaluating OoLoE scenarios. These include the need for containment, steady energy and material flows, and structured spatial heterogeneity from the outset. The Principle of Continuity, the fact that all life today was derived from first life, suggests favoring scenarios with fewer non-analog (not seen in life today) to analog (seen in life today) transitions in the inferred first biochemical pathways. Top-down data also indicate that a complex metabolism predated ribozymes and enzymes, and that full cellular autonomy and motility occurred post-LUCA. Using these criteria, we find the alkaline hydrothermal vent microchamber complex scenario with a late evolving exploitation of the natural occurring pH (or Na⁺ gradient) by ATP synthase the most compelling. However, there are as yet so many unknowns, we also advocate for the continued development of as many plausible scenarios as possible. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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18 pages, 2557 KB

Open AccessEditor’s ChoiceReview

In Vitro Measurements of Cellular Forces and their Importance in the Lung—From the Sub- to the Multicellular Scale

by Peter Kolb, Annika Schundner, Manfred Frick and Kay-E. Gottschalk

Life 2021, 11(7), 691; https://doi.org/10.3390/life11070691 - 14 Jul 2021

Cited by 4 | Viewed by 4156

Abstract

Throughout life, the body is subjected to various mechanical forces on the organ, tissue, and cellular level. Mechanical stimuli are essential for organ development and function. One organ whose function depends on the tightly connected interplay between mechanical cell properties, biochemical signaling, and [...] Read more.

Throughout life, the body is subjected to various mechanical forces on the organ, tissue, and cellular level. Mechanical stimuli are essential for organ development and function. One organ whose function depends on the tightly connected interplay between mechanical cell properties, biochemical signaling, and external forces is the lung. However, altered mechanical properties or excessive mechanical forces can also drive the onset and progression of severe pulmonary diseases. Characterizing the mechanical properties and forces that affect cell and tissue function is therefore necessary for understanding physiological and pathophysiological mechanisms. In recent years, multiple methods have been developed for cellular force measurements at multiple length scales, from subcellular forces to measuring the collective behavior of heterogeneous cellular networks. In this short review, we give a brief overview of the mechanical forces at play on the cellular level in the lung. We then focus on the technological aspects of measuring cellular forces at many length scales. We describe tools with a subcellular resolution and elaborate measurement techniques for collective multicellular units. Many of the technologies described are by no means restricted to lung research and have already been applied successfully to cells from various other tissues. However, integrating the knowledge gained from these multi-scale measurements in a unifying framework is still a major future challenge. Full article

(This article belongs to the Special Issue Mechanical Forces in the Cell)

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9 pages, 667 KB

Open AccessEditor’s ChoiceCase Report

Long-Term Maintained Response to Selective Internal Radiation Therapy in an Oligometastatic Uveal Melanoma Patient Treated with Concomitant Anti-PD-1 Therapy

by Ilaria Proietti, Nevena Skroza, Luca Filippi, Nicoletta Bernardini, Alessandra Mambrin, Ersilia Tolino, Giovanni Rossi, Anna Marchesiello, Federica Marraffa, Salvatore Volpe, Oreste Bagni and Concetta Potenza

Life 2021, 11(7), 692; https://doi.org/10.3390/life11070692 - 14 Jul 2021

Cited by 2 | Viewed by 2468

Abstract

Uveal melanoma (UM) is a primary neoplasm of the eye arising from the melanocytes residing in the iris, ciliary body or choroid. It is the most frequent intraocular malignancy and often determines metastases at distant sites, with a peculiar tropism for the liver. [...] Read more.

Uveal melanoma (UM) is a primary neoplasm of the eye arising from the melanocytes residing in the iris, ciliary body or choroid. It is the most frequent intraocular malignancy and often determines metastases at distant sites, with a peculiar tropism for the liver. Metastatic UM has a poor prognosis, as any treatment affects the natural course of this fatal disease. Herein, we report a case of a UM metastatic to the liver in a 54 year-old female patient, initially treated with nivolumab without success. The patient was then scheduled for selective internal radiation therapy (SIRT) while continuing immunotherapy. This combination led to a complete and durable response and the patient is currently free of disease, two years after the diagnosis of the hepatic metastases. The association between SIRT and immunotherapy (IT) has very promising perspectives for metastatic UM, especially considering the disappointing or contradictory results of classic chemotherapies, IT alone and targeted therapies. Furthermore, this combination has been shown to have a good security profile. However, further studies are needed to confirm the efficacy of associating SIRT and IT and to clarify some unsolved problems, such as the timing of administration of these two therapies. Full article

(This article belongs to the Special Issue Primitive and Metastatic Tumours of the Skin)

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14 pages, 2189 KB

Open AccessEditor’s ChoiceArticle

Perception of Thermal Comfort during Skin Cooling and Heating

by Igor B. Mekjavic, Daniel Yogev and Urša Ciuha

Life 2021, 11(7), 681; https://doi.org/10.3390/life11070681 - 12 Jul 2021

Cited by 13 | Viewed by 4360

Abstract

Due to the static and dynamic activity of the skin temperature sensors, the cutaneous thermal afferent information is dependent on the rate and direction of the temperature change, which would suggest different perceptions of temperature and of thermal comfort during skin heating and [...] Read more.

Due to the static and dynamic activity of the skin temperature sensors, the cutaneous thermal afferent information is dependent on the rate and direction of the temperature change, which would suggest different perceptions of temperature and of thermal comfort during skin heating and cooling. This hypothesis was tested in the present study. Subjects (N = 12; 6 females and 6 males) donned a water-perfused suit (WPS) in which the temperature was varied in a saw-tooth manner in the range from 27 to 42 °C. The rate of change of temperature of the water perfusing the suit (T_WPS) was 1.2 °C min⁻¹ during both the heating and cooling phases. The trial was repeated thrice, with subjects reporting their perception of the temperature and thermal comfort at each 3 °C change in T_WPS. In addition, subjects were instructed to report when they perceived T_WPS uncomfortably cool and warm during cooling and heating, respectively. Subjects reproducibly identified the boundaries of their Thermal Comfort Zone (TCZ), defined as the lower (T_low) and upper (T_high) temperatures at which subjects reported slight thermal discomfort. During the heating phase, T_low and T_high were 30.0 ± 1.5 °C and 35.1 ± 2.9 °C, respectively. During the cooling phase, the boundary temperatures of T_low and T_high were 35.4 ± 1.9 °C and 38.7 ± 2.3 °C, respectively. The direction of the change in the cutaneous temperature stimulus affects the boundaries of the TCZ, such that they are higher during cooling and lower during heating. These findings are explained on the basis of the neurophysiology of thermal perception. From an applied perspective, the most important observation of the present study was the strong correlation between the perception of thermal comfort and the behavioral regulation of thermal comfort. Although it is not surprising that the action of regulating thermal comfort is aligned with its perception, this link has not been proven for humans in previous studies. The results therefore provide a sound basis to consider ratings of thermal comfort as reflecting behavioral actions to achieve the sensation of thermal neutrality. Full article

(This article belongs to the Special Issue Human Thermophysiology)

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15 pages, 1594 KB

Open AccessEditor’s ChoiceReview

Cutaneous Wound Healing: An Update from Physiopathology to Current Therapies

by Lucas Fernando Sérgio Gushiken, Fernando Pereira Beserra, Jairo Kenupp Bastos, Christopher John Jackson and Cláudia Helena Pellizzon

Life 2021, 11(7), 665; https://doi.org/10.3390/life11070665 - 7 Jul 2021

Cited by 187 | Viewed by 41157

Abstract

The skin is the biggest organ of human body which acts as a protective barrier against deleterious agents. When this barrier is damaged, the organism promotes the healing process with several molecular and cellular mechanisms, in order to restore the physiological structure of [...] Read more.

The skin is the biggest organ of human body which acts as a protective barrier against deleterious agents. When this barrier is damaged, the organism promotes the healing process with several molecular and cellular mechanisms, in order to restore the physiological structure of the skin. The physiological control of wound healing depends on the correct balance among its different mechanisms. Any disruption in the balance of these mechanisms can lead to problems and delay in wound healing. The impairment of wound healing is linked to underlying factors as well as aging, nutrition, hypoxia, stress, infections, drugs, genetics, and chronic diseases. Over the years, numerous studies have been conducted to discover the correct approach and best therapies for wound healing, including surgical procedures and non-surgical treatments such as topical formulations, dressings, or skin substitutes. Thus, this general approach is necessary to facilitate the direction of further studies. This work provides updated concepts of physiological mechanisms, the factors that can interfere, and updated treatments used in skin wound healing. Full article

(This article belongs to the Section Medical Research)

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19 pages, 3329 KB

Open AccessEditor’s ChoiceArticle

Mitochondrial Genomic Landscape: A Portrait of the Mitochondrial Genome 40 Years after the First Complete Sequence

by Alessandro Formaggioni, Andrea Luchetti and Federico Plazzi

Life 2021, 11(7), 663; https://doi.org/10.3390/life11070663 - 6 Jul 2021

Cited by 26 | Viewed by 6783

Abstract

Notwithstanding the initial claims of general conservation, mitochondrial genomes are a largely heterogeneous set of organellar chromosomes which displays a bewildering diversity in terms of structure, architecture, gene content, and functionality. The mitochondrial genome is typically described as a single chromosome, yet many [...] Read more.

Notwithstanding the initial claims of general conservation, mitochondrial genomes are a largely heterogeneous set of organellar chromosomes which displays a bewildering diversity in terms of structure, architecture, gene content, and functionality. The mitochondrial genome is typically described as a single chromosome, yet many examples of multipartite genomes have been found (for example, among sponges and diplonemeans); the mitochondrial genome is typically depicted as circular, yet many linear genomes are known (for example, among jellyfish, alveolates, and apicomplexans); the chromosome is normally said to be “small”, yet there is a huge variation between the smallest and the largest known genomes (found, for example, in ctenophores and vascular plants, respectively); even the gene content is highly unconserved, ranging from the 13 oxidative phosphorylation-related enzymatic subunits encoded by animal mitochondria to the wider set of mitochondrial genes found in jakobids. In the present paper, we compile and describe a large database of 27,873 mitochondrial genomes currently available in GenBank, encompassing the whole eukaryotic domain. We discuss the major features of mitochondrial molecular diversity, with special reference to nucleotide composition and compositional biases; moreover, the database is made publicly available for future analyses on the MoZoo Lab GitHub page. Full article

(This article belongs to the Special Issue Molecular Phylogenetics and Mitochondrial Evolution)

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15 pages, 1204 KB

Open AccessEditor’s ChoiceArticle

Association of Circulating Tumor Cells with Inflammatory and Biomarkers in the Blood of Patients with Metastatic Castration-Resistant Prostate Cancer

by Gerit Theil, Carlotta Lindner, Joanna Bialek and Paolo Fornara

Life 2021, 11(7), 664; https://doi.org/10.3390/life11070664 - 6 Jul 2021

Cited by 5 | Viewed by 2900

Abstract

The identification of specific biomarkers that recognize the functional drivers of heterogeneity in prostate cancer (PCa) and personalized treatment remain challenging in systemic medicine. Liquid biopsy allows for the detection and analysis of personalized predictive biomarkers in single blood samples and specifies the [...] Read more.

The identification of specific biomarkers that recognize the functional drivers of heterogeneity in prostate cancer (PCa) and personalized treatment remain challenging in systemic medicine. Liquid biopsy allows for the detection and analysis of personalized predictive biomarkers in single blood samples and specifies the current stage of cancer. The aim of our preliminary study was to investigate the association between an elevated circulating tumor cell (CTC) count and the levels of inflammatory factors (IL-6 and IL-8) and biomarkers (DKK-1, PSA, sHER2, and CD44) in patients with metastasized castration-resistant PCa (mCPRC) under chemotherapy and those with localized PCa. Such an association could be used as a component of cancer progression monitoring. We compared the sensitivity and specificity of two CTC isolation platforms. Twenty-eight patients (12 mCRPC and 16 localized PCa patients) were enrolled. Over the study period, the CTC detection rates were 84% with CellCollector^® and 73.5% with CellSearch^® System in mCPRC patients. The CTC counts determined by the CellSearch^® System (CTC_CS) were correlated significantly with the DKK-1, sHER-2, and PSA concentrations in mCRPC patients. The CTC counts captured by CellCollector^® demonstrated no significant association with the concentrations of the tested blood-based biomarkers. The CTC_CS count (AUC = 0.9 (95% CI: 0.72–1.0)) and the PSA level (AUC = 0.95 (95% CI: 0.83–1.0)) presented approximately the same sensitivity and specificity for the overall survival of mCRPC patients. For better personalized characterization, further research on CTC phenotyping and their interactions with tumor-associated blood-released factors is needed. Full article

(This article belongs to the Special Issue Prostate Cancer)

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11 pages, 668 KB

Open AccessEditor’s ChoiceReview

The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

by Andrea L. Reid and Matthew S. Alexander

Life 2021, 11(7), 648; https://doi.org/10.3390/life11070648 - 4 Jul 2021

Cited by 33 | Viewed by 5655

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack [...] Read more.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways. Full article

(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)

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17 pages, 517 KB

Open AccessEditor’s ChoiceReview

Genomic Approaches for Conservation Management in Australia under Climate Change

by Isabelle R. Onley, Katherine E. Moseby and Jeremy J. Austin

Life 2021, 11(7), 653; https://doi.org/10.3390/life11070653 - 4 Jul 2021

Cited by 14 | Viewed by 7895

Abstract

Conservation genetics has informed threatened species management for several decades. With the advent of advanced DNA sequencing technologies in recent years, it is now possible to monitor and manage threatened populations with even greater precision. Climate change presents a number of threats and [...] Read more.

Conservation genetics has informed threatened species management for several decades. With the advent of advanced DNA sequencing technologies in recent years, it is now possible to monitor and manage threatened populations with even greater precision. Climate change presents a number of threats and challenges, but new genomics data and analytical approaches provide opportunities to identify critical evolutionary processes of relevance to genetic management under climate change. Here, we discuss the applications of such approaches for threatened species management in Australia in the context of climate change, identifying methods of facilitating viability and resilience in the face of extreme environmental stress. Using genomic approaches, conservation management practices such as translocation, targeted gene flow, and gene-editing can now be performed with the express intention of facilitating adaptation to current and projected climate change scenarios in vulnerable species, thus reducing extinction risk and ensuring the protection of our unique biodiversity for future generations. We discuss the current barriers to implementing conservation genomic projects and the efforts being made to overcome them, including communication between researchers and managers to improve the relevance and applicability of genomic studies. We present novel approaches for facilitating adaptive capacity and accelerating natural selection in species to encourage resilience in the face of climate change. Full article

(This article belongs to the Special Issue Evolutionary and Conservation Genetics)

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11 pages, 4645 KB

Open AccessEditor’s ChoiceArticle

Overexpression of p75^NTR in Human Seminoma: A New Biomarker?

by Anna Perri, Vittoria Rago, Rocco Malivindi, Lorenza Maltese, Danilo Lofaro, Emanuela Alessandra Greco, Luigi Tucci, Renzo Bonofiglio, Margherita Vergine, Sandro La Vignera, Eusebio Chiefari, Antonio Brunetti and Antonio Aversa

Life 2021, 11(7), 629; https://doi.org/10.3390/life11070629 - 29 Jun 2021

Cited by 5 | Viewed by 2455

Abstract

Several studies have demonstrated that the p75^NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75^NTR varies substantially depending on cell context, so that a dual role [...] Read more.

Several studies have demonstrated that the p75^NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75^NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75^NTR in human specimens (nr = 40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75^NTR was detected by immunohistochemistry in seminoma tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75^NTR signaling pathway and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75^NTR, p-JNK and p53 was related to staging progression, thus suggesting that p75^NTR may represent a specific marker for seminoma and staging in TGCTs. Full article

(This article belongs to the Section Reproductive and Developmental Biology)

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17 pages, 340 KB

Open AccessEditor’s ChoiceReview

mtDNA Heteroplasmy: Origin, Detection, Significance, and Evolutionary Consequences

by Maria-Eleni Parakatselaki and Emmanuel D. Ladoukakis

Life 2021, 11(7), 633; https://doi.org/10.3390/life11070633 - 29 Jun 2021

Cited by 69 | Viewed by 8909

Abstract

Mitochondrial DNA (mtDNA) is predominately uniparentally transmitted. This results in organisms with a single type of mtDNA (homoplasmy), but two or more mtDNA haplotypes have been observed in low frequency in several species (heteroplasmy). In this review, we aim to highlight several aspects [...] Read more.

Mitochondrial DNA (mtDNA) is predominately uniparentally transmitted. This results in organisms with a single type of mtDNA (homoplasmy), but two or more mtDNA haplotypes have been observed in low frequency in several species (heteroplasmy). In this review, we aim to highlight several aspects of heteroplasmy regarding its origin and its significance on mtDNA function and evolution, which has been progressively recognized in the last several years. Heteroplasmic organisms commonly occur through somatic mutations during an individual’s lifetime. They also occur due to leakage of paternal mtDNA, which rarely happens during fertilization. Alternatively, heteroplasmy can be potentially inherited maternally if an egg is already heteroplasmic. Recent advances in sequencing techniques have increased the ability to detect and quantify heteroplasmy and have revealed that mitochondrial DNA copies in the nucleus (NUMTs) can imitate true heteroplasmy. Heteroplasmy can have significant evolutionary consequences on the survival of mtDNA from the accumulation of deleterious mutations and for its coevolution with the nuclear genome. Particularly in humans, heteroplasmy plays an important role in the emergence of mitochondrial diseases and determines the success of the mitochondrial replacement therapy, a recent method that has been developed to cure mitochondrial diseases. Full article

(This article belongs to the Special Issue Molecular Phylogenetics and Mitochondrial Evolution)

15 pages, 853 KB

Open AccessEditor’s ChoiceReview

Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

by Monica L. Hu, Joel Quinn and Kanmin Xue

Life 2021, 11(7), 635; https://doi.org/10.3390/life11070635 - 29 Jun 2021

Cited by 35 | Viewed by 6356

Abstract

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its [...] Read more.

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer’s disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation. Full article

(This article belongs to the Collection Retinal Disease and Metabolism)

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15 pages, 2528 KB

Open AccessEditor’s ChoiceArticle

Relationship of the Pine Growth Promoting Pantoea eucalypti FBS135 with Type Strains P. eucalypti LMG 24197^T and P. vagans 24199^T

by Chunyue Wei, Zhongwen Song, Yiming Lu, Yinjuan Zhao and Ben Fan

Life 2021, 11(7), 608; https://doi.org/10.3390/life11070608 - 24 Jun 2021

Cited by 6 | Viewed by 2602

Abstract

Endophytes in woody plants are much less understood. Pantoea strain FBS135 is an endophytic bacterium isolated from Pinus massoniana with the ability to promote pine growth significantly. In this study, we demonstrated that FBS135 has the astonishing ability of low nitrogen tolerance but [...] Read more.

Endophytes in woody plants are much less understood. Pantoea strain FBS135 is an endophytic bacterium isolated from Pinus massoniana with the ability to promote pine growth significantly. In this study, we demonstrated that FBS135 has the astonishing ability of low nitrogen tolerance but no ability of nitrogen fixation. To exactly determine the phylogenetic status of FBS135, we sequenced the whole genomes of P. eucalypti LMG 24197^T and P. vagans 24199^T, type strains of two Pantoea species, which are evolutionarily closest to FBS135. P. eucalypti LMG 24197^T contained a single chromosome of 4,035,995 bp (C+G, 54.6%) plus three circular plasmids while LMG 24199^T comprises a single circular chromosome of 4,050,173 bp (C+G, 55.6%) and two circular plasmids. With the genomic information, FBS135 was finally identified as a P. eucalypti strain, although it showed some different physiological traits from the two type strains. Comparative genomic analyses were performed for the three strains, revealing their common molecular basis associated with plant lifecycle as well as the differences in their gene arrangements relating to nitrogen utilization. Full article

(This article belongs to the Section Plant Science)

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10 pages, 276 KB

Open AccessEditor’s ChoiceArticle

Psychological Traits and Behavioural Influences in Patients with Dystonia—An Observational Cohort Study in a Romanian Neurology Department

by Eugenia Irene Davidescu, Irina Odajiu, Delia Tulbă, Iulia Mitrea, Camelia Cucu and Bogdan Ovidiu Popescu

Life 2021, 11(7), 612; https://doi.org/10.3390/life11070612 - 24 Jun 2021

Cited by 5 | Viewed by 2774

Abstract

(1) Background: Emerging evidence indicates that non-motor symptoms significantly influence the quality of life in dystonic patients. Therefore, it is essential to evaluate their psychological characteristics and personality traits. (2) Methods: Subjects with idiopathic dystonia and a matched control group were enrolled in [...] Read more.

(1) Background: Emerging evidence indicates that non-motor symptoms significantly influence the quality of life in dystonic patients. Therefore, it is essential to evaluate their psychological characteristics and personality traits. (2) Methods: Subjects with idiopathic dystonia and a matched control group were enrolled in this prospective observational cohort study. Inclusion criteria for patient group included idiopathic dystonia diagnosis, evolution exceeding 1 year, and signed informed consent. Inclusion criteria for the control group included lack of neurological comorbidities and signed informed consent. All subjects completed the DECAS Personality Inventory along with an additional form of demographic factors. Data (including descriptive statistics and univariate and multivariate analysis) were analyzed with SPSS. (3) Results: In total, 95 participants were included, of which 57 were in the patient group. Females prevailed (80%), and the mean age was 54.64 ± 12.8 years. The most frequent clinical features of dystonia were focal distribution (71.9%) and progressive disease course (94.73%). The patients underwent regular treatment with botulinum toxin (85.95%). In addition, patients with dystonia obtained significantly higher openness scores than controls, even after adjusting for possible confounders (p = 0.006). Personality traits were also different between the two groups, with patients more often being fantasists (p = 0.007), experimenters (p = 0.022), sophists (p = 0.040), seldom acceptors (p = 0.022), and pragmatics (p = 0.022) than control subjects. (4) Conclusion: Dystonic patients tend to have different personality profiles compared to control subjects, which should be taken into consideration by the treating neurologist. Full article

(This article belongs to the Special Issue Dystonia and Related Disorders: From Bench to Bedside)

16 pages, 2113 KB

Open AccessEditor’s ChoiceArticle

Molecular Taxonomy and Diversification of Atlantic Skates (Chondrichthyes, Rajiformes): Adding More Pieces to the Puzzle of Their Evolutionary History

by Valentina Crobe, Alice Ferrari, Robert Hanner, Robin W. Leslie, Dirk Steinke, Fausto Tinti and Alessia Cariani

Life 2021, 11(7), 596; https://doi.org/10.3390/life11070596 - 22 Jun 2021

Cited by 9 | Viewed by 4032

Abstract

Conservation and long-term management plans of marine species need to be based upon the universally recognized key-feature of species identity. This important assignment is particularly challenging in skates (Rajiformes) in which the phenotypic similarity between some taxa and the individual variability in others, [...] Read more.

Conservation and long-term management plans of marine species need to be based upon the universally recognized key-feature of species identity. This important assignment is particularly challenging in skates (Rajiformes) in which the phenotypic similarity between some taxa and the individual variability in others, hampers accurate species identification. Here, 432 individual skate samples collected from four major ocean areas of the Atlantic were barcoded and taxonomically analysed. A BOLD project ELASMO ATL was implemented with the aim of establishing a new fully available and well curated barcode library containing both biological and molecular information. The evolutionary histories of the 38 skate taxa were estimated with two concatenated mitochondrial markers (COI and NADH2) through Maximum Likelihood and Bayesian inference. New evolutionary lineages within the genus Raja were discovered off Angola, where paleogeographic history coupled with oceanographic discontinuities could have contributed to the establishment of isolated refugia, playing a fundamental role among skates’ speciation events. These data successfully resolved many taxonomic ambiguities, identified cryptic diversity within valid species and demonstrated a highly cohesive monophyletic clustering among the order, laying the background for further inference of evolutionary patterns suitable for addressing management and conservation issues. Full article

(This article belongs to the Special Issue Evolutionary and Conservation Genetics)

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18 pages, 2236 KB

Open AccessEditor’s ChoiceArticle

Identification of Metabolic Phenotypes in Young Adults with Obesity by ¹H NMR Metabolomics of Blood Serum

by Khin Thandar Htun, Jie Pan, Duanghathai Pasanta, Montree Tungjai, Chatchanok Udomtanakunchai, Sirirat Chancharunee, Siriprapa Kaewjaeng, Hong Joo Kim, Jakrapong Kaewkhao and Suchart Kothan

Life 2021, 11(6), 574; https://doi.org/10.3390/life11060574 - 18 Jun 2021

Cited by 18 | Viewed by 3791

Abstract

(1) Since the obesity prevalence rate has been consistently increasing, it is necessary to find an effective way to prevent and treat it. Although progress is being made to reduce obesity in the young adult population, a better understanding of obesity-related metabolomics and [...] Read more.

(1) Since the obesity prevalence rate has been consistently increasing, it is necessary to find an effective way to prevent and treat it. Although progress is being made to reduce obesity in the young adult population, a better understanding of obesity-related metabolomics and related biochemical mechanisms is urgently needed for developing appropriate screening strategies. Therefore, the aim of this study is to identify the serum metabolic profile associated with young adult obesity and its metabolic phenotypes. (2) Methods: The serum metabolic profile of 30 obese and 30 normal-weight young adults was obtained using proton nuclear magnetic resonance spectroscopy (¹H NMR). ¹H NMR spectra were integrated into 24 integration regions, which reflect relative metabolites, and were used as statistical variables. (3) Results: The obese group showed increased levels of lipids, glucose, glutamate, N-acetyl glycoprotein, alanine, lactate, 3 hydroxybutyrate and branch chain amino acid (BCAA), and decreased levels of choline as compared with the normal-weight group. Non-hyperlipidemia obese adults showed lower levels of lipids and lactate, glutamate, acetoacetate, N-acetyl glycoprotein, isoleucine, and higher levels of choline and glutamine, as compared with hyperlipidemic obese adults. (4) Conclusions: This study reveals valuable findings in the field of metabolomics and young adult obesity. We propose several serum biomarkers that distinguish between normal weight and obese adults, i.e., glutamine (higher in the normal group, p < 0.05), and lactate, BCAAs, acetoacetate and 3-hydroxybutyrate (higher in the obese group, p < 0.05). In addition, visceral fat and serum TG, glutamate, acetoacetate, N-acetyl glycoprotein, unsaturated lipid, isoleucine, and VLDL/LDL are higher (p < 0.05) in the obese with hyperlipidemia. Therefore, they can be used as biomarkers to identify these two types of obesity. Full article

(This article belongs to the Special Issue A New Era of Multidisciplinary Radiology: Fast Growing of Medical Radiation/Imaging/Artificial Intelligence Research)

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20 pages, 459 KB

Open AccessEditor’s ChoiceReview

Blood Stream Infections from MDR Bacteria

by Sveva Di Franco, Aniello Alfieri, Maria Caterina Pace, Pasquale Sansone, Vincenzo Pota, Ciro Fittipaldi, Marco Fiore and Maria Beatrice Passavanti

Life 2021, 11(6), 575; https://doi.org/10.3390/life11060575 - 18 Jun 2021

Cited by 29 | Viewed by 5020

Abstract

Background: Bloodstream infections (BSIs) constitute a growing public health concern, are among the most severe nosocomial pathologies, and are considered a worldwide cause of unfaithful outcomes, increasing treatment costs and diagnostic uncertainties. BSIs are one of the most frequent lethal conditions that are [...] Read more.

Background: Bloodstream infections (BSIs) constitute a growing public health concern, are among the most severe nosocomial pathologies, and are considered a worldwide cause of unfaithful outcomes, increasing treatment costs and diagnostic uncertainties. BSIs are one of the most frequent lethal conditions that are managed in intensive care units (ICUs). In the case of septic shock, immune deficiency, and delayed treatment, even with adequate antimicrobial therapy and/or source control, the outcomes are often unfavorable. Methods: this review article summarizes the epidemiological and microbiological characteristics of BSIs with a particular focus on ICU acquired BSIs (ICU-BSIs), which are usually caused by multidrug-resistant (MDR) pathogens. For this reason, their antimicrobial resistance patterns and therapeutic options have also been compiled. Results: ICU-acquired BSIs prevail in 5–7% of ICU patients. Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosae are the pathogens most often responsible for MDR infections. MDR Enterobacteriaceae have seen their prevalence increase from 6.2% (1997–2000) to 15.8% (2013–2016) in recent years. Conclusions: Considering that prevention and treatment of sepsis is nowadays considered a global health priority by the World Health Organization, it is our obligation to invest more resources into solving or reducing the spread of these unfaithful infections. It is relevant to identify patients with risk factors that make them more susceptible to BSIs, to guarantee earlier molecular or microbiological diagnoses, and more rapidly appropriate treatment by using de-escalation strategies where possible. Full article

(This article belongs to the Collection Bacterial Infections, Treatment and Antibiotic Resistance)

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16 pages, 1073 KB

Open AccessEditor’s ChoiceReview

Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases

by Antonina Giammanco, Davide Noto, Carlo Maria Barbagallo, Emilio Nardi, Rosalia Caldarella, Marcello Ciaccio, Maurizio Rocco Averna and Angelo Baldassare Cefalù

Life 2021, 11(6), 581; https://doi.org/10.3390/life11060581 - 18 Jun 2021

Cited by 17 | Viewed by 5797

Abstract

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce [...] Read more.

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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18 pages, 4010 KB

Open AccessEditor’s ChoiceArticle

Multiscale Models for Fibril Formation: Rare Events Methods, Microkinetic Models, and Population Balances

by Armin Shayesteh Zadeh and Baron Peters

Life 2021, 11(6), 570; https://doi.org/10.3390/life11060570 - 17 Jun 2021

Cited by 4 | Viewed by 2682

Abstract

Amyloid fibrils are thought to grow by a two-step dock-lock mechanism. However, previous simulations of fibril formation (i) overlook the bi-molecular nature of the docking step and obtain rates with first-order units, or (ii) superimpose the docked and locked states when computing the [...] Read more.

Amyloid fibrils are thought to grow by a two-step dock-lock mechanism. However, previous simulations of fibril formation (i) overlook the bi-molecular nature of the docking step and obtain rates with first-order units, or (ii) superimpose the docked and locked states when computing the potential of mean force for association and thereby muddle the docking and locking steps. Here, we developed a simple microkinetic model with separate locking and docking steps and with the appropriate concentration dependences for each step. We constructed a simple model comprised of chiral dumbbells that retains qualitative aspects of fibril formation. We used rare events methods to predict separate docking and locking rate constants for the model. The rate constants were embedded in the microkinetic model, with the microkinetic model embedded in a population balance model for “bottom-up” multiscale fibril growth rate predictions. These were compared to “top-down” results using simulation data with the same model and multiscale framework to obtain maximum likelihood estimates of the separate lock and dock rate constants. We used the same procedures to extract separate docking and locking rate constants from experimental fibril growth data. Our multiscale strategy, embedding rate theories, and kinetic models in conservation laws should help to extract docking and locking rate constants from experimental data or long molecular simulations with correct units and without compromising the molecular description. Full article

(This article belongs to the Special Issue Computational Modeling of Kinetics in Biological Systems)

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14 pages, 290 KB

Open AccessEditor’s ChoiceReview

Screening, Diagnostic and Prognostic Tests for COVID-19: A Comprehensive Review

by Mariana Ulinici, Serghei Covantev, James Wingfield-Digby, Apostolos Beloukas, Alexander G. Mathioudakis and Alexandru Corlateanu

Life 2021, 11(6), 561; https://doi.org/10.3390/life11060561 - 14 Jun 2021

Cited by 22 | Viewed by 8716

Abstract

While molecular testing with real-time polymerase chain reaction (RT-PCR) remains the gold-standard test for COVID-19 diagnosis and screening, more rapid or affordable molecular and antigen testing options have been developed. More affordable, point-of-care antigen testing, despite being less sensitive compared to molecular assays, [...] Read more.

While molecular testing with real-time polymerase chain reaction (RT-PCR) remains the gold-standard test for COVID-19 diagnosis and screening, more rapid or affordable molecular and antigen testing options have been developed. More affordable, point-of-care antigen testing, despite being less sensitive compared to molecular assays, might be preferable for wider screening initiatives. Simple laboratory, imaging and clinical parameters could facilitate prognostication and triage. This comprehensive review summarises current evidence on the diagnostic, screening and prognostic tests for COVID-19. Full article

(This article belongs to the Special Issue Ecology, Evolution and Epidemiology of Coronaviruses)

11 pages, 2419 KB

Open AccessEditor’s ChoiceArticle

Analysis of the Innovation Trend in Cell-Free Synthetic Biology

by Conary Meyer, Yusuke Nakamura, Blake J. Rasor, Ashty S. Karim, Michael C. Jewett and Cheemeng Tan

Life 2021, 11(6), 551; https://doi.org/10.3390/life11060551 - 11 Jun 2021

Cited by 18 | Viewed by 7646

Abstract

Cell-free synthetic biology is a maturing field that aims to assemble biomolecular reactions outside cells for compelling applications in drug discovery, metabolic engineering, biomanufacturing, diagnostics, and education. Cell-free systems have several key features. They circumvent mechanisms that have evolved to facilitate species survival, [...] Read more.

Cell-free synthetic biology is a maturing field that aims to assemble biomolecular reactions outside cells for compelling applications in drug discovery, metabolic engineering, biomanufacturing, diagnostics, and education. Cell-free systems have several key features. They circumvent mechanisms that have evolved to facilitate species survival, bypass limitations on molecular transport across the cell wall, enable high-yielding and rapid synthesis of proteins without creating recombinant cells, and provide high tolerance towards toxic substrates or products. Here, we analyze ~750 published patents and ~2000 peer-reviewed manuscripts in the field of cell-free systems. Three hallmarks emerged. First, we found that both patent filings and manuscript publications per year are significantly increasing (five-fold and 1.5-fold over the last decade, respectively). Second, we observed that the innovation landscape has changed. Patent applications were dominated by Japan in the early 2000s before shifting to China and the USA in recent years. Finally, we discovered an increasing prevalence of biotechnology companies using cell-free systems. Our analysis has broad implications on the future development of cell-free synthetic biology for commercial and industrial applications. Full article

(This article belongs to the Special Issue Trends and Outlooks in Synthetic Biology: A Special Issue for Celebrating 10 Years of Life and Its Landmarks)

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15 pages, 1675 KB

Open AccessEditor’s ChoiceArticle

CEACAM6’s Role as a Chemoresistance and Prognostic Biomarker for Pancreatic Cancer: A Comparison of CEACAM6’s Diagnostic and Prognostic Capabilities with Those of CA19-9 and CEA

by Benediktas Kurlinkus, Marija Ger, Algirdas Kaupinis, Eugenijus Jasiunas, Mindaugas Valius and Audrius Sileikis

Life 2021, 11(6), 542; https://doi.org/10.3390/life11060542 - 9 Jun 2021

Cited by 12 | Viewed by 3713

Abstract

Survival rates from pancreatic cancer have remained stagnant for decades due to the heterogenic nature of the disease. This study aimed to find a new advanced biomarker and evaluate its clinical capabilities, thus enabling more individualised pancreatic cancer management. Between 2013 and 2020, [...] Read more.

Survival rates from pancreatic cancer have remained stagnant for decades due to the heterogenic nature of the disease. This study aimed to find a new advanced biomarker and evaluate its clinical capabilities, thus enabling more individualised pancreatic cancer management. Between 2013 and 2020, 267 patients were included in the study. Surgically collected pancreatic tissue samples were analysed via high-definition mass spectrometry. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was discovered as a possible promising pancreatic cancer biomarker. The predominance of CEACAM6 to pancreatic cancer was validated using antibodies in tissue samples. CEACAM6, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) blood serum concentrations were evaluated for clinical evaluation and comparison. Kaplan–Meier survival analyses were used to evaluate disease-free survival (DFS) and overall survival (OS). Poorer overall survival was significantly dependent on increased CEACAM6 blood serum concentrations (17.0 vs. 12.6 months, p = 0.017) in pancreatic cancer patients after radical treatment and adjuvant chemotherapy. Increased CEA and CA19-9 concentrations showed no significant dependencies with survival. Thus, CEACAM6 is a promising new biomarker with significant prognostic value and prediction of chemoresistance properties, enabling the improvement of individualised approaches to patients with pancreatic cancer. Full article

(This article belongs to the Special Issue Emerging Biomarkers: Recent Findings and Its Application in Pathological Conditions Detection)

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14 pages, 2526 KB

Open AccessEditor’s ChoiceArticle

Effect of the Chinese Herbal Medicine SS-1 on a Sjögren’s Syndrome-Like Disease in Mice

by Po-Chang Wu, Shih-Chao Lin, Lauren Panny, Yu-Kang Chang, Chi-Chien Lin, Yu-Tang Tung and Hen-Hong Chang

Life 2021, 11(6), 530; https://doi.org/10.3390/life11060530 - 7 Jun 2021

Cited by 3 | Viewed by 5628

Abstract

Sjögren’s syndrome (SS) is an inflammatory autoimmune disease primarily affecting the exocrine glands; it has a major impact on patients’ lives. The Chinese herbal formula SS-1 is composed of Gan Lu Yin, Sang Ju Yin, and Xuefu Zhuyu decoction, which exerts anti-inflammatory, immunomodulatory, [...] Read more.

Sjögren’s syndrome (SS) is an inflammatory autoimmune disease primarily affecting the exocrine glands; it has a major impact on patients’ lives. The Chinese herbal formula SS-1 is composed of Gan Lu Yin, Sang Ju Yin, and Xuefu Zhuyu decoction, which exerts anti-inflammatory, immunomodulatory, and antifibrotic effects. Our previous study demonstrated that SS-1 alleviates clinical SS. This study aimed to evaluate the efficacy and mechanism of the Chinese herbal formula SS-1 for salivary gland protein-induced experimental Sjögren’s syndrome (ESS). These results showed that ESS treatment with the Chinese herbal formula SS-1 (1500 mg/kg) significantly alleviated the severity of ESS. We found that SS-1 substantially improved saliva flow rates in SS mice and ameliorated lymphocytic infiltrations in submandibular glands. In addition, salivary gland protein-induced SS in mice treated with SS-1 significantly lowered proinflammatory cytokines (including IFN-γ, IL-6, and IL-17A) in mouse salivary glands and decreased serum anti-M3R autoantibody levels. In addition, we found that CD4+ T cells isolated from SS-1-treated SS mice significantly reduced the percentages of IFN-γ-producing CD4+ T cells (Th1) and IL-17A-producing CD4+ T cells (Th17). Our data show that SS-1 alleviates ESS through anti-inflammatory and immunomodulatory effects, which provides new insight into the clinical treatment of SS. Full article

(This article belongs to the Special Issue Regulation of Natural Products to Immunity)

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21 pages, 746 KB

Open AccessEditor’s ChoiceReview

Altered Bone Status in Rett Syndrome

by Alessandra Pecorelli, Valeria Cordone, Maria Lucia Schiavone, Carla Caffarelli, Carlo Cervellati, Gaetana Cerbone, Stefano Gonnelli, Joussef Hayek and Giuseppe Valacchi

Life 2021, 11(6), 521; https://doi.org/10.3390/life11060521 - 3 Jun 2021

Cited by 12 | Viewed by 5507

Abstract

Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad [...] Read more.

Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that MECP2 mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity. Full article

(This article belongs to the Special Issue Biochemical Modulators in Chronic Diseases: The Antioxidant /Anti-inflammatory Interdependence)

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19 pages, 1812 KB

Open AccessEditor’s ChoiceArticle

Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study

by Yo-Han Joo, Jeong-Hee Kim, Hang-Keun Kim, Young-Don Son, Paul Cumming and Jong-Hoon Kim

Life 2021, 11(6), 506; https://doi.org/10.3390/life11060506 - 30 May 2021

Cited by 4 | Viewed by 3848

Abstract

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [¹¹C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of [...] Read more.

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [¹¹C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [¹¹C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BP_ND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [¹¹C]ABP688 BP_ND in the middle temporal and inferior parietal cortices, and higher BP_ND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [¹¹C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects. Full article

(This article belongs to the Special Issue Glutamate Receptors)

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34 pages, 5672 KB

Open AccessEditor’s ChoiceReview

Advances in Cereal Crop Genomics for Resilience under Climate Change

by Tinashe Zenda, Songtao Liu, Anyi Dong and Huijun Duan

Life 2021, 11(6), 502; https://doi.org/10.3390/life11060502 - 29 May 2021

Cited by 44 | Viewed by 9336

Abstract

Adapting to climate change, providing sufficient human food and nutritional needs, and securing sufficient energy supplies will call for a radical transformation from the current conventional adaptation approaches to more broad-based and transformative alternatives. This entails diversifying the agricultural system and boosting productivity [...] Read more.

Adapting to climate change, providing sufficient human food and nutritional needs, and securing sufficient energy supplies will call for a radical transformation from the current conventional adaptation approaches to more broad-based and transformative alternatives. This entails diversifying the agricultural system and boosting productivity of major cereal crops through development of climate-resilient cultivars that can sustainably maintain higher yields under climate change conditions, expanding our focus to crop wild relatives, and better exploitation of underutilized crop species. This is facilitated by the recent developments in plant genomics, such as advances in genome sequencing, assembly, and annotation, as well as gene editing technologies, which have increased the availability of high-quality reference genomes for various model and non-model plant species. This has necessitated genomics-assisted breeding of crops, including underutilized species, consequently broadening genetic variation of the available germplasm; improving the discovery of novel alleles controlling important agronomic traits; and enhancing creation of new crop cultivars with improved tolerance to biotic and abiotic stresses and superior nutritive quality. Here, therefore, we summarize these recent developments in plant genomics and their application, with particular reference to cereal crops (including underutilized species). Particularly, we discuss genome sequencing approaches, quantitative trait loci (QTL) mapping and genome-wide association (GWAS) studies, directed mutagenesis, plant non-coding RNAs, precise gene editing technologies such as CRISPR-Cas9, and complementation of crop genotyping by crop phenotyping. We then conclude by providing an outlook that, as we step into the future, high-throughput phenotyping, pan-genomics, transposable elements analysis, and machine learning hold much promise for crop improvements related to climate resilience and nutritional superiority. Full article

(This article belongs to the Special Issue Research Advances in Plant Genomics)

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14 pages, 2995 KB

Open AccessEditor’s ChoiceArticle

Impact of TSPO Receptor Polymorphism on [¹⁸F]GE-180 Binding in Healthy Brain and Pseudo-Reference Regions of Neurooncological and Neurodegenerative Disorders

by Franziska J. Vettermann, Stefanie Harris, Julia Schmitt, Marcus Unterrainer, Simon Lindner, Boris-Stephan Rauchmann, Carla Palleis, Endy Weidinger, Leonie Beyer, Florian Eckenweber, Sebastian Schuster, Gloria Biechele, Christian Ferschmann, Vladimir M. Milenkovic, Christian H. Wetzel, Rainer Rupprecht, Daniel Janowitz, Katharina Buerger, Robert Perneczky, Günter U. Höglinger, Johannes Levin, Christian Haass, Joerg C. Tonn, Maximilian Niyazi, Peter Bartenstein, Nathalie L. Albert and Matthias Brendel Show full author list Hide full author list

Life 2021, 11(6), 484; https://doi.org/10.3390/life11060484 - 26 May 2021

Cited by 22 | Viewed by 5128

Abstract

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [¹⁸F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [¹⁸F]GE-180 [...] Read more.

TSPO-PET tracers are sensitive to a single-nucleotide polymorphism (rs6971-SNP), resulting in low-, medium- and high-affinity binders (LABs, MABs and HABS), but the clinical relevance of [¹⁸F]GE-180 is still unclear. We evaluated the impact of rs6971-SNP on in vivo [¹⁸F]GE-180 binding in a healthy brain and in pseudo-reference tissue in neuro-oncological and neurodegenerative diseases. Standardized uptake values (SUVs) of [¹⁸F]GE-180-PET were assessed using a manually drawn region of interest in the frontoparietal and cerebellar hemispheres. The SUVs were compared between the LABs, MABs and HABs in control, glioma, four-repeat tauopathy (4RT) and Alzheimer’s disease (AD) subjects. Second, the SUVs were compared between the patients and controls within their rs6971-subgroups. After excluding patients with prior therapy, 24 LABs (7 control, 5 glioma, 6 4RT and 6 AD) were analyzed. Age- and sex-matched MABs (n = 38) and HABs (n = 50) were selected. The LABs had lower frontoparietal and cerebellar SUVs when compared with the MABs and HABs, but no significant difference was observed between the MABs and HABs. Within each rs6971 group, no SUV difference between the patients and controls was detected in the pseudo-reference tissues. The rs6971-SNP affects [¹⁸F]GE-180 quantification, revealing lower binding in the LABs when compared to the MABs and HABs. The frontoparietal and cerebellar ROIs were successfully validated as pseudo-reference regions. Full article

(This article belongs to the Section Radiobiology and Nuclear Medicine)

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6 pages, 201 KB

Open AccessEditor’s ChoicePerspective

Deep Brain Stimulation and Hypoxemic Perinatal Encephalopathy: State of Art and Perspectives

by Gaëtan Poulen, Emilie Chan-Seng, Emily Sanrey and Philippe Coubes

Life 2021, 11(6), 481; https://doi.org/10.3390/life11060481 - 25 May 2021

Cited by 3 | Viewed by 2467

Abstract

Cerebral palsy (CP) is a heterogeneous group of non-progressive syndromes with lots of clinical variations due to the extent of brain damages and etiologies. CP is majorly defined by dystonia and spasticity. The treatment of acquired dystonia in CP is very difficult. Many [...] Read more.

Cerebral palsy (CP) is a heterogeneous group of non-progressive syndromes with lots of clinical variations due to the extent of brain damages and etiologies. CP is majorly defined by dystonia and spasticity. The treatment of acquired dystonia in CP is very difficult. Many pharmacological treatments have been tried and surgical treatment consists of deep brain stimulation (continuous electrical neuromodulation) of internal globus pallidus (GPi). A peculiar cause of CP is neonatal encephalopathy due to an anoxic event in the perinatal period. Many studies showed an improvement of dystonia in CP patients with bilateral GPi DBS. However, it remains a variability in the range of 1% to 50%. Published case-series concerned mainly small population with a majority of adult patients. Selection of patients according to the clinical pattern, to the brain lesions observed on classical imaging and to DTI is the key of a high success rate of DBS in children with perinatal hypoxemic encephalopathy. Only a large retrospective study with a high number of patients in a homogeneous pediatric population with a long-term follow-up or a prospective multicenter trial investigation could answer with a high degree of certitude of the real interest of this therapeutic in children with hypoxemic perinatal encephalopathy. Full article

(This article belongs to the Special Issue Dystonia and Related Disorders: From Bench to Bedside)

17 pages, 411 KB

Open AccessEditor’s ChoiceReview

BiTEs, DARTS, BiKEs and TriKEs—Are Antibody Based Therapies Changing the Future Treatment of AML?

by Cecily Allen, Amer M. Zeidan and Jan Philipp Bewersdorf

Life 2021, 11(6), 465; https://doi.org/10.3390/life11060465 - 23 May 2021

Cited by 46 | Viewed by 8989

Abstract

Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific [...] Read more.

Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells). Full article

(This article belongs to the Special Issue Bispecific Antibodies: Design, Isolation, Perspectives of Use)

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15 pages, 2680 KB

Open AccessEditor’s ChoiceArticle

Anti-Cancer and Immunomodulatory Activity of a Polyethylene Glycol-Betulinic Acid Conjugate on Pancreatic Cancer Cells

by Pascaline Nanga Fru, Ekene Emmanuel Nweke, Nompumelelo Mthimkhulu, Sindisiwe Mvango, Marietha Nel, Lynne Alison Pilcher and Mohammed Balogun

Life 2021, 11(6), 462; https://doi.org/10.3390/life11060462 - 21 May 2021

Cited by 10 | Viewed by 3093

Abstract

Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct [...] Read more.

Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct of polyethylene glycol (PEG), (PEG–BA), on PC cells (MIA PaCa-2), a normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG–BA, was tested for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways. The conjugate was significantly more toxic to PC cells (p < 0.001, IC₅₀ of 1.35 ± 0.11 µM) compared to BA (IC₅₀ of 12.70 ± 0.34 µM), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells. Cytotoxicity was confirmed by increased apoptotic cell death. PEG–BA inhibited the production of IL-6 by 4–5.5 fold compared to BA-treated cells. Furthermore, PEG–BA treatment of MIA PaCa-2 cells resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1 and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines such as IL-6 by the model polymer construct, PEG–BA, holds promise for further exploration in PC treatment. Full article

(This article belongs to the Special Issue Immune Reconstitution Disorders)

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15 pages, 1087 KB

Open AccessEditor’s ChoiceReview

Chronothyroidology: Chronobiological Aspects in Thyroid Function and Diseases

by Giuseppe Bellastella, Maria Ida Maiorino, Lorenzo Scappaticcio, Annamaria De Bellis, Silvia Mercadante, Katherine Esposito and Antonio Bellastella

Life 2021, 11(5), 426; https://doi.org/10.3390/life11050426 - 10 May 2021

Cited by 16 | Viewed by 4648

Abstract

Chronobiology is the scientific discipline which considers biological phenomena in relation to time, which assumes itself biological identity. Many physiological processes are cyclically regulated by intrinsic clocks and many pathological events show a circadian time-related occurrence. Even the pituitary–thyroid axis is under the [...] Read more.

Chronobiology is the scientific discipline which considers biological phenomena in relation to time, which assumes itself biological identity. Many physiological processes are cyclically regulated by intrinsic clocks and many pathological events show a circadian time-related occurrence. Even the pituitary–thyroid axis is under the control of a central clock, and the hormones of the pituitary–thyroid axis exhibit circadian, ultradian and circannual rhythmicity. This review, after describing briefly the essential principles of chronobiology, will be focused on the results of personal experiences and of other studies on this issue, paying particular attention to those regarding the thyroid implications, appearing in the literature as reviews, metanalyses, original and observational studies until 28 February 2021 and acquired from two databases (Scopus and PubMed). The first input to biological rhythms is given by a central clock located in the suprachiasmatic nucleus (SCN), which dictates the timing from its hypothalamic site to satellite clocks that contribute in a hierarchical way to regulate the physiological rhythmicity. Disruption of the rhythmic organization can favor the onset of important disorders, including thyroid diseases. Several studies on the interrelationship between thyroid function and circadian rhythmicity demonstrated that thyroid dysfunctions may affect negatively circadian organization, disrupting TSH rhythm. Conversely, alterations of clock machinery may cause important perturbations at the cellular level, which may favor thyroid dysfunctions and also cancer. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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28 pages, 3121 KB

Open AccessEditor’s ChoiceReview

The “Water Problem”(sic), the Illusory Pond and Life’s Submarine Emergence—A Review

by Michael J. Russell

Life 2021, 11(5), 429; https://doi.org/10.3390/life11050429 - 10 May 2021

Cited by 29 | Viewed by 10004

Abstract

The assumption that there was a “water problem” at the emergence of life—that the Hadean Ocean was simply too wet and salty for life to have emerged in it—is here subjected to geological and experimental reality checks. The “warm little pond” that would [...] Read more.

The assumption that there was a “water problem” at the emergence of life—that the Hadean Ocean was simply too wet and salty for life to have emerged in it—is here subjected to geological and experimental reality checks. The “warm little pond” that would take the place of the submarine alkaline vent theory (AVT), as recently extolled in the journal Nature, flies in the face of decades of geological, microbiological and evolutionary research and reasoning. To the present author, the evidence refuting the warm little pond scheme is overwhelming given the facts that (i) the early Earth was a water world, (ii) its all-enveloping ocean was never less than 4 km deep, (iii) there were no figurative “Icelands” or “Hawaiis”, nor even an “Ontong Java” then because (iv) the solidifying magma ocean beneath was still too mushy to support such salient loadings on the oceanic crust. In place of the supposed warm little pond, we offer a well-protected mineral mound precipitated at a submarine alkaline vent as life’s womb: in place of lipid membranes, we suggest peptides; we replace poisonous cyanide with ammonium and hydrazine; instead of deleterious radiation we have the appropriate life-giving redox and pH disequilibria; and in place of messy chemistry we offer the potential for life’s emergence from the simplest of geochemically available molecules and ions focused at a submarine alkaline vent in the Hadean—specifically within the nano-confined flexible and redox active interlayer walls of the mixed-valent double layer oxyhydroxide mineral, fougerite/green rust comprising much of that mound. Full article

(This article belongs to the Collection Feature Review Papers for Life)

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16 pages, 1458 KB

Open AccessEditor’s ChoiceReview

Chronic Kidney Disease as a Systemic Inflammatory Syndrome: Update on Mechanisms Involved and Potential Treatment

by Francesca Tinti, Silvia Lai, Annalisa Noce, Silverio Rotondi, Giulia Marrone, Sandro Mazzaferro, Nicola Di Daniele and Anna Paola Mitterhofer

Life 2021, 11(5), 419; https://doi.org/10.3390/life11050419 - 5 May 2021

Cited by 79 | Viewed by 8151

Abstract

Chronic kidney disease (CKD) is characterized by manifestations and symptoms involving systemic organs and apparatus, associated with elevated cardiovascular morbidity and mortality, bone disease, and other tissue involvement. Arterial hypertension (AH), diabetes mellitus (DM), and dyslipidemia, with glomerular or congenital diseases, are the [...] Read more.

Chronic kidney disease (CKD) is characterized by manifestations and symptoms involving systemic organs and apparatus, associated with elevated cardiovascular morbidity and mortality, bone disease, and other tissue involvement. Arterial hypertension (AH), diabetes mellitus (DM), and dyslipidemia, with glomerular or congenital diseases, are the traditional risk factors recognized as the main causes of progressive kidney dysfunction evolving into uremia. Acute kidney injury (AKI) has recently been considered an additional risk factor for the worsening of CKD or the development of CKD de novo. Evidence underlies the role of systemic inflammation as a linking factor between AKI and CKD, recognizing the role of inflammation in AKI evolution to CKD. Moreover, abnormal increases in oxidative stress (OS) and inflammatory status in CKD seem to exert an important pathogenetic role, with significant involvement in the clinical management of this condition. With our revision, we want to focus on and update the inflammatory mechanisms responsible for the pathologic conditions associated with CKD, with particular attention on the development of AKI and AKI-CKD de novo, the alteration of calcium-phosphorus metabolism with bone disease and CKD-MBD syndrome, the status of malnutrition and malnutrition–inflammation complex syndrome (MICS) and protein-energy wasting (PEW), uremic sarcopenia, the status of OS, and the different inflammatory pathways, highlighting a new approach to CKD. The depth comprehension of the mechanisms underlying the development of inflammation in CKD may present new possible therapeutic approaches in CKD and hopefully improve the management of correlated morbidities and provide a reduction in associated mortality. Full article

(This article belongs to the Collection Research Updates in Chronic Kidney Disease)

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22 pages, 3353 KB

Open AccessEditor’s ChoiceArticle

Loose Ends in the Cortinarius Phylogeny: Five New Myxotelamonoid Species Indicate a High Diversity of These Ectomycorrhizal Fungi with South American Nothofagaceae

by María Eugenia Salgado Salomón, Carolina Barroetaveña, Tuula Niskanen, Kare Liimatainen, Matthew E. Smith and Ursula Peintner

Life 2021, 11(5), 420; https://doi.org/10.3390/life11050420 - 5 May 2021

Cited by 11 | Viewed by 4003

Abstract

This paper is a contribution to the current knowledge of taxonomy, ecology and distribution of South American Cortinarius (Pers.) Gray. Cortinarius is among the most widely distributed and species-rich basidiomycete genera occurring with South American Nothofagaceae and species are found in many distinct [...] Read more.

This paper is a contribution to the current knowledge of taxonomy, ecology and distribution of South American Cortinarius (Pers.) Gray. Cortinarius is among the most widely distributed and species-rich basidiomycete genera occurring with South American Nothofagaceae and species are found in many distinct habitats, including shrublands and forests. Due to their ectomycorrhizal role, Cortinarius species are critical for nutrient cycling in forests, especially at higher latitudes. Some species have also been reported as edible fungi with high nutritional quality. Our aim is to unravel the taxonomy of selected Cortinarius belonging to phlegmacioid and myxotelamonioid species based on morphological and molecular data. After widely sampling Cortinarius specimens in Patagonian Nothofagaceae forests and comparing them to reference collections (including holotypes), we propose five new species of Cortinarius in this work. Phylogenetic analyses of concatenated rDNA ITS-LSU and RPB1 sequences failed to place these new species into known Cortinarius sections or lineages. These findings highlight our knowledge gaps regarding the fungal diversity of South American Nothofagaceae forests. Due to the high diversity of endemic Patagonian taxa, it is clear that the South American Cortinarius diversity needs to be discovered and described in order to understand the evolutionary history of Cortinarius on a global scale. Full article

(This article belongs to the Special Issue Biodiversity and Ecology of Fungi in Terrestrial and Marine Ecosystems)

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21 pages, 9239 KB

Open AccessEditor’s ChoiceArticle

Molecular Insights into the Genetic Variability of ORF Virus in a Mediterranean Region (Sardinia, Italy)

by Elisabetta Coradduzza, Daria Sanna, Angela M. Rocchigiani, Davide Pintus, Fabio Scarpa, Rosario Scivoli, Roberto Bechere, Maria A. Dettori, Maria A. Montesu, Vincenzo Marras, Renato Lobrano, Ciriaco Ligios and Giantonella Puggioni

Life 2021, 11(5), 416; https://doi.org/10.3390/life11050416 - 4 May 2021

Cited by 8 | Viewed by 3116

Abstract

Orf virus (ORFV) represents the causative agent of contagious ecthyma, clinically characterized by mild papular and pustular to severe proliferative lesions, mainly occurring in sheep and goats. In order to provide hints on the evolutionary history of this virus, we carried out a [...] Read more.

Orf virus (ORFV) represents the causative agent of contagious ecthyma, clinically characterized by mild papular and pustular to severe proliferative lesions, mainly occurring in sheep and goats. In order to provide hints on the evolutionary history of this virus, we carried out a study aimed to assess the genetic variation of ORFV in Sardinia that hosts a large affected small ruminant population. We also found a high worldwide mutational viral evolutionary rate, which resulted, in turn, higher than the rate we detected for the strains isolated in Sardinia. In addition, a well-supported genetic divergence was found between the viral strains isolated from sheep and those from goats, but no relevant connection was evidenced between the severity of lesions produced by ORFV and specific polymorphic patterns in the two species of hosts. Such a finding suggests that ORFV infection-related lesions are not necessarily linked to the expression of one of the three genes here analyzed and could rather be the effect of the expression of other genes or rather represents a multifactorial character. Full article

(This article belongs to the Special Issue Evolutionary and Conservation Genetics)

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13 pages, 3197 KB

Open AccessEditor’s ChoiceArticle

The Mitochondrial Genome of the Sea Anemone Stichodactyla haddoni Reveals Catalytic Introns, Insertion-Like Element, and Unexpected Phylogeny

by Steinar Daae Johansen, Sylvia I. Chi, Arseny Dubin and Tor Erik Jørgensen

Life 2021, 11(5), 402; https://doi.org/10.3390/life11050402 - 28 Apr 2021

Cited by 9 | Viewed by 4122

Abstract

A hallmark of sea anemone mitochondrial genomes (mitogenomes) is the presence of complex catalytic group I introns. Here, we report the complete mitogenome and corresponding transcriptome of the carpet sea anemone Stichodactyla haddoni (family Stichodactylidae). The mitogenome is vertebrate-like in size, organization, and [...] Read more.

A hallmark of sea anemone mitochondrial genomes (mitogenomes) is the presence of complex catalytic group I introns. Here, we report the complete mitogenome and corresponding transcriptome of the carpet sea anemone Stichodactyla haddoni (family Stichodactylidae). The mitogenome is vertebrate-like in size, organization, and gene content. Two mitochondrial genes encoding NADH dehydrogenase subunit 5 (ND5) and cytochrome c oxidase subunit I (COI) are interrupted with complex group I introns, and one of the introns (ND5-717) harbors two conventional mitochondrial genes (ND1 and ND3) within its sequence. All the mitochondrial genes, including the group I introns, are expressed at the RNA level. Nonconventional and optional mitochondrial genes are present in the mitogenome of S. haddoni. One of these gene codes for a COI-884 intron homing endonuclease and is organized in-frame with the upstream COI exon. The insertion-like orfA is expressed as RNA and translocated in the mitogenome as compared with other sea anemones. Phylogenetic analyses based on complete nucleotide and derived protein sequences indicate that S. haddoni is embedded within the family Actiniidae, a finding that challenges current taxonomy. Full article

(This article belongs to the Special Issue Molecular Phylogenetics and Mitochondrial Evolution)

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38 pages, 6064 KB

Open AccessEditor’s ChoiceReview

Proton Bridging in Catalysis by and Inhibition of Serine Proteases of the Blood Cascade System

by Ildiko M Kovach

Life 2021, 11(5), 396; https://doi.org/10.3390/life11050396 - 27 Apr 2021

Cited by 2 | Viewed by 4129

Abstract

Inquiries into the participation of short hydrogen bonds in stabilizing transition states and intermediate states in the thrombin, factor Xa, plasmin and activated protein C–catalyzed reactions revealed that specific binding of effectors at S_n, n = 1–4 and S’_n, [...] Read more.

Inquiries into the participation of short hydrogen bonds in stabilizing transition states and intermediate states in the thrombin, factor Xa, plasmin and activated protein C–catalyzed reactions revealed that specific binding of effectors at S_n, n = 1–4 and S’_n, n = 1–3 and at remote exosites elicit complex patterns of hydrogen bonding and involve water networks. The methods employed that yielded these discoveries include; (1) kinetics, especially partial or full kinetic deuterium solvent isotope effects with short cognate substrates and also with the natural substrates, (2) kinetic and structural probes, particularly low-field high-resolution nuclear magnetic resonance (¹H NMR), of mechanism-based inhibitors and substrate-mimic peptide inhibitors. Short hydrogen bonds form at the transition states of the catalytic reactions at the active site of the enzymes as they do with mechanism-based covalent inhibitors of thrombin. The emergence of short hydrogen bonds at the binding interface of effectors and thrombin at remote exosites has recently gained recognition. Herein, I describe our contribution, a confirmation of this discovery, by low-field ¹H NMR. The principal conclusion of this review is that proton sharing at distances below the sum of van der Waals radii of the hydrogen and both donor and acceptor atoms contribute to the remarkable catalytic prowess of serine proteases of the blood clotting system and other enzymes that employ acid-base catalysis. Proton bridges also play a role in tight binding in proteins and at exosites, i.e., allosteric sites, of enzymes. Full article

(This article belongs to the Special Issue Current Approaches in Molecular Enzymology)

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Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

by Sungjin Chung and Gheun-Ho Kim

Life 2021, 11(5), 389; https://doi.org/10.3390/life11050389 - 25 Apr 2021

Cited by 8 | Viewed by 6319

Abstract

New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, [...] Read more.

New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease. Full article

(This article belongs to the Collection Research Updates in Chronic Kidney Disease)

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