Life | Editor’s choice Articles

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22 pages, 1918 KiB

Open AccessEditor’s ChoiceReview

Third-Generation Sequencing: The Spearhead towards the Radical Transformation of Modern Genomics

by Konstantina Athanasopoulou, Michaela A. Boti, Panagiotis G. Adamopoulos, Paraskevi C. Skourou and Andreas Scorilas

Life 2022, 12(1), 30; https://doi.org/10.3390/life12010030 - 26 Dec 2021

Cited by 155 | Viewed by 28404

Abstract

Although next-generation sequencing (NGS) technology revolutionized sequencing, offering a tremendous sequencing capacity with groundbreaking depth and accuracy, it continues to demonstrate serious limitations. In the early 2010s, the introduction of a novel set of sequencing methodologies, presented by two platforms, Pacific Biosciences (PacBio) [...] Read more.

Although next-generation sequencing (NGS) technology revolutionized sequencing, offering a tremendous sequencing capacity with groundbreaking depth and accuracy, it continues to demonstrate serious limitations. In the early 2010s, the introduction of a novel set of sequencing methodologies, presented by two platforms, Pacific Biosciences (PacBio) and Oxford Nanopore Sequencing (ONT), gave birth to third-generation sequencing (TGS). The innovative long-read technologies turn genome sequencing into an ease-of-handle procedure by greatly reducing the average time of library construction workflows and simplifying the process of de novo genome assembly due to the generation of long reads. Long sequencing reads produced by both TGS methodologies have already facilitated the decipherment of transcriptional profiling since they enable the identification of full-length transcripts without the need for assembly or the use of sophisticated bioinformatics tools. Long-read technologies have also provided new insights into the field of epitranscriptomics, by allowing the direct detection of RNA modifications on native RNA molecules. This review highlights the advantageous features of the newly introduced TGS technologies, discusses their limitations and provides an in-depth comparison regarding their scientific background and available protocols as well as their potential utility in research and clinical applications. Full article

(This article belongs to the Special Issue Third-Generation Sequencing: Recent Advances and Applications in the Era of Genomics, Transcriptomics and Epitranscriptomics)

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19 pages, 9865 KiB

Open AccessEditor’s ChoiceReview

Pediatric Neuromyelitis Optica Spectrum Disorder: Case Series and Literature Review

by Michela Ada Noris Ferilli, Roberto Paparella, Ilaria Morandini, Laura Papetti, Lorenzo Figà Talamanca, Claudia Ruscitto, Fabiana Ursitti, Romina Moavero, Giorgia Sforza, Samuela Tarantino, Martina Proietti Checchi, Federico Vigevano and Massimiliano Valeriani

Life 2022, 12(1), 19; https://doi.org/10.3390/life12010019 - 23 Dec 2021

Cited by 12 | Viewed by 6161

Abstract

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray [...] Read more.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray matter. The aquaporin-4 antibody (AQP4-IgG) is specific for NMOSD. Recently, myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been found in a group of AQP4-IgG negative patients. NMOSD is rare among children and adolescents, but early diagnosis is important to start adequate therapy. In this report, we present cases of seven pediatric patients with NMOSD and we review the clinical and neuroimaging characteristics, diagnosis, and treatment of NMOSD in children. Full article

(This article belongs to the Special Issue Research Updates in Pediatric Neuroscience)

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19 pages, 1427 KiB

Open AccessEditor’s ChoiceReview

From Life in the Sea to the Clinic: The Marine Drugs Approved and under Clinical Trial

by Emiliano Cappello and Paola Nieri

Life 2021, 11(12), 1390; https://doi.org/10.3390/life11121390 - 11 Dec 2021

Cited by 47 | Viewed by 7720

Abstract

In the last decades Blue Growth policy in european and non-european countries produced a great impulse in applied marine sciences, comprehending the research of new bioactive molecules in marine organisms. These organisms are a great source of natural compounds with unique features resulting [...] Read more.

In the last decades Blue Growth policy in european and non-european countries produced a great impulse in applied marine sciences, comprehending the research of new bioactive molecules in marine organisms. These organisms are a great source of natural compounds with unique features resulting from the huge variability of marine habitats and species living in them. Most of the marine compounds in use and in clinical trials are drugs for cancer therapy and many of them are conjugated to antibody to form antibody-drug conjugates (ADCs). Severe pain, viral infections, hypertriglyceridemia, obesity, Alzheimer’s and other CNS diseases are further target conditions for these pharmaceuticals. This review summarizes the state-of-the-art marine drugs focusing on the most successful results in the fast expanding field of marine pharmacology. Full article

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

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17 pages, 1094 KiB

Open AccessEditor’s ChoiceReview

Potential Reasons for Unresponsiveness to Anti-PD1 Immunotherapy in Young Patients with Advanced Melanoma

by Devayani Machiraju, Sarah Schäfer and Jessica C. Hassel

Life 2021, 11(12), 1318; https://doi.org/10.3390/life11121318 - 30 Nov 2021

Cited by 15 | Viewed by 5173

Abstract

The impact of age on the clinical benefit of anti-PD1 immunotherapy in advanced melanoma patients has been evolving recently. Due to a reduced immune function in elderly patients, young patients with a robust immune system are theoretically expected to benefit more from the [...] Read more.

The impact of age on the clinical benefit of anti-PD1 immunotherapy in advanced melanoma patients has been evolving recently. Due to a reduced immune function in elderly patients, young patients with a robust immune system are theoretically expected to benefit more from the treatment approach. However, in contrast to this hypothesis, recent studies in patients with metastatic melanoma have demonstrated that immunotherapy, especially with anti-PD1 treatment, is less effective in patients below 65 years, on average, with significantly lower responses and reduced overall survival compared to patients above 65 years of age. Besides, data on young patients are even more sparse. Hence, in this review, we will focus on age-dependent differences in the previously described resistance mechanisms to the treatment and discuss the development of potential combination treatment strategies for enhancing the anti-tumor efficacy of anti-PD1 or PDL1 treatment in young melanoma patients. Full article

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

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12 pages, 415 KiB

Open AccessEditor’s ChoiceReview

Colorectal Cancer Screening: Impact of COVID-19 Pandemic and Possible Consequences

by Isabelle Harber, Dania Zeidan and Muhammad N. Aslam

Life 2021, 11(12), 1297; https://doi.org/10.3390/life11121297 - 26 Nov 2021

Cited by 28 | Viewed by 8493

Abstract

Colonoscopy procedure has been the key screening method to detect colorectal cancer (CRC). As a fatal disease, CRC needs early detection. The COVID-19 pandemic caused screening tests (colonoscopy) to be halted and delayed. As a result, there could be dire consequences such as [...] Read more.

Colonoscopy procedure has been the key screening method to detect colorectal cancer (CRC). As a fatal disease, CRC needs early detection. The COVID-19 pandemic caused screening tests (colonoscopy) to be halted and delayed. As a result, there could be dire consequences such as later-stage or missed diagnosis or greater mortality. This report will analyze scientific literature pertaining to interrupted CRC screenings due to COVID-19 while drawing historical parallels from the 1918 flu pandemic. We conducted literature searches in the PubMed database as well as in Google Scholar. One of the main lessons learned from the 1918 flu pandemic was to employ social distancing to stop the spread of the virus. So, the global response at the start and peak of the COVID-19 pandemic was decreased hospital visits for any non-emergency cases. That led to a halt and delays in cancer (including CRC) screenings. The Medical community predicted this lag will cause more CRC cases and deaths in the future. However, reorganizing and changing screening method strategies were helpful during the ongoing pandemic. In conclusion, COVID-19 greatly affected CRC screening, including how we view the future of CRC screening. We can learn from this prospect to better prepare for future pandemics or other public health crises. Full article

(This article belongs to the Special Issue Old and New Pandemics: Challenges for Humans)

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11 pages, 1577 KiB

Open AccessEditor’s ChoiceReview

The Need for Expanding Pulmonary Rehabilitation Services

by Aroub Lahham and Anne E. Holland

Life 2021, 11(11), 1236; https://doi.org/10.3390/life11111236 - 15 Nov 2021

Cited by 49 | Viewed by 8464

Abstract

Pulmonary rehabilitation is a strongly recommended and effective treatment for people with chronic lung disease. However, access to pulmonary rehabilitation is poor. Globally, pulmonary rehabilitation is accessed by less than 3% of people with chronic lung disease. Barriers to referral, uptake and completion [...] Read more.

Pulmonary rehabilitation is a strongly recommended and effective treatment for people with chronic lung disease. However, access to pulmonary rehabilitation is poor. Globally, pulmonary rehabilitation is accessed by less than 3% of people with chronic lung disease. Barriers to referral, uptake and completion of pulmonary rehabilitation are well documented and linked with organizational, practitioner and patient-related factors. Enhancing the knowledge of health care professionals, family carers, and people with chronic lung disease about the program and its benefits produces modest increases in referral and uptake rates, but evidence of the sustainability of such approaches is limited. Additionally, initiatives focusing on addressing organizational barriers to access, such as expanding services and implementing alternative models to the conventional center-based setting, are not yet widely used in clinical practice. The COVID-19 pandemic has highlighted the urgent need for health care systems to deliver pulmonary rehabilitation programs remotely, safely, and efficiently. This paper will discuss the pressing need to address the issue of the low accessibility of pulmonary rehabilitation. It will also highlight the distinctive challenges to pulmonary rehabilitation delivery in rural and remote regions, as well as low-income countries. Full article

(This article belongs to the Special Issue Utilizing Telemedicine as a Tool to Enhance Outcomes in Individuals with Chronic Respiratory Diseases)

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12 pages, 278 KiB

Open AccessEditor’s ChoiceReview

Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence

by Patrick Holford, Anitra C. Carr, Masuma Zawari and Marcela P. Vizcaychipi

Life 2021, 11(11), 1166; https://doi.org/10.3390/life11111166 - 1 Nov 2021

Cited by 19 | Viewed by 12290

Abstract

Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin. Administration of intravenous vitamin C to patients with pneumonia [...] Read more.

Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin. Administration of intravenous vitamin C to patients with pneumonia and sepsis appears to decrease the severity of the disease and potentially improve survival rate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes pneumonia, sepsis and acute respiratory distress syndrome (ARDS) in severe cases, and is referred to as coronavirus disease 2019 (COVID-19). Patients with COVID-19 infection also appear to have depleted vitamin C status and require additional supplementation of vitamin C during the acute phase of the disease. To date there have been 12 vitamin C and COVID-19 trials published, including five randomised controlled trials (RCTs) and seven retrospective cohort studies. The current level of evidence from the RCTs suggests that intravenous vitamin C intervention may improve oxygenation parameters, reduce inflammatory markers, decrease days in hospital and reduce mortality, particularly in the more severely ill patients. High doses of oral vitamin C supplementation may also improve the rate of recovery in less severe cases. No adverse events have been reported in published vitamin C clinical trials in COVID-19 patients. Upcoming findings from larger RCTs will provide additional evidence on vitamin supplementation in COVID-19 patients. Full article

(This article belongs to the Special Issue Antimicrobial Mechanisms of Vitamin C)

12 pages, 282 KiB

Open AccessEditor’s ChoiceReview

Using Telemedicine to Monitor the Patient with Chronic Respiratory Failure

by Nicolino Ambrosino and Paola Pierucci

Life 2021, 11(11), 1113; https://doi.org/10.3390/life11111113 - 20 Oct 2021

Cited by 13 | Viewed by 4283

Abstract

Background: Advances in management have improved mortality of individuals with chronic respiratory failure (CRF), leading to an increase in need for long-term oxygen therapy and/or ventilatory support. These individuals require frequent visits and monitoring of their physiological parameters as well as of [...] Read more.

Background: Advances in management have improved mortality of individuals with chronic respiratory failure (CRF), leading to an increase in need for long-term oxygen therapy and/or ventilatory support. These individuals require frequent visits and monitoring of their physiological parameters as well as of the functioning of their devices, such as ventilators or oxygen concentrators. Telemedicine is a clinical application of Information Communication Technology connecting patients to specialised care consultants. This narrative review aims to explore the current available telemonitoring options for individuals with CRF and reported or potential results. Methods: The research focused on EMBASE, CINALH, PubMed, and Scopus databases. Papers published between 2003 and 2021 in English were considered. Results: Different sensors, transmission devices and systems, and interventions are used with promising but not conclusive clinical results. However, legal problems are still unsolved, and economic advantages for health care systems, although potentially high, are still under debate. Conclusions: Telemonitoring systems for individuals with CRF are increasingly used; with promising results still to be clarified, legal, economical and organisational issues must be defined. Full article

(This article belongs to the Special Issue Utilizing Telemedicine as a Tool to Enhance Outcomes in Individuals with Chronic Respiratory Diseases)

21 pages, 7336 KiB

Open AccessEditor’s ChoiceReview

Bioactive Natural Compounds with Antiplatelet and Anticoagulant Activity and Their Potential Role in the Treatment of Thrombotic Disorders

by Stefania Lamponi

Life 2021, 11(10), 1095; https://doi.org/10.3390/life11101095 - 15 Oct 2021

Cited by 27 | Viewed by 10899

Abstract

Natural anticoagulant drugs can be obtained from plants, rich in secondary bioactive metabolites which, in addition to being effective antioxidants, also possess anticoagulant and antiplatelet properties and, for this reason, can be excellent candidates for the treatment of thrombotic diseases. This review reports [...] Read more.

Natural anticoagulant drugs can be obtained from plants, rich in secondary bioactive metabolites which, in addition to being effective antioxidants, also possess anticoagulant and antiplatelet properties and, for this reason, can be excellent candidates for the treatment of thrombotic diseases. This review reports an overview of the hemostatic process and thrombotic disorders together with data on plants, more and less common from around the world, containing bioactive compounds characterized by antiplatelet and anticoagulant activity. The reported literature was obtained from Medline, PubMed, Elsevier, Web of Science, Google Scholar considering only articles in the English language, published in peer-reviewed journals. The number of citations of the articles and the impact factor of the journals were other parameters used to select the scientific papers to be included in the review. The analysis of the literature data selected demonstrates that many plants’ bioactive compounds show antiplatelet and anticoagulant activity that make them potential candidates to be used as new natural compounds able to interfere with both primary and secondary hemostasis. Moreover, they could be used together with anticoagulants currently administered in clinical practice to increase their efficacy and to reduce complications in the treatment of thrombotic disorders. Full article

(This article belongs to the Special Issue Bioactive Natural Compounds for Pharmaceutical and Nutraceutical Applications)

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24 pages, 395 KiB

Open AccessEditor’s ChoiceReview

Current Therapeutic Approach to Acute Myocardial Infarction in Patients with Congenital Hemophilia

by Minerva Codruta Badescu, Manuela Ciocoiu, Elena Rezus, Oana Viola Badulescu, Daniela Maria Tanase, Anca Ouatu, Nicoleta Dima, Ana Roxana Ganceanu-Rusu, Diana Popescu, Petronela Nicoleta Seritean Isac, Tudor-Marcel Genes and Ciprian Rezus

Life 2021, 11(10), 1072; https://doi.org/10.3390/life11101072 - 11 Oct 2021

Cited by 13 | Viewed by 3286

Abstract

Advances in the treatment of hemophilia have made the life expectancy of hemophiliacs similar to that of the general population. Physicians have begun to face age-related diseases not previously encountered in individuals with hemophilia. Treatment of acute myocardial infarction (AMI) is particularly challenging [...] Read more.

Advances in the treatment of hemophilia have made the life expectancy of hemophiliacs similar to that of the general population. Physicians have begun to face age-related diseases not previously encountered in individuals with hemophilia. Treatment of acute myocardial infarction (AMI) is particularly challenging because the therapeutic strategies influence both the patient’s thrombotic and hemorrhagic risk. As progress has been made in the treatment of AMI over the last decade, we performed an in-depth analysis of the available literature, highlighting the latest advances in the therapy of AMI in hemophiliacs. It is generally accepted that after the optimal substitution therapy has been provided, patients with hemophilia should be treated in the same way as those in the general population. New-generation stents that allow short dual antiplatelet therapy and potent P2Y₁₂ receptor inhibitors have begun to be successfully used. At a time when specific recommendations and relevant data are scarce, our study provides up-to-date information to physicians involved in the treatment of AMI in hemophiliacs. Full article

(This article belongs to the Special Issue Myocardial Infarction 2021)

13 pages, 1361 KiB

Open AccessEditor’s ChoiceReview

Cardiac Transplantation and the Use of Cannabis

by Hirak Shah, Meg Fraser, Arianne C. Agdamag, Valmiki Maharaj, Bellony Nzemenoh, Cindy M. Martin, Tamas Alexy and Daniel J. Garry

Life 2021, 11(10), 1063; https://doi.org/10.3390/life11101063 - 9 Oct 2021

Cited by 4 | Viewed by 3350

Abstract

Cardiac transplantation requires the careful allocation of a limited number of precious organs. Therefore, it is critical to select candidates that will receive the greatest anticipated medical benefit but will also serve as the best stewards of the organ. Individual transplant teams have [...] Read more.

Cardiac transplantation requires the careful allocation of a limited number of precious organs. Therefore, it is critical to select candidates that will receive the greatest anticipated medical benefit but will also serve as the best stewards of the organ. Individual transplant teams have established prerequisites pertaining to recreational drug, tobacco, alcohol, and controlled substance use in potential organ recipients and post-transplantation. Legalization of cannabis and implementation of its prescription-based use for the management of patients with chronic conditions have been increasing over the past years. Center requirements regarding abstinence from recreational and medical cannabis use vary due to rapidly changing state regulations, as well as the lack of clinical safety data in this population. This is evident by the results of the multicenter survey presented in this paper. Developing uniform guidelines around cannabis use will be imperative not only for providers but also for patients. Full article

(This article belongs to the Collection Heart Failure and Heart Transplantation)

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25 pages, 8146 KiB

Open AccessEditor’s ChoiceReview

Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19

by Eliza Dąbrowska, Beata Galińska-Skok and Napoleon Waszkiewicz

Life 2021, 11(10), 1056; https://doi.org/10.3390/life11101056 - 8 Oct 2021

Cited by 28 | Viewed by 4859

Abstract

The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a [...] Read more.

The dysfunctional effects of the coronavirus disease 2019 (COVID-19) infection on the nervous system are established. The manifestation of neuropsychiatric symptoms during and after infection is influenced by the neuroinvasive and neurotrophic properties of SARS-CoV-2 as well as strong inflammation characterised by a specific “cytokine storm”. Research suggests that a strong immune response to a SARS-CoV-2 infection and psychological stressors related to the pandemic may cause chronic inflammatory processes in the body with elevated levels of inflammatory markers contributing to the intensification of neurodegenerative processes. It is suggested that neuroinflammation and associated central nervous system changes may significantly contribute to the etiopathogenesis of depressive disorders. In addition, symptoms after a COVID-19 infection may persist for up to several weeks after an acute infection as a post-COVID-19 syndrome. Moreover, previous knowledge indicates that among SSRI (selective serotonin reuptake inhibitor) group antidepressants, fluoxetine is a promising drug against COVID-19. In conclusion, further research, observation and broadening of the knowledge of the pathomechanism of a SARS-CoV-2 infection and the impact on potential complications are necessary. It is essential to continue research in order to assess the long-term neuropsychiatric effects in COVID-19 patients and to find new therapeutic strategies. Full article

(This article belongs to the Special Issue Depressive Disorders-New Challenges)

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12 pages, 541 KiB

Open AccessEditor’s ChoiceReview

Is There a Link between COVID-19 Infection, Periodontal Disease and Acute Myocardial Infarction?

by Ioana-Patricia Rodean, Carmen-Ioana Biriș, Vasile-Bogdan Halațiu, Andrei Modiga, Luminița Lazăr, Imre Benedek and Theodora Benedek

Life 2021, 11(10), 1050; https://doi.org/10.3390/life11101050 - 7 Oct 2021

Cited by 12 | Viewed by 3596

Abstract

Both periodontal disease and atherosclerosis are chronic disorders with an inflammatory substrate that leads to alteration of the host’s immune response. In PD, inflammation is responsible for bone tissue destruction, while in atherosclerosis, it leads to atheromatous plaque formation. These modifications result from [...] Read more.

Both periodontal disease and atherosclerosis are chronic disorders with an inflammatory substrate that leads to alteration of the host’s immune response. In PD, inflammation is responsible for bone tissue destruction, while in atherosclerosis, it leads to atheromatous plaque formation. These modifications result from the action of pro-inflammatory cytokines that are secreted both locally at gingival or coronary sites, and systemically. Recently, it was observed that in patients with PD or with cardiovascular disease, COVID-19 infection is prone to be more severe. While the association between PD, inflammation and cardiovascular disease is well-known, the impact of COVID-19-related inflammation on the systemic complications of these conditions has not been established yet. The purpose of this review is to bring light upon the latest advances in understanding the link between periodontal–cardiovascular diseases and COVID-19 infection. Full article

(This article belongs to the Special Issue Myocardial Infarction 2021)

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21 pages, 4786 KiB

Open AccessEditor’s ChoiceReview

The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

by Apolonia Witecka, Sebastian Kwiatkowski, Takao Ishikawa and Jakub Drozak

Life 2021, 11(10), 1040; https://doi.org/10.3390/life11101040 - 2 Oct 2021

Cited by 12 | Viewed by 4719

Abstract

SETD3 has been recently identified as a long sought, actin specific histidine methyltransferase that catalyzes the Nτ-methylation reaction of histidine 73 (H73) residue in human actin or its equivalent in other metazoans. Its homologs are widespread among multicellular eukaryotes and expressed in [...] Read more.

SETD3 has been recently identified as a long sought, actin specific histidine methyltransferase that catalyzes the Nτ-methylation reaction of histidine 73 (H73) residue in human actin or its equivalent in other metazoans. Its homologs are widespread among multicellular eukaryotes and expressed in most mammalian tissues. SETD3 consists of a catalytic SET domain responsible for transferring the methyl group from S-adenosyl-L-methionine (AdoMet) to a protein substrate and a RuBisCO LSMT domain that recognizes and binds the methyl-accepting protein(s). The enzyme was initially identified as a methyltransferase that catalyzes the modification of histone H3 at K4 and K36 residues, but later studies revealed that the only bona fide substrate of SETD3 is H73, in the actin protein. The methylation of actin at H73 contributes to maintaining cytoskeleton integrity, which remains the only well characterized biological effect of SETD3. However, the discovery of numerous novel methyltransferase interactors suggests that SETD3 may regulate various biological processes, including cell cycle and apoptosis, carcinogenesis, response to hypoxic conditions, and enterovirus pathogenesis. This review summarizes the current advances in research on the SETD3 protein, its biological importance, and role in various diseases. Full article

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

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19 pages, 8963 KiB

Open AccessEditor’s ChoiceReview

Anthropogenic Drivers Leading to Population Decline and Genetic Preservation of the Eurasian Griffon Vulture (Gyps fulvus)

by Monica Pirastru, Paolo Mereu, Laura Manca, Daniela Bebbere, Salvatore Naitana and Giovanni G. Leoni

Life 2021, 11(10), 1038; https://doi.org/10.3390/life11101038 - 1 Oct 2021

Cited by 9 | Viewed by 4538

Abstract

Human activities are having increasingly devastating effects on the health of marine and terrestrial ecosystems. Studying the adaptive responses of animal species to changes in their habitat can be useful in mitigating this impact. Vultures represent one of the most virtuous examples of [...] Read more.

Human activities are having increasingly devastating effects on the health of marine and terrestrial ecosystems. Studying the adaptive responses of animal species to changes in their habitat can be useful in mitigating this impact. Vultures represent one of the most virtuous examples of adaptation to human-induced environmental changes. Once dependent on wild ungulate populations, these birds have adapted to the epochal change resulting from the birth of agriculture and livestock domestication, maintaining their essential role as ecological scavengers. In this review, we retrace the main splitting events characterising the vultures’ evolution, with particular emphasis on the Eurasian griffon Gyps fulvus. We summarise the main ecological and behavioural traits of this species, highlighting its vulnerability to elements introduced into the habitat by humans. We collected the genetic information available to date, underlining their importance for improving the management of this species, as an essential tool to support restocking practices and to protect the genetic integrity of G. fulvus. Finally, we examine the difficulties in implementing a coordination system that allows genetic information to be effectively transferred into management programs. Until a linking network is established between scientific research and management practices, the risk of losing important wildlife resources remains high. Full article

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

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19 pages, 2462 KiB

Open AccessEditor’s ChoiceReview

Compendium of Plant-Specific CRISPR Vectors and Their Technical Advantages

by Anshu Alok, Hanny Chauhan, Santosh Kumar Upadhyay, Ashutosh Pandey, Jitendra Kumar and Kashmir Singh

Life 2021, 11(10), 1021; https://doi.org/10.3390/life11101021 - 28 Sep 2021

Cited by 34 | Viewed by 7128

Abstract

CRISPR/Cas mediated genome editing is a revolutionary approach for manipulating the plant genome. However, the success of this technology is highly dependent on selection of a specific vector and the other components. A plant-specific CRISPR/Cas vector usually consists of a Cas gene, target-specific [...] Read more.

CRISPR/Cas mediated genome editing is a revolutionary approach for manipulating the plant genome. However, the success of this technology is highly dependent on selection of a specific vector and the other components. A plant-specific CRISPR/Cas vector usually consists of a Cas gene, target-specific gRNA, leader sequence, selectable marker gene, precise promoters, and other accessories. It has always been challenging to select the specific vector for each study due to a lack of comprehensive information on CRISPR vectors in one place. Herein, we have discussed every technical aspect of various important elements that will be highly useful in vector selection and efficient editing of the desired plant genome. Various factors such as the promoter regulating the expression of Cas and gRNA, gRNA size, Cas variants, multicistronic gRNA, and vector backbone, etc. influence transformation and editing frequency. For example, the use of polycistronic tRNA-gRNA, and Csy4-gRNA has been documented to enhance the editing efficiency. Similarly, the selection of an efficient selectable marker is also a very important factor. Information on the availability of numerous variants of Cas endonucleases, such as Cas9, Cas12a, Cas12b, Casɸ, and CasMINI, etc., with diverse recognition specificities further broadens the scope of editing. The development of chimeric proteins such as Cas fused to cytosine or adenosine deaminase domain and modified reverse transcriptase using protein engineering enabled base and prime editing, respectively. In addition, the newly discovered Casɸ and CasMINI would increase the scope of genetic engineering in plants by being smaller Cas variants. All advancements would contribute to the development of various tools required for gene editing, targeted gene insertion, transcriptional activation/suppression, multiplexing, prime editing, base editing, and gene tagging. This review will serve as an encyclopedia for plant-specific CRISPR vectors and will be useful for researchers. Full article

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

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24 pages, 1723 KiB

Open AccessEditor’s ChoiceReview

Microfluidic Platforms to Unravel Mysteries of Alzheimer’s Disease: How Far Have We Come?

by Pragya Prasanna, Shweta Rathee, Vedanabhatla Rahul, Debabrata Mandal, Macherla Sharath Chandra Goud, Pardeep Yadav, Susan Hawthorne, Ankur Sharma, Piyush Kumar Gupta, Shreesh Ojha, Niraj Kumar Jha, Chiara Villa and Saurabh Kumar Jha

Life 2021, 11(10), 1022; https://doi.org/10.3390/life11101022 - 28 Sep 2021

Cited by 17 | Viewed by 12482

Abstract

Alzheimer’s disease (AD) is a significant health concern with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and [...] Read more.

Alzheimer’s disease (AD) is a significant health concern with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and drugs in clinical practice present numerous side effects. Lack of effective diagnostic techniques prevents the early prognosis of disease, resulting in a gradual deterioration in the quality of life. Furthermore, the mechanism of cognitive impairment and AD pathophysiology is poorly understood. Microfluidics exploits different microscale properties of fluids to mimic environments on microfluidic chip-like devices. These miniature multichambered devices can be used to grow cells and 3D tissues in vitro, analyze cell-to-cell communication, decipher the roles of neural cells such as microglia, and gain insights into AD pathophysiology. This review focuses on the applications and impact of microfluidics on AD research. We discuss the technical challenges and possible solutions provided by this new cutting-edge technique to understand disease-associated pathways and mechanisms. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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22 pages, 5041 KiB

Open AccessEditor’s ChoiceReview

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

by Sixuan Li, Hongquan Zhang and Xiaofan Wei

Life 2021, 11(9), 965; https://doi.org/10.3390/life11090965 - 14 Sep 2021

Cited by 10 | Viewed by 4479

Abstract

Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug [...] Read more.

Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug targets. DUBs have shown significant roles in regulating breast cancer growth, metastasis, resistance to current therapies, and several canonical oncogenic signaling pathways. In addition, specific DUB inhibitors have been identified and are expected to benefit breast cancer patients in the future. Here, we review current knowledge about the effects and molecular mechanisms of DUBs in breast cancer, providing novel insight into treatments of breast cancer-targeting DUBs. Full article

(This article belongs to the Collection Tumor Progression, Microenvironments, and Therapeutics)

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22 pages, 2454 KiB

Open AccessEditor’s ChoiceReview

Structure, Activity and Function of the Protein Arginine Methyltransferase 6

by Somlee Gupta, Rajashekar Varma Kadumuri, Anjali Kumari Singh, Sreenivas Chavali and Arunkumar Dhayalan

Life 2021, 11(9), 951; https://doi.org/10.3390/life11090951 - 11 Sep 2021

Cited by 26 | Viewed by 5256

Abstract

Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. [...] Read more.

Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections. Full article

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

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16 pages, 348 KiB

Open AccessEditor’s ChoiceReview

Laparoscopy in Emergency: Why Not? Advantages of Laparoscopy in Major Emergency: A Review

by Giuseppe Ietto, Francesco Amico, Giuseppe Pettinato, Valentina Iori and Giulio Carcano

Life 2021, 11(9), 917; https://doi.org/10.3390/life11090917 - 3 Sep 2021

Cited by 16 | Viewed by 5162

Abstract

A laparoscopic approach is suggested with the highest grade of recommendation for acute cholecystitis, perforated gastroduodenal ulcers, acute appendicitis, gynaecological disorders, and non-specific abdominal pain (NSAP). To date, the main qualities of laparoscopy for these acute surgical scenarios are clearly stated: quicker surgery, [...] Read more.

A laparoscopic approach is suggested with the highest grade of recommendation for acute cholecystitis, perforated gastroduodenal ulcers, acute appendicitis, gynaecological disorders, and non-specific abdominal pain (NSAP). To date, the main qualities of laparoscopy for these acute surgical scenarios are clearly stated: quicker surgery, faster recovery and shorter hospital stay. For the remaining surgical emergencies, as well as for abdominal trauma, the role of laparoscopy is still a matter of debate. Patients might benefit from a laparoscopic approach only if performed by experienced teams and surgeons which guarantee a high standard of care. More precisely, laparoscopy can limit damage to the tissue and could be effective for the reduction of the overall amount of cell debris, which is a result of the intensity with which the immune system reacts to the injury and the following symptomatology. In fact, these fragments act as damage-associated molecular patterns (DAMPs). DAMPs, as well as pathogen associated molecular patterns (PAMPs), are recognised by both surface and intracellular receptors of the immune cells and activate the cascade which, in critically ill surgical patients, is responsible for a deranged response. This may result in the development of progressive and multiple organ dysfunctions, manifesting with acute respiratory distress syndrome (ARDS), coagulopathy, liver dysfunction and renal failure. In conclusion, none of the emergency surgical scenarios preclude laparoscopy, provided that the surgical tactic could ensure sufficient cleaning of the abdomen in addition to resolving the initial tissue damage caused by the “trauma”. Full article

(This article belongs to the Special Issue Trauma and Emergency: Beyond Damage Control Surgery)

16 pages, 880 KiB

Open AccessEditor’s ChoiceReview

Elevation Mechanisms and Diagnostic Consideration of Cardiac Troponins under Conditions Not Associated with Myocardial Infarction. Part 1

by Aleksey M. Chaulin

Life 2021, 11(9), 914; https://doi.org/10.3390/life11090914 - 2 Sep 2021

Cited by 46 | Viewed by 7550

Abstract

Although cardiac troponins are considered the most specific biomarkers for the diagnosis of acute myocardial infarction (AMI), their diagnostic consideration goes far beyond the detection of this dangerous disease. The mechanisms of cardiac troponin elevation are extremely numerous and not limited to ischemic [...] Read more.

Although cardiac troponins are considered the most specific biomarkers for the diagnosis of acute myocardial infarction (AMI), their diagnostic consideration goes far beyond the detection of this dangerous disease. The mechanisms of cardiac troponin elevation are extremely numerous and not limited to ischemic necrosis of cardiac myocytes. Practitioners should be well aware of the underlying pathological and physiological conditions that can lead to elevated serum levels of cardiac troponins to avoid differential diagnostic errors, which will be greatly increased if clinicians rely on laboratory data alone. This article presents a classification of the main causes of an elevation in cardiac troponins and discusses in detail the mechanisms of such elevation and the diagnostic consideration of cardiac troponins in some conditions not associated with AMI, such as physical exertion, inflammatory heart diseases (myocarditis and endocarditis), pulmonary embolism (PE), renal failure, and systemic inflammation (sepsis). Full article

(This article belongs to the Special Issue Myocardial Infarction 2021)

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14 pages, 1088 KiB

Open AccessEditor’s ChoiceReview

3D Printing—A Cutting Edge Technology for Treating Post-Infarction Patients

by Daniel Cernica, Imre Benedek, Stefania Polexa, Cosmin Tolescu and Theodora Benedek

Life 2021, 11(9), 910; https://doi.org/10.3390/life11090910 - 1 Sep 2021

Cited by 4 | Viewed by 4840

Abstract

The increasing complexity of cardiovascular interventions requires advanced peri-procedural imaging and tailored treatment. Three-dimensional printing technology represents one of the most significant advances in the field of cardiac imaging, interventional cardiology or cardiovascular surgery. Patient-specific models may provide substantial information on intervention planning [...] Read more.

The increasing complexity of cardiovascular interventions requires advanced peri-procedural imaging and tailored treatment. Three-dimensional printing technology represents one of the most significant advances in the field of cardiac imaging, interventional cardiology or cardiovascular surgery. Patient-specific models may provide substantial information on intervention planning in complex cardiovascular diseases, and volumetric medical imaging from CT or MRI can be translated into patient-specific 3D models using advanced post-processing applications. 3D printing and additive manufacturing have a great variety of clinical applications targeting anatomy, implants and devices, assisting optimal interventional treatment and post-interventional evaluation. Although the 3D printing technology still lacks scientific evidence, its benefits have been shown in structural heart diseases as well as for treatment of complex arrhythmias and corrective surgery interventions. Recent development has enabled transformation of conventional 3D printing into complex 3D functional living tissues contributing to regenerative medicine through engineered bionic materials such hydrogels, cell suspensions or matrix components. This review aims to present the most recent clinical applications of 3D printing in cardiovascular medicine, highlighting also the potential for future development of this revolutionary technology in the medical field. Full article

(This article belongs to the Section Medical Research)

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21 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Influencing Factors and Molecular Pathogenesis of Sarcopenia and Osteosarcopenia in Chronic Liver Disease

by Chisato Saeki and Akihito Tsubota

Life 2021, 11(9), 899; https://doi.org/10.3390/life11090899 - 30 Aug 2021

Cited by 25 | Viewed by 4916

Abstract

The liver plays a pivotal role in nutrient/energy metabolism and storage, anabolic hormone regulation, ammonia detoxification, and cytokine production. Impaired liver function can cause malnutrition, hyperammonemia, and chronic inflammation, leading to an imbalance between muscle protein synthesis and proteolysis. Patients with chronic liver [...] Read more.

The liver plays a pivotal role in nutrient/energy metabolism and storage, anabolic hormone regulation, ammonia detoxification, and cytokine production. Impaired liver function can cause malnutrition, hyperammonemia, and chronic inflammation, leading to an imbalance between muscle protein synthesis and proteolysis. Patients with chronic liver disease (CLD) have a high prevalence of sarcopenia, characterized by progressive loss of muscle mass and function, affecting health-related quality of life and prognosis. Recent reports have revealed that osteosarcopenia, defined as the concomitant occurrence of sarcopenia and osteoporosis, is also highly prevalent in patients with CLD. Since the differentiation and growth of muscles and bones are closely interrelated through mechanical and biochemical communication, sarcopenia and osteoporosis often progress concurrently and affect each other. Osteosarcopenia further exacerbates unfavorable health outcomes, such as vertebral fracture and frailty. Therefore, a comprehensive assessment of sarcopenia, osteoporosis, and osteosarcopenia, and an understanding of the pathogenic mechanisms involving the liver, bones, and muscles, are important for prevention and treatment. This review summarizes the molecular mechanisms of sarcopenia and osteosarcopenia elucidated to data in hopes of promoting advances in treating these musculoskeletal disorders in patients with CLD. Full article

(This article belongs to the Special Issue New Mechanism and Insights into Sarcopenia)

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12 pages, 1188 KiB

Open AccessEditor’s ChoiceReview

Horizontal Gene Transfers in Plants

by Emilie Aubin, Moaine El Baidouri and Olivier Panaud

Life 2021, 11(8), 857; https://doi.org/10.3390/life11080857 - 21 Aug 2021

Cited by 22 | Viewed by 7776

Abstract

In plants, as in all eukaryotes, the vertical transmission of genetic information through reproduction ensures the maintenance of the integrity of species. However, many reports over the past few years have clearly shown that horizontal gene transfers, referred to as HGTs (the interspecific [...] Read more.

In plants, as in all eukaryotes, the vertical transmission of genetic information through reproduction ensures the maintenance of the integrity of species. However, many reports over the past few years have clearly shown that horizontal gene transfers, referred to as HGTs (the interspecific transmission of genetic information across reproductive barriers) are very common in nature and concern all living organisms including plants. The advent of next-generation sequencing technologies (NGS) has opened new perspectives for the study of HGTs through comparative genomic approaches. In this review, we provide an up-to-date view of our current knowledge of HGTs in plants. Full article

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

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14 pages, 508 KiB

Open AccessEditor’s ChoiceReview

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

by Luca Magistrelli, Elena Contaldi and Cristoforo Comi

Life 2021, 11(8), 804; https://doi.org/10.3390/life11080804 - 9 Aug 2021

Cited by 38 | Viewed by 9463

Abstract

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, [...] Read more.

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD. Full article

(This article belongs to the Special Issue Alpha-Synuclein and Non-Motor Symptoms of Parkinson’s Disease)

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17 pages, 1014 KiB

Open AccessEditor’s ChoiceReview

Dystonia and Cerebellum: From Bench to Bedside

by Ryoma Morigaki, Ryosuke Miyamoto, Taku Matsuda, Kazuhisa Miyake, Nobuaki Yamamoto and Yasushi Takagi

Life 2021, 11(8), 776; https://doi.org/10.3390/life11080776 - 31 Jul 2021

Cited by 17 | Viewed by 4827

Abstract

Dystonia pathogenesis remains unclear; however, findings from basic and clinical research suggest the importance of the interaction between the basal ganglia and cerebellum. After the discovery of disynaptic pathways between the two, much attention has been paid to the cerebellum. Basic research using [...] Read more.

Dystonia pathogenesis remains unclear; however, findings from basic and clinical research suggest the importance of the interaction between the basal ganglia and cerebellum. After the discovery of disynaptic pathways between the two, much attention has been paid to the cerebellum. Basic research using various dystonia rodent models and clinical studies in dystonia patients continues to provide new pieces of knowledge regarding the role of the cerebellum in dystonia genesis. Herein, we review basic and clinical articles related to dystonia focusing on the cerebellum, and clarify the current understanding of the role of the cerebellum in dystonia pathogenesis. Given the recent evidence providing new hypotheses regarding dystonia pathogenesis, we discuss how the current evidence answers the unsolved clinical questions. Full article

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

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16 pages, 633 KiB

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 10 | Viewed by 4397

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 KiB

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 3877

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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37 pages, 5057 KiB

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 18 | Viewed by 12281

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 KiB

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 5491

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 KiB

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 4157

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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15 pages, 3968 KiB

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 31 | Viewed by 7578

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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26 pages, 2065 KiB

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 17 | Viewed by 6929

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 KiB

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 4009

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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15 pages, 1594 KiB

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 179 | Viewed by 38342

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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11 pages, 668 KiB

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 30 | Viewed by 5470

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 KiB

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 7697

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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17 pages, 340 KiB

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 68 | Viewed by 8252

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 KiB

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 6181

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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20 pages, 459 KiB

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 28 | Viewed by 4866

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 KiB

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 15 | Viewed by 5629

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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14 pages, 290 KiB

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 8584

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)

21 pages, 746 KiB

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 11 | Viewed by 5372

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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34 pages, 5672 KiB

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 43 | Viewed by 9126

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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17 pages, 411 KiB

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 42 | Viewed by 8773

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, 1087 KiB

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 4399

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 KiB

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 9725

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 KiB

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 77 | Viewed by 7818

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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38 pages, 6064 KiB

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 3915

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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21 pages, 1586 KiB

Open AccessEditor’s ChoiceReview

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 9 | Viewed by 6121

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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