Life | Editor’s choice Articles

11 pages, 288 KB

Open AccessEditor’s ChoiceReview

Impact of Exercise Intensity on Calprotectin Levels in Healthy Volunteers and Patients with Inflammatory Rheumatic Diseases

by Andy Xavier and Annabelle Cesaro

Life 2021, 11(5), 377; https://doi.org/10.3390/life11050377 - 22 Apr 2021

Cited by 1 | Viewed by 3167

Abstract

Exercise influences inflammatory response and immune system performance. The regular practice of a moderate activity positively regulates immunity and the inflammatory process, while intensive training depresses it and enhances inflammatory marker secretion. Calprotectin is involved in the inflammatory process, promoting neutrophil recruitment, cell [...] Read more.

Exercise influences inflammatory response and immune system performance. The regular practice of a moderate activity positively regulates immunity and the inflammatory process, while intensive training depresses it and enhances inflammatory marker secretion. Calprotectin is involved in the inflammatory process, promoting neutrophil recruitment, cell degranulation, and inflammatory mediators. Furthermore, calprotectin has been associated with various inflammatory diseases, including inflammatory rheumatic diseases. The present review explores the effect of exercise on calprotectin levels in both healthy and inflammatory rheumatic conditions. Data show that the intensity duration and the type of exercise modulate calprotectin levels and participant inflammatory status. The exact role of calprotectin in the exercise response is yet unknown. Calprotectin could constitute an interesting biomarker for monitoring both the effect of exercise on the inflammatory process in healthy volunteers and the efficiency of exercise treatment programs in a patient with inflammatory rheumatic disease. Full article

(This article belongs to the Special Issue Impact of Physical Exercises on Bone Activities)

7 pages, 5284 KB

Open AccessEditor’s ChoiceReview

The Three Pillars of COVID-19 Convalescent Plasma Therapy

by Massimo Franchini, Giancarlo Maria Liumbruno, Giorgio Piacentini, Claudia Glingani and Marco Zaffanello

Life 2021, 11(4), 354; https://doi.org/10.3390/life11040354 - 18 Apr 2021

Cited by 18 | Viewed by 3865

Abstract

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world in the last year causing the coronavirus disease 2019 (COVID-19), which still is a severe threat for public health. The therapeutic management of COVID-19 is challenging as, [...] Read more.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world in the last year causing the coronavirus disease 2019 (COVID-19), which still is a severe threat for public health. The therapeutic management of COVID-19 is challenging as, up until now, no specific and efficient pharmacological therapy has been validated. Translating the experience from previous viral epidemics, passive immunotherapy by means of plasma from individuals recovered from COVID-19 has been intensively investigated since the beginning of the pandemic. In this narrative review, we critically analyze the three factors, named “pillars”, that play a key role in determining the clinical effectiveness of this biologic therapy: the convalescent plasma, the disease (COVID-19), and the patients. Full article

(This article belongs to the Special Issue Neutralizing-Antibody-Based Treatments for COVID-19: Achievements and Lessons Learnt for Future Pandemics)

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20 pages, 7513 KB

Open AccessEditor’s ChoiceReview

The “Genomic Code”: DNA Pervasively Moulds Chromatin Structures Leaving no Room for “Junk”

by Giorgio Bernardi

Life 2021, 11(4), 342; https://doi.org/10.3390/life11040342 - 13 Apr 2021

Cited by 9 | Viewed by 4302

Abstract

The chromatin of the human genome was analyzed at three DNA size levels. At the first, compartment level, two “gene spaces” were found many years ago: A GC-rich, gene-rich “genome core” and a GC-poor, gene-poor “genome desert”, the former corresponding to open chromatin [...] Read more.

The chromatin of the human genome was analyzed at three DNA size levels. At the first, compartment level, two “gene spaces” were found many years ago: A GC-rich, gene-rich “genome core” and a GC-poor, gene-poor “genome desert”, the former corresponding to open chromatin centrally located in the interphase nucleus, the latter to closed chromatin located peripherally. This bimodality was later confirmed and extended by the discoveries (1) of LADs, the Lamina-Associated Domains, and InterLADs; (2) of two “spatial compartments”, A and B, identified on the basis of chromatin interactions; and (3) of “forests and prairies” characterized by high and low CpG islands densities. Chromatin compartments were shown to be associated with the compositionally different, flat and single- or multi-peak DNA structures of the two, GC-poor and GC-rich, “super-families” of isochores. At the second, sub-compartment, level, chromatin corresponds to flat isochores and to isochore loops (due to compositional DNA gradients) that are susceptible to extrusion. Finally, at the short-sequence level, two sets of sequences, GC-poor and GC-rich, define two different nucleosome spacings, a short one and a long one. In conclusion, chromatin structures are moulded according to a “genomic code” by DNA sequences that pervade the genome and leave no room for “junk”. Full article

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

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21 pages, 2131 KB

Open AccessEditor’s ChoiceReview

Theranostics in Boron Neutron Capture Therapy

by Wolfgang A. G. Sauerwein, Lucie Sancey, Evamarie Hey-Hawkins, Martin Kellert, Luigi Panza, Daniela Imperio, Marcin Balcerzyk, Giovanna Rizzo, Elisa Scalco, Ken Herrmann, PierLuigi Mauri, Antonella De Palma and Andrea Wittig

Life 2021, 11(4), 330; https://doi.org/10.3390/life11040330 - 10 Apr 2021

Cited by 55 | Viewed by 6878

Abstract

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: ¹⁰B [...] Read more.

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: ¹⁰B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of ¹⁰B in the tumor but also on the organs at risk. It is not yet possible to determine the ¹⁰B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the ¹⁰B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of ¹⁰B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the ¹⁰B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach. Full article

(This article belongs to the Special Issue Theranostics: Current and Future Perspectives)

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9 pages, 1134 KB

Open AccessEditor’s ChoiceArticle

Long Noncoding RNA NEAT1 as a Potential Candidate Biomarker for Prostate Cancer

by Diana Nitusca, Anca Marcu, Alis Dema, Loredana Balacescu, Ovidiu Balacescu, Razvan Bardan, Alin Adrian Cumpanas, Ioan Ovidiu Sirbu, Bogdan Petrut, Edward Seclaman and Catalin Marian

Life 2021, 11(4), 320; https://doi.org/10.3390/life11040320 - 6 Apr 2021

Cited by 13 | Viewed by 3451

Abstract

Background: Prostate cancer (PCa) remains one of the leading causes of cancer-related mortality in men worldwide, mainly due to unsatisfactory diagnostic methods used at present, which lead to overdiagnosis, unnecessary biopsies and treatment, or misdiagnosis in early asymptomatic stages. New diagnostic biomarkers are [...] Read more.

Background: Prostate cancer (PCa) remains one of the leading causes of cancer-related mortality in men worldwide, mainly due to unsatisfactory diagnostic methods used at present, which lead to overdiagnosis, unnecessary biopsies and treatment, or misdiagnosis in early asymptomatic stages. New diagnostic biomarkers are needed for a correct and early diagnosis. Long noncoding RNAs (lncRNAs) have been broadly studied for their involvement in PCa biology, as well as for their potential role as diagnostic biomarkers. Methods: We conducted lncRNA profiling in plasma and microdissected formalin-fixed paraffin-embedded (FFPE) tissues of PCa patients and attempted validation for commonly dysregulated individual lncRNAs. Results: Plasma profiling revealed eight dysregulated lncRNAs, while microarray analysis revealed 717 significantly dysregulated lncRNAs, out of which only nuclear-enriched abundant transcript 1 (NEAT1) was commonly upregulated in plasma samples and FFPE tissues. NEAT1’s individual validation revealed statistically significant upregulation (FC = 2.101, p = 0.009). Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) value of 0.7298 for NEAT1 (95% CI = 0.5812–0.8785), suggesting a relatively high diagnostic value, thus having a potential biomarker role for this malignancy. Conclusions: We present herein data suggesting that NEAT1 could serve as a diagnostic biomarker for PCa. Additional studies of larger cohorts are needed to confirm our findings, as well as the oncogenic mechanism of NEAT1 in the development of PCa. Full article

(This article belongs to the Special Issue Prostate Cancer)

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12 pages, 1809 KB

Open AccessEditor’s ChoiceArticle

Transcription Factor Activity Inference in Systemic Lupus Erythematosus

by Raul Lopez-Dominguez, Daniel Toro-Dominguez, Jordi Martorell-Marugan, Adrian Garcia-Moreno, Christian H. Holland, Julio Saez-Rodriguez, Daniel Goldman, Michelle A. Petri, Marta E. Alarcon-Riquelme and Pedro Carmona-Saez

Life 2021, 11(4), 299; https://doi.org/10.3390/life11040299 - 1 Apr 2021

Cited by 9 | Viewed by 4667

Abstract

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the [...] Read more.

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets—one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets. Full article

(This article belongs to the Special Issue Genomics and Epigenomics of Human Complex Diseases)

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21 pages, 3019 KB

Open AccessEditor’s ChoiceArticle

Priming by High Temperature Stress Induces MicroRNA Regulated Heat Shock Modules Indicating Their Involvement in Thermopriming Response in Rice

by Akhilesh Kumar Kushawaha, Ambreen Khan, Sudhir Kumar Sopory and Neeti Sanan-Mishra

Life 2021, 11(4), 291; https://doi.org/10.3390/life11040291 - 29 Mar 2021

Cited by 39 | Viewed by 5630

Abstract

Rice plants often encounter high temperature stress, but the associated coping strategies are poorly understood. It is known that a prior shorter exposure to high temperature, called thermo-priming, generally results in better adaptation of the plants to subsequent exposure to high temperature stress. [...] Read more.

Rice plants often encounter high temperature stress, but the associated coping strategies are poorly understood. It is known that a prior shorter exposure to high temperature, called thermo-priming, generally results in better adaptation of the plants to subsequent exposure to high temperature stress. High throughput sequencing of transcript and small RNA libraries of rice seedlings primed with short exposure to high temperature followed by high temperature stress and from plants exposed to high temperature without priming was performed. This identified a number of transcripts and microRNAs (miRs) that are induced or down regulated. Among them osa-miR531b, osa-miR5149, osa-miR168a-5p, osa-miR1846d-5p, osa-miR5077, osa-miR156b-3p, osa-miR167e-3p and their respective targets, coding for heat shock activators and repressors, showed differential expression between primed and non-primed plants. These findings were further validated by qRT-PCR. The results indicate that the miR-regulated heat shock proteins (HSPs)/heat shock transcription factors (HSFs) may serve as important regulatory nodes which are induced during thermo-priming for plant survival and development under high temperatures. Full article

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

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21 pages, 2371 KB

Open AccessEditor’s ChoiceReview

MicroRNAs: Potential Targets for Developing Stress-Tolerant Crops

by Saurabh Chaudhary, Atul Grover and Prakash Chand Sharma

Life 2021, 11(4), 289; https://doi.org/10.3390/life11040289 - 28 Mar 2021

Cited by 43 | Viewed by 9766

Abstract

Crop yield is challenged every year worldwide by changing climatic conditions. The forecasted climatic scenario urgently demands stress-tolerant crop varieties to feed the ever-increasing global population. Molecular breeding and genetic engineering approaches have been frequently exploited for developing crops with desired agronomic traits. [...] Read more.

Crop yield is challenged every year worldwide by changing climatic conditions. The forecasted climatic scenario urgently demands stress-tolerant crop varieties to feed the ever-increasing global population. Molecular breeding and genetic engineering approaches have been frequently exploited for developing crops with desired agronomic traits. Recently, microRNAs (miRNAs) have emerged as powerful molecules, which potentially serve as expression markers during stress conditions. The miRNAs are small non-coding endogenous RNAs, usually 20–24 nucleotides long, which mediate post-transcriptional gene silencing and fine-tune the regulation of many abiotic- and biotic-stress responsive genes in plants. The miRNAs usually function by specifically pairing with the target mRNAs, inducing their cleavage or repressing their translation. This review focuses on the exploration of the functional role of miRNAs in regulating plant responses to abiotic and biotic stresses. Moreover, a methodology is also discussed to mine stress-responsive miRNAs from the enormous amount of transcriptome data available in the public domain generated using next-generation sequencing (NGS). Considering the functional role of miRNAs in mediating stress responses, these molecules may be explored as novel targets for engineering stress-tolerant crop varieties. Full article

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

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15 pages, 2586 KB

Open AccessEditor’s ChoiceArticle

SOX11, SOX10 and MITF Gene Interaction: A Possible Diagnostic Tool in Malignant Melanoma

by Marius-Alexandru Beleaua, Ioan Jung, Cornelia Braicu, Doina Milutin and Simona Gurzu

Life 2021, 11(4), 281; https://doi.org/10.3390/life11040281 - 27 Mar 2021

Cited by 13 | Viewed by 4117

Abstract

Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. [...] Read more.

Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. In 105 consecutive cases of MMs and 44 of naevi, the IHC examination was performed using the five-abovementioned markers, along with microphthalmia transcription factor (MITF), S100, and Ki67. Correlation with the clinicopathological factors and a long-term follow-up was also done. Survival analysis was performed with Kaplan–Meier curves and compared with TCGA public datasets. None of the 44 naevi expressed SOX11, but its positivity was seen in 52 MMs (49.52%), being directly correlated with lymphovascular invasion, the Ki67 index, and SOX10 expression. HMB-45, SOX10, and tyrosinase, but not melan-A, proved to differentiate the naevi from MMs successfully, with high specificity. Triple MITF/SOX10/SOX11 co-expression was seen in 9 out of 15 negative conventional pan-melanoma-cocktail cases. The independent prognostic value was proved for the conventional pan-melanoma cocktail (triple positivity for HMB-45, melan-A, and tyrosinase) and, independently for HMB-45 and tyrosinase, but not for melan-A, SOX10, or SOX11. As consequence, to differentiate MMs from benign naevi, melan-A should be substituted by SOX10 in the conventional cocktail. Although the conventional pan-melanoma cocktail, along with S100 can be used for the identification of melanocytic origin of tumor cells and predicting prognosis of MMs, the conventional-adapted cocktail (triple positivity for HMB-45, SOX10, and tyrosinase) has a slightly higher diagnostic specificity. SOX11 can be added to identify the aggressive MMs with risk for lymphatic dissemination and the presence of circulating tumor cells. Full article

(This article belongs to the Special Issue Serum and Tissue Biomarkers in Cancer: A Translational Approach)

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20 pages, 20644 KB

Open AccessEditor’s ChoiceArticle

Stability and Robustness of Unbalanced Genetic Toggle Switches in the Presence of Scarce Resources

by Chentao Yong and Andras Gyorgy

Life 2021, 11(4), 271; https://doi.org/10.3390/life11040271 - 24 Mar 2021

Cited by 5 | Viewed by 4428

Abstract

While the vision of synthetic biology is to create complex genetic systems in a rational fashion, system-level behaviors are often perplexing due to the context-dependent dynamics of modules. One major source of context-dependence emerges due to the limited availability of shared resources, coupling [...] Read more.

While the vision of synthetic biology is to create complex genetic systems in a rational fashion, system-level behaviors are often perplexing due to the context-dependent dynamics of modules. One major source of context-dependence emerges due to the limited availability of shared resources, coupling the behavior of disconnected components. Motivated by the ubiquitous role of toggle switches in genetic circuits ranging from controlling cell fate differentiation to optimizing cellular performance, here we reveal how their fundamental dynamic properties are affected by competition for scarce resources. Combining a mechanistic model with nullcline-based stability analysis and potential landscape-based robustness analysis, we uncover not only the detrimental impacts of resource competition, but also how the unbalancedness of the switch further exacerbates them. While in general both of these factors undermine the performance of the switch (by pushing the dynamics toward monostability and increased sensitivity to noise), we also demonstrate that some of the unwanted effects can be alleviated by strategically optimized resource competition. Our results provide explicit guidelines for the context-aware rational design of toggle switches to mitigate our reliance on lengthy and expensive trial-and-error processes, and can be seamlessly integrated into the computer-aided synthesis of complex genetic systems. Full article

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

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11 pages, 1597 KB

Open AccessEditor’s ChoiceArticle

A Relationship between NTP and Cell Extract Concentration for Cell-Free Protein Expression

by Katsuki Takahashi, Gaku Sato, Nobuhide Doi and Kei Fujiwara

Life 2021, 11(3), 237; https://doi.org/10.3390/life11030237 - 13 Mar 2021

Cited by 9 | Viewed by 4373

Abstract

The cell-free protein synthesis (CFPS) that synthesizes mRNA and protein from a template DNA has been featured as an important tool to emulate living systems in vitro. However, an obstacle to emulate living cells by CFPS is the loss of activity in the [...] Read more.

The cell-free protein synthesis (CFPS) that synthesizes mRNA and protein from a template DNA has been featured as an important tool to emulate living systems in vitro. However, an obstacle to emulate living cells by CFPS is the loss of activity in the case of usage of high concentration cell extracts. In this study, we found that a high concentration of NTP which inhibits in the case of lower concentration cell extract restored the loss of CFPS activity using high concentration cell extracts. The NTP restoration was independent of the energy regeneration system used, and NTP derivatives also restored the levels of CFPS using a high concentration cell extract. Experiments using dialysis mode of CFPS showed that continuous exchange of small molecule reduced levels of NTP requirement and improved reaction speed of CFPS using the high concentration of cell extract. These findings contribute to the development of a method to understand the condition of living cells by in vitro emulation, and are expected to lead to the achievement of the reconstitution of living cells from biomolecule mixtures. Full article

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

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11 pages, 740 KB

Open AccessEditor’s ChoiceArticle

Pro-Oxidant/Antioxidant Balance during a Prolonged Exposure to Moderate Altitude in Athletes Exhibiting Exercise-Induced Hypoxemia at Sea-Level

by Antoine Raberin, Elie Nader, Jorge Lopez Ayerbe, Gauthier Alfonsi, Patrick Mucci, Chantal L. Rytz, Vincent Pialoux and Fabienne Durand

Life 2021, 11(3), 228; https://doi.org/10.3390/life11030228 - 11 Mar 2021

Cited by 6 | Viewed by 3818

Abstract

This study examined to what extent athletes exhibiting exercise-induced hypoxemia (EIH) possess an altered redox status at rest, in response to exercise at sea level (SL) and during moderate altitude exposure. EIH was defined as a fall in arterial O₂ saturation of [...] Read more.

This study examined to what extent athletes exhibiting exercise-induced hypoxemia (EIH) possess an altered redox status at rest, in response to exercise at sea level (SL) and during moderate altitude exposure. EIH was defined as a fall in arterial O₂ saturation of at least 4% during exercise. Nine endurance athletes with EIH and ten without (NEIH) performed a maximal incremental test under three conditions: SL, one (H1) and five (H2) days after arrival to 2400 m. Gas exchange and peripheral capillary oxygen saturation (SpO₂) were continuously monitored. Blood was sampled before exercise and after exercise cessation. Advanced oxidation protein products (AOPP), catalase, ferric-reducing antioxidant power, glutathione peroxidase, superoxide dismutase (SOD) and nitric oxide metabolites (NOx) were measured in plasma by spectrophotometry. EIH athletes had higher AOPP and NOx concentrations at pre- and post-exercise stages compared to NEIH at SL, H2 but not at H1. Only the EIH group experienced increased SOD activity between pre- and post-exercise exercise at SL and H2 but not at H1. EIH athletes had exacerbated oxidative stress compared to the NEIH athletes at SL and H2. These differences were blunted at H1. Oxidative stress did not alter the EIH groups’ aerobic performance and could lead to higher minute ventilation at H2. These results suggest that higher oxidative stress response EIH athletes could be involved in improved aerobic muscle functionality and a greater ventilatory acclimatization during prolonged hypoxia. Full article

(This article belongs to the Special Issue Cellular and Functional Response to Hypoxia)

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19 pages, 2501 KB

Open AccessEditor’s ChoiceArticle

The Mitochondrial Genome of a Plant Fungal Pathogen Pseudocercospora fijiensis (Mycosphaerellaceae), Comparative Analysis and Diversification Times of the Sigatoka Disease Complex Using Fossil Calibrated Phylogenies

by Juliana E. Arcila-Galvis, Rafael E. Arango, Javier M. Torres-Bonilla and Tatiana Arias

Life 2021, 11(3), 215; https://doi.org/10.3390/life11030215 - 9 Mar 2021

Cited by 11 | Viewed by 4061

Abstract

Mycosphaerellaceae is a highly diverse fungal family containing a variety of pathogens affecting many economically important crops. Mitochondria play a crucial role in fungal metabolism and in the study of fungal evolution. This study aims to: (i) describe the mitochondrial genome of Pseudocercospora [...] Read more.

Mycosphaerellaceae is a highly diverse fungal family containing a variety of pathogens affecting many economically important crops. Mitochondria play a crucial role in fungal metabolism and in the study of fungal evolution. This study aims to: (i) describe the mitochondrial genome of Pseudocercospora fijiensis, and (ii) compare it with closely related species (Sphaerulina musiva, S. populicola, P. musae and P. eumusae) available online, paying particular attention to the Sigatoka disease’s complex causal agents. The mitochondrial genome of P. fijiensis is a circular molecule of 74,089 bp containing typical genes coding for the 14 proteins related to oxidative phosphorylation, 2 rRNA genes and a set of 38 tRNAs. P. fijiensis mitogenome has two truncated cox1 copies, and bicistronic transcription of nad2-nad3 and atp6-atp8 confirmed experimentally. Comparative analysis revealed high variability in size and gene order among selected Mycosphaerellaceae mitogenomes likely to be due to rearrangements caused by mobile intron invasion. Using fossil calibrated Bayesian phylogenies, we found later diversification times for Mycosphaerellaceae (66.6 MYA) and the Sigatoka disease complex causal agents, compared to previous strict molecular clock studies. An early divergent Pseudocercospora fijiensis split from the sister species P. musae + P. eumusae 13.31 MYA while their sister group, the sister species P. eumusae and P. musae, split from their shared common ancestor in the late Miocene 8.22 MYA. This newly dated phylogeny suggests that species belonging to the Sigatoka disease complex originated after wild relatives of domesticated bananas (section Eumusae; 27.9 MYA). During this time frame, mitochondrial genomes expanded significantly, possibly due to invasions of introns into different electron transport chain genes. Full article

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

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18 pages, 1796 KB

Open AccessEditor’s ChoiceReview

Biosensors: A Sneak Peek into Plant Cell’s Immunity

by Valentina Levak, Tjaša Lukan, Kristina Gruden and Anna Coll

Life 2021, 11(3), 209; https://doi.org/10.3390/life11030209 - 7 Mar 2021

Cited by 5 | Viewed by 5013

Abstract

Biosensors are indispensable tools to understand a plant’s immunity as its spatiotemporal dimension is key in withstanding complex plant immune signaling. The diversity of genetically encoded biosensors in plants is expanding, covering new analytes with ever higher sensitivity and robustness, but their assortment [...] Read more.

Biosensors are indispensable tools to understand a plant’s immunity as its spatiotemporal dimension is key in withstanding complex plant immune signaling. The diversity of genetically encoded biosensors in plants is expanding, covering new analytes with ever higher sensitivity and robustness, but their assortment is limited in some respects, such as their use in following biotic stress response, employing more than one biosensor in the same chassis, and their implementation into crops. In this review, we focused on the available biosensors that encompass these aspects. We show that in vivo imaging of calcium and reactive oxygen species is satisfactorily covered with the available genetically encoded biosensors, while on the other hand they are still underrepresented when it comes to imaging of the main three hormonal players in the immune response: salicylic acid, ethylene and jasmonic acid. Following more than one analyte in the same chassis, upon one or more conditions, has so far been possible by using the most advanced genetically encoded biosensors in plants which allow the monitoring of calcium and the two main hormonal pathways involved in plant development, auxin and cytokinin. These kinds of biosensor are also the most evolved in crops. In the last section, we examine the challenges in the use of biosensors and demonstrate some strategies to overcome them. Full article

(This article belongs to the Special Issue Plant Synthetic Biology)

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17 pages, 5829 KB

Open AccessEditor’s ChoiceArticle

Chronological Incongruences between Mitochondrial and Nuclear Phylogenies of Aedes Mosquitoes

by Nicola Zadra, Annapaola Rizzoli and Omar Rota-Stabelli

Life 2021, 11(3), 181; https://doi.org/10.3390/life11030181 - 25 Feb 2021

Cited by 18 | Viewed by 4555

Abstract

One-third of all mosquitoes belong to the Aedini, a tribe comprising common vectors of viral zoonoses such as Aedes aegypti and Aedes albopictus. To improve our understanding of their evolution, we present an updated multigene estimate of Aedini phylogeny and divergence, focusing [...] Read more.

One-third of all mosquitoes belong to the Aedini, a tribe comprising common vectors of viral zoonoses such as Aedes aegypti and Aedes albopictus. To improve our understanding of their evolution, we present an updated multigene estimate of Aedini phylogeny and divergence, focusing on the disentanglement between nuclear and mitochondrial phylogenetic signals. We first show that there are some phylogenetic discrepancies between nuclear and mitochondrial markers which may be caused by wrong taxa assignment in samples collections or by some stochastic effect due to small gene samples. We indeed show that the concatenated dataset is model and framework dependent, indicating a general paucity of signal. Our Bayesian calibrated divergence estimates point toward a mosquito radiation in the mid-Jurassic and an Aedes radiation from the mid-Cretaceous on. We observe, however a strong chronological incongruence between mitochondrial and nuclear data, the latter providing divergence times within the Aedini significantly younger than the former. We show that this incongruence is consistent over different datasets and taxon sampling and that may be explained by either peculiar evolutionary event such as different levels of saturation in certain lineages or a past history of hybridization throughout the genus. Overall, our updated picture of Aedini phylogeny, reveal a strong nuclear-mitochondrial incongruence which may be of help in setting the research agenda for future phylogenomic studies of Aedini mosquitoes. Full article

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

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9 pages, 263 KB

Open AccessEditor’s ChoiceArticle

Metabolic Phenotypes and Chronic Kidney Disease: A Cross-Sectional Assessment of Patients from a Large Federally Qualified Health Center

by Kathleen E. Adair, Nicholas von Waaden, Matthew Rafalski, Burritt W. Hess, Sally P. Weaver and Rodney G. Bowden

Life 2021, 11(2), 175; https://doi.org/10.3390/life11020175 - 23 Feb 2021

Cited by 12 | Viewed by 3319

Abstract

The purpose of this study is to determine if renal function varies by metabolic phenotype. A total of 9599 patients from a large Federally Qualified Health Center (FQHC) were included in the analysis. Metabolic health was classified as the absence of metabolic abnormalities [...] Read more.

The purpose of this study is to determine if renal function varies by metabolic phenotype. A total of 9599 patients from a large Federally Qualified Health Center (FQHC) were included in the analysis. Metabolic health was classified as the absence of metabolic abnormalities defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, excluding waist circumference. Obesity was defined as body mass index >30 kg/m² and renal health as an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m². Linear and logistic regressions were used to analyze the data. The metabolically healthy overweight (MHO) phenotype had the highest eGFR (104.86 ± 28.76 mL/min/1.72 m²) and lowest unadjusted odds of chronic kidney disease (CKD) (OR = 0.46, 95%CI = 0.168, 1.267, p = 0.133), while the metabolically unhealthy normal weight (MUN) phenotype demonstrated the lowest eGFR (91.34 ± 33.28 mL/min/1.72 m²) and the highest unadjusted odds of CKD (OR = 3.63, p < 0.0001). After controlling for age, sex, and smoking status, the metabolically unhealthy obese (MUO) (OR = 1.80, 95%CI = 1.08, 3.00, p = 0.024) was the only phenotype with significantly higher odds of CKD as compared to the reference. We demonstrate that the metabolically unhealthy phenotypes have the highest odds of CKD compared to metabolically healthy individuals. Full article

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

16 pages, 1354 KB

Open AccessEditor’s ChoiceReview

Post-Infectious Guillain–Barré Syndrome Related to SARS-CoV-2 Infection: A Systematic Review

by Pasquale Sansone, Luca Gregorio Giaccari, Caterina Aurilio, Francesco Coppolino, Valentina Esposito, Marco Fiore, Antonella Paladini, Maria Beatrice Passavanti, Vincenzo Pota and Maria Caterina Pace

Life 2021, 11(2), 167; https://doi.org/10.3390/life11020167 - 21 Feb 2021

Cited by 29 | Viewed by 4976

Abstract

Background. Guillain-Barré syndrome (GBS) is the most common cause of flaccid paralysis, with about 100,000 people developing the disorder every year worldwide. Recently, the incidence of GBS has increased during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemics. We reviewed the literature to [...] Read more.

Background. Guillain-Barré syndrome (GBS) is the most common cause of flaccid paralysis, with about 100,000 people developing the disorder every year worldwide. Recently, the incidence of GBS has increased during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemics. We reviewed the literature to give a comprehensive overview of the demographic characteristics, clinical features, diagnostic investigations, and outcome of SARS-CoV-2-related GBS patients. Methods. Embase, MEDLINE, Google Scholar, and Cochrane Central Trials Register were systematically searched on 24 September 2020 for studies reporting on GBS secondary to COVID-19. Results. We identified 63 articles; we included 32 studies in our review. A total of 41 GBS cases with a confirmed or probable COVID-19 infection were reported: 26 of them were single case reports and 6 case series. Published studies on SARS-CoV-2-related GBS typically report a classic sensorimotor type of GBS often with a demyelinating electrophysiological subtype. Miller Fisher syndrome was reported in a quarter of the cases. In 78.1% of the cases, the response to immunomodulating therapy is favourable. The disease course is frequently severe and about one-third of the patients with SARS-CoV-2-associated GBS requires mechanical ventilation and Intensive Care Unit (ICU) admission. Rarely the outcome is poor or even fatal (10.8% of the cases). Conclusion. Clinical presentation, course, response to treatment, and outcome are similar in SARS-CoV-2-associated GBS and GBS due to other triggers. Full article

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

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15 pages, 339 KB

Open AccessEditor’s ChoiceReview

Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation

by Hany Elmariah, Claudio G. Brunstein and Nelli Bejanyan

Life 2021, 11(2), 102; https://doi.org/10.3390/life11020102 - 29 Jan 2021

Cited by 13 | Viewed by 4201

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant [...] Read more.

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant platform. Here, we review immune reconstitution after allogeneic HCT with a specific focus on two alternative donor platforms that have dramatically improved access to allogeneic HCT for patients who lack an HLA-matched related or unrelated donor: haploidentical and umbilical cord blood HCT. Despite challenges, interventions are available to mitigate the risks during the immunocompromised period including antimicrobial prophylaxis, modified immune suppression strategies, graft manipulation, and emerging adoptive cell therapies. Such interventions can improve the potential for long-term overall survival after allogeneic HCT. Full article

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

18 pages, 389 KB

Open AccessEditor’s ChoiceReview

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

by Vânia Maria Sabadoto Brienze, Júlio César André, Elisabete Liso and Irina Vlasova-St. Louis

Life 2021, 11(2), 95; https://doi.org/10.3390/life11020095 - 27 Jan 2021

Cited by 18 | Viewed by 5387

Abstract

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage human immunodeficiency virus (HIV) infection who have commenced antiretroviral treatments (ART). Virtually any opportunistic pathogen can provoke this type of immune [...] Read more.

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage human immunodeficiency virus (HIV) infection who have commenced antiretroviral treatments (ART). Virtually any opportunistic pathogen can provoke this type of immune restoration disorder. In this review, we focus on recent developments in the identification of risk factors for Cryptococcal IRIS and on advancements in our understanding of C-IRIS immunopathogenesis. We overview new findings in blood and cerebrospinal fluid which can potentially be useful in the prediction and diagnosis of cryptococcal meningitis IRIS (CM-IRIS). We assess current therapeutic regimens and novel treatment approaches to combat CM-IRIS. We discuss the utility of biomarkers for clinical monitoring and adjusting treatment modalities in acquired immunodeficiency syndrome (AIDS) patients co-infected with Cryptococcus who have initiated ART. Full article

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

13 pages, 1362 KB

Open AccessEditor’s ChoiceArticle

Effect of Chlorination on Microbiological Quality of Effluent of a Full-Scale Wastewater Treatment Plant

by Ioanna Zerva, Nikolaos Remmas, Ifigeneia Kagalou, Paraschos Melidis, Marina Ariantsi, Georgios Sylaios and Spyridon Ntougias

Life 2021, 11(1), 68; https://doi.org/10.3390/life11010068 - 19 Jan 2021

Cited by 30 | Viewed by 5270

Abstract

The evaluation of effluent wastewater quality mainly relies on the assessment of conventional bacterial indicators, such as fecal coliforms and enterococci; however, little is known about opportunistic pathogens, which can resist chlorination and may be transmitted in aquatic environments. In contrast to conventional [...] Read more.

The evaluation of effluent wastewater quality mainly relies on the assessment of conventional bacterial indicators, such as fecal coliforms and enterococci; however, little is known about opportunistic pathogens, which can resist chlorination and may be transmitted in aquatic environments. In contrast to conventional microbiological methods, high-throughput molecular techniques can provide an accurate evaluation of effluent quality, although a limited number of studies have been performed in this direction. In this work, high-throughput amplicon sequencing was employed to assess the effectiveness of chlorination as a disinfection method for secondary effluents. Common inhabitants of the intestinal tract, such as Bacteroides, Arcobacter and Clostridium, and activated sludge denitrifiers capable of forming biofilms, such as Acidovorax, Pseudomonas and Thauera, were identified in the chlorinated effluent. Chloroflexi with dechlorination capability and the bacteria involved in enhanced biological phosphorus removal, i.e., Candidatus Accumulibacter and Candidatus Competibacter, were also found to resist chlorination. No detection of Escherichia indicates the lack of fecal coliform contamination. Mycobacterium spp. were absent in the chlorinated effluent, whereas toxin-producing cyanobacteria of the genera Anabaena and Microcystis were identified in low abundances. Chlorination significantly affected the filamentous bacteria Nocardioides and Gordonia, whereas Zoogloea proliferated in the disinfected effluent. Moreover, perchlorate/chlorate- and organochlorine-reducing bacteria resisted chlorination. Full article

(This article belongs to the Special Issue Microbial Degradation and Biosorbents)

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12 pages, 710 KB

Open AccessEditor’s ChoiceReview

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases

by Peng-Zhou Hang, Hua Zhu, Pei-Feng Li, Jie Liu, Feng-Qin Ge, Jing Zhao and Zhi-Min Du

Life 2021, 11(1), 70; https://doi.org/10.3390/life11010070 - 19 Jan 2021

Cited by 47 | Viewed by 6538

Abstract

Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the central nervous system. Numerous studies suggest that BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing [...] Read more.

Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the central nervous system. Numerous studies suggest that BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing evidence highlights that the BDNF/TrkB pathway is expressed in the cardiovascular system and closely associated with the development and outcome of cardiovascular diseases (CVD), including coronary artery disease, heart failure, cardiomyopathy, hypertension, and metabolic diseases. Furthermore, circulating BDNF has also been revealed as a new potential biomarker for both diagnosis and prognosis of CVD. In this review, we discuss the current evidence of the emerging role of BDNF/TrkB signaling and address the challenges that remain in translating these discoveries to novel therapeutic strategies for CVD. Full article

(This article belongs to the Special Issue Regulating Energy Balance: Uncovering the Involvement of Neurotrophins)

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17 pages, 3438 KB

Open AccessEditor’s ChoiceReview

Cancer, Retrogenes, and Evolution

by Klaudia Staszak and Izabela Makałowska

Life 2021, 11(1), 72; https://doi.org/10.3390/life11010072 - 19 Jan 2021

Cited by 8 | Viewed by 5369

Abstract

This review summarizes the knowledge about retrogenes in the context of cancer and evolution. The retroposition, in which the processed mRNA from parental genes undergoes reverse transcription and the resulting cDNA is integrated back into the genome, results in additional copies of existing [...] Read more.

This review summarizes the knowledge about retrogenes in the context of cancer and evolution. The retroposition, in which the processed mRNA from parental genes undergoes reverse transcription and the resulting cDNA is integrated back into the genome, results in additional copies of existing genes. Despite the initial misconception, retroposition-derived copies can become functional, and due to their role in the molecular evolution of genomes, they have been named the “seeds of evolution”. It is convincing that retrogenes, as important elements involved in the evolution of species, also take part in the evolution of neoplastic tumors at the cell and species levels. The occurrence of specific “resistance mechanisms” to neoplastic transformation in some species has been noted. This phenomenon has been related to additional gene copies, including retrogenes. In addition, the role of retrogenes in the evolution of tumors has been described. Retrogene expression correlates with the occurrence of specific cancer subtypes, their stages, and their response to therapy. Phylogenetic insights into retrogenes show that most cancer-related retrocopies arose in the lineage of primates, and the number of identified cancer-related retrogenes demonstrates that these duplicates are quite important players in human carcinogenesis. Full article

(This article belongs to the Section Evolutionary Biology)

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8 pages, 1279 KB

Open AccessEditor’s ChoiceCommunication

Dysfunction of Mitochondrial Dynamics in Drosophila Model of Diabetic Nephropathy

by Kiyoung Kim, Sun Joo Cha, Hyun-Jun Choi, Jeong Suk Kang and Eun Young Lee

Life 2021, 11(1), 67; https://doi.org/10.3390/life11010067 - 18 Jan 2021

Cited by 8 | Viewed by 4214

Abstract

Although mitochondrial dysfunction is associated with the development and progression of diabetic nephropathy (DN), its mechanisms are poorly understood, and it remains debatable whether mitochondrial morphological change is a cause of DN. In this study, a Drosophila DN model was established by treating [...] Read more.

Although mitochondrial dysfunction is associated with the development and progression of diabetic nephropathy (DN), its mechanisms are poorly understood, and it remains debatable whether mitochondrial morphological change is a cause of DN. In this study, a Drosophila DN model was established by treating a chronic high-sucrose diet that exhibits similar phenotypes in animals. Results showed that flies fed a chronic high-sucrose diet exhibited a reduction in lifespan, as well as increased lipid droplets in fat body tissue. Furthermore, the chronic high-sucrose diet effectively induced the morphological abnormalities of nephrocytes in Drosophila. High-sucrose diet induced mitochondria fusion in nephrocytes by increasing Opa1 and Marf expression. These findings establish Drosophila as a useful model for studying novel regulators and molecular mechanisms for imbalanced mitochondrial dynamics in the pathogenesis of DN. Furthermore, understanding the pathology of mitochondrial dysfunction regarding morphological changes in DN would facilitate the development of novel therapeutics. Full article

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

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14 pages, 11167 KB

Open AccessEditor’s ChoiceArticle

Efficient Production of Chimeric Hepatitis B Virus-Like Particles Bearing an Epitope of Hepatitis E Virus Capsid by Transient Expression in Nicotiana benthamiana

by Gergana Zahmanova, Milena Mazalovska, Katerina Takova, Valentina Toneva, Ivan Minkov, Hadrien Peyret and George Lomonossoff

Life 2021, 11(1), 64; https://doi.org/10.3390/life11010064 - 17 Jan 2021

Cited by 20 | Viewed by 5724

Abstract

The core antigen of hepatitis B virus (HBcAg) is capable of self-assembly into virus-like particles (VLPs) when expressed in a number of heterologous systems. Such VLPs are potential carriers of foreign antigenic sequences for vaccine design. In this study, we evaluated the production [...] Read more.

The core antigen of hepatitis B virus (HBcAg) is capable of self-assembly into virus-like particles (VLPs) when expressed in a number of heterologous systems. Such VLPs are potential carriers of foreign antigenic sequences for vaccine design. In this study, we evaluated the production of chimeric HBcAg VLPs presenting a foreign epitope on their surface, the 551–607 amino acids (aa) immunological epitope of the ORF2 capsid protein of hepatitis E virus. A chimeric construct was made by the insertion of 56 aa into the immunodominant loop of the HBcAg. The sequences encoding the chimera were inserted into the pEAQ-HT vector and infiltrated into Nicotiana benthamiana leaves. The plant-expressed chimeric HBcHEV ORF2 551–607 protein was recognized by an anti-HBcAg mAb and anti-HEV IgG positive swine serum. Electron microscopy showed that plant-produced chimeric protein spontaneously assembled into “knobbly” ~34 nm diameter VLPs. This study shows that HBcAg is a promising carrier platform for the neutralizing epitopes of hepatitis E virus (HEV) and the chimeric HBcAg/HEV VLPs could be a candidate for a bivalent vaccine. Full article

(This article belongs to the Special Issue Capsid Protein)

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9 pages, 246 KB

Open AccessEditor’s ChoiceArticle

Obstructive Sleep Apnea as a Risk Factor of Insulin Resistance in Nondiabetic Adults

by Monika Michalek-Zrabkowska, Piotr Macek, Helena Martynowicz, Pawel Gac, Grzegorz Mazur, Magda Grzeda and Rafal Poreba

Life 2021, 11(1), 50; https://doi.org/10.3390/life11010050 - 13 Jan 2021

Cited by 22 | Viewed by 3328

Abstract

Objective: The aim of this research was to assess the relationship between prevalence and severity of obstructive sleep apnea (OSA) and insulin resistance among patients with increased risk of OSA without diabetes mellitus. Method and materials: our study group involved 102 individuals with [...] Read more.

Objective: The aim of this research was to assess the relationship between prevalence and severity of obstructive sleep apnea (OSA) and insulin resistance among patients with increased risk of OSA without diabetes mellitus. Method and materials: our study group involved 102 individuals with suspected OSA, mean age 53.02 ± 12.37 years. Data on medical history, medication usage, sleep habits, sleep quality and daytime sleepiness, were obtained using questionnaires. All patients underwent standardized full night polysomnography. Serum fasting insulin and glucose concentration were analyzed, the homeostatic model assessment-insulin resistance (HOMA-IR) index was calculated. Results: polysomnographic study indicated that in the group with OSA mean values of apnea–hypopnea index (AHI), oxygen desaturation index (ODI), duration of SpO₂ < 90% and average desaturation drop were significantly higher compared to the group without OSA, while the minimum SpO2 was significantly lower. The carbohydrate metabolism parameters did not differ within those groups. Significantly higher fasting insulin concentration and HOMA-IR index were found in the group with AHI ≥ 15 compared to the group with AHI < 15 and in the group with AHI ≥ 30 compared to the group with AHI < 30. Higher AHI and ODI were independent risk factors for higher fasting insulin concentration and higher HOMA-IR index. Increased duration of SpO2 < 90% was an independent risk factor for higher fasting glucose concentration. Conclusions: Individuals with moderate to severe OSA without diabetes mellitus had a higher prevalence of insulin resistance. Full article

(This article belongs to the Special Issue New Radiological, Electrocardiographic and Biochemical Cardiovascular Risk Factors)

15 pages, 3009 KB

Open AccessEditor’s ChoiceArticle

Downregulation of miR-17-92 Cluster by PERK Fine-Tunes Unfolded Protein Response Mediated Apoptosis

by Danielle E. Read, Ananya Gupta, Karen Cawley, Laura Fontana, Patrizia Agostinis, Afshin Samali and Sanjeev Gupta

Life 2021, 11(1), 30; https://doi.org/10.3390/life11010030 - 6 Jan 2021

Cited by 7 | Viewed by 3372

Abstract

An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated [...] Read more.

An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster. Full article

(This article belongs to the Special Issue UPR Regulated Noncoding RNAs in Diseases)

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16 pages, 1572 KB

Open AccessEditor’s ChoiceArticle

Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus

by Vladimir Grubelnik, Jan Zmazek, Rene Markovič, Marko Gosak and Marko Marhl

Life 2020, 10(12), 348; https://doi.org/10.3390/life10120348 - 14 Dec 2020

Cited by 24 | Viewed by 7103

Abstract

Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different [...] Read more.

Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases. Full article

(This article belongs to the Special Issue Impaired Mitochondrial Bioenergetics under Pathological Conditions)

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13 pages, 1725 KB

Open AccessEditor’s ChoiceBrief Report

Sex-Specific Differences in Extracellular Vesicle Protein Cargo in Synovial Fluid of Patients with Osteoarthritis

by Ravindra Kolhe, Virgenal Owens, Ashok Sharma, Tae Jin Lee, Wenbo Zhi, Umar Ghilzai, Ashis K. Mondal, Yutao Liu, Carlos M. Isales, Mark W. Hamrick, Monte Hunter and Sadanand Fulzele

Life 2020, 10(12), 337; https://doi.org/10.3390/life10120337 - 10 Dec 2020

Cited by 34 | Viewed by 4500

Abstract

Women are at a significantly higher risk of developing osteoarthritis (OA) compared to males. The pathogenesis of osteoarthritis (OA) in women is poorly understood. Extracellular vesicles (EVs) have been shown to play an essential role in numerous signaling processes during the pathogenesis of [...] Read more.

Women are at a significantly higher risk of developing osteoarthritis (OA) compared to males. The pathogenesis of osteoarthritis (OA) in women is poorly understood. Extracellular vesicles (EVs) have been shown to play an essential role in numerous signaling processes during the pathogenesis of age-related diseases via paracrine signaling. Molecular profiling of the synovial fluid-derived EVs cargo in women may help in the discovery of novel biomarkers and therapeutics for the treatment of OA in women. Previously, we reported that synovial fluid-derived EV miRNA cargo differs in a sex-specific manner. This study aims to characterize synovial fluid-derived EV protein cargo in OA patients. Our data showed sex-specific EVs protein content in OA. We found haptoglobin, orosomucoid, and ceruloplasmin significantly up-regulated, whereas apolipoprotein down-regulated in female OA EVs. In males, we discovered β-2-glycoprotein, and complement component 5 proteins significantly up-regulated and Spt-Ada-Gcn5 acetyltransferase (SAGA)-associated factor 29 down-regulated in male OA EVs. Database for Annotation, Visualization, and Integrated Discovery (DAVID) and QuickGO analysis revealed OA-specific protein involvement in several biological, molecular, and cellular pathways, specifically in inflammatory processes. In conclusion, synovial fluid EV protein content is altered in a sex-specific manner with OA, explaining the increased prevalence and severity of OA in women. Full article

(This article belongs to the Special Issue Osteoarthritis Pathology and Treatment)

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11 pages, 2041 KB

Open AccessEditor’s ChoiceArticle

Independent Evolution of Sex Chromosomes in Eublepharid Geckos, A Lineage with Environmental and Genotypic Sex Determination

by Eleonora Pensabene, Lukáš Kratochvíl and Michail Rovatsos

Life 2020, 10(12), 342; https://doi.org/10.3390/life10120342 - 10 Dec 2020

Cited by 17 | Viewed by 5239

Abstract

Geckos demonstrate a remarkable variability in sex determination systems, but our limited knowledge prohibits accurate conclusions on the evolution of sex determination in this group. Eyelid geckos (Eublepharidae) are of particular interest, as they encompass species with both environmental and genotypic sex determination. [...] Read more.

Geckos demonstrate a remarkable variability in sex determination systems, but our limited knowledge prohibits accurate conclusions on the evolution of sex determination in this group. Eyelid geckos (Eublepharidae) are of particular interest, as they encompass species with both environmental and genotypic sex determination. We identified for the first time the X-specific gene content in the Yucatán banded gecko, Coleonyx elegans, possessing X₁X₁X₂X₂/X₁X₂Y multiple sex chromosomes by comparative genome coverage analysis between sexes. The X-specific gene content of Coleonyx elegans was revealed to be partially homologous to genomic regions linked to the chicken autosomes 1, 6 and 11. A qPCR-based test was applied to validate a subset of X-specific genes by comparing the difference in gene copy numbers between sexes, and to explore the homology of sex chromosomes across eleven eublepharid, two phyllodactylid and one sphaerodactylid species. Homologous sex chromosomes are shared between Coleonyx elegans and Coleonyx mitratus, two species diverged approximately 34 million years ago, but not with other tested species. As far as we know, the X-specific gene content of Coleonyx elegans / Coleonyx mitratus was never involved in the sex chromosomes of other gecko lineages, indicating that the sex chromosomes in this clade of eublepharid geckos evolved independently. Full article

(This article belongs to the Section Evolutionary Biology)

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25 pages, 25235 KB

Open AccessEditor’s ChoiceArticle

Any Role of PIK3CA and PTEN Biomarkers in the Prognosis in Oral Squamous Cell Carcinoma?

by Anna Starzyńska, Paulina Adamska, Aleksandra Sejda, Monika Sakowicz-Burkiewicz, Łukasz Jan Adamski, Giulia Marvaso, Piotr Wychowański and Barbara Alicja Jereczek-Fossa

Life 2020, 10(12), 325; https://doi.org/10.3390/life10120325 - 3 Dec 2020

Cited by 12 | Viewed by 3081

Abstract

Oral squamous cell carcinoma (OSCC) accounts for 95% of the lesions in the oral cavity. Despite development in OSCC management, the outcome is still unsatisfactory. Identification of new therapies in OSCC is urgently needed. One objective of such treatment may be a signaling [...] Read more.

Oral squamous cell carcinoma (OSCC) accounts for 95% of the lesions in the oral cavity. Despite development in OSCC management, the outcome is still unsatisfactory. Identification of new therapies in OSCC is urgently needed. One objective of such treatment may be a signaling pathway of phosphatidylinositol 3-kinase. The study group included 92 patients treated for OSCC at the University Clinical Centre in Gdańsk, Poland. Study was performed on formalin-fixed paraffin-embedded samples from primary OSCC. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) and phosphatase and tensin homolog encoded on chromosome 10 (PTEN) protein expression was assessed by immunohistochemistry (IHC). PIK3CA gene copy number was analyzed using chromogenic and silver in situ hybridization where molecular probes are marked by chromogens and silver ions. PIK3CA IHC H-score ≥ 70 was found in 51.65% patients, and loss of PTEN protein was noticed in 31.46% cases. PIK3CA amplification was detected in 5 tumors. In the case of PTEN protein expression, there was an inverse correlation with the T stage of the primary tumor (r = −0.243) and positive correlation with a 5-year survival (r = 0.235). The number of copies of the PIK3CA gene was associated with the tumor grading (r = 0.208). The present study shows that loss of PTEN protein and the grading (p = 0.040), distant metastases (p = 0.033), smoking (p = 0.016), and alcohol abuse (p = 0.042) were prognostic factors for the survival of patients with OSCC. In contrast, the presence of amplification and OSCC on the floor of the mouth resulted in a nearly six-fold increase in the risk of shortening survival (p = 0.037). Our finding suggests a potential prognostic significance of PTEN loss and PIK3CA amplification in OSCC. Future studies are needed to confirm our results. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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11 pages, 4206 KB

Open AccessEditor’s ChoiceArticle

AFM Images of Viroid-Sized Rings That Self-Assemble from Mononucleotides through Wet–Dry Cycling: Implications for the Origin of Life

by Tue Hassenkam, Bruce Damer, Gabriel Mednick and David Deamer

Life 2020, 10(12), 321; https://doi.org/10.3390/life10120321 - 30 Nov 2020

Cited by 22 | Viewed by 4238

Abstract

It is possible that early life relied on RNA polymers that served as ribozyme-like catalysts and for storing genetic information. The source of such polymers is uncertain, but previous investigations reported that wet–dry cycles simulating prebiotic hot springs provide sufficient energy to drive [...] Read more.

It is possible that early life relied on RNA polymers that served as ribozyme-like catalysts and for storing genetic information. The source of such polymers is uncertain, but previous investigations reported that wet–dry cycles simulating prebiotic hot springs provide sufficient energy to drive condensation reactions of mononucleotides to form oligomers. The aim of the study reported here was to visualize the products by atomic force microscopy. In addition to globular oligomers, ring-like structures ranging from 10–200 nm in diameter, with an average around 30–40 nm, were abundant, particularly when nucleotides capable of base pairing were present. The thickness of the rings was consistent with single stranded products, but some had thicknesses indicating base pair stacking. Others had more complex structures in the form of short polymer attachments and pairing of rings. These observations suggest the possibility that base-pairing may promote polymerization during wet–dry cycling followed by solvation of the rings. We conclude that RNA-like rings and structures could have been synthesized non-enzymatically on the prebiotic Earth, with sizes sufficient to fold into ribozymes and genetic molecules required for life to begin. Full article

(This article belongs to the Collection Experimentally Testing Origin of Life Hypotheses in the Laboratory, at Field Analogs and Computationally)

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12 pages, 2004 KB

Open AccessEditor’s ChoiceArticle

Numerical Investigation on the Role of Mechanical Factors Contributing to Globe Flattening in States of Elevated Intracranial Pressure

by Jafar A. Mehr, Heather E. Moss and Hamed Hatami-Marbini

Life 2020, 10(12), 316; https://doi.org/10.3390/life10120316 - 28 Nov 2020

Cited by 6 | Viewed by 4395

Abstract

Flattening of the posterior eye globe in the magnetic resonance (MR) images is a sign associated with elevated intracranial pressure (ICP), often seen in people with idiopathic intracranial hypertension (IIH). The exact underlying mechanisms of globe flattening (GF) are not fully known but [...] Read more.

Flattening of the posterior eye globe in the magnetic resonance (MR) images is a sign associated with elevated intracranial pressure (ICP), often seen in people with idiopathic intracranial hypertension (IIH). The exact underlying mechanisms of globe flattening (GF) are not fully known but mechanical factors are believed to play a role. In the present study, we investigated the effects of material properties and pressure loads on GF. For this purpose, we used a generic finite element model to investigate the deformation of the posterior eyeball. The degree of GF in numerical models and the significance of different mechanical factors on GF were characterized using an automated angle-slope technique and a statistical measure. From the numerical models, we found that ICP had the most important role in GF. We also showed that the angle-slope graphs pertaining to MR images from five people with high ICP can be represented numerically by manipulating the parameters of the finite element model. This numerical study suggests that GF observed in IIH patients can be accounted for by the forces caused by elevation of ICP from its normal level, while material properties of ocular tissues, such as sclera (SC), peripapillary sclera (PSC), and optic nerve (ON), would impact its severity. Full article

(This article belongs to the Special Issue Idiopathic Intracranial Hypertension)

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21 pages, 1274 KB

Open AccessEditor’s ChoiceReview

Genome Editing by CRISPR-Cas: A Game Change in the Genetic Manipulation of Chlamydomonas

by Manel Ghribi, Serge Basile Nouemssi, Fatma Meddeb-Mouelhi and Isabel Desgagné-Penix

Life 2020, 10(11), 295; https://doi.org/10.3390/life10110295 - 20 Nov 2020

Cited by 41 | Viewed by 8791

Abstract

Microalgae are promising photosynthetic unicellular eukaryotes among the most abundant on the planet and are considered as alternative sustainable resources for various industrial applications. Chlamydomonas is an emerging model for microalgae to be manipulated by multiple biotechnological tools in order to produce high-value [...] Read more.

Microalgae are promising photosynthetic unicellular eukaryotes among the most abundant on the planet and are considered as alternative sustainable resources for various industrial applications. Chlamydomonas is an emerging model for microalgae to be manipulated by multiple biotechnological tools in order to produce high-value bioproducts such as biofuels, bioactive peptides, pigments, nutraceuticals, and medicines. Specifically, Chlamydomonas reinhardtii has become a subject of different genetic-editing techniques adapted to modulate the production of microalgal metabolites. The main nuclear genome-editing tools available today include zinc finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs), and more recently discovered the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein (Cas) nuclease system. The latter, shown to have an interesting editing capacity, has become an essential tool for genome editing. In this review, we highlight the available literature on the methods and the applications of CRISPR-Cas for C. reinhardtii genetic engineering, including recent transformation methods, most used bioinformatic tools, best strategies for the expression of Cas protein and sgRNA, the CRISPR-Cas mediated gene knock-in/knock-out strategies, and finally the literature related to CRISPR expression and modification approaches. Full article

(This article belongs to the Special Issue Plant Synthetic Biology)

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17 pages, 2821 KB

Open AccessEditor’s ChoiceArticle

Novel Methylation Patterns Predict Outcome in Uveal Melanoma

by Sarah Tadhg Ferrier and Julia Valdemarin Burnier

Life 2020, 10(10), 248; https://doi.org/10.3390/life10100248 - 20 Oct 2020

Cited by 9 | Viewed by 3284

Abstract

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few [...] Read more.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few studies exist on methylation changes in UM. Our aim was to identify methylation events associated with UM prognosis. Matched clinical, genetic, and methylation data for 80 UM cases were obtained from The Cancer Genome Atlas (TCGA). Top differentially methylated loci were sorted through hierarchical clustering based on methylation patterns, and these patterns were compared to tumor characteristics, genomic aberrations, and patient outcome. Hierarchical clustering revealed two distinct groups. These classifications effectively separated high and low-risk cases, with significant differences between groups in patient survival (p < 0.0001) and correlation with known prognostic factors. Major differences in methylation of specific genes, notably NFIA, HDAC4, and IL12RB2, were also seen. The methylation patterns identified in this study indicate potential novel prognostic indicators of UM and highlight the power of methylation changes in predicting outcome. The methylation events enriched in the high-risk group suggest that epigenetic modulating drugs may be useful in reducing metastatic potential, and that specific differentially methylated loci could act as biomarkers of therapeutic response. Full article

(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)

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16 pages, 2227 KB

Open AccessEditor’s ChoiceArticle

Multiple Non-Species-Specific Pathogens Possibly Triggered the Mass Mortality in Pinna nobilis

by Fabio Scarpa, Daria Sanna, Ilenia Azzena, Davide Mugetti, Francesco Cerruti, Sepideh Hosseini, Piero Cossu, Stefania Pinna, Daniele Grech, David Cabana, Viviana Pasquini, Giuseppe Esposito, Nicoletta Cadoni, Fabrizio Atzori, Elisabetta Antuofermo, Piero Addis, Leonardo Antonio Sechi, Marino Prearo, Simone Peletto, Marianna A. Mossa, Tiziana Saba, Vittorio Gazale and Marco Casu Show full author list Hide full author list

Life 2020, 10(10), 238; https://doi.org/10.3390/life10100238 - 13 Oct 2020

Cited by 45 | Viewed by 6258

Abstract

The fan mussel, Pinna nobilis, represents the largest bivalve endemic to the Mediterranean Sea. Since 2016, dramatic mass mortality of this species has been observed in several areas. The first surveys suggested that Haplosporidium pinnae (currently considered species-specific) was the main etiological [...] Read more.

The fan mussel, Pinna nobilis, represents the largest bivalve endemic to the Mediterranean Sea. Since 2016, dramatic mass mortality of this species has been observed in several areas. The first surveys suggested that Haplosporidium pinnae (currently considered species-specific) was the main etiological agent, but recent studies have indicated that a multifactorial disease may be responsible for this phenomenon. In this study, we performed molecular diagnostic analyses on P. nobilis, P. rudis, and bivalve heterologous host species from the island of Sardinia to shed further light on the pathogens involved in the mass mortality. The results support the occurrence of a multifactorial disease and that Mycobacterium spp. and H. pinnae are not necessarily associated with the illness. Indeed, our analyses revealed that H. pinnae is not species-specific for P. nobilis, as it was present in other bivalves at least three years before the mass mortality began, and species of Mycobacterium were also found in healthy individuals of P. nobilis and P. rudis. We also detected the species Rhodococcus erythropolis, representing the first report in fan mussels of a bacterium other than Mycobacterium spp. and Vibrio spp. These results depict a complicated scenario, further demonstrating how the P. nobilis mass mortality event is far from being fully understood. Full article

(This article belongs to the Section Evolutionary Biology)

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15 pages, 340 KB

Open AccessEditor’s ChoiceReview

Treatment of Advanced Melanoma: Past, Present and Future

by Taku Fujimura, Yumi Kambayashi, Kentaro Ohuchi, Yusuke Muto and Setsuya Aiba

Life 2020, 10(9), 208; https://doi.org/10.3390/life10090208 - 16 Sep 2020

Cited by 24 | Viewed by 4423

Abstract

Therapeutic options for treating advanced melanoma are progressing rapidly. Until six years ago, the regimen for treating advanced melanoma mainly comprised cytotoxic agents such as dacarbazine, and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have become recognized as anchor [...] Read more.

Therapeutic options for treating advanced melanoma are progressing rapidly. Until six years ago, the regimen for treating advanced melanoma mainly comprised cytotoxic agents such as dacarbazine, and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have become recognized as anchor drugs for treating advanced melanoma with or without additional combination drugs such as ipilimumab. In addition, v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase inhibitors in combination with mitogen-activated protein kinase kinase (MEK) inhibitors are among the most promising chemotherapeutic regimens for treating advanced BRAF-mutant melanoma, especially in patients with low tumor burden. Since anti-PD1 antibodies are widely applicable for the treatment of both BRAF wild-type and mutated advanced melanomas, several clinical trials for drugs in combination with anti-PD1 antibodies are ongoing. This review focuses on the development of the anti-melanoma therapies available today, and discusses the clinical trials of novel regimens for the treatment of advanced melanoma. Full article

(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)

15 pages, 2947 KB

Open AccessEditor’s ChoiceArticle

Muscle Hypertrophy and Architectural Changes in Response to Eight-Week Neuromuscular Electrical Stimulation Training in Healthy Older People

by Tereza Jandova, Marco V. Narici, Michal Steffl, Danilo Bondi, Moreno D’Amico, Dagmar Pavlu, Vittore Verratti, Stefania Fulle and Tiziana Pietrangelo

Life 2020, 10(9), 184; https://doi.org/10.3390/life10090184 - 8 Sep 2020

Cited by 15 | Viewed by 7206

Abstract

Loss of muscle mass of the lower limbs and of the spine extensors markedly impairs locomotor ability and spine stability in old age. In this study, we investigated whether 8 w of neuromuscular electrical stimulation (NMES) improves size and architecture of the lumbar [...] Read more.

Loss of muscle mass of the lower limbs and of the spine extensors markedly impairs locomotor ability and spine stability in old age. In this study, we investigated whether 8 w of neuromuscular electrical stimulation (NMES) improves size and architecture of the lumbar multifidus (LM) and vastus lateralis (VL) along with locomotor ability in healthy older individuals. Eight volunteers (aged 65 ≥ years) performed NMES 3 times/week. Eight sex- and age-matched individuals served as controls. Functional tests (Timed Up and Go test (TUG) and Five Times Sit-to-Stand Test (FTSST)), VL muscle architecture (muscle thickness (MT), pennation angle (PA), and fiber length (FL)), along with VL cross-sectional area (CSA) and both sides of LM were measured before and after by ultrasound. By the end of the training period, MT and CSA of VL increased by 8.6% and 11.4%, respectively. No significant increases were observed in FL and PA. LM CSA increased by 5.6% (left) and 7.1% (right). Interestingly, all VL architectural parameters significantly decreased in the control group. The combined NMES had a large significant effect on TUG (r = 0.50, p = 0.046). These results extend previous findings on the hypertrophic effects of NMES training, suggesting to be a useful mean for combating age-related sarcopenia. Full article

(This article belongs to the Special Issue Sarcopenia and Liver Disease: Current and Future Perspectives)

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13 pages, 271 KB

Open AccessEditor’s ChoiceReview

“Primum Non Nocere” in Interventional Oncology for Liver Cancer: How to Reduce the Risk for Complications?

by Roberto Iezzi, Tiago Bilhim, Laura Crocetti, Bora Peynircioglu, Shraga Goldberg, Josè Ignacio Bilbao, Ahmed Sami, Okan Akhan, Paola Scalise, Felice Giuliante, Maurizio Pompili, Vincenzo Valentini, Antonio Gasbarrini, Cesare Colosimo and Riccardo Manfredi

Life 2020, 10(9), 180; https://doi.org/10.3390/life10090180 - 6 Sep 2020

Cited by 4 | Viewed by 3657

Abstract

Interventional oncology represents a relatively new clinical discipline based upon minimally invasive therapies applicable to almost every human organ and disease. Over the last several decades, rapidly evolving research developments have introduced a newer generation of treatment devices, reagents, and image-guidance systems to [...] Read more.

Interventional oncology represents a relatively new clinical discipline based upon minimally invasive therapies applicable to almost every human organ and disease. Over the last several decades, rapidly evolving research developments have introduced a newer generation of treatment devices, reagents, and image-guidance systems to expand the armamentarium of interventional oncology across a wide spectrum of disease sites, offering potential cure, control, or palliative care for many types of cancer patients. Due to the widespread use of locoregional procedures, a comprehensive review of the methodologic and technical considerations to optimize patient selection with the aim of performing a safe procedure is mandatory. This article summarizes the expert discussion and report from the Mediterranean Interventional Oncology Live Congress (MIOLive 2020) held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions as a means for providing guidance on prudent ways to reduce complications. The aim of the paper is to provide an updated guiding tool not only to residents and fellows but also to colleagues approaching locoregional treatments. Full article

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

16 pages, 2743 KB

Open AccessEditor’s ChoiceArticle

Potential for Applying Continuous Directed Evolution to Plant Enzymes: An Exploratory Study

by Jorge D. García-García, Jaya Joshi, Jenelle A. Patterson, Lidimarie Trujillo-Rodriguez, Christopher R. Reisch, Alex A. Javanpour, Chang C. Liu and Andrew D. Hanson

Life 2020, 10(9), 179; https://doi.org/10.3390/life10090179 - 5 Sep 2020

Cited by 21 | Viewed by 7596

Abstract

Plant evolution has produced enzymes that may not be optimal for maximizing yield and quality in today’s agricultural environments and plant biotechnology applications. By improving enzyme performance, it should be possible to alleviate constraints on yield and quality currently imposed by kinetic properties [...] Read more.

Plant evolution has produced enzymes that may not be optimal for maximizing yield and quality in today’s agricultural environments and plant biotechnology applications. By improving enzyme performance, it should be possible to alleviate constraints on yield and quality currently imposed by kinetic properties or enzyme instability. Enzymes can be optimized more quickly than naturally possible by applying directed evolution, which entails mutating a target gene in vitro and screening or selecting the mutated gene products for the desired characteristics. Continuous directed evolution is a more efficient and scalable version that accomplishes the mutagenesis and selection steps simultaneously in vivo via error-prone replication of the target gene and coupling of the host cell’s growth rate to the target gene’s function. However, published continuous systems require custom plasmid assembly, and convenient multipurpose platforms are not available. We discuss two systems suitable for continuous directed evolution of enzymes, OrthoRep in Saccharomyces cerevisiae and EvolvR in Escherichia coli, and our pilot efforts to adapt each system for high-throughput plant enzyme engineering. To test our modified systems, we used the thiamin synthesis enzyme THI4, previously identified as a prime candidate for improvement. Our adapted OrthoRep system shows promise for efficient plant enzyme engineering. Full article

(This article belongs to the Special Issue Plant Synthetic Biology)

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15 pages, 2629 KB

Open AccessEditor’s ChoiceArticle

Improving Phylogenetic Signals of Mitochondrial Genes Using a New Method of Codon Degeneration

by Xuhua Xia

Life 2020, 10(9), 171; https://doi.org/10.3390/life10090171 - 30 Aug 2020

Cited by 2 | Viewed by 3102

Abstract

Recovering deep phylogeny is challenging with animal mitochondrial genes because of their rapid evolution. Codon degeneration decreases the phylogenetic noise and bias by aiming to achieve two objectives: (1) alleviate the bias associated with nucleotide composition, which may lead to homoplasy and long-branch [...] Read more.

Recovering deep phylogeny is challenging with animal mitochondrial genes because of their rapid evolution. Codon degeneration decreases the phylogenetic noise and bias by aiming to achieve two objectives: (1) alleviate the bias associated with nucleotide composition, which may lead to homoplasy and long-branch attraction, and (2) reduce differences in the phylogenetic results between nucleotide-based and amino acid (AA)-based analyses. The discrepancy between nucleotide-based analysis and AA-based analysis is partially caused by some synonymous codons that differ more from each other at the nucleotide level than from some nonsynonymous codons, e.g., Leu codon TTR in the standard genetic code is more similar to Phe codon TTY than to synonymous CTN codons. Thus, nucleotide similarity conflicts with AA similarity. There are many such examples involving other codon families in various mitochondrial genetic codes. Proper codon degeneration will make synonymous codons more similar to each other at the nucleotide level than they are to nonsynonymous codons. Here, I illustrate a “principled” codon degeneration method that achieves these objectives. The method was applied to resolving the mammalian basal lineage and phylogenetic position of rheas among ratites. The codon degeneration method was implemented in the user-friendly and freely available DAMBE software for all known genetic codes (genetic codes 1 to 33). Full article

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

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42 pages, 2508 KB

Open AccessEditor’s ChoiceReview

The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

by James Chapman, Yi Shiau Ng and Thomas J. Nicholls

Life 2020, 10(9), 164; https://doi.org/10.3390/life10090164 - 26 Aug 2020

Cited by 61 | Viewed by 8475

Abstract

Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several [...] Read more.

Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure. Full article

(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)

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32 pages, 2158 KB

Open AccessEditor’s ChoiceReview

Functional Mammalian Amyloids and Amyloid-Like Proteins

by Maria S. Rubel, Sergey A. Fedotov, Anastasia V. Grizel, Julia V. Sopova, Oksana A. Malikova, Yury O. Chernoff and Aleksandr A. Rubel

Life 2020, 10(9), 156; https://doi.org/10.3390/life10090156 - 21 Aug 2020

Cited by 42 | Viewed by 7985

Abstract

Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, [...] Read more.

Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, in particular T2D and AD, are widespread and affect hundreds of millions of people all over the world. However, recently it has become evident that many amyloids, termed “functional amyloids,” are involved in various activities that are beneficial to organisms. Functional amyloids were discovered in diverse taxa, ranging from bacteria to mammals. These amyloids are involved in vital biological functions such as long-term memory, storage of peptide hormones and scaffolding melanin polymerization in animals, substrate attachment, and biofilm formation in bacteria and fungi, etc. Thus, amyloids undoubtedly are playing important roles in biological and pathological processes. This review is focused on functional amyloids in mammals and summarizes approaches used for identifying new potentially amyloidogenic proteins and domains. Full article

(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)

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20 pages, 1859 KB

Open AccessEditor’s ChoiceReview

Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

by Federica Scollo and Carmelo La Rosa

Life 2020, 10(8), 144; https://doi.org/10.3390/life10080144 - 8 Aug 2020

Cited by 38 | Viewed by 5652

Abstract

Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The [...] Read more.

Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers. Full article

(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)

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19 pages, 1378 KB

Open AccessEditor’s ChoiceArticle

Evaluation of GammaH2AX in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer’s Disease in the AIBL Study of Ageing

by Mohammad Sabbir Siddiqui, Maxime Francois, Stephanie Rainey-Smith, Ralph Martins, Colin L. Masters, David Ames, Christopher C. Rowe, Lance S. Macaulay, Michael F. Fenech and Wayne R. Leifert

Life 2020, 10(8), 141; https://doi.org/10.3390/life10080141 - 6 Aug 2020

Cited by 6 | Viewed by 3608

Abstract

In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses [...] Read more.

In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer’s disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in P-trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 (p = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD. Full article

(This article belongs to the Special Issue Cellular Senescence in Health, Disease and Aging: Blessing or Curse?)

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28 pages, 2112 KB

Open AccessEditor’s ChoiceReview

Emerging Roles of Long Non-Coding RNAs in Renal Fibrosis

by Jinwen Lin, Zhengqian Jiang, Chenxi Liu, Dawei Zhou, Jiayu Song, Yuxuan Liao and Jianghua Chen

Life 2020, 10(8), 131; https://doi.org/10.3390/life10080131 - 1 Aug 2020

Cited by 20 | Viewed by 5501

Abstract

Renal fibrosis is an unavoidable consequence that occurs in nearly all of the nephropathies. It is characterized by a superabundant deposition and accumulation of extracellular matrix (ECM). All compartments in the kidney can be affected, including interstitium, glomeruli, vasculature, and other connective tissue, [...] Read more.

Renal fibrosis is an unavoidable consequence that occurs in nearly all of the nephropathies. It is characterized by a superabundant deposition and accumulation of extracellular matrix (ECM). All compartments in the kidney can be affected, including interstitium, glomeruli, vasculature, and other connective tissue, during the pathogenesis of renal fibrosis. The development of this process eventually causes destruction of renal parenchyma and end-stage renal failure, which is a devastating disease that requires renal replacement therapies. Recently, long non-coding RNAs (lncRNAs) have been emerging as key regulators governing gene expression and affecting various biological processes. These versatile roles include transcriptional regulation, organization of nuclear domains, and the regulation of RNA molecules or proteins. Current evidence proposes the involvement of lncRNAs in the pathologic process of kidney fibrosis. In this review, the biological relevance of lncRNAs in renal fibrosis will be clarified as important novel regulators and potential therapeutic targets. The biology, and subsequently the current understanding, of lncRNAs in renal fibrosis are demonstrated—highlighting the involvement of lncRNAs in kidney cell function, phenotype transition, and vascular damage and rarefaction. Finally, we discuss challenges and future prospects of lncRNAs in diagnostic markers and potential therapeutic targets, hoping to further inspire the management of renal fibrosis. Full article

(This article belongs to the Section Physiology and Pathology)

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13 pages, 1951 KB

Open AccessEditor’s ChoiceReview

The Conformational Plasticity Vista of PDZ Domains

by Javier Murciano-Calles

Life 2020, 10(8), 123; https://doi.org/10.3390/life10080123 - 27 Jul 2020

Cited by 9 | Viewed by 3879

Abstract

The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in [...] Read more.

The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in this domain family, based just on a static perspective of the structure–activity relationship, might fall short. More dynamic and conformational aspects in the protein fold can be the reasons for such functionality. Folding studies indeed showed an ample and malleable folding landscape for PDZ domains where multiple intermediate states were experimentally detected. Allosteric phenomena that resemble energetic coupling between residues have also been found in PDZ domains. Additionally, several PDZ domains are modulated by post-translational modifications, which introduce conformational switches that affect binding. Altogether, the ability to connect diverse partners might arise from the intrinsic plasticity of the PDZ fold. Full article

(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)

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21 pages, 3825 KB

Open AccessEditor’s ChoiceArticle

Profiling and Identification of Omeprazole Metabolites in Mouse Brain and Plasma by Isotope Ratio-Monitoring Liquid Chromatography-Mass Spectrometric Method

by Seok-Ho Shin, Yuri Park, Min-Ho Park, Jin-Ju Byeon, Byeong ill Lee, Jangmi Choi and Young G. Shin

Life 2020, 10(7), 115; https://doi.org/10.3390/life10070115 - 19 Jul 2020

Cited by 8 | Viewed by 5642

Abstract

Neuro–inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand [...] Read more.

Neuro–inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand for CNS drugs, which could be safer and more effective. Omeprazole, a well-known proton-pump inhibitor (PPI) is generally prescribed for the treatment of peptic ulcer. In addition to the anti-gastric acid secretion mechanism, recent studies showed that omeprazole or PPIs would likely have anti-inflammation effects in vitro and in vivo, but their effects on anti-inflammation in brain are still unknown. In this study, omeprazole and its metabolites in a mouse’s brain after various routes of administration have been explored by stable isotope ratio-patterning liquid chromatography–mass spectrometric method. First, a simple liquid chromatography–mass spectrometric (LC–MS) method was established for the quantification of omeprazole in mouse plasma and brain. After that, omeprazole and its stable isotope (D3–omeprazole) were concomitantly administered through various routes to mice in order to identify novel metabolites characteristically observed in the mouse brain and were analyzed using a different LC–MS method with information-dependent analysis (IDA) scan. With this unique approach, several new metabolites of omeprazole were identified by the mass difference between omeprazole and stable isotope in both brain and plasma samples. A total of seventeen metabolites were observed, and the observed metabolites were different from each administration route or each matrix (brain or plasma). The brain pharmacokinetic profiles and brain-to-plasma partition coefficient (Kp) were also evaluated in a satellite study. Overall, these results provide better insights to understand the CNS-related biological effects of omeprazole and its metabolites in vivo. Full article

(This article belongs to the Special Issue Drug Metabolism and Pharmacokinetics 2020)

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20 pages, 4161 KB

Open AccessEditor’s ChoiceArticle

Optimization of Molecular Dynamics Simulations of c-MYC^1-88—An Intrinsically Disordered System

by Sandra S. Sullivan and Robert O.J. Weinzierl

Life 2020, 10(7), 109; https://doi.org/10.3390/life10070109 - 10 Jul 2020

Cited by 12 | Viewed by 5523

Abstract

Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the [...] Read more.

Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC^1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins. Full article

(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)

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14 pages, 1079 KB

Open AccessEditor’s ChoiceReview

Interaction of Oxidative Stress and Misfolded Proteins in the Mechanism of Neurodegeneration

by Andrey Y. Abramov, Elena V. Potapova, Viktor V. Dremin and Andrey V. Dunaev

Life 2020, 10(7), 101; https://doi.org/10.3390/life10070101 - 30 Jun 2020

Cited by 97 | Viewed by 7792

Abstract

Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones—Alzheimer’s and Parkinson’s disease. Activity and toxicity of these proteins depends [...] Read more.

Aggregation of the misfolded proteins β-amyloid, tau, huntingtin, and α-synuclein is one of the most important steps in the pathology underlying a wide spectrum of neurodegenerative disorders, including the two most common ones—Alzheimer’s and Parkinson’s disease. Activity and toxicity of these proteins depends on the stage and form of aggregates. Excessive production of free radicals, including reactive oxygen species which lead to oxidative stress, is proven to be involved in the mechanism of pathology in most of neurodegenerative disorders. Both reactive oxygen species and misfolded proteins play a physiological role in the brain, and only deregulation in redox state and aggregation of the proteins leads to pathology. Here, we review the role of misfolded proteins in the activation of ROS production from various sources in neurons and glia. We discuss if free radicals can influence structural changes of the key toxic intermediates and describe the putative mechanisms by which oxidative stress and oligomers may cause neuronal death. Full article

(This article belongs to the Collection Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins)

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35 pages, 2166 KB

Open AccessEditor’s ChoiceReview

Neuroprotection or Neurotoxicity of Illicit Drugs on Parkinson’s Disease

by Carla Ferreira, Catarina Almeida, Sandra Tenreiro and Alexandre Quintas

Life 2020, 10(6), 86; https://doi.org/10.3390/life10060086 - 11 Jun 2020

Cited by 10 | Viewed by 13228

Abstract

Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown [...] Read more.

Parkinson’s Disease (PD) is currently the most rapid growing neurodegenerative disease and over the past generation, its global burden has more than doubled. The onset of PD can arise due to environmental, sporadic or genetic factors. Nevertheless, most PD cases have an unknown etiology. Chemicals, such as the anthropogenic pollutant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amphetamine-type stimulants, have been associated with the onset of PD. Conversely, cannabinoids have been associated with the treatment of the symptoms’. PD and medical cannabis is currently under the spotlight, and research to find its benefits on PD is on-going worldwide. However, the described clinical applications and safety of pharmacotherapy with cannabis products are yet to be fully supported by scientific evidence. Furthermore, the novel psychoactive substances are currently a popular alternative to classical drugs of abuse, representing an unknown health hazard for young adults who may develop PD later in their lifetime. This review addresses the neurotoxic and neuroprotective impact of illicit substance consumption in PD, presenting clinical evidence and molecular and cellular mechanisms of this association. This research area is utterly important for contemporary society since illicit drugs’ legalization is under discussion which may have consequences both for the onset of PD and for the treatment of its symptoms. Full article

(This article belongs to the Section Pharmaceutical Science)

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