Life | Editor’s choice

16 pages, 1354 KiB

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 27 | Viewed by 3653

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 KiB

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 9 | Viewed by 2743

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 KiB

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 9 | Viewed by 3194

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)

12 pages, 710 KiB

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 25 | Viewed by 3748

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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13 pages, 1362 KiB

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 15 | Viewed by 3515

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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17 pages, 3438 KiB

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 5 | Viewed by 3834

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 KiB

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 6 | Viewed by 3052

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 KiB

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 15 | Viewed by 4084

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 KiB

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 15 | Viewed by 2352

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 KiB

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 - 06 Jan 2021

Cited by 5 | Viewed by 2338

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 KiB

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 17 | Viewed by 4838

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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11 pages, 2041 KiB

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 16 | Viewed by 4047

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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13 pages, 1725 KiB

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 22 | Viewed by 3306

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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25 pages, 25235 KiB

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 - 03 Dec 2020

Cited by 8 | Viewed by 2056

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 KiB

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 17 | Viewed by 2919

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 KiB

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 3267

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 KiB

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 29 | Viewed by 5903

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 KiB

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 6 | Viewed by 2399

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 KiB

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 31 | Viewed by 4851

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 KiB

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 19 | Viewed by 3196

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 KiB

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 - 08 Sep 2020

Cited by 12 | Viewed by 4550

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 KiB

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 - 06 Sep 2020

Cited by 4 | Viewed by 2603

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 KiB

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 - 05 Sep 2020

Cited by 16 | Viewed by 5580

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 KiB

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 1 | Viewed by 2443

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 KiB

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 42 | Viewed by 6184

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 KiB

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 31 | Viewed by 5642

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 KiB

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 - 08 Aug 2020

Cited by 24 | Viewed by 4361

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 KiB

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 - 06 Aug 2020

Cited by 2 | Viewed by 2721

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 KiB

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 - 01 Aug 2020

Cited by 17 | Viewed by 4089

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 KiB

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 8 | Viewed by 2936

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 KiB

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 5 | Viewed by 3606

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 KiB

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 9 | Viewed by 4122

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 KiB

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 61 | Viewed by 5411

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 KiB

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 6 | Viewed by 8054

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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17 pages, 4264 KiB

Open AccessEditor’s ChoiceReview

Enigmatic Histamine Receptor H₄ for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases

by Pakhuri Mehta, Przemysław Miszta, Przemysław Rzodkiewicz, Olga Michalak, Piotr Krzeczyński and Sławomir Filipek

Life 2020, 10(4), 50; https://doi.org/10.3390/life10040050 - 24 Apr 2020

Cited by 23 | Viewed by 10014

Abstract

The histamine H₄ receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H₄R ligands are being studied for the treatment of several inflammatory, [...] Read more.

The histamine H₄ receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H₄R ligands are being studied for the treatment of several inflammatory, allergic, and autoimmune disorders, including pulmonary fibrosis. Activation of H₄R is involved in cytokine production and mediates mast cell activation and eosinophil chemotaxis. The importance of this receptor has also been shown in inflammatory models: peritonitis, respiratory tract inflammation, colitis, osteoarthritis, and rheumatoid arthritis. Recent studies suggest that H₄R acts as a modulator in cancer, neuropathic pain, vestibular disorders, and type-2 diabetes, however, its role is still not fully understood. Full article

(This article belongs to the Section Pharmaceutical Science)

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27 pages, 38043 KiB

Open AccessEditor’s ChoiceArticle

Synthetic Biology for Terraformation Lessons from Mars, Earth, and the Microbiome

by Nuria Conde-Pueyo, Blai Vidiella, Josep Sardanyés, Miguel Berdugo, Fernando T. Maestre, Victor de Lorenzo and Ricard Solé

Life 2020, 10(2), 14; https://doi.org/10.3390/life10020014 - 09 Feb 2020

Cited by 27 | Viewed by 13058

Abstract

What is the potential for synthetic biology as a way of engineering, on a large scale, complex ecosystems? Can it be used to change endangered ecological communities and rescue them to prevent their collapse? What are the best strategies for such ecological engineering [...] Read more.

What is the potential for synthetic biology as a way of engineering, on a large scale, complex ecosystems? Can it be used to change endangered ecological communities and rescue them to prevent their collapse? What are the best strategies for such ecological engineering paths to succeed? Is it possible to create stable, diverse synthetic ecosystems capable of persisting in closed environments? Can synthetic communities be created to thrive on planets different from ours? These and other questions pervade major future developments within synthetic biology. The goal of engineering ecosystems is plagued with all kinds of technological, scientific and ethic problems. In this paper, we consider the requirements for terraformation, i.e., for changing a given environment to make it hospitable to some given class of life forms. Although the standard use of this term involved strategies for planetary terraformation, it has been recently suggested that this approach could be applied to a very different context: ecological communities within our own planet. As discussed here, this includes multiple scales, from the gut microbiome to the entire biosphere. Full article

(This article belongs to the Section Synthetic Biology and Systems Biology)

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15 pages, 2706 KiB

Open AccessEditor’s ChoiceArticle

A Strategy for Combinatorial Cavity Design in De Novo Proteins

by Christina Karas and Michael Hecht

Life 2020, 10(2), 9; https://doi.org/10.3390/life10020009 - 23 Jan 2020

Cited by 8 | Viewed by 3915

Abstract

Protein sequence space is vast; nature uses only an infinitesimal fraction of possible sequences to sustain life. Are there solutions to biological problems other than those provided by nature? Can we create artificial proteins that sustain life? To investigate these questions, we have [...] Read more.

Protein sequence space is vast; nature uses only an infinitesimal fraction of possible sequences to sustain life. Are there solutions to biological problems other than those provided by nature? Can we create artificial proteins that sustain life? To investigate these questions, we have created combinatorial collections, or libraries, of novel sequences with no homology to those found in living organisms. Previously designed libraries contained numerous functional proteins. However, they often formed dynamic, rather than well-ordered structures, which complicated structural and mechanistic characterization. To address this challenge, we describe the development of new libraries based on the de novo protein S-824, a 4-helix bundle with a very stable 3-dimensional structure. Distinct from previous libraries, we targeted variability to a specific region of the protein, seeking to create potential functional sites. By characterizing variant proteins from this library, we demonstrate that the S-824 scaffold tolerates diverse amino acid substitutions in a putative cavity, including buried polar residues suitable for catalysis. We designed and created a DNA library encoding 1.7 × 10⁶ unique protein sequences. This new library of stable de novo α-helical proteins is well suited for screens and selections for a range of functional activities in vitro and in vivo. Full article

(This article belongs to the Special Issue Design and Validation of Tools for Microbial Synthetic Biology Applications)

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41 pages, 4490 KiB

Open AccessEditor’s ChoiceConcept Paper

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

by Didier Auboeuf

Life 2020, 10(2), 7; https://doi.org/10.3390/life10020007 - 21 Jan 2020

Cited by 14 | Viewed by 6771

Abstract

The current framework of evolutionary theory postulates that evolution relies on random mutations generating a diversity of phenotypes on which natural selection acts. This framework was established using a top-down approach as it originated from Darwinism, which is based on observations made of [...] Read more.

The current framework of evolutionary theory postulates that evolution relies on random mutations generating a diversity of phenotypes on which natural selection acts. This framework was established using a top-down approach as it originated from Darwinism, which is based on observations made of complex multicellular organisms and, then, modified to fit a DNA-centric view. In this article, it is argued that based on a bottom-up approach starting from the physicochemical properties of nucleic and amino acid polymers, we should reject the facts that (i) natural selection plays a dominant role in evolution and (ii) the probability of mutations is independent of the generated phenotype. It is shown that the adaptation of a phenotype to an environment does not correspond to organism fitness, but rather corresponds to maintaining the genome stability and integrity. In a stable environment, the phenotype maintains the stability of its originating genome and both (genome and phenotype) are reproduced identically. In an unstable environment (i.e., corresponding to variations in physicochemical parameters above a physiological range), the phenotype no longer maintains the stability of its originating genome, but instead influences its variations. Indeed, environment- and cellular-dependent physicochemical parameters define the probability of mutations in terms of frequency, nature, and location in a genome. Evolution is non-deterministic because it relies on probabilistic physicochemical rules, and evolution is driven by a bidirectional interplay between genome and phenotype in which the phenotype ensures the stability of its originating genome in a cellular and environmental physicochemical parameter-depending manner. Full article

(This article belongs to the Section Evolutionary Biology)

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28 pages, 6302 KiB

Open AccessEditor’s ChoiceReview

Synthetic Approaches for Nucleic Acid Delivery: Choosing the Right Carriers

by Rong Ni, Ruilu Feng and Ying Chau

Life 2019, 9(3), 59; https://doi.org/10.3390/life9030059 - 09 Jul 2019

Cited by 51 | Viewed by 7796

Abstract

The discovery of the genetic roots of various human diseases has motivated the exploration of different exogenous nucleic acids as therapeutic agents to treat these genetic disorders (inherited or acquired). However, the physicochemical properties of nucleic acids render them liable to degradation and [...] Read more.

The discovery of the genetic roots of various human diseases has motivated the exploration of different exogenous nucleic acids as therapeutic agents to treat these genetic disorders (inherited or acquired). However, the physicochemical properties of nucleic acids render them liable to degradation and also restrict their cellular entrance and gene translation/inhibition at the correct cellular location. Therefore, gene condensation/protection and guided intracellular trafficking are necessary for exogenous nucleic acids to function inside cells. Diversified cationic formulation materials, including natural and synthetic lipids, polymers, and proteins/peptides, have been developed to facilitate the intracellular transportation of exogenous nucleic acids. The chemical properties of different formulation materials determine their special features for nucleic acid delivery, so understanding the property–function correlation of the formulation materials will inspire the development of next-generation gene delivery carriers. Therefore, in this review, we focus on the chemical properties of different types of formulation materials and discuss how these formulation materials function as protectors and cellular pathfinders for nucleic acids, bringing them to their destination by overcoming different cellular barriers. Full article

(This article belongs to the Special Issue Modelling Life-Like Behavior in Systems Chemistry)

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14 pages, 324 KiB

Open AccessEditor’s ChoiceArticle

Molecular Diversity Required for the Formation of Autocatalytic Sets

by Wim Hordijk, Mike Steel and Stuart A. Kauffman

Life 2019, 9(1), 23; https://doi.org/10.3390/life9010023 - 01 Mar 2019

Cited by 18 | Viewed by 4967

Abstract

Systems chemistry deals with the design and study of complex chemical systems. However, such systems are often difficult to investigate experimentally. We provide an example of how theoretical and simulation-based studies can provide useful insights into the properties and dynamics of complex chemical [...] Read more.

Systems chemistry deals with the design and study of complex chemical systems. However, such systems are often difficult to investigate experimentally. We provide an example of how theoretical and simulation-based studies can provide useful insights into the properties and dynamics of complex chemical systems, in particular of autocatalytic sets. We investigate the issue of the required molecular diversity for autocatalytic sets to exist in random polymer libraries. Given a fixed probability that an arbitrary polymer catalyzes the formation of other polymers, we calculate this required molecular diversity theoretically for two particular models of chemical reaction systems, and then verify these calculations by computer simulations. We also argue that these results could be relevant to an origin of life scenario proposed recently by Damer and Deamer. Full article

(This article belongs to the Special Issue Modelling Life-Like Behavior in Systems Chemistry)

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17 pages, 36310 KiB

Open AccessEditor’s ChoiceReview

Bottom-Up Approaches to Synthetic Cooperation in Microbial Communities

by Daniel Rodríguez Amor and Martina Dal Bello

Life 2019, 9(1), 22; https://doi.org/10.3390/life9010022 - 26 Feb 2019

Cited by 37 | Viewed by 11123

Abstract

Microbial cooperation pervades ecological scales, from single-species populations to host-associated microbiomes. Understanding the mechanisms promoting the stability of cooperation against potential threats by cheaters is a major question that only recently has been approached experimentally. Synthetic biology has helped to uncover some of [...] Read more.

Microbial cooperation pervades ecological scales, from single-species populations to host-associated microbiomes. Understanding the mechanisms promoting the stability of cooperation against potential threats by cheaters is a major question that only recently has been approached experimentally. Synthetic biology has helped to uncover some of these basic mechanisms, which were to some extent anticipated by theoretical predictions. Moreover, synthetic cooperation is a promising lead towards the engineering of novel functions and enhanced productivity of microbial communities. Here, we review recent progress on engineered cooperation in microbial ecosystems. We focus on bottom-up approaches that help to better understand cooperation at the population level, progressively addressing the challenges of tackling higher degrees of complexity: spatial structure, multispecies communities, and host-associated microbiomes. We envisage cooperation as a key ingredient in engineering complex microbial ecosystems. Full article

(This article belongs to the Special Issue Synthetic Biology: From Living Computers to Terraformation)

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24 pages, 963 KiB

Open AccessEditor’s ChoiceReview

Unity Makes Strength: A Review on Mutualistic Symbiosis in Representative Insect Clades

by Rosario Gil and Amparo Latorre

Life 2019, 9(1), 21; https://doi.org/10.3390/life9010021 - 25 Feb 2019

Cited by 22 | Viewed by 6544

Abstract

Settled on the foundations laid by zoologists and embryologists more than a century ago, the study of symbiosis between prokaryotes and eukaryotes is an expanding field. In this review, we present several models of insect–bacteria symbioses that allow for the detangling of most [...] Read more.

Settled on the foundations laid by zoologists and embryologists more than a century ago, the study of symbiosis between prokaryotes and eukaryotes is an expanding field. In this review, we present several models of insect–bacteria symbioses that allow for the detangling of most known features of this distinctive way of living, using a combination of very diverse screening approaches, including molecular, microscopic, and genomic techniques. With the increasing the amount of endosymbiotic bacteria genomes available, it has been possible to develop evolutionary models explaining the changes undergone by these bacteria in their adaptation to the intracellular host environment. The establishment of a given symbiotic system can be a root cause of substantial changes in the partners’ way of life. Furthermore, symbiont replacement and/or the establishment of bacterial consortia are two ways in which the host can exploit its interaction with environmental bacteria for endosymbiotic reinvigoration. The detailed study of diverse and complex symbiotic systems has revealed a great variety of possible final genomic products, frequently below the limit considered compatible with cellular life, and sometimes with unanticipated genomic and population characteristics, raising new questions that need to be addressed in the near future through a wider exploration of new models and empirical observations. Full article

(This article belongs to the Special Issue Evolution of Mutualistic Symbiosis)

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12 pages, 2318 KiB

Open AccessEditor’s ChoiceArticle

Dynamical Task Switching in Cellular Computers

by Angel Goñi-Moreno, Fernando de la Cruz, Alfonso Rodríguez-Patón and Martyn Amos

Life 2019, 9(1), 14; https://doi.org/10.3390/life9010014 - 26 Jan 2019

Cited by 4 | Viewed by 4842

Abstract

We present a scheme for implementing a version of task switching in engineered bacteria, based on the manipulation of plasmid copy numbers. Our method allows for the embedding of multiple computations in a cellular population, whilst minimising resource usage inefficiency. We describe the [...] Read more.

We present a scheme for implementing a version of task switching in engineered bacteria, based on the manipulation of plasmid copy numbers. Our method allows for the embedding of multiple computations in a cellular population, whilst minimising resource usage inefficiency. We describe the results of computational simulations of our model, and discuss the potential for future work in this area. Full article

(This article belongs to the Special Issue Synthetic Biology: From Living Computers to Terraformation)

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18 pages, 3143 KiB

Open AccessEditor’s ChoiceArticle

Metatranscriptomic Analysis of the Bacterial Symbiont Dactylopiibacterium carminicum from the Carmine Cochineal Dactylopius coccus (Hemiptera: Coccoidea: Dactylopiidae)

by Rafael Bustamante-Brito, Arturo Vera-Ponce de León, Mónica Rosenblueth, Julio César Martínez-Romero and Esperanza Martínez-Romero

Life 2019, 9(1), 4; https://doi.org/10.3390/life9010004 - 03 Jan 2019

Cited by 15 | Viewed by 6814

Abstract

The scale insect Dactylopius coccus produces high amounts of carminic acid, which has historically been used as a pigment by pre-Hispanic American cultures. Nowadays carmine is found in food, cosmetics, and textiles. Metagenomic approaches revealed that Dactylopius spp. cochineals contain two Wolbachia strains, [...] Read more.

The scale insect Dactylopius coccus produces high amounts of carminic acid, which has historically been used as a pigment by pre-Hispanic American cultures. Nowadays carmine is found in food, cosmetics, and textiles. Metagenomic approaches revealed that Dactylopius spp. cochineals contain two Wolbachia strains, a betaproteobacterium named Candidatus Dactylopiibacterium carminicum and Spiroplasma, in addition to different fungi. We describe here a transcriptomic analysis indicating that Dactylopiibacterium is metabolically active inside the insect host, and estimate that there are over twice as many Dactylopiibacterium cells in the hemolymph than in the gut, with even fewer in the ovary. Albeit scarce, the transcripts in the ovaries support the presence of Dactylopiibacterium in this tissue and a vertical mode of transmission. In the cochineal, Dactylopiibacterium may catabolize plant polysaccharides, and be active in carbon and nitrogen provisioning through its degradative activity and by fixing nitrogen. In most insects, nitrogen-fixing bacteria are found in the gut, but in this study they are shown to occur in the hemolymph, probably delivering essential amino acids and riboflavin to the host from nitrogen substrates derived from nitrogen fixation. Full article

(This article belongs to the Special Issue Evolution of Mutualistic Symbiosis)

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