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1.
Exercise as a countermeasure for latent viral reactivation during long duration space flight.
Agha, NH, Mehta, SK, Rooney, BV, Laughlin, MS, Markofski, MM, Pierson, DL, Katsanis, E, Crucian, BE, Simpson, RJ
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;(2):2869-2881
Abstract
Latent viral reactivation is a commonly reported manifestation of immune system dysregulation during spaceflight. As physical fitness and exercise training have been shown to benefit multiple arms of the immune system, we hypothesized that higher levels of preflight physical fitness and/or maintaining fitness during a mission would protect astronauts from latent viral reactivation. Standardized tests of maximal strength, muscular endurance, flexibility, and cardiorespiratory fitness (CRF) were performed in 22 international space station (ISS) crewmembers before and after a ~6-month mission. Reactivation of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella zoster virus (VZV) was determined in crewmembers and ground-based controls before, during, and after spaceflight. Crewmembers with higher CRF before spaceflight had a 29% reduced risk of latent viral reactivation compared to crew with lower CRF. Higher preflight upper body muscular endurance was associated with a 39% reduced risk of viral reactivation, a longer time to viral reactivation, and lower peak viral DNA concentrations, particularly for EBV and VZV. Latent viral reactivation rates were highest in crew with lower preflight CRF and higher levels of CRF deconditioning on return to Earth. We conclude that physical fitness may protect astronauts from latent viral reactivation during long duration spaceflight missions.
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2.
Hormesis and Ginseng: Ginseng Mixtures and Individual Constituents Commonly Display Hormesis Dose Responses, Especially for Neuroprotective Effects.
Calabrese, EJ
Molecules (Basel, Switzerland). 2020;(11)
Abstract
This paper demonstrates that ginseng mixtures and individual ginseng chemical constituents commonly induce hormetic dose responses in numerous biological models for endpoints of biomedical and clinical relevance, typically providing a mechanistic framework. The principal focus of ginseng hormesis-related research has been directed toward enhancing neuroprotection against conditions such as Alzheimer's and Parkinson's Diseases, stroke damage, as well as enhancing spinal cord and peripheral neuronal damage repair and reducing pain. Ginseng was also shown to reduce symptoms of diabetes, prevent cardiovascular system damage, protect the kidney from toxicities due to immune suppressant drugs, and prevent corneal damage, amongst other examples. These findings complement similar hormetic-based chemoprotective reports for other widely used dietary-type supplements such as curcumin, ginkgo biloba, and green tea. These findings, which provide further support for the generality of the hormetic dose response in the biomedical literature, have potentially important public health and clinical implications.
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3.
The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials.
Carretero-González, A, Lora, D, Martín Sobrino, I, Sáez Sanz, I, Bourlon, MT, Anido Herranz, U, Martínez Chanzá, N, Castellano, D, de Velasco, G
Cancers. 2020;(7)
Abstract
Immune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown.
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4.
All Roads Lead to Susceptibility: The Many Modes of Action of Fungal and Oomycete Intracellular Effectors.
He, Q, McLellan, H, Boevink, PC, Birch, PRJ
Plant communications. 2020;(4):100050
Abstract
The ability to secrete effector proteins that can enter plant cells and manipulate host processes is a key determinant of what makes a successful plant pathogen. Here, we review intracellular effectors from filamentous (fungal and oomycete) phytopathogens and the host proteins and processes that are targeted to promote disease. We cover contrasting virulence strategies and effector modes of action. Filamentous pathogen effectors alter the fates of host proteins that they target, changing their stability, their activity, their location, and the protein partners with which they interact. Some effectors inhibit target activity, whereas others enhance or utilize it, and some target multiple host proteins. We discuss the emerging topic of effectors that target negative regulators of immunity or other plant proteins with activities that support susceptibility. We also highlight the commonly targeted host proteins that are manipulated by effectors from multiple pathogens, including those representing different kingdoms of life.
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5.
MAMP-triggered Medium Alkalinization of Plant Cell Cultures.
Fiorin, GL, Sánchez-Vallet, A, Thomma, BPHJ, Pereira, GAG, Teixeira, PJPL
Bio-protocol. 2020;(8):e3588
Abstract
Plants recognize a wide variety of microbial molecules to detect and respond to potential invaders. Recognition of Microbe-Associated Molecular Patterns (MAMPs) by cell surface receptors initiate a cascade of biochemical responses that include, among others, ion fluxes across the plasma membrane. A consequence of such event is a decrease in the concentration of extracellular H+ ions, which can be experimentally detected in plant cell suspensions as a shift in the pH of the medium. Thus, similarly to reactive oxygen species (ROS) accumulation, phosphorylation of MAP kinases and induction of defense-related genes, MAMP-induced medium alkalinization can be used as a proxy for the activation of plant immune responses. Here, we describe a detailed protocol for the measurement of medium alkalinization of tobacco BY-2 cell suspensions upon treatment with two different MAMPs: chitohexamers derived from fungal cell walls (NAG6; N-acetylglucosamine) and the flagellin epitope flg22, found in the bacterial flagellum. This method provides a reliable and fast platform to access MAMP-Triggered Immunity (MTI) in tobacco cell suspensions and can be easily adapted to other plant species as well as to other MAMPs.
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6.
Thermodynamic Integration in 3n Dimensions without Biases or Alchemy for Protein Interactions.
Chen, LY
Frontiers in physics. 2020
Abstract
Thermodynamic integration (TI), a powerful formalism for computing Gibbs free energy, has been implemented for many biophysical processes with alchemical schemes that require delicate human efforts to choose/design biasing potentials for sampling the desired biophysical events and to remove their artifactitious consequences afterwards. Theoretically, an alchemical scheme is exact but practically, an unsophisticated implementation of this exact formula can cause error amplifications. Small relative errors in the input parameters can be amplified many times in their propagation into the computed free energy [due to subtraction of similar numbers such as (105 ± 5)‒(100 ± 5) = 5 ± 7]. In this paper, we present an unsophisticated implementation of TI in 3n dimensions (3nD) (n=1,2,3…) for the potential of mean force along a 3nD path connecting one state in the bound state ensemble to one state in the unbound state ensemble. Fluctuations in these 3nD are integrated in the bound and unbound state ensembles but not along the 3nD path. Using TI3nD, we computed the standard binding free energies of three protein complexes: trometamol in Salmonella effector SpvD (n=1), biotin-avidin (n=2), and Colicin E9 endonuclease with cognate immunity protein Im9 (n=3). We employed three different protocols in three independent computations of E9-Im9 to show TI3nD's robustness. We also computed the hydration energies of ten biologically relevant compounds (n=1 for water, acetamide, urea, glycerol, trometamol, ammonium and n=2 for erythritol, 1,3-propanediol, xylitol, biotin). Each of the 15 computations is accomplishable within one (for hydration) to ten (for E9-Im9) days on an inexpensive GPU workstation. The computed results all agree with the available experimental data.
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7.
Origin and role of hepatic myofibroblasts in hepatocellular carcinoma.
Yavuz, BG, Pestana, RC, Abugabal, YI, Krishnan, S, Chen, J, Hassan, MM, Wolff, RA, Rashid, A, Amin, HM, Kaseb, AO
Oncotarget. 2020;(13):1186-1201
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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8.
Gut instincts: vitamin D/vitamin D receptor and microbiome in neurodevelopment disorders.
Ogbu, D, Xia, E, Sun, J
Open biology. 2020;(7):200063
Abstract
The gut microbiome regulates a relationship with the brain known as the gut-microbiota-brain (GMB) axis. This interaction is influenced by immune cells, microbial metabolites and neurotransmitters. Recent findings show gut dysbiosis is prevalent in autism spectrum disorder (ASD) as well as attention deficit hyperactivity disorder (ADHD). There are previously established negative correlations among vitamin D, vitamin D receptor (VDR) levels and severity of ASD as well as ADHD. Both vitamin D and VDR are known to regulate homeostasis in the brain and the intestinal microbiome. This review summarizes the growing relationship between vitamin D/VDR signalling and the GMB axis in ASD and ADHD. We focus on current publications and summarize the progress of GMB in neurodevelopmental disorders, describe effects and mechanisms of vitamin D/VDR in regulating the microbiome and synoptically highlight the potential applications of targeting vitamin D/VDR signalling in neurodevelopment disorders.
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9.
Elderly at time of COronaVIrus disease 2019 (COVID-19): possible role of immunosenescence and malnutrition.
Bencivenga, L, Rengo, G, Varricchi, G
GeroScience. 2020;(4):1089-1092
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Abstract
The unprecedented COVID-19 pandemic is rapidly and unpredictably evolving and the majority of deaths are occurring in older people. A partial description of the magnitude of the scenario is provided by numbers and statistics, which probably underestimate the ongoing tragedy. In the present opinion paper, we have focused our attention on the evidence of the relationship among malnutrition, immunosenescence, and the higher morbidity and mortality in elderly patients. In particular, we propose the intriguing hypothesis that correction of nutritional deficits may attenuate the age-dependent alterations of the innate and adaptive immune system which participate in the increased susceptibility and worse outcome observed in the elderly COVID-19 patients.
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10.
[Exploration of omics mechanism and drug prediction of coronavirus-induced heart failure based on clinical bioinformatics].
Chen, XM, Cao, F, Zhang, HM, Chen, HR, Zhang, JD, Zhi, P, Li, ZY, Wang, YX, Lu, XC
Zhonghua xin xue guan bing za zhi. 2020;(7):587-592
Abstract
Objective: Present study investigated the mechanism of heart failure associated with coronavirus infection and predicted potential effective therapeutic drugs against heart failure associated with coronavirus infection. Methods: Coronavirus and heart failure were searched in the Gene Expression Omnibus (GEO) and omics data were selected to meet experimental requirements. Differentially expressed genes were analyzed using the Limma package in R language to screen for differentially expressed genes. The two sets of differential genes were introduced into the R language cluster Profiler package for gene ontology (GO) and Kyoto gene and genome encyclopedia (KEGG) pathway enrichment analysis. Two sets of intersections were taken. A protein interaction network was constructed for all differentially expressed genes using STRING database and core genes were screened. Finally, the apparently accurate treatment prediction platform (EpiMed) independently developed by the team was used to predict the therapeutic drug. Results: The GSE59185 coronavirus data set was searched and screened in the GEO database, and divided into wt group, ΔE group, Δ3 group, Δ5 group according to different subtypes, and compared with control group. After the difference analysis, 191 up-regulated genes and 18 down-regulated genes were defined. The GEO126062 heart failure data set was retrieved and screened from the GEO database. A total of 495 differentially expressed genes were screened, of which 165 were up-regulated and 330 were down-regulated. Correlation analysis of differentially expressed genes between coronavirus and heart failure was performed. After cross processing, there were 20 GO entries, which were mainly enriched in virus response, virus defense response, type Ⅰ interferon response, γ interferon regulation, innate immune response regulation, negative regulation of virus life cycle, replication regulation of viral genome, etc. There were 5 KEGG pathways, mainly interacting with tumor necrosis factor (TNF) signaling pathway, interleukin (IL)-17 signaling pathway, cytokine and receptor interaction, Toll-like receptor signaling pathway, human giant cells viral infection related. All differentially expressed genes were introduced into the STRING online analysis website for protein interaction network analysis, and core genes such as signal transducer and activator of transcription 3, IL-10, IL17, TNF, interferon regulatory factor 9, 2'-5'-oligoadenylate synthetase 1, mitogen-activated protein kinase 3, radical s-adenosyl methionine domain containing 2, c-x-c motif chemokine ligand 10, caspase 3 and other genes were screened. The drugs predicted by EpiMed's apparent precision treatment prediction platform for disease-drug association analysis were mainly TNF-α inhibitors, resveratrol, ritonavir, paeony, retinoic acid, forsythia, and houttuynia cordata. Conclusions: The abnormal activation of multiple inflammatory pathways may be the cause of heart failure in patients after coronavirus infection. Resveratrol, ritonavir, retinoic acid, amaranth, forsythia, houttuynia may have therapeutic effects. Future basic and clinical research is warranted to validate present results and hypothesis.
