bluuebunny/crossref_metadata_2025_split huggingface dataset:
Docking Molecular analysis of potential Drug Paritaprevir against Mycobacterium tuberculosis (Mtb)
Authors: Ferrari Ivan Vito , Patrizio Paolo 
Published: July 2021

AbstractBackgroundMycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. This is an infectious disease generally affects the lungs, but can also affect other parts of the body. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug Rifampin (Rif). We report first time a Potential Drug Paritaprevir against with severe infectious disease, by in Silico approach, using Autodock Vina and Autodock 4 (or MGL Tool), estimated with Pyrx and AMDock Software, calculating three different important parameters: Binding Affinity (kcal/mol), estimated Ki (in nM units) and Ligand Efficiency (L.E. in kcal/mol). After a selective analysis of over 1000 drugs, processed with Pyrx (a Virtual Screening software for Computational Drug Discovery) in the Ligand Binding site pocket of the protein (ID PDB 5UHB chain C,DNA-directed RNA polymerase subunit beta), we noticed high values of these 3 parameters mentioned above of Paritaprevir, concluding that it could be an excellent candidate drug for this type of infection. Indeed, from the results of Autodock Vina and Autodock 4 (or Autodock 4.2), implemented with lamarckian genetic algorithm, LGA, trough AMDock Software, This oral drug, approved by FDA in 2014, both by Autodock Vina and Autodock Vina 4 has excellent Binding affinity value, ca. −10.00 kcal/mol, a Ki value 40 nM and Ligand efficiency ca −0.15 kcal/mol. These results are comparable to the drug crystallized in the above-mentioned protein, currently used against TBC.
Biomechanical effects of the addition of a precision constraint on a collective load carriage task
Authors: Sghaier Nour , Fumery Guillaume , Fourcassié Vincent , Turpin Nicolas A. , Moretto Pierre 
Published: July 2021

1AbstractTeam lifting is a complex and collective motor task that possesses both motor and cognitive components. The purpose of this study was to investigate to what extent the biomechanics of a collective load carriage is affected when a dyad of individuals is performing a carrying task with an additional accuracy constraint. Ten dyads performed a first condition in which they collectively transported a load (CC), and a second one in which they transported the same load while maintaining a ball in a target position on its top (PC).The recovery-rate, amplitude, and period of the center-of-mass (COM) trajectory were computed for the whole system (dyad + table = PACS). We analyzed the forces and moments exerted at each joint of the upper limbs of the subjects. We observed a decrease in the overall performance of the dyads when the Precision task was added, i.e., i) the velocity and amplitude of CoMPACS decreased by 1,7% and 5,8%, respectively, ii) inter-subject variability of the Moment-Cost-Function decreased by 95% and recovery rate decreased by 19,2% during PC. A kinetic synergy analysis showed that the subjects reorganized their coordination in the PC.Our results demonstrate that adding a precision task affects the economy of collective load carriage. Notwithstanding, the joint moments at the upper-limbs are better balanced and co-vary more across the paired subjects during the precision task. Our study results may find applications in domains such as Ergonomics, Robotics-developments, and Rehabilitation.
NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses
Authors: Wang Hongyun , Zhang Lu , Zeng Cong , Feng Jiangpeng , Wang Dehe , He Miao , Jiang Ao , Cao Yuanyuan , Guo Xiao , Liu Jiejie , Yan Kun , Tang Hao , Xu Ke , Fan Chengpeng , Guo Deyin , Lan Ke , Zhou Yu , Chen Yu 
Published: July 2021

Abstract5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, can negatively regulate type I interferon responses during viral infection. NSUN2 specifically mediates m5C methylation ofIRF3mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 could enhance type I interferon responses and downstream ISG expression after viral infectionin vitro. Andin vivo, the antiviral innate responses is more dramatically enhanced inNsun2+/−mice than inNsun2+/+mice. Four highly m5C methylated cytosines inIRF3mRNA were identified, and their mutation could enhance the cellularIRF3mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), Zika virus (ZIKV), or especially SARS-CoV-2 resulted in a reduction in endogenous levels of NSUN2. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover ofIRF3mRNA, while endogenous NSUN2 levels decrease after viral infection to boost antiviral responses for the effective elimination of viruses. Our results suggest a paradigm of innate antiviral immune responses ingeniously involving NSUN2-mediated m5C modification.
The PD-1 checkpoint receptor maintains tolerance of self-reactive CD8 T cell in skin
Authors: Damo Martina , Cui Can , William Ivana , Hornick Noah I. , Kwok Darwin , Clulo Kathryn , Damsky William E. , Leventhal Jonathan S. , Joshi Nikhil S. 
Published: July 2021

SummaryPeripheral tolerance is thought to result from anergy or deletion of self-reactive T cells shortly after antigen encounter. However, the frequent occurrences of immune-related Adverse Events (irAEs) following checkpoint inhibitor (CPI) treatment suggest a hypothesis that immunologically healthy individuals have self-reactive effector T cells that are kept in a non-pathogenic state through checkpoint receptor-mediated suppression, instead of anergy or deletion. We expressed self-antigens in healthy skin and found that antigen-specific CD8 T cells infiltrated the tissue, but remained tolerant, despite having a transcriptional program that resembled effector T cells found after CPIs. These self-reactive PD-1+ CD8 T cells drove IFNγ-dependent increases in PD-L1 on skin myeloid cells. Blockade of PD-1 or PD-1/CTLA-4 led to post-transcriptional upregulation of effector proteins by antigen-specific CD8 T cells and elimination of antigen-expressing epithelial cells, resulting in localized tissue pathology with features of human cutaneous irAEs. This data supports the hypothesis that myeloid cells in healthy skin prevent pathology from self-reactive effector CD8 T cells through the PD-1/PD-L1 pathway.
Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington’s disease progression
Authors: Sönmez Aynur , Mustafa Rasem , Ryll Salome T. , Tuorto Francesca , Wacheul Ludivine , Ponti Donatella , Litke Christian , Hering Tanja , Kojer Kerstin , Koch Jenniver , Pitzer Claudia , Kirsch Joachim , Neueder Andreas , Kreiner Grzegorz , Lafontaine Denis L.J. , Orth Michael , Liss Birgit , Parlato Rosanna 
Published: July 2021

AbstractTranscriptional and cellular stress surveillance deficits are hallmarks of Huntington’s disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT)gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiologyin vivois elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusionsin vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.
Effects of blue monochromatic light directed at one eye of pregnant horse mares on gestation, parturition and foal maturity
Authors: Lutzer Anne , Nagel Christina , Murphy Barbara A. , Aurich Jörg , Wulf Manuela , Gautier Camille , Aurich Christine 
Published: July 2021

AbstractBlue light directed at one eye advances the equine ovulatory season but can also advance foaling. In this study, effects of blue LED light on pregnancy outcome were assessed. Twenty mares with singleton pregnancies were studied over two consecutive years in a cross-over design. In one year, mares received an extended photoperiod using 50 lux of blue LED light (468 nm) directed at a single eye from 08:00 until 23:00 daily via head-worn light masks starting mid-December and in the other year remained untreated as controls. Gestation was shorter in blue LED light-treated (333.2±1.0 days,±SEM) than in control pregnancies (337.9±1.8 days, p<0.05). Colostral IgG content was lower in treated than in control pregnancies (p<0.05) but was adequate to ensure sufficient IgG transfer to newborn foals with a single exception. Foals born to blue LED light-treated mares had lower wither heights (102.5±1.1 vs. 105.2±1.0 cm, p<0.01), similar weights (55.0±1.3 vs. 55.5±1.1 kg) and took less time to stand after birth than control foals (39±3 vs. 56±4 min, p<0.05). The neutrophil/lymphocyte ratio, was higher in foals born to blue LED light-treated mares than controls (3.2±0.2 vs. 2.7±0.2; p<0.05). Foals born to blue LED light-treated mares had reduced hair length compared to controls (13.1±0.8 vs. 20.9±0.1 mm; p<0.001) and hair regrowth in treated mares was reduced (p<0.05). Maternal plasma prolactin concentration was increased in treated mares (p=0.05) and peaked at foaling (p<0.001). In conclusion, blue LED light directed at one eye advanced foaling and influenced height, hair coat and maturity in foals.
TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus
Authors: Jayaraman Anusha , Htike Thein Than , James Rachel , Picon Carmen , Reynolds Richard 
Published: July 2021

AbstractThe pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3+ and phosphoMLKL+ neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.
Sphingolipids are involved in Pieris brassicae egg-induced cell death in Arabidopsis thaliana
Authors: Groux Raphaël , Fouillen Laetitia , Mongrand Sébastien , Reymond Philippe 
Published: July 2021

AbstractIn Brassicaceae, hypersensitive-like (HR-like) cell death is a central component of direct defenses triggered against eggs of the large white butterfly Pieris brassicae. The signaling pathway leading to HR-like in Arabidopsis is mainly dependent on salicylic acid (SA) accumulation, but downstream components are unclear. Here, we found that treatment with P. brassicae egg extract (EE) trigger changes in expression of sphingolipid metabolism genes in Arabidopsis and Brassica nigra. Disruption of ceramide synthase activity led to a significant decrease of EE-induced HR-like whereas SA signaling and reactive oxygen species levels were unchanged, suggesting that ceramides are downstream activators of HR-like. Sphingolipid quantifications showed that ceramides with C16:0 side-chains accumulated in both species, and this response was independent on SA accumulation. Finally, we provide genetic evidence that the modification of fatty acyl chains of sphingolipids modulates HR-like. Altogether, these results show that sphingolipids play a key and specific role during insect egg-triggered HR-like.
An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function
Authors: Steenwyk Jacob L. , Phillips Megan A. , Yang Feng , Date Swapneeta S. , Graham Todd R. , Berman Judith , Hittinger Chris Todd , Rokas Antonis 
Published: July 2021

AbstractOrthologous gene coevolution—which refers to gene pairs whose evolutionary rates covary across speciation events—is often observed among functionally related genes. We present a comprehensive gene coevolution network inferred from the examination of nearly three million orthologous gene pairs from 332 budding yeast species spanning ∼400 million years of eukaryotic evolution. Modules within the network provide insight into cellular and genomic structure and function, such as genes functioning in distinct cellular compartments and DNA replication. Examination of the phenotypic impact of network perturbation across 14 environmental conditions using deletion mutant data from the baker’s yeast Saccharomyces cerevisiae suggests that fitness in diverse environments is impacted by orthologous gene neighborhood and connectivity. By mapping the network onto the chromosomes of S. cerevisiae and the opportunistic human pathogen Candida albicans, which diverged ∼235 million years ago, we discovered that coevolving orthologous genes are not clustered in either species; rather, they are most often located on different chromosomes or far apart on the same chromosome. The budding yeast coevolution network captures the hierarchy of eukaryotic cellular structure and function, provides a roadmap for genotype-to-phenotype discovery, and portrays the genome as an extensively linked ensemble of genes.
Contribution of Uremia to Ureaplasma-Induced Hyperammonemia
Authors: Fleming Derek , Patel Robin 
Published: July 2021

AbstractLung transplant recipients (LTRs) are vulnerable to unexplained hyperammonemia syndrome (HS) in the early post-operative period, a condition typically unresponsive to non-antibiotic interventions. Recently, we showed that HS in LTRs is strongly correlated with Ureaplasma infection of the respiratory tract. It is not well-understood what makes LTRs preferentially susceptible to this phenomenon, compared to other immunocompromised hosts. Ureaplasma species harbor highly active ureases that convert urea to ammonia and CO2, utilizing the generated transmembrane potential to synthesize ATP. Post-operative LTRs commonly experience renal failure, resulting in uremia. We hypothesized that uremia could be a potentiating comorbidity to the development of HS secondary to Ureaplasma infection in LTRs by providing increased substrate for ureaplasmal ureases. We designed a novel dialyzed flow system to test the ammonia producing capacity of four isolates of Ureaplasma parvum and six isolates of Ureaplasma urealyticum in media formulations relating to normal and uremic host conditions. For all isolates, growth under uremic conditions resulted in significantly increased ammonia production over 24 hours, despite similar end-point bacterial quantities. Specifically, the isolates produced, on average, 1776.52 [standard deviation=263.98] μmol/L more ammonia when grown under uremic compared to normal conditions. This suggests that uremia, common in early post-operative LTRs, is a plausible contributing factor to the phenomenon of Ureaplasma-induced HS in this patient population.
Minimal synthetic enhancers reveal control of the probability of transcriptional engagement and its timing by a morphogen gradient
Authors: Reimer Armando , Alamos Simon , Westrum Clay , Turner Meghan A. , Talledo Paul , Zhao Jiaxi , Garcia Hernan G 
Published: July 2021

AbstractHow enhancers interpret morphogen gradients to generate spatial patterns of gene expression is a central question in developmental biology. Although recent studies have begun to elucidate that enhancers can dictate whether, when, and at what rate a promoter will engage in transcription, the complexity of endogenous enhancers calls for theoretical models with too many free parameters to quantitatively dissect these regulatory strategies. To overcome this limitation, we established a minimal synthetic enhancer system in embryos of the fruit 2y Drosophila melanogaster. Here, a gradient of the Dorsal activator is read by a single Dorsal binding site. By quantifying transcriptional activity using live imaging, our experiments revealed that this single Dorsal binding site is capable of regulating whether promoters engage in transcription in a Dorsal concentration-speci1c manner. By modulating binding-site aZnity, we determined that a gene’s decision to engage in transcription and its transcriptional onset time can be explained by a simple theoretical model where the promoter has to traverse multiple kinetic barriers before transcription can ensue. The experimental platform developed here pushes the boundaries of live-imaging in studying gene regulation in the early embryo by enabling the quanti1cation of the transcriptional activity driven by a single transcription factor binding site, and making it possible to build more complex enhancers from the ground up in the context of a dialogue between theory and experiment.
Borgs are giant extrachromosomal elements with the potential to augment methane oxidation
Authors: Al-Shayeb Basem , Schoelmerich Marie C. , West-Roberts Jacob , Valentin-Alvarado Luis E. , Sachdeva Rohan , Mullen Susan , Crits-Christoph Alexander , Wilkins Michael J. , Williams Kenneth H. , Doudna Jennifer A. , Banfield Jillian F. 
Published: July 2021

SummaryAnaerobic methane oxidation exerts a key control on greenhouse gas emissions1, yet factors that modulate the activity of microorganisms performing this function remain little explored. In studying groundwater, sediments, and wetland soil where methane production and oxidation occur, we discovered extraordinarily large, diverse DNA sequences that primarily encode hypothetical proteins. Four curated, complete genomes are linear, up to ~1 Mbp in length and share genome organization, including replicore structure, long inverted terminal repeats, and genome-wide unique perfect tandem direct repeats that are intergenic or generate amino acid repeats. We infer that these are a new type of archaeal extrachromosomal element with a distinct evolutionary origin. Gene sequence similarity, phylogeny, and local divergence of sequence composition indicate that many of their genes were assimilated from methane-oxidizingMethanoperedensarchaea. We refer to these elements as “Borgs”. We identified at least 19 different Borg types coexisting withMethanoperedensin four distinct ecosystems. Borg genes expand redox and respiratory capacity (e.g., clusters of multiheme cytochromes), ability to respond to changing environmental conditions, and likely augmentMethanoperedenscapacity for methane oxidation (e.g., methyl coenzyme M reductase). By this process, Borgs could play a previously unrecognized role in controlling greenhouse gas emissions.
Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death
Authors: Arif Waqar , Mathur Bhoomika , Saikali Michael F. , Chembazhi Ullas V. , Blue Steven M. , Yee Brian A. , Van Nostrand Eric L. , Bangru Sushant , Hao Qinyu , Yeo Gene W. , Prasanth Kannanganattu V. , Anakk Sayeepriyadarshini , Cummins Carolyn L. , Kalsotra Auinash 
Published: July 2021

AbstractRegulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver failure.
A mouse-adapted SARS-CoV-2 strain replicating in standard laboratory mice
Authors: Montagutelli Xavier , Prot Matthieu , Jouvion Grégory , Levillayer Laurine , Conquet Laurine , Reyes-Gomez Edouard , Donati Flora , Albert Melanie , van der Werf Sylvie , Jaubert Jean , Simon-Lorière Etienne 
Published: July 2021

AbstractSARS-CoV-2 has infected almost 200 million humans and caused over 4 million deaths worldwide. Evaluating countermeasures and improving our understanding of COVID-19 pathophysiology require access to animal models that replicate the hallmarks of human disease. Mouse infection with SARS-CoV-2 is limited by poor affinity between the virus spike protein and its cellular receptor ACE2. We have developed by serial passages the MACo3 virus strain which efficiently replicates in the lungs of standard mouse strains and induces age-dependent lung lesions. Compared to other mouse-adapted strains and severe mouse models, infection with MACo3 results in mild to moderate disease and will be useful to investigate the role of host genetics and other factors modulating COVID-19 severity.