bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness
Authors: Nichenko Anna S. , Sorensen Jacob R. , Southern W. Michael , Qualls Anita E. , Schifino Albino G. , McFaline-Figueroa Jennifer , Blum Jamie E. , Thalacker-Mercer Anna E. , Greising Sarah M. , Call Jarrod A. 
Published: August 2020

AbstractThe accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of sarcopenia resulting in reduced contractile and metabolic function. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. We found that Ulk1 phosphorylation declines in both human and mouse muscle tissue with age, therefore the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% survival rate), muscle contractile and metabolic function were assessed using electrophysiology in muscle specific Ulk1 knockout mice (MKO) and their littermate controls (LM). Specific peak-isometric torque of the ankle dorsiflexors (normalized by tibialis anterior muscle cross-sectional area) and specific force of the fast-twitch extensor digitorum longus muscles were reduced in MKO mice compared to LM mice (p<0.03). Permeabilized muscle fibers from MKO mice had greater mitochondrial content, yet lower mitochondrial oxygen consumption and greater reactive oxygen species production compared to fibers from LM mice (p≤ 0.04). Altered neuromuscular junction innervation patterns and changes in autophagosome numbers and/or flux in muscles from MKO may have contributed to decrements in contractile and metabolic function. Results from this study support an important role of Ulk1-mediated autophagy in skeletal muscle with age, reflecting Ulk1’s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation. A lifetime of insufficient Ulk-1-mediated autophagy in skeletal muscle exacerbates age-related contractile and metabolic dysfunction.
α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
Authors: Eichmann Cédric , Jacob Reeba Susan , Dema Alessandro , Mercadante Davide , Selenko Philipp 
Published: August 2020

AbstractThe Parkinson’s disease protein α-synuclein (αSyn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of αSyn are poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), two highly acidic components of inner PM leaflets, mediate plasma membrane localization of endogenous pools of αSyn in A2780, HeLa, SH-SY5Y and SK-MEL-2 cells. We demonstrate that αSyn binds reconstituted PIP2-membranes in a helical conformationin vitroand that PIP2synthesizing kinases and hydrolyzing phosphatases reversibly redistribute αSyn in cells. We further delineate that αSyn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP2and PIP3levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn’s cellular function(s) at the plasma membrane.
A protease-mediated mechanism regulates the cytochromec6/ plastocyanin switch inSynechocystissp. PCC 6803
Authors: García-Cañas Raquel , Giner-Lamia Joaquín , Florencio Francisco J. , López-Maury Luis 
Published: August 2020

AbstractAfter the Great Oxidation Event (GOE), iron availability was greatly decreased and photosynthetic organisms evolved several alternative proteins and mechanisms. One of these proteins, plastocyanin, is a type I blue-copper protein that can replace cytochromec6as a soluble electron carrier between cytochromeb6fand photosystem I. In most cyanobacteria, expression of these two alternative proteins is regulated by copper availability, but the regulatory system remains unknown. Herein, we provide evidence that the regulatory system is composed of a BlaI/CopY family transcription factor (PetR) and a BlaR membrane protease (PetP). PetR repressespetE(plastocyanin) expression and activatespetJ(cytochromec6), while PetP controls PetR levelsin vivo. Using whole-cell extracts, we demonstrated that PetR degradation requires both PetP and copper. Transcriptomic analysis revealed that the PetRP system regulates only four genes (petE,petJ,slr0601, andslr0602), highlighting its specificity. Furthermore, the presence ofpetEandpetRPin early branching cyanobacteria indicates that acquisition of these genes could represent an early adaptation to decreased iron bioavailability following the GOE.Significance StatementAfter the appearance of oxygenic photosynthesis, Fe became oxidized and its solubility and availability were greatly decreased. This generated a problem for most organisms since they are strongly dependent on Fe, especially photosynthetic organisms. In response, organisms evolved alternatives to Fe-containing proteins such as plastocyanin, a copper protein that substitutes for cytochromec6in photosynthesis. Expression of these two proteins in cyanobacteria is regulated by Cu availability, but the regulatory system remains unknown. Herein, we describe the regulatory system for these alternative proteins in photosynthesis in cyanobacteria. The mechanism involves a transcription factor (PetR) and a membrane protease (PetP) that degrades PetR in the presence of Cu.
Independent mechanisms of temporal and linguistic cue correspondence benefiting audiovisual speech processing
Authors: Fiscella Sara , Cappelloni Madeline S , Maddox Ross K 
Published: August 2020

ABSTRACTWhen listening is difficult, seeing the face of the talker aids speech comprehension. Faces carry both temporal (low-level physical correspondence of mouth movement and auditory speech) and linguistic (learned physical correspondences of mouth shape (viseme) and speech sound (phoneme)) cues. Listeners participated in two experiments investigating how these cues may be used to process sentences when maskers are present. In Experiment I, faces were rotated to disrupt linguistic but not temporal cue correspondence. Listeners suffered a deficit in speech comprehension when the faces were rotated, indicating that visemes are processed in a rotation-dependent manner, and that linguistic cues aid comprehension. In Experiment II, listeners were asked to detect pitch modulation in the target speech with upright and inverted faces that either matched the target or masker speech such that performance differences could be explained by binding, an early multisensory integration mechanism distinct from traditional late integration. Performance in this task replicated previous findings that temporal integration induces binding, but there was no behavioral evidence for a role of linguistic cues in binding. Together these experiments point to temporal cues providing a speech processing benefit through binding and linguistic cues providing a benefit through late integration.
A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling
Authors: Li Haiyan , Bagué Tyler , Kirschner Alexander , Weisenthal Robert W. , Patteson Alison E. , Annabi Nasim , Stamer W. Daniel , Ganapathy Preethi S. , Herberg Samuel 
Published: August 2020

AbstractPurposeAbnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG). Most current cellular HTM model systems do not sufficiently replicate the complex native three dimensional (3D) cell-ECM interface, which makes them less than ideal to investigate POAG pathology. Tissue-engineered protein-based hydrogels are ideally positioned to overcome shortcomings of current models. Here, we report a novel biomimetic HTM hydrogel and test its utility as a POAG disease model.MethodsHTM hydrogels were engineered by mixing normal donor-derived HTM cells with collagen type I, elastin-like polypeptide and hyaluronic acid, each containing photoactive functional groups, followed by UV light-activated free-radical crosslinking. Glaucomatous conditions were induced with dexamethasone (DEX), and therapeutic effects of the Rho-associated kinase (ROCK) inhibitor Y27632 on cytoskeletal organization and tissue-level function, contingent on HTM cell-ECM interactions, were assessed.ResultsDEX exposure increased HTM hydrogel contractility, f-actin and alpha smooth muscle actin abundance and rearrangement, ECM remodeling, and fibronectin and collagen type IV deposition, all contributing to HTM hydrogel condensation and stiffening consistent with recent data from normal vs. glaucomatous HTM tissue. Y27632 treatment produced precisely the opposite effects and attenuated the DEX-induced pathologic changes, resulting in HTM hydrogel relaxation and softening.ConclusionsWe have developed a biomimetic HTM hydrogel model for detailed investigation of 3D cell-ECM interactions under normal and simulated glaucomatous conditions. Its bidirectional responsiveness to pharmaceutical challenge and rescue suggests promising potential to serve as screening platform for new POAG treatments with focus on HTM biomechanics.
Cohesin in space and time: architecture and oligomerizationin vivo
Authors: Xiang Siheng , Koshland Douglas 
Published: August 2020

AbstractCohesin helps mediate sister chromatid cohesion, chromosome condensation, DNA repair and transcription regulation. Cohesin can tether two regions of DNA and can also extrude DNA loops. We interrogated cohesin architecture, oligomerization state and function of cohesin oligomersin vivothrough proximity-dependent labeling of cohesin domains. Our results suggest that the hinge and head domains of cohesin both bind DNA, and that cohesin coiled coils bend, bringing the head and hinge together to form a butterfly conformation. Our data also suggest that cohesin efficiently oligomerizes on and off DNA. The levels of oligomers and their distribution on chromosomes are cell cycle regulated. Cohesin oligomerization is blocked by mutations in distinct domains of Smc3p and Mcd1p, or depletion of Pds5p. This unusual subset of mutations specifically blocks the maintenance of cohesion and condensation, suggesting that cohesin oligomerization plays a critical role in these biological functions.
Effect of β-chitosan on the binding interaction between SARS-CoV-2 S-RBD and ACE2
Authors: Alitongbieke Gulimiran , Li Xiu-min , Wu Qi-Ci , Lin Zhi-Chao , Huang Jia-Fu , Xue Yu , Liu Jing-Na , Lin Jin-Mei , Pan Tao , Chen Yi-Xuan , Su Yi , Zhang Guo-Guang , Leng Bo , Liu Shu-Wen , Pan Yu-Tian 
Published: August 2020

ABSTRACTSARS-CoV-2 invades human respiratory epithelial cells via an interaction between its spike RBD protein (SARS-CoV-2 S-RBD) and the host cell receptor angiotensin converting enzyme II (ACE2). Blocking this interaction provides a potent approach to preventing and controlling SARS-CoV-2 infection. In this work, the ability of β-chitosan to block the binding interaction between SARS-CoV-2 S-RBD and ACE2 was investigated. The inhibitory effect of β-chitosan on inflammation induced by the SARS-CoV-2 S-RBD was also studied. Native-PAGE analysis indicated that β-chitosan could bind with ACE2 and the SARS-CoV-2 S-RBD and a conjugate of β-chitosan and ACE2 could no longer bind with the SARS-CoV-2 S-RBD. HPLC analysis suggested that a conjugate of β-chitosan and the SARS-CoV-2 S-RBD displayed high binding affinity without dissociation under high pressure (40 MPa) compared with that of β-chitosan and ACE2. Furthermore, immunofluorescent staining of Vero E6 cells and lungs from hACE2 mice showed that the presence of β-chitosan prevented SARS-CoV-2 S-RBD from binding to ACE2. Meanwhile, β-chitosan could dramatically suppress the inflammation caused by the presence of the SARS-CoV-2 S-RBD bothin vitroandvivo. Moreover, the decreased expression of ACE2 caused by β-chitosan treatment was restored by addition of TAPI-1, an inhibitor of the transmembrane protease ADAM17. Our findings demonstrated that β-chitosan displays an antibody-like function capable of neutralizing the SARS-CoV-2 S-RBD and effectively preventing the binding of the SARS-CoV-2 S-RBD to ACE2. Moreover, ADAM17 activation induced by β-chitosan treatment can enhance the cleavage of the extracellular domain of ACE2, releasing the active ectodomain into the extracellular environment, which can prevent the binding, internalization, and degradation of ACE2 bound to the SARS-CoV-2 S-RBD and thus diminish inflammation. Our study provides an alternative avenue for preventing SARS-CoV-2 infection using β-chitosan.
CD20 as a gatekeeper of the resting stage of human B cells
Authors: Kläsener Kathrin , Jellusova Julia , Andrieux Geoffroy , Salzer Ulrich , Böhler Chiara , Steiner Sebastian N. , Albinus Jonas B. , Cavallari Marco , Süß Beatrix , Boerries Melanie , Voll Reinhard E. , Wollscheid Bernd , Reth Michael 
Published: August 2020

AbstractCD20 is a B cell specific membrane protein and a target of therapeutic antibodies such as rituximab (RTX)1. In spite of the prominent usage of anti-CD20 antibodies in the clinic little is known about the biological function of CD202. Here we show that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. A CRISPR/Cas-based ablation of CD20 in Ramos B cells results in a relocalisation of the IgM B cell antigen receptor (IgM-BCR) and the co-receptor CD19. The resulting IgM-BCR/CD19 signaling synapse leads to transient B cell activation followed by plasma cell differentiation. Similarly to CD20-deficient Ramos cells, naïve human B cells treated with rituximab in vitro or isolated from patients during rituximab administration display hallmarks of transient activation characterized by the formation of the IgM-BCR/CD19 signaling synapse, followed by CD19 and IgM-BCR downregulation. Moreover, increased expression of specific plasma cell genes can be observed after rituximab treatment in relapsed CLL patients. In summary we identify CD20 as a gatekeeper of the resting state on human B cells and demonstrate that a disruption of the nanoscale organization of the B cell surface via CD20 deletion or anti-CD20 treatment profoundly alters B cell fate.
A collaborative resource platform for non-human primate neuroimaging
Authors: Messinger Adam , Sirmpilatze Nikoloz , Heuer Katja , Loh Kep Kee , Mars Rogier B. , Sein Julien , Xu Ting , Glen Daniel , Jung Benjamin , Seidlitz Jakob , Taylor Paul , Toro Roberto , Garza-Villarreal Eduardo A. , Sponheim Caleb , Wang Xindi , Benn R. Austin , Cagna Bastien , Dadarwal Rakshit , Evrard Henry C. , Garcia-Saldivar Pamela , Giavasis Steven , Hartig Renée , Lepage Claude , Liu Cirong , Majka Piotr , Merchant Hugo , Milham Michael P. , Rosa Marcello G.P. , Tasserie Jordy , Uhrig Lynn , Margulies Daniel S. , Klink P. Christiaan 
Published: August 2020

AbstractNeuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field.
Multiplex-GAM: genome-wide identification of chromatin contacts yields insights not captured by Hi-C
Authors: Beagrie Robert A. , Thieme Christoph J. , Annunziatella Carlo , Baugher Catherine , Zhang Yingnan , Schueler Markus , Kukalev Alexander , Kempfer Rieke , Chiariello Andrea M. , Bianco Simona , Li Yichao , Scialdone Antonio , Welch Lonnie R. , Nicodemi Mario , Pombo Ana 
Published: August 2020

SummaryTechnologies for measuring 3D genome topology are increasingly important for studying mechanisms of gene regulation, for genome assembly and for mapping of genome rearrangements. Hi-C and other ligation-based methods have become routine but have specific biases. Here, we develop multiplex-GAM, a faster and more affordable version of Genome Architecture Mapping (GAM), a ligation-free technique to map chromatin contacts genome-wide. We perform a detailed comparison of contacts obtained by multiplex-GAM and Hi-C using mouse embryonic stem (mES) cells. We find that both methods detect similar topologically associating domains (TADs). However, when examining the strongest contacts detected by either method, we find that only one third of these are shared. The strongest contacts specifically found in GAM often involve “active” regions, including many transcribed genes and super-enhancers, whereas in Hi-C they more often contain “inactive” regions. Our work shows that active genomic regions are involved in extensive complex contacts that currently go under-estimated in genome-wide ligation-based approaches, and highlights the need for orthogonal advances in genome-wide contact mapping technologies.
Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription
Authors: Arnaiz Esther , Miar Ana , Dias Antonio Gregorio , Prasad Naveen , Schulze Ulrike , Waithe Dominic , Rehwinkel Jan , Harris Adrian L. 
Published: August 2020

ABSTRACTHypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.
Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis
Authors: Xu Hongzhen , Tong Lin , Gao Peng , Hu Yan , Wang Huijuan , Chen Zhimin , Fang Luo 
Published: August 2020

AbstractBackgroundA combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice.ObjectiveTo evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents.MethodsThe MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the date of database inception to 02/09/2019 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO.ResultsOf the 637 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66–0.95; p = 0.01; I2= 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.71; 95% CI 0.60–0.85; p = 0.0001; I2= 0%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50–0.96; p = 0.03; I2= 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63–4.98).ConclusionIB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. Future prospective research on these subgroup population are needed.
MASSpy: Building, simulating, and visualizing dynamic biological models in Python using mass action kinetics
Authors: Haiman Zachary B. , Zielinski Daniel C. , Koike Yuko , Yurkovich James T. , Palsson Bernhard O. 
Published: August 2020

AbstractMathematical models of metabolic networks utilize simulation to study system-level mechanisms and functions. Various approaches have been used to model the steady state behavior of metabolic networks using genome-scale reconstructions, but formulating dynamic models from such reconstructions continues to be a key challenge. Here, we present the Mass Action Stoichiometric Simulation Python (MASSpy) package, an open-source computational framework for dynamic modeling of metabolism. MASSpy utilizes mass action kinetics and detailed chemical mechanisms to build dynamic models of complex biological processes. MASSpy adds dynamic modeling tools to the COnstraint-Based Reconstruction and Analysis Python (COBRApy) package to provide an unified framework for constraint-based and kinetic modeling of metabolic networks. MASSpy supports high-performance dynamic simulation through its implementation of libRoadRunner; the Systems Biology Markup Language (SBML) simulation engine. Three case studies demonstrate how to use MASSpy: 1) to simulate dynamics of detailed mechanisms of enzyme regulation; 2) to generate an ensemble of kinetic models using Monte Carlo sampling to approximate missing numerical values of parameters and to quantify uncertainty, and 3) to overcome issues that arise when integrating experimental data with the computation of functional states of detailed biological mechanisms. MASSpy represents a powerful tool to address challenge that arise in dynamic modeling of metabolic networks, both at a small and large scale.Author SummaryGenome-scale reconstructions of metabolism appeared shortly after the first genome sequences became available. Constraint-based models are widely used to compute steady state properties of such reconstructions, but the attainment of dynamic models has remained elusive. We thus developed the MASSpy software package, a framework that enables the construction, simulation, and visualization of dynamic metabolic models. MASSpy is based on the mass action kinetics for each elementary step in an enzymatic reaction mechanism. MASSpy seamlessly unites existing software packages within its framework to provide the user with various modeling tools in one package. MASSpy integrates community standards to facilitate the exchange of models, giving modelers the freedom to use the software for different aspects of their own modeling workflows. Furthermore, MASSpy contains methods for generating and simulating ensembles of models, and for explicitly accounting for biological uncertainty. MASSpy has already demonstrated success in a classroom setting. We anticipate that the suite of modeling tools incorporated into MASSpy will enhance the ability of the modeling community to construct and interrogate complex dynamic models of metabolism.