Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Dynamics Revealing a Detour-Forward Release Mechanism of Tacrine: Implication for the Specific Binding Characteristics in Butyrylcholinesterase

Butyrylcholinesterase (BChE) is a non-specific enzyme with clinical pharmacological and toxicological significance, which was a renewed interest as therapeutic target in Alzheimer's disease (AD) nowadays. Here, all-atom molecular dynamics simulations of butyrylcholinesterase with tacrine complex were designed to characterize inhibitor binding modes, strengths, and the hydrogen-bond dependent non-covalent release mechanism. Four possible release channels were identified, and the most favorable channel was determined by random acceleration molecular dynamics molecular dynamics (RAMD MD) simulations. The thermodynamic and dynamic properties as well as the corresponding Detour-forward delivery mechanism were determined according to the classical molecular dynamics (MD) simulations accompanied with umbrella sampling. The free energy barrier of the tacrine release process for the most beneficial pathway is about 10.95 kcal/mol, which is related to the non-covalent interactions from the surrounding residues, revealing the specific binding characteristics in the active site. The residues including Asp70, Ser79, Trp82, Gly116, Thr120, Tyr332, and His438 were identified to play major roles in the stabilization of tacrine in the pocket of BChE, where hydrogen bonding and π-π interactions are significant factors. Tyr332 and Asp70, which act as gate keepers, play crucial roles in the substrate delivery. The present results provide a basic understanding for the ligand transport mechanism depending on the BChE enzymatic environment, which is useful for the design of BChE inhibitors in the future.
The Anti-apoptotic Murine Cytomegalovirus Protein vMIA-m38.5 Induces Mast Cell Degranulation

Mast cells (MC) represent “inbetweeners” of the immune system in that they are part of innate immunity by acting as first-line sentinels for environmental antigens but also provide a link to adaptive immunity by secretion of chemokines that recruit CD8 T cells to organ sites of infection. An interrelationship between MC and cytomegalovirus (CMV) has been a blank area in science until recently when the murine model revealed a role for MC in the resolution of pulmonary infection by murine CMV (mCMV). As to the mechanism, MC were identified as a target cell type of mCMV. Infected MC degranulate and synthesize the CC-chemokine ligand-5 (CCL-5), which is released to attract protective virus-specific CD8 T cells to infected host tissue for confining and eventually resolving the productive, cytopathogenic infection. In a step forward in our understanding of how mCMV infection of MC triggers their degranulation, we document here a critical role for the mCMV m38.5 gene product, a mitochondria-localized inhibitor of apoptosis (vMIA). We show an involvement of mCMV vMIA-m38.5 in MC degranulation by two reciprocal approaches: first, by enhanced degranulation after m38.5 gene transfection of bone marrow-derived cell culture-grown MC (BMMC) and, second, by reduced degranulation of MC in peritoneal exudate cell populations infected ex corpore or in corpore with mutant virus mCMV-Δm38.5. These studies thus reveal a so far unknown function of mCMV vMIA-m38.5 and offer a previously unconsidered but biologically relevant cell system for further analyzing functional analogies between vMIAs of different CMV species.
A Decade of mTBI Experience: What Have We Learned? A Summary of Proceedings From a NATO Lecture Series on Military mTBI

Mild traumatic brain injury (mTBI, also known as a concussion) as a consequence of battlefield blast exposure or blunt force trauma has been of increasing concern to militaries during recent conflicts. This concern is due to the frequency of exposure to improvised explosive devices for forces engaged in operations both in Iraq and Afghanistan coupled with the recognition that mTBI may go unreported or undetected. Blasts can lead to mTBI through a variety of mechanisms. Debate continues as to whether exposure to a primary blast wave alone is sufficient to create brain injury in humans, and if so, exactly how this occurs with an intact skull. Resources dedicated to research in this area have also varied substantially among contributing NATO countries. Most of the research has been conducted in the US, focused on addressing uncertainties in management practices. Development of objective diagnostic tests should be a top priority to facilitate both diagnosis and prognosis, thereby improving management. It is expected that blast exposure and blunt force trauma to the head will continue to be a potential source of injury during future conflicts. An improved understanding of the effects of blast exposure will better enable military medical providers to manage mTBI cases and develop optimal protective measures. Without the immediate pressures that come with a high operational tempo, the time is right to look back at lessons learned, make full use of available data, and modify mitigation strategies with both available evidence and new evidence as it comes to light. Toward that end, leveraging our cooperation with the civilian medical community is critical because the military experience over the past 10 years has led to a renewed interest in many similar issues pertaining to mTBI in the civilian world. Such cross-fertilization of knowledge will undoubtedly benefit all. This paper highlights similarities and differences in approach to mTBI patient care in NATO and partner countries and provides a summary of and lessons learned from a NATO lecture series on the topic of mTBI, demonstrating utility of having patients present their experiences to a medical audience, linking practical clinical care to policy approaches.
Variable Branching Characteristics of Peripheral Taste Neurons Indicates Differential Convergence

Taste neurons are functionally and molecularly diverse, but their morphologic diversity remains completely unexplored. Using sparse cell genetic labeling, we provide the first reconstructions of peripheral taste neurons. The branching characteristics across 96 taste neurons show surprising diversity in their complexities. Individual neurons had 1–17 separate arbors entering between one and seven taste buds, 18 of these neurons also innervated non-taste epithelia. Axon branching characteristics are similar in gustatory neurons from male and female mice. Cluster analysis separated the neurons into four groups according to branch complexity. The primary difference between clusters was the amount of the nerve fiber within the taste bud available to contact taste-transducing cells. Consistently, we found that the maximum number of taste-transducing cells capable of providing convergent input onto individual gustatory neurons varied with a range of 1–22 taste-transducing cells. Differences in branching characteristics across neurons indicate that some neurons likely receive input from a larger number of taste-transducing cells than other neurons (differential convergence). By dividing neurons into two groups based on the type of taste-transducing cell most contacted, we found that neurons contacting primarily sour transducing cells were more heavily branched than those contacting primarily sweet/bitter/umami transducing cells. This suggests that neuron morphologies may differ across functional taste quality. However, the considerable remaining variability within each group also suggests differential convergence within each functional taste quality. Each possibility has functional implications for the system. SIGNIFICANCE STATEMENT Taste neurons are considered relay cells, communicating information from taste-transducing cells to the brain, without variation in morphology. By reconstructing peripheral taste neuron morphologies for the first time, we found that some peripheral gustatory neurons are simply branched, and can receive input from only a few taste-transducing cells. Other taste neurons are heavily branched, contacting many more taste-transducing cells than simply branched neurons. Based on the type of taste-transducing cell contacted, branching characteristics are predicted to differ across (and within) quality types (sweet/bitter/umami vs sour). Therefore, functional differences between neurons likely depends on the number of taste-transducing cells providing input and not just the type of cell providing input.
Theta and alpha power across fast and slow timescales in cognitive control

Theta and alpha frequency neural oscillations are important for learning and cognitive control, but their exact role has remained obscure. In particular, it is unknown whether they operate at similar timescales, and whether they support different cognitive processes. We recorded EEG in 30 healthy human participants while they performed a procedural learning task containing both (block-unique) novel and repeating stimuli. Learning occurred at two timescales (fast and slow). Behaviorally, both response time and accuracy improved (resp. decrease and increase) over both fast and slow timescales. However, on the spectral level, theta power significantly decreased along the slow timescale, whereas alpha power instead significantly increased along the fast timescale. We thus demonstrate that theta and alpha both play a role during learning, but operate at different timescales. This result poses important empirical constraints for theories on learning, cognitive control, and neural oscillations. Author Note We have no known conflict of interest to disclose.
Mutually Beneficial Symbiosis Between Human and Gut-Dominant Bacteroides Species Through Bacterial Assimilation of Host Mucosubstances

The composition of gut microbiota is influenced by the quantity and type of nutrients in host. Even with some Bacteroides species being categorized as pathogens, Bacteroides is one of the most dominant gut bacteria. Here we indicate the physiological determinants of the species of Bacteroides for being dominant in human gut microbiota. Each of the host extracellular mucosubstances including glycosaminoglycans (GAGs) and mucin has grown human gut microbiota. In spite of the differences among initial microbiota profiles, Bacteroides species dominated the community when GAG (e.g., chondroitin sulfate or hyaluronan) was used as a sole carbon source. In fact, GAGs and the Bacteroides genes which are vital for the degradation of GAGs were commonly detected in human feces. Mucin has encouraged the growth of Bacteroides and several other genera. A comprehensive analysis on the degradation and assimilation of mucosubstances by the genus Bacteroides using around 30 species has shown that most species degrade and assimilate GAGs and mucin, showing that Bacteroides species can survive even in the undernutrition condition including the fasting state. In the assimilation of GAG or mucin, Bacteroides species significantly secreted essential amino acids, γ-amino butyrate (GABA), and/or short-chain fatty acids which are needed for human health. This is the first report as regards mutually beneficial interaction between human and Bacteroides species via bacterial assimilation of host mucosubstances and secretion of metabolites for host health promotion. Significance The genus Bacteroides is one of the most dominant gut bacteria, although its beneficial effects on human health have not been well understood. Here, we show modes of action in human-Bacteroides interrelationship. Mucosubstances including GAGs and mucin secreted by human host are abundant in gut for microbiota to grow well. Bacteroides species are dominant in the community in the presence of GAGs, and provide human host with a considerable amount of essential amino acids, γ-amino butyrate, and short-chain fatty acids produced from mucosubstances. These results postulate mutually beneficial symbiosis system between human and Bacteroides through bacterial assimilation of host mucosubstances and secretion of metabolites for human body and mental health promotion even in the undernutrition condition including the fasting state.
Evaluation of Compatibility of 16S rRNA V3V4 and V4 Amplicon Libraries for Clinical Microbiome Profiling

Sequencing of the 16S rRNA gene by Illumina next-generation sequencing is broadly used in microbiome studies. Different hypervariable regions of the 16S rRNA gene, V3V4 (amplified with primers 341F–805R) or V4 (V4O; primers 515F–806R), are selected, depending on the targeted resolution. However, in population-based clinical studies, combining V3V4 and V4 data from different studies for a meta-analysis is challenging. Reads generated by short-read (150-bp) high-throughput sequencing platforms do not fully recover the V4 region read-length. Here, we evaluated the compatibility of 16S rRNA V3V4 and V4 amplicons for microbiome profiling. We compared taxonomic compositions obtained by the analysis of V3V4 and V4 amplicons, and V4 fragments trimmed from V3V4 amplicons. We also evaluated an alternative V4 region (V4N; primers 519F–798R) designed for efficient stitching with 150-bp paired-end sequencing. First, we simulated a global investigation of environmental prokaryotes in silico. This revealed that V4O primers recovered the highest proportion of fragments (81.7%) and most phyla, including archaea. Empirical sequencing of standard (mock) and human fecal samples revealed biased patterns of each primer that were similar to the ones determined by in silico simulation. Further, for human fecal microbiome profiling, the between-sample variance was greater than the systematic bias of each primer. The use of trimmed V4 fragments and single-end amplicons resulted in the same systematic bias. In conclusion, paired-end V4O sequencing yielded the most accurate data for both, simulation and mock community sequencing; the V4O amplicons were compatible with trimmed V4 sequences for microbiome profiling. IMPORTANCE Next-generation sequencing of the 16S rRNA gene is a commonly used approach for clinical microbiome studies. Different amplicons of the 16S rRNA hypervariable regions are used in different studies, which creates incompatible sequence features when comparing and integrating data among studies by using 16S denoising pipelines. Here we compared the type of data and coverage obtained when different 16S rRNA amplicons were analyzed. In silico and empirical analyses of the human fecal microbiome revealed that the V3V4 amplicons are compatible with V4 amplicons after trimming up to the same region. These observations demonstrate that reconciling the compatibility of clinical microbiome data from different studies improve not only the sample size but also the confidence of the hypothesis tested.
DNA oxidation induced by fetal exposure to BPA agonists impairs female meiosis

Many endocrine disruptors have been proven to impair the meiotic process that is mandatory to produce healthy gametes. Bisphenol A is emblematic as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing uses of BPA analogs raise concerns for public health. Here, we investigated the effect on oogenesis in mouse of fetal exposure to two BPA analogs, Bisphenol A Diglycidyl Ether (BADGE) or Bisphenol AF (BPAF). These analogs delay meiosis initiation, increase MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by a deregulation of gene expression and aberrant mRNA splicing in fetal premeiotic germ cells. Interestingly, we observed an increase in DNA oxidation after exposure to BPA analogs. Specific induction of oxidative DNA damages during fetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-Oxoguanine DNA Glycosylase (OGG1) deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damages. Moreover, the supplementation of N-acetylcysteine (NAC) with BPA analogs counteracts the bisphenol-induced meiotic effect. Together our results position oxidative stress as a central event that negatively impacts the female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for so called endocrine disruptors pollutants and it could lead to novel strategies for reprotoxic compounds.
Astrocytic Neurexin-1 Orchestrates Functional Synapse Assembly

At tripartite synapses, astrocytes surround synaptic contacts, but how astrocytes contribute to the assembly and function of synapses remains unclear. Here we show that neurexin-1α, a presynaptic adhesion molecule that controls synapse properties, is also abundantly expressed by astrocytes. Strikingly, astrocytic neurexin-1α, but not neuronal neurexin-1α, is highly modified by heparan sulfate. Moreover, astrocytic neurexin-1α is uniquely alternatively spliced and invariably contains an insert in splice-site #4, thereby restricting the range of ligands to which it binds. Deletion of neurexin-1 from astrocytes or neurons does not alter synapse numbers or synapse ultrastructure, but differentially impairs synapse function. At hippocampal Schaffer-collateral synapses, neuronal neurexin-1 is essential for normal NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 is required for normal AMPA-receptor-mediated synaptic responses and for long-term potentiation of these responses. Thus, astrocytes directly shape synapse properties via a neurexin-1-dependent mechanism that involves a specific molecular program distinct from that of neuronal neurexin-1.
An acentriolar centrosome at the C. elegans ciliary base

In animal cells the functions of the cytoskeleton are coordinated by centriole-based centrosomes via microtubule-nucleating γ-tubulin complexes embedded in the pericentriolar material or PCM [1]. PCM assembly has been best studied in the context of mitosis, where centriolar SPD-2 recruits PLK-1, which in turn phosphorylates key scaffolding components such as SPD-5 and CNN to promote expansion of the PCM polymer [2–4]. To what extent these mechanisms apply to centrosomes in interphase or in differentiated cells remains unclear [5]. Here, we examine a novel type of centrosome found at the ciliary base of C. elegans sensory neurons, which we show plays important roles in neuronal morphogenesis, cellular trafficking and ciliogenesis. These centrosomes display similar dynamic behavior to canonical, mitotic centrosomes, with a stable PCM scaffold and dynamically localized client proteins. Unusually, however, they are not organized by centrioles, which degenerate early in terminal differentiation [6]. Yet, PCM not only persists but continues to grow with key scaffolding proteins including SPD-5 expressed under control of the RFX transcription factor DAF-19. This assembly occurs in the absence of the mitotic regulators SPD-2, AIR-1 and PLK-1, but requires tethering by PCMD-1, a protein which also plays a role in the initial, interphase recruitment of PCM in early embryos [7]. These results argue for distinct mechanisms for mitotic and non-mitotic PCM assembly, with only the former requiring PLK-1 phosphorylation to drive rapid expansion of the scaffold polymer. ETOC BLURB Centrioles play a critical role in mitotic centrosome assembly. Here, Garbrecht et al. show that pericentriolar material (PCM) persists at the ciliary base of C. elegans sensory neurons after centriole degeneration, where it contributes to neuronal morphogenesis and cellular trafficking. Remarkably, this PCM displays dynamic properties similar to canonical centrosomes, yet its continued assembly and maintenance is independent of known mitotic regulators, suggesting differential mechanisms for mitotic and non-mitotic centrosome assembly. HIGHLIGHTS PCM persists at the acentriolar ciliary base in C. elegans PCM assembles in a SPD-2, AIR-1 and PLK-1-independent manner PCMD-1 tethers PCM at the ciliary base in the absence of centrioles PCM is required for neuronal morphogenesis and cilium assembly
Rethinking glottal midline detection

A healthy voice is crucial for verbal communication and hence in daily as well as professional life. The basis for a healthy voice are the sound producing vocal folds in the larynx. A hallmark of healthy vocal fold oscillation is the symmetric motion of the left and right vocal fold. Clinically, videoendoscopy is applied to assess the symmetry of the oscillation and evaluated subjectively. High-speed videoendoscopy, an emerging method that allows quantification of the vocal fold oscillation, is more commonly employed in research due to the amount of data and the complex, semi-automatic analysis. In this study, we provide a comprehensive evaluation of methods that detect fully automatically the glottal midline. We used a biophysical model to simulate different vocal fold oscillations, extended the openly available BAGLS dataset using manual annotations, utilized both, simulations and annotated endoscopic images, to train deep neural networks at different stages of the analysis workflow, and compared these to established computer vision algorithms. We found that classical computer vision perform well on detecting the glottal midline in glottis segmentation data, but are outperformed by deep neural networks on this task. We further suggest GlottisNet, a multi-task neural architecture featuring the simultaneous prediction of both, the opening between the vocal folds and the symmetry axis, leading to a huge step forward towards clinical applicability of quantitative, deep learning-assisted laryngeal endoscopy, by fully automating segmentation and midline detection.
SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle. One-sentence summary SARS-CoV-2 ORF9c is the first human coronavirus protein localized to membrane, suppressing antiviral response, resembling full viral infection.