Miracle-dz/UniFAR-FTUs huggingface dataset:
Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the CNS. Myelin sheath length is a key property that determines axonal conduction velocity and is known to be variable across the CNS. Myelin sheath length can be modified by neuronal activity, suggesting that dynamic regulation of sheath length might contribute to the functional plasticity of neural circuits. Although the mechanisms that establish and refine myelin sheath length are important determinants of brain function, our understanding of these remains limited. In recent years, the membranes of myelin sheaths have been increasingly recognized to contain ion channels and transporters that are associated with specific important oligodendrocyte functions, including metabolic support of axons and the regulation of ion homeostasis, but none have been shown to influence sheath architecture. In this study, we determined that hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, typically associated with neuronal and cardiac excitability, regulate myelin sheath length. Using both in vivo and in vitro approaches, we show that oligodendrocytes abundantly express functional, predominantly HCN2 subunit-containing ion channels. These HCN ion channels retain key pharmacological and biophysical features and regulate the resting membrane potential of myelinating oligodendrocytes. Further, reduction of their function via pharmacological blockade or generation of transgenic mice with two independent oligodendrocyte-specific HCN2 knock-out strategies reduced myelin sheath length. We conclude that HCN2 ion channels are key determinants of myelin sheath length in the CNS. SIGNIFICANCE STATEMENT Myelin sheath length is a critical determinant of axonal conduction velocity, but the signaling mechanisms responsible for determining sheath length are poorly understood. Here we find that oligodendrocytes express functional hyperpolarization-activated, cyclic nucleotide-gated 2 (HCN2) ion channels that regulate the length of myelin sheaths formed by oligodendrocytes in myelinating cultures and in the mouse brain and spinal cord. These results suggest that the regulation of HCN2 channel activity is well placed to refine sheath length and conduction along myelinated axons, providing a potential mechanism for alterations in conduction velocity and circuit function in response to axonal signals such as those generated by increased activity.
Hippo signaling effectors YAP and TAZ induce Epstein-Barr Virus (EBV) lytic reactivation through TEADs in epithelial cells

The Epstein-Barr virus (EBV) human herpesvirus is associated with B-cell and epithelial-cell malignancies, and both the latent and lytic forms of viral infection contribute to the development of EBV-associated tumors. Here we show that the Hippo signaling effectors, YAP and TAZ, promote lytic EBV reactivation in epithelial cells. The transcriptional co-activators YAP/TAZ (which are inhibited by Hippo signaling) interact with DNA-binding proteins, particularly TEADs, to induce transcription. We demonstrate that depletion of either YAP or TAZ inhibits the ability of phorbol ester (TPA) treatment, cellular differentiation or the EBV BRLF1 immediate-early (IE) protein to induce lytic EBV reactivation in oral keratinocytes, and show that over-expression of constitutively active forms of YAP and TAZ reactivate lytic EBV infection in conjunction with TEAD family members. Mechanistically, we find that YAP and TAZ interact with, and activate, the EBV BZLF1 immediate-early promoter. Furthermore, we demonstrate that YAP, TAZ, and TEAD family members are expressed at much higher levels in epithelial cell lines in comparison to B-cell lines, and find that EBV infection of oral keratinocytes increases the level of activated (dephosphorylated) YAP and TAZ. Finally, we have discovered that lysophosphatidic acid (LPA), a known YAP/TAZ activator that plays an important role in inflammation, induces EBV lytic reactivation in epithelial cells through a YAP/TAZ dependent mechanism. Together these results establish that YAP/TAZ are powerful inducers of the lytic form of EBV infection and suggest that the ability of EBV to enter latency in B cells at least partially reflects the extremely low levels of YAP/TAZ and TEADs in this cell type.
Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

NMDA receptors (NMDARs) are glutamate‐gated ion channels that play key roles in synaptic transmission and plasticity. Both hyper‐ and hypo‐activation of NMDARs are deleterious to neuronal function. In particular, NMDAR hypofunction is involved in a wide range of neurological and psychiatric conditions like schizophrenia, intellectual disability, age‐dependent cognitive decline, or Alzheimer's disease. While early medicinal chemistry efforts were mostly focused on the development of NMDAR antagonists, the last 10 years have seen a boom in the development of NMDAR positive allosteric modulators (PAMs). Here we review the currently developed NMDAR PAMs, their pharmacological profiles and mechanisms of action, as well as their physiological effects in healthy animals and animal models of NMDAR hypofunction. In light of the complexity of physiological outcomes of NMDAR PAMs in vivo, we discuss the remaining challenges and questions that need to be addressed to better grasp and predict the therapeutic potential of NMDAR positive allosteric modulation.
Towards the Translation of Electroconductive Organic Materials for Regeneration of Neural Tissues

Carbon-based conductive and electroactive materials (e.g., derivatives of graphene, fullerenes, polypyrrole, polythiophene, polyaniline) have been studied since the 1970s for use in a broad range of applications. These materials have electrical properties comparable to those of commonly used metals, while providing other benefits such as flexibility in processing and modification with biologics (e.g., cells, biomolecules), to yield electroactive materials with biomimetic mechanical and chemical properties. In this review, we focus on the uses of these electroconductive materials in the context of the central and peripheral nervous system, specifically recent studies in the peripheral nerve, spinal cord, brain, eye, and ear. We also highlight in vivo studies and clinical trials, as well as a snapshot of emerging classes of electroconductive materials (e.g., biodegradable materials). We believe such specialized electrically conductive biomaterials will clinically impact the field of tissue regeneration in the foreseeable future. STATEMENT OF SIGNIFICANCE: This review addresses the use of conductive and electroactive materials for neural tissue regeneration, which is of significant interest to a broad readership, and of particular relevance to the growing community of scientists, engineers and clinicians in academia and industry who develop novel medical devices for tissue engineering and regenerative medicine. The review covers the materials that may be employed (primarily focusing on derivatives of fullerenes, graphene and conjugated polymers) and techniques used to analyze materials composed thereof, followed by sections on the application of these materials to nervous tissues (i.e., peripheral nerve, spinal cord, brain, optical, and auditory tissues) throughout the body.
Informal caregiver experiences at the end-of-life of individuals living with dementia with Lewy bodies: An interview study

Individuals with dementia with Lewy bodies (DLB) commonly die from dementia-related causes, but little is known regarding caregiver experiences during the end-of-life period in DLB. This reflects a critical knowledge gap given the high frequency of informal caregiving for individuals with dementia, high caregiver burden in DLB, and the fact that most individuals with DLB die from this disease. Investigators conducted telephone interviews with family members of individuals who died with DLB in the last 5 years. Investigators used a qualitative descriptive approach to analyze interview transcripts. Participants included 15 children, 13 spouses, and 2 other family members. Interviews averaged 31 min. Major themes included caregivers as the main drivers of care for individuals with DLB throughout the disease course and at the end of life, the impact of DLB features (e.g., fluctuations, hallucinations, and delusions) on end-of-life experiences, experiences relating to the caregiving role, death and post-death experiences, and supports employed by caregivers in the end-of-life period. End-of-life experiences for caregivers of individuals with DLB built on the accumulated burden of the disease course, where caregivers were often responsible for driving DLB care—from making the diagnosis to educating healthcare professionals and double-checking medical decisions. While some end-of-life experiences were consistent with those described in dementia palliative care more generally (e.g., financial stresses, poor sleep, being overwhelmed, and needing increased education and support), many DLB features specifically affected end-of-life caregiver experiences, such as the presence of delusions. Improving caregiver experiences at the end of life in DLB will require improved diagnosis and care for individuals with DLB throughout the disease course and also better strategies for treating behavioral symptoms. More research is needed regarding drivers of quality end-of-life experiences for individuals with DLB and their families and how drivers and strategies may differ between dementias.
Integrating virtual realities and psychotherapy: SWOT analysis on VR and MR based treatments of anxiety and stress-related disorders

ABSTRACT The use of virtual reality (VR) and mixed reality (MR) technology in clinical psychology is growing. Efficacious VR-based treatments for a variety of disorders have been developed. However, the field of technology-assisted psychotherapy is constantly changing with the advancement in technology. Factors such as interdisciplinary collaboration, consumer familiarity and adoption of VR products, and progress in clinical science all need to be taken into consideration when integrating virtual technologies into psychotherapies. We aim to present an overview of current expert opinions on the use of virtual technologies in the treatment of anxiety and stress-related disorders. An anonymous survey was distributed to a select group of researchers and clinicians, using an analytic framework known as Strengths, Weaknesses, Opportunities, and Threats (SWOT). Overall, the respondents had an optimistic outlook regarding the current use as well as future development and implementation of technology-assisted interventions. VR and MR psychotherapies offer distinct advantages that can overcome shortcomings associated with traditional therapy. The respondents acknowledged and discussed current limitations of VR and MR psychotherapies. They recommended consolidation of existing knowledge and encouraged standardisation in both theory and practice. Continued research is needed to leverage the strengths of VR and MR to develop better treatments. Abbreviations: AR: Augmented Reality; MR: Mixed Reality; RCT: Randomised Controlled Trial; SWOT: Strengths, Weaknesses, Opportunities, and Threats; VR: Virtual Reality; VR-EBT: Virtual Reality Exposure-Based Therapy
The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19

The causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), requires host cell surface proteases for membrane fusion and entry into airway epithelia. We tested the hypothesis that inhibitors of these proteases, the serine protease inhibitors camostat and nafamostat, block infection by SARS-CoV-2. ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality on a global scale. The etiologic agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initiates host cell entry when its spike protein (S) binds to its receptor, angiotensin-converting enzyme 2 (ACE2). In airway epithelia, the spike protein is cleaved by the cell surface protease TMPRSS2, facilitating membrane fusion and entry at the cell surface. This dependence on TMPRSS2 and related proteases suggests that protease inhibitors might limit SARS-CoV-2 infection in the respiratory tract. Here, we tested two serine protease inhibitors, camostat mesylate and nafamostat mesylate, for their ability to inhibit entry of SARS-CoV-2 and that of a second pathogenic coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV). Both camostat and nafamostat reduced infection in primary human airway epithelia and in the Calu-3 2B4 cell line, with nafamostat exhibiting greater potency. We then assessed whether nafamostat was protective against SARS-CoV-2 in vivo using two mouse models. In mice sensitized to SARS-CoV-2 infection by transduction with human ACE2, intranasal nafamostat treatment prior to or shortly after SARS-CoV-2 infection significantly reduced weight loss and lung tissue titers. Similarly, prophylactic intranasal treatment with nafamostat reduced weight loss, viral burden, and mortality in K18-hACE2 transgenic mice. These findings establish nafamostat as a candidate for the prevention or treatment of SARS-CoV-2 infection and disease pathogenesis. IMPORTANCE The causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), requires host cell surface proteases for membrane fusion and entry into airway epithelia. We tested the hypothesis that inhibitors of these proteases, the serine protease inhibitors camostat and nafamostat, block infection by SARS-CoV-2. We found that both camostat and nafamostat reduce infection in human airway epithelia, with nafamostat showing greater potency. We then asked whether nafamostat protects mice against SARS-CoV-2 infection and subsequent COVID-19 lung disease. We performed infections in mice made susceptible to SARS-CoV-2 infection by introducing the human version of ACE2, the SARS-CoV-2 receptor, into their airway epithelia. We observed that pretreating these mice with nafamostat prior to SARS-CoV-2 infection resulted in better outcomes, in the form of less virus-induced weight loss, viral replication, and mortality than that observed in the untreated control mice. These results provide preclinical evidence for the efficacy of nafamostat in treating and/or preventing COVID-19.
Electroconvulsive therapy increases temporarily plasma vascular endothelial growth factor in patients with major depressive disorder

Vascular endothelial growth factor (VEGF) has been related to the etiology of major depressive disorder (MDD). The findings involving the effects of electroconvulsive therapy (ECT) on the VEGF levels have been conflicting. The aim was to examine the possible changes in the VEGF levels and their associations with clinical outcome in patients with MDD during ECT.
Flexible parametric copula modeling approaches for clustered survival data

Copula‐based survival regression models, which consist of a copula function and marginal distribution (i.e., marginal survival function), have been widely used for analyzing clustered multivariate survival data. Archimedean copula functions are useful for modeling such dependence. For the likelihood inference, one‐stage and two‐stage estimation methods have been usually used. The two‐stage procedure can give inefficient estimation results because of separate estimation of the marginal and copula's dependence parameters. The more efficient one‐stage procedure has been mainly developed under a restrictive parametric assumption of marginal distribution due to complexity of the full likelihood with unknown marginal baseline hazard functions. In this paper, we propose a flexible parametric Archimedean copula modeling approach using a one‐stage likelihood procedure. In order to reduce the complexity of the full likelihood, the unknown marginal baseline hazards are modeled based on a cubic M‐spline basis function that does not require a specific parametric form. Simulation results demonstrate that the proposed one‐stage estimation method gives a consistent estimator and also provides more efficient results over existing one‐ and two‐stage methods. The new method is illustrated with three clinical data sets. The Appendix provides an R function so that the proposed method becomes directly accessible to interested readers.
The Mammalian Membrane Microenvironment Regulates the Sequential Attachment of Bacteria to Host Cells

Microbial adhesion to host cells is the initial step toward many infections. Despite playing a pivotal role in the onset of disease, we still know little about how bacteria attach in an in vivo-like context. ABSTRACT Pathogen attachment to host tissue is critical in the progress of many infections. Bacteria use adhesion in vivo to stabilize colonization and subsequently regulate the deployment of contact-dependent virulence traits. To specifically target host cells, they decorate themselves with adhesins, proteins that bind to mammalian cell surface receptors. One common assumption is that adhesin-receptor interactions entirely govern bacterial attachment. However, how adhesins engage with their receptors in an in vivo-like context remains unclear, in particular under the influence of a heterogeneous mechanical microenvironment. We here investigate the biophysical processes governing bacterial adhesion to host cells using a tunable adhesin-receptor system. By dynamically visualizing attachment, we found that bacterial adhesion to host cell surface, unlike adhesion to inert surfaces, involves two consecutive steps. Bacteria initially attach to their host without engaging adhesins. This step lasts about 1 min, during which bacteria can easily detach. We found that at this stage, the glycocalyx, a layer of glycosylated proteins and lipids, shields the host cell by keeping adhesins away from their receptor ligand. In a second step, adhesins engage with their target receptors to strengthen attachment for minutes to hours. The active properties of the membrane, endowed by the actin cytoskeleton, strengthen specific adhesion. Altogether, our results demonstrate that adhesin-ligand binding is not the sole regulator of bacterial adhesion. In fact, the host cell’s surface mechanical microenvironment mediates the physical interactions between host and bacteria, thereby playing an essential role in the onset of infection. IMPORTANCE Microbial adhesion to host cells is the initial step toward many infections. Despite playing a pivotal role in the onset of disease, we still know little about how bacteria attach in an in vivo-like context. By employing a biophysical approach where we investigated host-microbe physical interactions at the single-cell level, we unexpectedly discovered that bacteria attach to mammalian cell membranes in two successive steps. We found that mechanical factors of the cell microenvironment regulate each of these steps, and even dominate biochemical factors, thereby challenging preconceptions on how pathogens interact with their hosts.
Why All the Fury over Furin?

Analysis of the SARS-CoV-2 sequence revealed a multibasic furin cleavage site at the S1/S2 boundary of the spike protein distinguishing this virus from SARS-CoV. Furin, the best-characterized member of the mammalian proprotein convertases, is an ubiquitously expressed single pass type 1 transmembrane protein. Cleavage of SARS-CoV-2 spike protein by furin promotes viral entry into lung cells. While furin knockout is embryonically lethal, its knockout in differentiated somatic cells is not, thus furin provides an exciting therapeutic target for viral pathogens including SARS-CoV-2 and bacterial infections. Several peptide-based and small-molecule inhibitors of furin have been recently reported, and select cocrystal structures have been solved, paving the way for further optimization and selection of clinical candidates. This perspective highlights furin structure, substrates, recent inhibitors, and crystal structures with emphasis on furin’s role in SARS-CoV-2 infection, where the current data strongly suggest its inhibition as a promising therapeutic intervention for SARS-CoV-2.
Conservative Novelty Synthesizing Network for Malware Recognition in an Open-Set Scenario

We study the challenging task of malware recognition on both known and novel unknown malware families, called malware open-set recognition (MOSR). Previous works usually assume the malware families are known to the classifier in a close-set scenario, i.e., testing families are the subset or at most identical to training families. However, novel unknown malware families frequently emerge in real-world applications, and as such, require recognizing malware instances in an open-set scenario, i.e., some unknown families are also included in the test set, which has been rarely and nonthoroughly investigated in the cyber-security domain. One practical solution for MOSR may consider jointly classifying known and detecting unknown malware families by a single classifier (e.g., neural network) from the variance of the predicted probability distribution on known families. However, conventional well-trained classifiers usually tend to obtain overly high recognition probabilities in the outputs, especially when the instance feature distributions are similar to each other, e.g., unknown versus known malware families, and thus, dramatically degrade the recognition on novel unknown malware families. To address the problem and construct an applicable MOSR system, we propose a novel model that can conservatively synthesize malware instances to mimic unknown malware families and support a more robust training of the classifier. More specifically, we build upon the generative adversarial networks to explore and obtain marginal malware instances that are close to known families while falling into mimical unknown ones to guide the classifier to lower and flatten the recognition probabilities of unknown families and relatively raise that of known ones to rectify the performance of classification and detection. A cooperative training scheme involving the classification, synthesizing and rectification are further constructed to facilitate the training and jointly improve the model performance. Moreover, we also build a new large-scale malware dataset, named MAL-100, to fill the gap of lacking a large open-set malware benchmark dataset. Experimental results on two widely used malware datasets and our MAL-100 demonstrate the effectiveness of our model compared with other representative methods.
Maintenance therapies in acute myeloid leukemia: the renaissance of an old therapeutic concept

Purpose of review Disease relapse remains the major cause of death in patients with acute myeloid leukemia (AML) and is driven by the persistence of leukemic cells following induction chemotherapy or allogeneic hematopoietic cell transplant (allo-HCT). Maintenance therapies to extend the duration of remission and to improve survival have been proposed for several years with mixed results but have experienced a renaissance recently. Recent findings The oral hypomethylating agent CC-486 has been the first agent to show an overall survival (OS) benefit compared with observation in AML patients in remission following intensive chemotherapy who are not proceeding to allo-HCT. In the realm of maintenance therapy following allo-HCT, the FLT3 inhibitor sorafenib has yielded superior results in terms of OS and relapse-free survival in randomized trials compared with observation. Several open questions remain regarding patient selection, timing, duration and safety of maintenance therapies. Various targeted agents are currently tested in clinical trials and could potentially enable an even more individualized therapeutic approach. Summary Maintenance therapies following intensive chemotherapy or allo-HCT offer a new therapeutic paradigm for an increasing number of AML patients and have been shown to result in an OS benefit in selected patients.