The rockefeller university

BackgroundHybrid effectiveness-implementation designs evaluate the effectiveness and implementation of interventions. We retrospectively evaluated the implementation of a stepped-wedge cluster randomized controlled trial of a facilitated telemedicine model (experimental) integrated into opioid treatment programs (OTPs) compared to offsite referral (control) for hepatitis C virus (HCV) treatment. The trial period was March 2017-October 2022. We compared organizational and implementation characteristics associated with an HCV cure and with high satisfaction with healthcare delivery.MethodsWe used the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework to guide data collection and evaluation. We evaluated the clinical effectiveness outcome (HCV cure) and patient-centered outcomes (changes between in-person and telemedicine patient satisfaction questionnaire subscales: Time Spent With Doctor and General Satisfaction). We evaluated 7 organizational and 16 implementation variables. We used random forests to obtain a list of variables with total importance weight of at least 95%. We subsequently conducted a configurational comparative method of coincidence analysis (CNA) to identify the variable combinations that are associated with the best outcomes.ResultsThe effectiveness of reach was enhanced by site identification of HCV RNA positive individuals. We found that low patient load per provider or counselor, site liaison presence, and high case manager availability increased clinical effectiveness (i.e., HCV cure). Adoption and implementation, assessed by high healthcare delivery satisfaction among participants in both arms, was associated with site liaisons, frequent case manager onsite presence and consistency, and low provider patient volume. Among telemedicine participants, onsite notifications and provider involvement in recruitment were additional variables associated with high healthcare satisfaction. In referral, providing patient education, low counselor patient volume, case manager involvement in site activities, and high case manager education levels were additional variables associated with high healthcare delivery satisfaction. Intervention maintenance has occurred at 10 sites.ConclusionsCompared to referral, facilitated telemedicine requires fewer variables for high effectiveness and patient satisfaction. The frequent onsite presence and consistency of the case manager and low provider and counselor volumes improved outcomes among both approaches. Improved outcomes among referral participants required more publicity, patient education, higher case manager education, more involvement in site activities, and occurred in university-affiliated sites.Trial registrationClintrials.gov registration number NCT02933970; Comparison of Telemedicine to Usual Care for HCV Management for Methadone-maintained Individuals Full Text View ClinicalTrials.gov.

Zika virus (ZIKV) is an emerging arbovirus, and its infection is often asymptomatic or mild; however, it can lead to severe neurological disorders. Currently, there are no approved treatments or vaccines for ZIKV, highlighting the urgent need to explore potential therapeutic options. In this study, we evaluated the antiviral activity of a novel synthetic peptide (GA-peptide) against ZIKV in vitro. The GA-peptide exhibited dose-dependent inhibition of the virus, affecting multiple stages of the ZIKV replication cycle. It demonstrated virucidal activity and effectively protected Vero cells from ZIKV infection. Additionally, the GA-peptide disrupted viral entry by targeting both the attachment and internalization phases, as well as post-entry stages of the infection. In silico analyses identified potential viral targets that interact with the GA-peptide. These findings underscore the GApeptide's promising potential as a therapeutic agent against ZIKV and its relevance in the development of new antiviral drugs.

Motivation Large sequencing datasets are being produced and deposited into public archives at unprecedented rates. The availability of tools that can reliably and efficiently generate and store sequencing read summary statistics has become critical.Results As part of the effort by the Vertebrate Genomes Project (VGP) to generate high-quality reference genomes at scale, we sought to address the community's need for efficient sequence data evaluation by developing rdeval, a standalone tool to quickly compute and interactively display sequencing read metrics. Rdeval can either run on the fly or store key sequence data metrics in tiny read 'snapshot' files. Statistics can then be efficiently recalled from snapshots for additional processing. Rdeval can convert fa*[.gz] files to and from other popular formats including BAM and CRAM for better compression. Overall, while CRAM achieves the best compression, the gain compared to BAM is marginal, and BAM achieves the best compromise between data compression and access speed. Rdeval also generates a detailed visual report with multiple data analytics that can be exported in various formats. We showcase rdeval's functionalities using long-read data from different sequencing platforms and species, including human. For PacBio long-read sequencing, our analysis shows dramatic improvements in both read length and quality over time, as well as the benefit of increased coverage for genome assembly, though the magnitude varies by taxa.Availability and implementation Rdeval is implemented in C++ for data processing and in R for data visualization. Precompiled releases (Linux, MacOS, Windows) and commented source code for rdeval are available under MIT license at https://github.com/vgl-hub/rdeval. Documentation is available on ReadTheDocs (https://rdeval-documentation.readthedocs.io). Rdeval is also available in Bioconda and in Galaxy (https://usegalaxy.org). An automated test workflow ensures the consistency of software updates.

The transporter associated with antigen processing (TAP) delivers peptide antigens from the cytoplasm into the endoplasmic reticulum (ER) for loading onto major histocompatibility complex class I (MHC-I) molecules. To examine the mechanisms of peptide transport and release into the ER, we determined cryo-electron microscopy structures of the human TAP heterodimer in multiple functional states along the transport cycle. In the inward-facing conformation, when the peptide translocation cavity within the TAP heterodimer is exposed to the cytosol, ATP binding strengthened intradomain assembly. Transition to the outward-facing conformation, when the transporter opens to the ER lumen, led to a complete reconfiguration of the peptide-binding site, facilitating peptide release. ATP hydrolysis opened the catalytically active nucleotide-binding consensus site, and the subsequent separation of the nucleotide-binding domains reset the transport cycle. These findings establish a comprehensive structural framework for understanding unilateral peptide transport, vanadate trapping, and trans-inhibition-an internal feedback mechanism that prevents excessive peptide accumulation and activation of the ER stress response.

A goal of data visualization is to advance the understanding of multiparameter, large-scale datasets. In astrophysics, scientists map celestial objects to understand the hierarchical structure of the universe. In biology, genetic sequences and biological characteristics uncover evolutionary relationships and patterns (e.g., variation within species and ecological associations). Our highly interdisciplinary project entitled "A Cosmic View of Life on Earth" adapts an immersive astrophysics visualization platform called OpenSpace to contextualize diverse biological data. Dimensionality reduction techniques harmonize biological information to create spatial representations in which data are interactively explored on flat screens and planetarium domes. Visualizations are enriched with geographic metadata, 3-D scans of specimens, and species-specific sonifications (e.g., bird songs). The "Cosmic View" project eases the dissemination of stories related to biological domains (e.g., insects, birds, mammals, and human migrations) and facilitates scientific discovery.

Neurodegenerative diseases present one of the most significant global health challenges. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuroprotective. Variants in FBXO7/ PARK15 cause Parkinsonian Pyramidal Syndrome, an early-onset parkinsonian neurodegenerative disorder in humans, and inactivation of this gene in mice recapitulates many phenotypes seen in patients. The proteasome regulator PI31 is a direct binding partner of Fbxo7 and promotes local protein degradation at synapses by mediating fast proteasome transport in neurites. PI31 protein levels are reduced when the function of Fbxo7 is impaired. Here we show that restoring PI31 levels in Fbxo7 mutant fly and mouse strains prevents neuronal degeneration and significantly improves neuronal function, health, and lifespan. Notably, Fbxo7 inactivation in mouse neurons causes hyperphosphorylation of tau, and this was suppressed by transgenic expression of PI31. Our results demonstrate that PI31 is a crucial biological target through which Fbxo7 deficiency drives pathology. Therefore, targeting the PI31-pathway may represent a promising therapeutic approach for treating neurodegenerative disorders.

The Tyrrhenian tree frog (Hyla sarda) is a small cryptically coloured amphibian found in Corsica, Sardinia, and the Tuscan Archipelago. Investigation into the species' evolutionary history has revealed phenotypic changes triggered by glaciation-induced range expansion, but understanding the genetic basis of this trait variation has been hampered by the lack of a reference genome. To address this, we assembled a chromosome-level genome of Hyla sarda using PacBio HiFi long reads, Bionano optical maps, and Hi-C data. The assembly comprises 13 assembled chromosomes, spanning a total length of 4.15 Gb with a scaffold N50 of 385 Mb, a BUSCO completeness of 94.60%, and a k-mer completeness of 98.30%. Approximately 75% of the genome consists of repetitive elements. We annotated 22,847 protein-coding genes with a BUSCO completeness of 94.60% and an OMArk completeness of 93.74%. This high-quality assembly provides a valuable resource for studying phenotypic evolution and its genomic basis during range expansion, and will assist future investigations into the population and conservation genomics of Hyla sarda.

Wnt signaling plays a crucial role for many developmental processes. It is also pivotal in the generation and limited treatment outcomes of glioblastoma (GBM). Here, we identified Wnt7b, which is markedly upregulated in GBM patients, as a determinant of resistance to immune checkpoint blockers (alpha PD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, alpha PD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and beta-- catenin correlated with the resistance to alpha PD1. Treatment combining a porcupine inhibitor WNT974 with alpha PD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors. Our causal studies revealed that WNT974 potentiated alpha PD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with alpha PD1 was associated with a reduction in immune suppressive granulocytic myeloid-derived suppressor cells (MDSCs), an increase in the Ki67+CD8/Ki67+regulatory T cells (Treg) ratio, tilting the CD8:Treg balance in the TME toward antitumor immune response, and more pronounced GrzB+CD8+ effector T cells. Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/beta-- catenin inhibition with alpha PD1 therapy in GBM patients with elevated Wnt7b/beta-- catenin signaling.