The rockefeller university

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.

Nuclear pore complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargoes, including preribosomes and viral capsids. Our model quantifies how flexible phenylalanine-glycine (FG) repeat proteins create an entropic barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by "fuzzy" multivalent interactions, redundant FG repeat mass, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.

Over the past decade, radio frequency (RF) sensing or radar has garnered great interest as an emerging modality to enable human-computer interaction via gesture recognition. Current approaches involve utilization of a radar system that transmits a fixed signal with predetermined frequency, bandwidth, and other waveform parameters. However, gesture recognition accuracy can be greatly impacted by radar transmission parameters, which affect computational load and performance. In this work, we introduce a human-centered, fully adaptive radar (HC-FAR) system for ambient gesture recognition in which a programmable, software-defined radar system dynamically changes its RF transmission in response to human behavior. We design and switch between different transmission modes for different human-computer interaction tasks-human presence detection, trigger detection, and command translation-as well as alter processing so as to minimize computational load. In this way, the proposed HC-FAR paradigm enables dynamic management of the tradeoffs between dimensionality of RF data representations and their resulting computational load with real-time classification accuracy. Our results show that HC-FAR significantly reduces the allocation of computational and spectral resources, while enhancing fine-grain gesture recognition via a joint domain multi-input deep neural network, which takes as input the RF micro-Doppler signature, range, and angle profile.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a method for estimating mLOY from exome or whole-genome sequencing data. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated it using data from 212,062 male participants in the UK Biobank, comparing the results to those obtained using genotyping-or whole-genome-sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. We validated our approach by replicating known mLOY associations with age, smoking, all-cause mortality, and germline genetic loci. We further confirmed the robustness of our method at lower sequencing depth and demonstrated its applicability in single-sample analysis. Finally, we used data from The Cancer Genome Atlas to demonstrate that MosCoverY can also reliably detect variable mLOY in tumoral genomes. MosCoverY offers a valuable tool for detecting mLOY from exome or genome data in population-scale studies.

Background: Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being approved by the US Food and Drug Administration. Although vitiligo is primarily regarded as a TH1/interferon-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear. Objective: We sought to obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo. Methods: We performed bulk RNA sequencing combined with real-time PCR and immunohistochemistry of skin biopsy samples from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing. Results: Robust inflammatory dysregulation was captured not only in lesional but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of TH1 (OASL, CXCL9, CXCL10), TH2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and TH17/22 (IL20, S100A7, S100A8, S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of TH1 (CXCL9, OASL), TH2 (IL4R, IL10, CCL13, CCL17, CCL22), and TH17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (Vitiligo Area Scoring Index and/or Vitiligo Disease Activity Index) significantly and positively correlated with multiple inflammatory mediators (ie, CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively. Conclusions: Our findings show that immune dysregulation in vitiligo involves immune axes beyond TH1/Tc1, with particular upregulation of type 2 markers already observed in nonlesional skin, suggesting a role during early lesion formation. (J Allergy Clin Immunol 2025;156:993-1007.)

T helper cell subsets-Th1, Th2, and Th17-coordinate pathogen-specific immune responses. Candida albicans-specific T cells include protective Th17 cells alongside other Th subsets. However, the role of alternative Th subsets remains unclear, particularly in individuals with impaired Th17 responses and recurrent candidiasis. Here, we show that patients with STAT1 gain-of-function mutations and chronic mucocutaneous candidiasis have a numerically normal but functionally altered pool of C. albicans-specific Th cells, skewed toward Th1 and Th2. This imbalance persisted even when assessing responses to the known and the newly identified immunodominant C. albicans antigens MP65 (65-kilodalton mannoprotein), HYR1 (hyphally regulated cell wall protein 1), and SAP4-6 (secreted aspartic proteinases 4-6), suggesting that antigen recognition and priming remain intact despite qualitative defects in T cell polarization. Using mucosal infection mouse models, we demonstrate that C. albicans-specific transgenic Th17 cells are sufficient to control infection, whereas Th1 and Th2 cells fail to protect, even in high numbers. Moreover, co-transfer of Th2 cells with Th17 cells impaired fungal control via an IL-4-dependent mechanism. These findings highlight the essential role of Th17 cells in protective immunity against C. albicans and reveal that non-Th17 responses are ineffective and may contribute to susceptibility in both humans and mice.

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.

Purpose of review Whipple's disease (WD), triggered by Tropheryma whipplei ( T. whipplei ), is a rare, chronic, inflammatory, systemic infectious disease that typically manifests in adults. The most frequent initial manifestations include arthritis, followed by diarrhea, abdominal pain, and weight loss. Half the world's population is exposed to T. whipplei , but only one in a million develop WD. This suggests that acquired or inborn errors of immunity (IEI) may underlie WD. Anti-TNF treatment is a well established risk factor for flare-ups of WD. Recent findings We have also reported two rare IEI in patients with WD. Six WD patients from two unrelated kindreds were found to have autosomal dominant IRF4 deficiency acting via a mechanism of haploinsufficiency. These patients were otherwise healthy. In addition, a single patient with a history of WD and other infections was found to have autosomal recessive CD4 deficiency. Summary Rare IEI can underlie WD. Human genetic studies of patients with WD are warranted for the development of precision medicine for affected kindreds and to improve our understanding of the pathogenesis of this rare infectious disease.