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The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the ‘arms race’ with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.

Crimean-Congo haemorrhagic fever virus (CCHFV) is a pathogen of increasing public health concern, being a widely distributed arbovirus and the causative agent of the potentially fatal Crimean-Congo haemorrhagic fever. Hazara virus (HAZV) is a genetically and serologically related virus that has been proposed as a surrogate for antiviral and vaccine testing for CCHFV. Glycosylation analysis of HAZV has been limited; first, we confirmed for the first time the occupation of two N-glycosylation sites in the HAZV glycoprotein. Despite this, there was no apparent antiviral efficacy of a panel of iminosugars against HAZV, as determined by quantification of the total secretion and infectious virus titres produced following infection of SW13 and Vero cells. This lack of efficacy was not due to an inability of deoxynojirimycin (DNJ)-derivative iminosugars to access and inhibit endoplasmic reticulum α-glucosidases, as demonstrated by free oligosaccharide analysis in uninfected and infected SW13 and uninfected Vero cells. Even so, iminosugars may yet have potential as antivirals for CCHFV since the positions and importance of N-linked glycans may differ between the viruses, a hypothesis requiring further evaluation.

Introduction: We sought to determine a distance threshold where mode of transportation impacted treatment options for potential thrombectomy patients. Methods: We retrospectively reviewed transferred stroke patients to our comprehensive stroke center within 8 hours of onset from January 2017 to December 2019. In our analysis, all patients had a CTA confirmed large vessel occlusion, NIHSS >10 and arrived within 8 hours of onset as a candidate for thrombectomy. Patients were not treated with thrombectomy if they presented with a completed infarct or hemorrhagic conversion. Patients were transferred by air or ground based on availability and safety. Transfers were grouped based on distance: 0–30 miles, 31–60 miles, 61–90 and > 90 miles. We performed a binomial logistic regression for each distance group to determine a threshold where the odds of receiving thrombectomy statistically decoupled based on mode of transportation. Results: Of the 243 patients reviewed, 52.1% (126) received thrombectomy. Transport for 50.8% (123) patients was by air. Hospitals transferring within 0–30 miles accounted for 26.6% (65); 31–60 miles accounted for 22.1% (54); 61–90 miles accounted for25.8% (63) and >90 miles accounted for 24.8% (60). The odds of receiving a thrombectomy were significantly higher with air transportation (OR 3.0, CI 1.04‐8.74, p = 0.043) at a distance threshold of >90 miles. At a distance threshold of 10 to 30 miles, the odds of receiving a thrombectomy were significantly higher with ground transportation (OR 5.5, CI 1.15‐26.14, p = 0.032). There was no difference between modes of transportation for 31 to 90 miles. Conclusions: Our analysis suggests that air transport beyond 90 miles increases the odds of receiving a thrombectomy for patients arriving within 8 hours of symptom onset. Ground transport, rather than air transport, between 10 and 30 miles may be more beneficial. Our results suggest that specific regional transport thresholds based on distance do exist and if recognized and altered can result in more favorable transfers.

The circadian clock can affect pathogen replication, but underlying molecular mechanisms are unclear. Here the authors demonstrate that the circadian components BMAL1 and REV-ERBα affect entry of hepatitis C virus (HCV) into hepatocytes and genome replication of HCV and related flaviviruses dengue and zika.

Abstract The pupillary light reflex (PLR) describes the response when light hits the retina and sends a signal (cranial nerve II) to the Edinger-Westphal Nucleus which via cranial nerve III results in pupillary constriction. The Neurological Pupil indexTM (NPi) and pupil constriction velocity (CV) are two distinct variables that can be observed and measured using a pupillometer. We examine NPi and CV in 27,462 pupil readings (1,617 subjects). NPi values

Pulmonary metastasis is the major untreatable complication of osteosarcoma (OS) resulting in 10-20% long-term survival. The factors and pathways regulating these processes remain unclear, yet their identification is crucial in order to find new therapeutic targets. In this study we used a multi-omics approach to identify molecules in metastatic and non-metastatic OS cells that may contribute to OS metastasis, followed by validation in vitro and in vivo. We found elevated levels of the urokinase plasminogen activator (uPA) and of the uPA receptor (uPAR) exclusively in metastatic OS cells. uPA was secreted in soluble form and as part of the protein cargo of OS-secreted extracellular vesicles, including exosomes. In addition, in the tumour microenvironment, uPA was expressed and secreted by bone marrow cells (BMC), and OS- and BMC-derived uPA significantly and specifically stimulated migration of metastatic OS cells via uPA-dependent signaling pathways. Silencing of uPAR in metastatic OS cells abrogated the migratory response to uPA in vitro and decreased metastasis in vivo. Finally, a novel small-molecule inhibitor of uPA significantly (P = 0.0004) inhibited metastasis in an orthotopic mouse model of OS. Thus, we show for the first time that malignant conversion of OS cells to a metastatic phenotype is defined by activation of the uPA/uPAR axis in both an autocrine and paracrine fashion. Furthermore, metastasis is driven by changes in OS cells as well as in the microenvironment. Finally, our data show that pharmacological inhibition of the uPA/uPAR axis with a novel small-molecule inhibitor can prevent the emergence of metastatic foci.

Summary: Regulatory T cells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of Tregs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive Tregs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. Treg-specific deletion of ST2 alters the evolution of effector Treg diversity, increases infiltration of CD8+ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention. : Li et al. show in a genetic mouse model of lung adenocarcinoma that during tumor development regulatory T cell (Treg) diversity shifts from an interferon-responsive to a ST2-positive, Klrg1+Areg+ effector-like phenotype. Treg-specific deletion of ST2 alters Treg heterogeneity, increases tumor infiltration by CD8+ T cells, and decreases tumor burden. Keywords: regulatory T cell, autochthonous mouse model of cancer, lung adenocarcinoma, tumor immunosuppression, single cell RNA sequencing, Treg heterogeneity, interleukin-33, ST2, Il1rl1

Este documento propone herramientas para profesoras/es de la educación superior interesadas/os en realizar la transversalización de género desde una perspectiva interseccional. Planteamos que las y los educadores deben empezar su camino hacia una pedagogía no discriminatoria analizando sus propias prácticas y presuposiciones - en la clase y fuera de ella - para poder evaluar y transformar sus creencias y pedagogías, con el objetivo de encontrar una forma de aprender y de enseñar más crítica, política, personal y democrática; que avance en el objetivo de eliminar desigualdades basadas en género y otras diferencias. Este artículo incluye herramientas y estrategias para los ámbitos educativos, institucionales y personales, con la idea que deben ser trabajados de manera integral para generar cambios reales.