Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy.

Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold.

Relapses in canine leishmaniosis: risk factors identified through mixed-effects logistic regression.

Background: Canine leishmaniosis (CanL), caused by Leishmania infantum, is an important vector-borne parasitic disease in dogs with implications for human health. Despite advancements, managing CanL remains challenging due to its complexity, especially in chronic, relapsing cases. Mathematical modeling has emerged as a powerful tool in various medical fields, but its application in understanding CanL relapses remains unexplored.

Nirmatrelvir and molnupiravir maintain potent in vitro and in vivo antiviral activity against circulating SARS-CoV-2 omicron subvariants.

Variants of SARS-CoV-2 pose significant challenges in public health due to their increased transmissibility and ability to evade natural immunity, vaccine protection, and monoclonal antibody therapeutics. The emergence of the highly transmissible Omicron variant and subsequent subvariants, characterized by an extensive array of over 32 mutations within the spike protein, intensifies concerns regarding vaccine evasion. In response, multiple antiviral therapeutics have received FDA emergency use approval, targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) regions, known to have relatively fewer mutations across novel variants.

Synthesis and Properties of Hydrophilic and Hydrophobic Deep Eutectic Solvents via Heating-Stirring and Ultrasound.

Deep eutectic solvents (DESs) have emerged as a greener alternative to other more polluting traditional solvents and have attracted a lot of interest in the last two decades. The DESs are less toxic dissolvents and have a lower environmental footprint. This paper presents an alternative synthesis method to the classical heating-stirring method.

JRK binds satellite III DNA and is necessary for the heat shock response.

JRK is a DNA-binding protein of the pogo superfamily of transposons, which includes the well-known centromere binding protein B (CENP-B). Jrk null mice exhibit epilepsy, and growth and reproductive disorders, consistent with its relatively high expression in the brain and reproductive tissues. Human JRK DNA variants and gene expression levels are implicated in cancers and neuropsychiatric disorders.

Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC.

SOX11/PRDX2 axis modulates redox homeostasis and chemoresistance in aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell neoplasm characterized by an aggressive behavior, short responses to conventional therapies and SOX11 overexpression, which is associated with aggressive disease features and inferior clinical outcome of patients. Oxidative stress is known to induce tumorigenesis and tumor progression, whereas high expression levels of antioxidant genes have been associated with chemoresistance in different cancers. However, the role of oxidative stress in MCL pathogenesis and the involvement of SOX11 regulating redox homeostasis in MCL cells are largely unknown.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice.

A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors.

SARS-CoV-2 variants evolve convergent strategies to remodel the host response.

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions.

Chagas disease treatment efficacy markers: experiences from a Phase III study with nifurtimox in children.

Determining the success of antitrypanosomal therapy for Chagas disease is challenging, particularly in the chronic phase of the disease, because seropositivity persists for a long time after successful antitrypanosomal treatment and is known to be related to the duration of infection. Seroconversion to negative by two or more conventional serologic tests is the currently accepted measure of efficacy, and studies suggest no significant change in seropositivity if left untreated. However, there is no guidance for industry on how to establish the effectiveness of drugs intended for the treatment of Chagas disease.

Convergent trends and spatiotemporal patterns of Aedes-borne arboviruses in Mexico and Central America.

Background: Aedes-borne arboviruses cause both seasonal epidemics and emerging outbreaks with a significant impact on global health. These viruses share mosquito vector species, often infecting the same host population within overlapping geographic regions. Thus, comparative analyses of the virus evolutionary and epidemiological dynamics across spatial and temporal scales could reveal convergent trends.

Structures of SARS-CoV-2 N7-methyltransferase with DOT1L and PRMT7 inhibitors provide a platform for new antivirals.

The RNA N7-methyltransferase (MTase) activity of SARS-CoV-2's nsp14 protein is essential for viral replication and is a target for the development of new antivirals. Nsp14 uses S-adenosyl methionine (SAM) as the methyl donor to cap the 5' end of the SARS-CoV-2 mRNA and generates S-adenosyl homocysteine (SAH) as the reaction byproduct. Due to the central role of histone MTases in cancer, many SAM/SAH analogs with properties of cell permeability have recently been developed for the inhibition of these MTases.

Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase.

An under-explored target for SARS-CoV-2 is the -adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.

Characterization of Integrase and Excisionase Activity in a Cell-Free Protein Expression System Using a Modeling and Analysis Pipeline.

We present a full-stack modeling, analysis, and parameter identification pipeline to guide the modeling and design of biological systems starting from specifications to circuit implementations and parametrizations. We demonstrate this pipeline by characterizing the integrase and excisionase activity in a cell-free protein expression system. We build on existing Python tools─BioCRNpyler, AutoReduce, and Bioscrape─to create this pipeline.

SARS-CoV-2 Inhibitors Identified by Phenotypic Analysis of a Collection of Viral RNA-Binding Molecules.

Antiviral agents are needed for the treatment of SARS-CoV-2 infections and to control other coronavirus outbreaks that may occur in the future. Here we report the identification and characterization of RNA-binding compounds that inhibit SARS-CoV-2 replication. The compounds were detected by screening a small library of antiviral compounds previously shown to bind HIV-1 or HCV RNA elements with a live-virus cellular assay detecting inhibition of SARS-CoV-2 replication.

Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma.

SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown.

Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial.

Purpose: High-flow nasal cannula (HFNC) oxygen therapy was noninferior to noninvasive ventilation (NIV) for preventing reintubation in a heterogeneous population at high-risk for extubation failure. However, outcomes might differ in certain subgroups of patients. Thus, we aimed to determine whether NIV with active humidification is superior to HFNC in preventing reintubation in patients with ≥ 4 risk factors (very high risk for extubation failure).

Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis.

Background: High-flow nasal cannula (HFNC) was shown to be non-inferior to noninvasive ventilation (NIV) for preventing reintubation in a general population of high-risk patients. However, some subgroups of high-risk patients might benefit more from NIV. We aimed to determine whether the presence of many risk factors or overweight (body mass index (BMI) ≥ 25 kg/m) patients could have different response to any preventive therapy, NIV or HFNC in terms of reduced reintubation rate.

Appendicular agenesis as an unusual intraoperative finding in acute abdomen: Case report and literature review.

Introduction: Appendicular agenesis is a rare condition that accounts for 1 of every 100,000 exploratory laparotomies, usually in clinical suspicion of appendiceal inflammatory processes with higher incidence in adults.

Clinical Findings: We present a case of a 19-year-old female with appendicular agenesis who underwent exploratory laparoscopy in the context of appendiceal inflammatory process.

Conclusion: Vermiform appendix agenesis is a challenging diagnosis made in most cases as an intraoperatively finding.