Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. We designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2, providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement.

Large language models for science and medicine.

Large language models (LLMs) are a type of machine learning model that learn statistical patterns over text, such as predicting the next words in a sequence of text. Both general purpose and task-specific LLMs have demonstrated potential across diverse applications. Science and medicine have many data types that are highly suitable for LLMs, such as scientific texts (publications, patents and textbooks), electronic medical records, large databases of DNA and protein sequences and chemical compounds. Carefully validated systems that can understand and reason across all these modalities may maximize benefits. Despite the inevitable limitations and caveats of any new technology and some uncertainties specific to LLMs, LLMs have the potential to be transformative in science and medicine.

Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. Here, we designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2 providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among human type 2 transmembrane serine proteases. We found that human, rat, hamster and camel TMPRSS2 promote HKU1 S-mediated entry into cells and identified key residues governing host receptor usage. Our data show that serum antibodies targeting the HKU1 RBD TMPRSS2 binding-site are key for neutralization and that HKU1 uses conformational masking and glycan shielding to balance immune evasion and receptor engagement.

Case-control study on post-COVID-19 conditions reveals severe acute infection and chronic pulmonary disease as potential risk factors.

Post-COVID-19 conditions (long COVID) has impacted many individuals, yet risk factors for this condition are poorly understood. This retrospective analysis of 88,943 COVID-19 patients at a multi-state US health system compares phenotypes, laboratory tests, medication orders, and outcomes for 1,086 long-COVID patients and their matched controls. We found that history of chronic pulmonary disease (CPD) (odds ratio: 1.9, 95% CI: [1.5, 2.6]), migraine (OR: 2.2, [1.6, 3.1]), and fibromyalgia (OR: 2.3, [1.3, 3.8]) were more common for long-COVID patients. During the acute infection phase long COVID patients exhibited high triglycerides, low HDL cholesterol, and a high neutrophil-lymphocyte ratio; and were more likely hospitalized (5% vs. 1%). Our findings suggest severity of acute infection and history of CPD, migraine, chronic fatigue syndrome (CFS), or fibromyalgia as risk factors for long COVID. These results suggest that suppressing acute disease severity proactively, especially in patients at high risk, can reduce incidence of long COVID.

Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety.

In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitro efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.

Ensuring Trust in Genomics Research.

Reproducibility, transparency, representation, and privacy underpin the trust on genomics research in general and genome-wide association studies (GWAS) in particular. Concerns about these issues can be mitigated by technologies that address privacy protection, quality control, and verifiability of GWAS. However, many of the existing technological solutions have been developed in isolation and may address one aspect of reproducibility, transparency, representation, and privacy of GWAS while unknowingly impacting other aspects. As a consequence, the current patchwork of technological tools only partially and in an overlapping manner address issues with GWAS, sometimes even creating more problems. This paper addresses the progress in a field that creates technological solutions that augment the acceptance and security of population genetic analyses. The text identifies areas that are falling behind in technical implementation or where there is insufficient research. We make the case that a full understanding of the different GWAS settings, technological tools and new research directions can holistically address the requirements for the acceptance of GWAS.

Conceptos generales y métodos de estudio en farmacogenética / General concepts and study methods in pharmacogenetics

La farmacogenética, la ciencia que permite identificar lasbases genéticas de las diferencias interindividuales en larespuesta a los fármacos, es un tema de gran interés. Losresultados de los diferentes tipos de estudiosfarmacogenéticos en diferentes campos de la medicinapueden servir para que en un futuro se pueda ofrecer unaverdadera medicina personalizada. En este capítulodefinimos los conceptos más relevantes de esta disciplina,así como los métodos de estudio utilizados actualmente(AU)

Pharmacogenetics, the study of how individual geneticprofiles influence the response to drugs, is an importanttopic. Results from pharmacogenetics studies in variousclinical settings may lead to personalized medicine. Herein,we present the most important concepts of this discipline,as well as currently-used study methods(AU)

Presente y futuro de la virología clínica / The present and future of clinical virology

La virología clínica se enfrenta a desafíos importantes y de signo opuesto. Por un lado se perfila una necesidad de dar respuesta a un número creciente de infecciones por nuevos virus con capacidad patogénica, un aumento en la demanda de análisis de resistencia en una era de terapia antiviral, y la apuesta por la revolución tecnológica. Por otro lado, las responsabilidades de la virología clínica se están transfiriendo al laboratorio de microbiología general, con la consecuente amenaza para la formación futura de un número suficiente de especialistas en virología

Clinical virology faces challenges of opposing sign. On one hand, there will be an increasing demand for identification of novel pathogenic viruses, for resistance testing in a new era of antiviral therapy, and for full participation in the molecular revolution in diagnostic technologies. On the other hand, the responsibilities of clinical virology are being transferred to the general diagnostic microbiology laboratory, that risks limiting the numbers of specialists in virology available for meeting future challenges and demands

Las cohortes genéticas: nuevos retos en enfermedades infecciosas. El modelo VIH / The genetic cohorts: facing the new challenges in infectious diseases. The HIV model

Todos los clínicos se enfrentan a la diversidad en la susceptibilidad que presentan los pacientes frente a las infecciones infecciosas o en su respuesta frente a la medicación. Se han efectuado avances importantes para caracterizar los factores de virulencia de los patógenos, aunque hay menos información acerca del factor huésped (ser humano). Dos personas genéticamente no relacionadas comparten aproximadamente el 99,9 por ciento de sus secuencias de ADN, mientras que el 0,1 por ciento restante presenta las variantes genéticas que influyen en sus diferentes riesgos de enfermedad o en sus distintas respuestas frente a los medicamentos. La finalización del Proyecto Genoma Humano hace que se abra una nueva era en el campo de la susceptibilidad genética del huésped. En esta revisión se subrayan los aspectos éticos y prácticos del desarrollo de cohortes genéticas mediante el modelo del Swis HIV Cohort Study (AU)