A Global Collaborative Comparison of SARS-CoV-2 Antigenicity Across 15 Laboratories.

Setting up a global SARS-CoV-2 surveillance system requires an understanding of how virus isolation and propagation practices, use of animal or human sera, and different neutralisation assay platforms influence assessment of SARS-CoV-2 antigenicity. In this study, with the contribution of 15 independent laboratories across all WHO regions, we carried out a controlled analysis of neutralisation assay platforms using the first WHO International Standard for antibodies to SARS-CoV-2 variants of concern (source: NIBSC). Live virus isolates (source: WHO BioHub or individual labs) or spike plasmids (individual labs) for pseudovirus production were used to perform neutralisation assays using the same serum panels.

Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.

GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.

Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function.

Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called "RING-Bait," which employs an aggregating protein sequence combined with an E3 ubiquitin ligase.

Omega-3 Polyunsaturated Fatty Acids as a Protective Factor for Myopia.

Purpose: Animal models suggest omega-3 polyunsaturated fatty acids (PUFAs) may protect against myopia by modulating choroidal blood perfusion, but clinical evidence is scarce and mixed. We aimed to determine the causality between omega-3 PUFAs and myopia using Mendelian randomization (MR) analysis.

Design: Two-sample MR analysis.

Aggregate-selective removal of pathological tau by clustering-activated degraders.

Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif-containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state-specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins.

Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming.

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms.

Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II hepatocellular carcinoma undergoing surgery? An observational cohort study.

Introduction: The influence of deranged body composition on stage I/II hepatocellular carcinoma (HCC) after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed.

Cholesterol reduction by immunization with a PCSK9 mimic.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively.

Cell-free RNA Liquid Biopsy to Monitor Hematopoietic Stem Cell Transplantation.

Hematopoietic Stem Cell Transplantation (HSCT) is one of the oldest and most successful immunotherapies. Yet, despite long-standing success in the use of HSCT for the treatment of blood cancers and severe immune disorders, monitoring post-transplant complications remains a challenge due to a lack of informative diagnostic tests. Here, we investigate the utility of cell-free RNA (cfRNA) in plasma as a liquid biopsy to monitor allogeneic HSCT recipients during and after treatment.

Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay.

Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yielding the highest protein outputs due to their slow rates of mRNA decay. Here, we demonstrate that CDS-dependent differences in translation initiation and elongation rates lead to differences in translation- and deadenylation-dependent mRNA decay rates, thus explaining the effect of CDS on mRNA half-life.

Engagement in Distance Healthcare Simulation Debriefing: A Concept Development and Framework.

Understanding distance health care simulation debriefing is crucial in light of the increased use of and emerging technology in remote education for reasons of accessibility, global collaboration, and continuous professional development. This article is a confluence of a number of previously published studies designed to serve as a foundation to develop the concept of "engagement in health care distance simulation debriefing" using the Schwartz-Barcott & Kim hybrid mixed methods model. The model uses 3 phases: theoretical (a realist systematic review of the literature), fieldwork (3 exploratory studies and 2 pilot experimental studies), and analytical (analysis of the theoretical and fieldwork findings through expert discussion).

Naturally occurring T cell mutations enhance engineered T cell therapies.

Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells.

Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.

Inherited retinal dystrophies caused by dominant mutations in photoreceptor (PR) cell expressed genes are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery.