Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.

TREM2 is a signaling receptor expressed on microglia that has emerged as an important drug target for Alzheimer's disease and other neurodegenerative diseases. While a number of TREM2 ligands have been identified, little is known regarding the structural details of how they engage. To better understand this, we created a protein library of 28 different TREM2 variants that could be used to map interactions with various ligands using biolayer interferometry.

Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.

TREM2 is a signaling receptor expressed on microglia that has emerged as an important drug target for Alzheimer's disease and other neurodegenerative diseases. While a number of TREM2 ligands have been identified, little is known regarding the structural details of how they engage. To better understand this, we created a protein library of 28 different TREM2 variants that could be used to map interactions with various ligands using biolayer interferometry.

Harnessing private sector strategies for family planning to deliver the Dual Prevention Pill, the first multipurpose prevention technology with pre-exposure prophylaxis, in an expanding HIV prevention landscape.

Introduction: The Dual Prevention Pill (DPP) combines oral pre-exposure prophylaxis (PrEP) with oral contraception (OC) to prevent HIV and pregnancy. Noting the significant role played by the private sector in delivering family planning (FP) services in countries with high HIV burden, high level of private sector OC uptake, and the recent growth in self-care and technology-based private sector channels, we undertook qualitative research in Kenya, South Africa and Zimbabwe to prioritize private sector service delivery approaches for the introduction of the DPP.

Methods: Between March 2022 and February 2023, we conducted a literature review and key informant interviews with 34 donors and implementing partners, 19 government representatives, 17 private sector organizations, 13 pharmacy and drug shop representatives, and 12 telehealth agencies to assess the feasibility of DPP introduction in private sector channels.

Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells.

The Ca-activated Cl channel regulator CLCA1 potentiates the activity of the Ca-activated Cl channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca-dependent Cl current (I) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate I in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA.

Institutions and institutionalisation: They're part of everyday life.

Background: Institutions are established patterns of recurrent social relationships playing a fundamental part in all our lives. The family is the best-known institution, but other 'total' institutions serve as organisations directly affecting the lives of many individuals in the healthcare sector.

Objective: This paper examines the sociological theory of institutionalisation as applied to individuals admitted to aged-care facilities, where the complete life-rounds of inmates occur within clearly defined limits.

Maternal pertussis immunization and the blunting of routine vaccine effectiveness: a meta-analysis and modeling study.

A key goal of pertussis control is to protect infants too young to be vaccinated, the age group most vulnerable to this highly contagious respiratory infection. In the last decade, maternal immunization has been deployed in many countries, successfully reducing pertussis in this age group. Because of immunological blunting, however, this strategy may erode the effectiveness of primary vaccination at later ages.

Barriers to and Facilitators of Implementing Guidelines for Detecting Familial Hypercholesterolaemia in Australia.

Background: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings.

Charting the spatial dynamics of early SARS-CoV-2 transmission in Washington state.

The spread of SARS-CoV-2 has been geographically uneven. To understand the drivers of this spatial variation in SARS-CoV-2 transmission, in particular the role of stochasticity, we used the early stages of the SARS-CoV-2 invasion in Washington state as a case study. We analysed spatially-resolved COVID-19 epidemiological data using two distinct statistical analyses.

Enhancing the Detection and Care of Heterozygous Familial Hypercholesterolemia in Primary Care: Cost-Effectiveness and Return on Investment.

Background: Heterozygous familial hypercholesterolemia (HeFH) is under-detected and undertreated. A general practitioner-led screening and care program for HeFH effectively identified and managed patients with HeFH. We evaluated the cost-effectiveness and the return on investment of an enhanced-care strategy for HeFH in primary care in Australia.

Disentangling the causes of mumps reemergence in the United States.

Over the past two decades, multiple countries with high vaccine coverage have experienced resurgent outbreaks of mumps. Worryingly, in these countries, a high proportion of cases have been among those who have completed the recommended vaccination schedule, raising alarm about the effectiveness of existing vaccines. Two putative mechanisms of vaccine failure have been proposed as driving observed trends: 1) gradual waning of vaccine-derived immunity (necessitating additional booster doses) and 2) the introduction of novel viral genotypes capable of evading vaccinal immunity.

Assessment of spatial transcriptomics for oncology discovery.

Tumor heterogeneity is a major challenge for oncology drug discovery and development. Understanding of the spatial tumor landscape is key to identifying new targets and impactful model systems. Here, we test the utility of spatial transcriptomics (ST) for oncology discovery by profiling 40 tissue sections and 80,024 capture spots across a diverse set of tissue types, sample formats, and RNA capture chemistries.

Containing novel SARS-CoV-2 variants at source is possible with high-intensity sequencing.

Throughout the COVID-19 pandemic, control of transmission has been repeatedly thwarted by the emergence of variants of concern (VOC) and their geographic spread. Key questions remain regarding effective means of minimizing the impact of VOC, in particular the feasibility of containing them at source, in light of global interconnectedness. By analysing a stochastic transmission model of COVID-19, we identify the appropriate monitoring requirements that make containment at source feasible.

Participant experiences of intervention to detect and manage familial hypercholesterolaemia in Australian general practice: A qualitative descriptive study.

Background And Objectives: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting.

Method: Qualitative descriptive methodology was used.

Production of Eukaryotic Glycoproteins for Structural and Functional Studies Using Expi293F Cells.

Milligram quantities of pure proteins are required for structural, functional, and pharmaceutical screening studies. These requirements can be challenging for a majority of important therapeutic targets that are secreted glycoproteins, receptors, membrane proteins, or large cytosolic complexes. Here, we present protocols for producing and purifying large amounts of secreted glycoproteins using the mammalian cell-based Expi293F system via large-scale transient transfection.

Early warning signals of infectious disease transitions: a review.

Early warning signals (EWSs) are a group of statistical time-series signals which could be used to anticipate a critical transition before it is reached. EWSs are model-independent methods that have grown in popularity to support evidence of disease emergence and disease elimination. Theoretical work has demonstrated their capability of detecting disease transitions in simple epidemic models, where elimination is reached through vaccination, to more complex vector transmission, age-structured and metapopulation models.

Lrp1 is a host entry factor for Rift Valley fever virus.

Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection.

Awareness of familial hypercholesterolaemia in Australian primary care: A qualitative descriptive study.

Background And Objectives: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices.

Method: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH.

Implications of new clinical practice guidance on familial hypercholesterolaemia for Australian general practitioners.

Background: Familial hypercholesterolaemia (FH) is a monogenic lipid disorder that may be overlooked in the diagnostic process.

Objective: The aim of this article is to review the key areas for identification and management of FH that affect Australian general practitioners (GPs).

Discussion: Recent consensus advice on the care of patients with FH in Australia provides an opportunity for GPs to increase their awareness and skills in diagnosing and managing FH.