Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation.

The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (mA), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between mA and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation.

Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Tracing the transmission of carbapenem-resistant Enterobacterales at the patient: ward environmental nexus.

Introduction: Colonisation and infection with Carbapenem-resistant Enterobacterales (CRE) in healthcare settings poses significant risks, especially for vulnerable patients. Genomic analysis can be used to trace transmission routes, supporting antimicrobial stewardship and informing infection control strategies. Here we used genomic analysis to track the movement and transmission of CREs within clinical and environmental samples.

Leveraging Dual-Ligase Recruitment to Enhance Protein Degradation via a Heterotrivalent Proteolysis Targeting Chimera.

Proteolysis targeting chimera (PROTAC) degraders are typically bifunctional with one E3 ligase ligand connected to one target protein ligand via a linker. While augmented valency has been shown with trivalent PROTACs targeting two binding sites within a given target protein, or used to recruit two different targets, the possibility of recruiting two different E3 ligases within the same compound has not been demonstrated. Here we present dual-ligase recruitment as a strategy to enhance targeted protein degradation.

Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). With the aim of understanding and modulating neosubstrate specificity, we recently reported the discovery of SJ3149 (), a selective and potent molecular glue degrader of CK1α, that is active in multiple cancer cell lines. Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders.

KCL TEST: an open-source inspired asymptomatic SARS-CoV-2 surveillance programme in an academic institution.

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings.

Quality of asynchronous webchats in-person consultations for postpartum depression in China: a cross-sectional, mixed methods study using standardized patients.

Background: Prompt professional care for postpartum depression (PPD) is difficult to obtain in China. Though online consultations improve accessibility and reduce stigma, the quality of services compared to in-person consultations is unclear.

Methods: Five trained, undisclosed "standardized patients" (SPs) made "asynchronous webchats" visits and in-person visits with psychiatrists.

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins.

Prevalence of and optimal screening tool for postpartum depression in a community-based population in China.

Background: Postpartum depression (PPD) is an important public health problem worldwide. China is planning to launch PPD screening in community settings, but there are questions on the community prevalence of PPD and validated screening tools.

Methods: We sought to recruit all eligible new mothers during postnatal home visits in two districts of Changsha, China, and after informed consent, screened them for PPD using three self-administered questionnaires-the Edinburgh Postpartum Depression Scale (EPDS), the Patient Health Questionnaire (PHQ-9), and Whooley Questions for Depression Screening.

Monitoring PROTAC interactions in biochemical assays using Lumit immunoassays.

The discovery of new PROTAC molecules is dependent on robust and high-throughput assays to measure PROTAC-protein interactions and ternary complex formation. Here we present the optimization and execution of Lumit Immunoassays to measure PROTAC binding and ternary complex formation in a biochemical format. We demonstrate how Lumit can be used to rank order affinities of small molecules and PROTACs to BRD4(BD1, BD2) and how to measure PROTAC-mediated ternary complex formation of BRD4(BD1, BD2) and E3 Ligase VHL.

Effectiveness of a community-based peer support service among persons suffering severe mental illness in China.

Background: Community-based peer support service is widely and effectively deployed for persons suffering severe mental illness (SMI) in countries with well-developed outpatient mental health systems. The objective of this study is to evaluate the effectiveness of a 1-year peer service project among persons with SMI implemented in China.

Methods: A total of 101 consumers (service recipients) and 66 family caregivers were recruited at baseline from communities located in Beijing and Chengdu.

Use of a Novel Standardized Administration Protocol Reduces Agitation Pro Re Nata (PRN) Medication Requirements: The Birmingham Agitation Management (BAM) Initiative.

Background: Agitation management is a principal challenge on inpatient psychiatric units. Overreliance on common prescribing strategies of pro re nata (PRN) medication administration is problematic, given the tendencies to have overlapping or unclear indications.

Objective: Piloted project to determine whether a standardized protocol for agitation intervention may reduce PRN medication administration.

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation.

Targeted protein degradation has exploded over the past several years due to preclinical and early clinical therapeutic success of numerous compounds, and the emergence of new degradation modalities, which has broadened the definition of what a degrader is. The most characterized and well-studied small molecule degraders are molecular glues and proteolysis targeting chimeras (PROTACs). These degraders induce a ternary complex between a target protein, degrader, and E3 ligase component, resulting in ubiquitination and subsequent degradation of the target protein the ubiquitin proteasomal system (UPS).

"Whose Fault Is It?" How Rural Chinese Women Explain Intimate Partner Violence: A Qualitative Study.

Women are often the victims of intimate partner violence (IPV). Though China has established its first statute against domestic violence, the service developments for victims fall behind. It is important to assess community members' perceptions of what causes IPV to create interventions to prevent and address IPV.