Continuous collective analysis of chemical reactions.

The automated synthesis of small organic molecules from modular building blocks has the potential to transform our capacity to create medicines and materials. Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed.

Advances in antimicrobial orthopaedic devices and FDA regulatory challenges.

Implant-associated infections, caused by the formation of biofilms especially antibiotic resistant organisms, are among the leading causes of orthopaedic implant failure. Current strategies to combat infection and biofilm focus on either inhibiting bacterial growth or preventing bacterial adherence that could lead to biofilm creation. Despite research on developing numerous antimicrobial orthopaedic devices, to date, no robust solution has been translated to the clinic.

Molecular and genetic characterization of sex-linked orange coat color in the domestic cat.

The mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X-inactivation in female tortoiseshell and calico cats. Unlike the situation for most coat color genes, there is no apparent homolog for in other mammals. We show that the is caused by a 5 kb deletion that leads to ectopic and melanocyte-specific expression of the ( ) gene.

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.

Symbiosis between the Javan rhinoceros and slender-billed crow: A novel inferred cleaning mutualism.

Over the past century, the Javan rhinoceroses' () secluded nature and low population size have led to a gap in knowledge of their ecology. With fewer than 80 individuals surviving in a single population in West Java, Indonesia, the Javan rhinoceros is one of the most critically endangered mammals in the world. As part of a pilot bioacoustics study of the Javan rhinoceros in 2019, we systematically reviewed camera trap footage from the core Javan rhinoceros range in Ujung Kulon National Park (UKNP).

Malignant Pericardial Effusion: A Systematic Review.

Background: Malignant pericardial effusion (Eff) is often asymptomatic and has an unknown prevalence, due to its occult presentation. The condition often is identified postmortem on autopsy, and it is associated with a poor prognosis. Given the late presentation of malignant pericardial Effs, a minimal volume of literature has examined the epidemiology, clinical characteristics, and outcomes of these complex patients.

Transgender Women With Suppressed Testosterone Display Lower Burden of Coronary Disease Than Matched Cisgender Men.

Context: Cardiovascular disease (CVD) in transgender women (TW) may be affected by gender-affirming hormone therapy (GAHT) and HIV, but few data compare TW on contemporary GAHT to well-matched controls.

Objective: We compared CVD burden and biomarker profiles between TW and matched cisgender men (CM).

Methods: Adult TW on GAHT (n = 29) were recruited for a cross-sectional study (2018-2020).

Nascent transcription reveals regulatory changes in extremophile fishes inhabiting hydrogen sulfide-rich environments.

Regulating transcription allows organisms to respond to their environment, both within a single generation (plasticity) and across generations (adaptation). We examined transcriptional differences in gill tissues of fishes in the species complex (family Poeciliidae), which have colonized toxic springs rich in hydrogen sulfide (HS) in southern Mexico. There are gene expression differences between sulfidic and non-sulfidic populations, yet regulatory mechanisms mediating this gene expression variation remain poorly studied.

Evolutionary Rate Shifts in Coding and Regulatory Regions Underpin Repeated Adaptation to Sulfidic Streams in Poeciliid Fishes.

Adaptation to extreme environments often involves the evolution of dramatic physiological changes. To better understand how organisms evolve these complex phenotypic changes, the repeatability and predictability of evolution, and possible constraints on adapting to an extreme environment, it is important to understand how adaptive variation has evolved. Poeciliid fishes represent a particularly fruitful study system for investigations of adaptation to extreme environments due to their repeated colonization of toxic hydrogen sulfide-rich springs across multiple species within the clade.

Immune checkpoint inhibitors and pericardial disease: a systematic review.

Introduction: Despite the growing use of immune checkpoint inhibitors (ICI) in cancer treatment, data regarding ICI-associated pericardial disease are primarily derived from case reports and case series. ICI related pericardial disease can be difficult to diagnose and is associated with significant morbidity. We conducted a systematic review to further characterize the epidemiology, clinical presentation, and outcomes of this patient population.

Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease.

The leading cause of death among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte-specific peroxisome proliferator-activated receptor alpha knockout ( ), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance.

sequence type 147: a high-risk clone increasingly associated with plasmids carrying both resistance and virulence elements.

The first hybrid resistance/virulence plasmid, combining elements from virulence plasmids described in hypervirulent types of with those from conjugative resistance plasmids, was described in an isolate of sequence type (ST) 147 from 2016. Subsequently, this type has been increasingly associated with these plasmids. The extent of carriage of hybrid virulence/resistance plasmids in nosocomial isolates of requires further investigation.

Ancestry dynamics and trait selection in a designer cat breed.

The Bengal cat breed was developed from intercrosses between the Asian leopard cat, Prionailurus bengalensis, and the domestic cat, Felis catus, with a last common ancestor approximately 6 million years ago. Predicted to derive ∼94% of their genome from domestic cats, regions of the leopard cat genome are thought to account for the unique pelage traits and ornate color patterns of the Bengal breed, which are similar to those of ocelots and jaguars. We explore ancestry distribution and selection signatures in the Bengal breed by using reduced representation and whole-genome sequencing from 947 cats.

Multicenter evaluation of left ventricular assist device implantation with or without ECMO bridge in cardiogenic shock.

Background: The efficacy of extracorporeal membrane oxygenation (ECMO) as a bridge to left ventricular assist device (LVAD) remains unclear, and recipients of the more contemporary HeartMate 3 (HM3) LVAD are not well represented in previous studies. We therefore undertook a multicenter, retrospective study of this population.

Methods And Results: INTERMACS 1 LVAD recipients from five U.

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.

A Systematic Review and Meta-analysis of Chemical Exposures and Attention-Deficit/Hyperactivity Disorder in Children.

Exposure to certain chemicals prenatally and in childhood can impact development and may increase risk for attention-deficit/hyperactivity disorder (ADHD). Leveraging a larger set of literature searches conducted to synthesize results from longitudinal studies of potentially modifiable risk factors for childhood ADHD, we present meta-analytic results from 66 studies that examined the associations between early chemical exposures and later ADHD diagnosis or symptoms. Studies were eligible for inclusion if the chemical exposure occurred at least 6 months prior to measurement of ADHD diagnosis or symptomatology.

Stakeholders' preferences for the design and delivery of virtual care services: A systematic review of discrete choice experiments.

This systematic review aimed to synthesise evidence from discrete choice experiments (DCEs) eliciting preferences for virtual models of care, as well as to assess the quality of those DCEs and compare the relative preferences for different stakeholder groups. Articles were included if published between January 2010 and December 2022. Data were synthesised narratively, and attributes were assessed for frequency, significance, and relative importance using a semi-quantitative approach.

The role of diabetes distress in Diabulimia.

Importance: Diabulimia is a disordered eating behavior in which a person with type 1 diabetes withholds insulin injections to lose weight. It is thought that the psychosocial stress of managing this chronic disease, which is termed diabetes distress, may contribute to developing diabulimia.

Objective: This paper explores links between diabetes distress and diabulimia and their relevance to the diagnosis and treatment of diabulimia by assessing whether people with diabulimia report measurable evidence of diabetes distress.

Region-specific Wnt signaling responses promote gastric polyp formation in patients with familial adenomatous polyposis.

Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding nonpolyp corpus biopsies and organoids from patients with FAP for comparative studies.

Prospective diagnostic test accuracy of transvaginal ultrasound posterior approach for uterosacral ligament and torus uterinus deep endometriosis.

Objective: To determine the diagnostic test accuracy of transvaginal ultrasound (TVS) using a standardized technique for the diagnosis of deep endometriosis (DE) of the uterosacral ligaments (USLs) and adjacent torus uterinus (TU).

Methods: This was a prospective diagnostic test accuracy study conducted at the McMaster University Medical Center Tertiary Endometriosis Clinic, Hamilton, ON, Canada. Consecutive participants were enrolled if they successfully underwent TVS and surgery by our team from 10 August 2020 to 31 October 2021.

Dental referrals for patients with diabetes: survey of barriers and enablers for medical and health professionals.

Background: Oral health care improves diabetes management; however, medical and other health practitioners do not commonly refer their patients with diabetes for oral health care. This study aimed to understand barriers to and enablers of dental referrals for patients with diabetes.

Methods: Quantitative data were collected from a cross-sectional survey of health care providers attending a virtual Grand Rounds on the relationship between oral health and diabetes.

Differential sensitivity to Wnt signaling gradients in human gastric organoids derived from corpus and antrum.

Wnt signaling regulates gastric stem cell proliferation and differentiation. Although similar Wnt gradients exist within the corpus and antrum of the human stomach, there are striking differences in gland architecture and disease manifestation that suggest Wnt may differentially regulate progenitor cell function in each compartment. In this study, we tested sensitivities to Wnt activation in human gastric corpus and antral organoids to determine whether progenitor cells have region-specific differences in Wnt responsiveness.

Increased genetic diversity and immigration after West Nile virus emergence in American crows: No evidence for a genetic bottleneck.

Infectious diseases can cause steep declines in wildlife populations, leading to changes in genetic diversity that may affect the susceptibility of individuals to infection and the overall resilience of populations to pathogen outbreaks. Here, we examine evidence for a genetic bottleneck in a population of American crows (Corvus brachyrhynchos) before and after the emergence of West Nile virus (WNV). More than 50% of marked birds in this population were lost over the 2-year period of the epizootic, representing a 10-fold increase in adult mortality.