Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

"Just clearly the right thing to do": perspectives of correctional services leaders on moving governance of health-care in custody.

Purpose: Governance models are a defining characteristic of health-care systems, yet little research is available about the governance of health-care delivered in correctional facilities. This study aims to explore the perspectives of correctional services leaders in British Columbia, Canada, on the motivations for transferring responsibility for health-care services in provincial correctional facilities to the Ministry of Health, as well as key lessons learned.

Design/methodology/approach: Eight correctional services leaders participated in one-on-one interviews between September 2019 and February 2020.

RG7774 (Vicasinabin), an orally bioavailable cannabinoid receptor 2 (CB2R) agonist, decreases retinal vascular permeability, leukocyte adhesion, and ocular inflammation in animal models.

Introduction: Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents.

Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry.

Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon-carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners.

Impact of connected dispensing technology with advanced analytics in a multicenter health system.

Purpose: This study was designed to evaluate the impact of enterprise inventory optimization (EIO) technology and analytics on pharmacy labor, costs, and medication availability within a large integrated delivery network (IDN).

Methods: This article describes a mixed-methods, postmarket observational study assessing the impact of a solution of disparate technologies including automated dispensing cabinets (ADCs), centralized pharmacy inventory software, and controlled substance vaults connected by an inventory optimization analytics (IOA) tool. Four study modules were implemented over a 10-month period.

Receipt of Opioid Agonist Treatment in provincial correctional facilities in British Columbia is associated with a reduced hazard of nonfatal overdose in the month following release.

Background: In many jurisdictions, policies restrict access to Opioid Agonist Treatment (OAT) in correctional facilities. Receipt of OAT during incarceration is associated with reduced risk of fatal overdose after release but little is known about the effect on nonfatal overdose. This study aimed to examine the association between OAT use during incarceration and nonfatal overdose in the 30 days following release.

sp -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp -rich molecules.

The effect of reef morphology on coral recruitment at multiple spatial scales.

Coral reefs are in decline worldwide, making it increasingly important to promote coral recruitment in new or degraded habitat. Coral reef morphology-the structural form of reef substrate-affects many aspects of reef function, yet the effect of reef morphology on coral recruitment is not well understood. We used structure-from-motion photogrammetry and airborne remote sensing to measure reef morphology (rugosity, curvature, slope, and fractal dimension) across a broad continuum of spatial scales and evaluated the effect of morphology on coral recruitment in three broadcast-spawning genera.

"A different sense of what we do here, who we are and what we deliver": Provider perspectives on the effects of a change in governance of healthcare services in correctional facilities in British Columbia.

In 2017, British Columbia (BC) transferred responsibility for healthcare services in provincial correctional facilities from the Ministry of Public Safety and Solicitor General to the Ministry of Health. This study explored how healthcare leadership perceived the impact of the transfer on services, work-life, and job satisfaction. We conducted one-on-one interviews ( = 8) with healthcare managers and medical and administrative leadership within Correctional Health Services.

Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning.

Late-stage functionalization is an economical approach to optimize the properties of drug candidates. However, the chemical complexity of drug molecules often makes late-stage diversification challenging. To address this problem, a late-stage functionalization platform based on geometric deep learning and high-throughput reaction screening was developed.

Identifying opportunities for late-stage C-H alkylation with high-throughput experimentation and in silico reaction screening.

Enhancing the properties of advanced drug candidates is aided by the direct incorporation of specific chemical groups, avoiding the need to construct the entire compound from the ground up. Nevertheless, their chemical intricacy often poses challenges in predicting reactivity for C-H activation reactions and planning their synthesis. We adopted a reaction screening approach that combines high-throughput experimentation (HTE) at a nanomolar scale with computational graph neural networks (GNNs).

Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions.

mRNA LNPs can experience a decline in activity over short periods (ranging from weeks to months). As a result, they require frozen storage and transportation conditions to maintain their full functionality when utilized. Currently approved commercially available mRNA LNP vaccines also necessitate frozen storage and supply chain management.

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties.

Antisense-oligonucleotides (ASOs) are a promising drug modality for the treatment of neurological disorders, but the currently established route of administration intrathecal delivery is a major limitation to its broader clinical application. An attractive alternative is the conjugation of the ASO to an antibody that facilitates access to the central nervous system (CNS) after peripheral application and target engagement at the blood-brain barrier, followed by transcytosis. Here, we show that the diligent conjugate design of Brainshuttle-ASO conjugates is the key to generating promising delivery vehicles and thereby establishing design principles to create optimized molecules with drug-like properties.

Neural signals predict information sharing across cultures.

Information sharing influences which messages spread and shape beliefs, behavior, and culture. In a preregistered neuroimaging study conducted in the United States and the Netherlands, we demonstrate replicability, predictive validity, and generalizability of a brain-based prediction model of information sharing. Replicating findings in Scholz et al.

Inbred SJL mice recapitulate human resistance to infection due to differential immune activation.

Cryptococcosis studies often utilize the common C57BL/6J mouse model. Unfortunately, infection in these mice fails to replicate the basic course of human disease, particularly hampering immunological studies. This work demonstrates that SJL/J mice can recapitulate human infection better than other mouse strains.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study.

Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer.

Novelty and uncertainty differentially drive exploration across development.

Across the lifespan, individuals frequently choose between exploiting known rewarding options or exploring unknown alternatives. A large body of work has suggested that children may explore more than adults. However, because novelty and reward uncertainty are often correlated, it is unclear how they differentially influence decision-making across development.

Leaf spectroscopy of resistance to Ceratocystis wilt of 'Ōhi'a.

Plant pathogens are increasingly compromising forest health, with impacts to the ecological, economic, and cultural goods and services these global forests provide. One response to these threats is the identification of disease resistance in host trees, which with conventional methods can take years or even decades to achieve. Remote sensing methods have accelerated host resistance identification in agricultural crops and for a select few forest tree species, but applications are rare.

Foliar functional and genetic variation in a keystone Hawaiian tree species estimated through spectroscopy.

Imaging spectroscopy has the potential to map closely related plant taxa at landscape scales. Although spectral investigations at the leaf and canopy levels have revealed relationships between phylogeny and reflectance, understanding how spectra differ across, and are inherited from, genotypes of a single species has received less attention. We used a common-garden population of four varieties of the keystone canopy tree, Metrosideros polymorpha, from Hawaii Island and four F1-hybrid genotypes derived from controlled crosses to determine if reflectance spectra discriminate sympatric, conspecific varieties of this species and their hybrids.

HEMATOLOGICAL INDICES RELATED TO VITAMIN D DEFICIENCY IN OBESE CHILDREN.

Introduction: Vitamin D is involved in differentiation and induction of erythropoiesis in bone marrow cells.

Aim: We compared the serum 25(OH) vitamin D level in obese children control and found correlations between vitamin D level and hematological indices in obese children.

Materials And Methods: 25 overweight and obese patients and 15 normal weight children were enrolled in an observational study .

Diagnosis of vascular parkinsonism: A new tool for gait hypokinesia occurring in older persons.

Introduction: Reliable diagnosis of vascular parkinsonism (VaP) in the presence of a gait hypokinesia is an issue that is encountered in geriatrics. The EVAMAR-AGEX study was focusing on the phenomenon of recurrent falls in older persons (OP) with this parkinsonian gait. The present study is focusing on the diagnosis of VaP-related parkinsonian gait by developing a diagnostic guidance model adapted to OP.

In silico, in vitro and in vivo characterization of host-associated Latilactobacillus curvatus strains for potential probiotic applications in farmed Atlantic salmon (Salmo salar).

Salmon aquaculture is the fastest growing animal protein production system in the world; however, intensive farming leads to poor weight gain, stress, and disease outbreaks. Probiotics offer the potential to enhance growth performance and feed efficiency in Atlantic salmon, as well as immunostimulate fish against common pathogens, benefitting farmers and consumers with more efficient production. Here, we isolated and identified 900 native microbial isolates including 18 Lactobacilli from the farmed salmon intestines.

Rapid F- and F-Difluoromethylation through Desulfurative Fluorination of Transient N-, O-, and C-Linked Dithioles.

The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O-H, N-H and C-H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride.

Reactive oxygen species function as signaling molecules in controlling plant development and hormonal responses.

Reactive oxygen species (ROS) serve as second messengers in plant signaling pathways to remodel plant growth and development. New insights into how enzymatic ROS-producing machinery is regulated by hormones or localized during development have provided a framework for understanding the mechanisms that control ROS accumulation patterns. Signaling-mediated increases in ROS can then modulate the activity of proteins through reversible oxidative modification of specific cysteine residues.