Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma.

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression.

Ship collision risk threatens whales across the world's oceans.

After the near-complete cessation of commercial whaling, ship collisions have emerged as a primary threat to large whales, but knowledge of collision risk is lacking across most of the world's oceans. We compiled a dataset of 435,000 whale locations to generate global distribution models for four globally ranging species. We then combined >35 billion positions from 176,000 ships to produce a global estimate of whale-ship collision risk.

Lateralized nodose ganglia gene expression implicates cholecystokinin receptors in interoceptive reward signaling.

The vagus nerves are important carriers of sensory information from the viscera to the central nervous system. Emerging evidence suggests that sensory signaling through the right, but not the left, vagus nerve evokes striatal dopamine release and reinforces appetitive behaviors. However, the extent to which differential gene expression within vagal sensory neurons contributes to this asymmetric reward-related signaling remains unknown.

The GPCR adaptor protein Norbin controls the trafficking of C5aR1 and CXCR4 in mouse neutrophils.

Norbin (Neurochondrin, NCDN) is a G protein-coupled receptor (GPCR) adaptor protein known for its importance in neuronal function. Norbin works by binding to numerous GPCRs, controlling their steady-state trafficking and sometimes their agonist-induced internalization, as well as their signaling. We recently showed that Norbin is expressed in neutrophils, limits the surface levels of the GPCRs C5aR1 and CXCR4 in neutrophils, and suppresses neutrophil-mediated innate immunity.

ERS statement on benign pleural effusions in adults.

The incidence of non-malignant pleural effusions far outweighs that of malignant pleural effusions and is estimated to be at least 3-fold higher. These so-called benign effusions do not follow a "benign course" in many cases, with mortality rates matching and sometimes exceeding those of malignant pleural effusions. In addition to the impact on patients, healthcare systems are also significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on non-malignant pleural effusions (excluding empyema).

Transformation of metallo-elastomer grafts in a carotid artery interposition model over a year.

Current vascular grafts, primarily Gore-Tex® and Dacron®, don't integrate with the host and have low patency in small-diameter vessels (<6 mm). Biomaterials that possess appropriate viscoelasticity, compliance, and high biocompatibility are essential for their application in small blood vessels. We have developed metal ion crosslinked poly(propanediol-co-(hydroxyphenyl methylene)amino-propanediol sebacate) (M-PAS), a biodegradable elastomer with a wide range of mechanical properties.

Budget impact of the Walk With Ease program for knee osteoarthritis.

Objective: Walk With Ease (WWE) is an effective low-cost walking program. We estimated the budget impact of implementing WWE in persons with knee osteoarthritis (OA) as a measure of affordability that can inform payers' funding decisions.

Methods: We estimated changes in two-year healthcare costs with and without WWE.

Frequency Specific Optogenetic Stimulation of the Locus Coeruleus Induces Task-Relevant Plasticity in the Motor Cortex.

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production.

The Rac-GEF Tiam1 controls integrin-dependent neutrophil responses.

Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere.

Ecological forecasts for marine resource management during climate extremes.

Forecasting weather has become commonplace, but as society faces novel and uncertain environmental conditions there is a critical need to forecast ecology. Forewarning of ecosystem conditions during climate extremes can support proactive decision-making, yet applications of ecological forecasts are still limited. We showcase the capacity for existing marine management tools to transition to a forecasting configuration and provide skilful ecological forecasts up to 12 months in advance.

Expressed emotion and early treatment response in family-based treatment for adolescent anorexia nervosa.

This study examined the effect of pre-treatment levels of parental expressed emotion (EE) on early treatment response for adolescent anorexia nervosa (AN). Data were collected from 121 adolescents, ages 12-18, who met DSM-IV criteria for AN excluding the amenorrhea criterion, and their parents. Participants were randomized to family-based treatment (FBT) or adolescent-focused therapy (AFT).

The GPCR adaptor protein Norbin regulates S1PR1 trafficking and the morphology, cell cycle and survival of PC12 cells.

Norbin is an adaptor protein that binds numerous G protein-coupled receptors (GPCRs), is highly expressed in neurons, and is essential for a functioning nervous system in rodent models. Yet, beyond its control of neurite outgrowth and synaptic plasticity, few cellular roles of Norbin have been investigated to date. Furthermore, while Norbin is known to regulate the steady-state cell surface levels of several GPCRs, only in one case has the protein been shown to control the agonist-induced receptor internalisation which serves to attenuate GPCR signalling.

Selection of planning unit size in dynamic management strategies to reduce human-wildlife conflict.

Conservation planning traditionally relies upon static reserves; however, there is increasing emphasis on dynamic management (DM) strategies that are flexible in space and time. Due to its novelty, DM lacks best practices to guide design and implementation. We assessed the effect of planning unit size in a DM tool designed to reduce entanglement of protected whales in vertical ropes of surface buoys attached to crab traps in the lucrative U.

Clinical characteristics of chylothorax: results from the International Collaborative Effusion database.

Background: Chylothorax is an uncommon medical condition for which limited data are available regarding the contemporary aetiology, management and outcomes. The goal of this study was to better define these poorly characterised features.

Methods: The medical records of adult patients diagnosed with chylothorax at 12 centres across Europe, America and South Africa from 2009-2021 were retrospectively reviewed.

Cancer Screening, Incidental Detection, and Overdiagnosis.

Background: In the past, patients were only diagnosed with cancer because they had symptoms. Now, because of screening and incidental detection, some patients are diagnosed with cancer when they are asymptomatic. While this shift is typically viewed as desirable, it has produced an unfortunate side-effect: it is now possible to be diagnosed with a cancer not destined to cause symptoms or death-a phenomenon labeled as overdiagnosis.

Impacts of marine heatwaves on top predator distributions are variable but predictable.

Marine heatwaves cause widespread environmental, biological, and socio-economic impacts, placing them at the forefront of 21st-century management challenges. However, heatwaves vary in intensity and evolution, and a paucity of information on how this variability impacts marine species limits our ability to proactively manage for these extreme events. Here, we model the effects of four recent heatwaves (2014, 2015, 2019, 2020) in the Northeastern Pacific on the distributions of 14 top predator species of ecological, cultural, and commercial importance.