Intrinsic and environmental drivers of pairwise cohesion in wild Canis social groups.

Animals within social groups respond to costs and benefits of sociality by adjusting the proportion of time they spend in close proximity to other individuals in the group (cohesion). Variation in cohesion between individuals, in turn, shapes important group-level processes such as subgroup formation and fission-fusion dynamics. Although critical to animal sociality, a comprehensive understanding of the factors influencing cohesion remains a gap in our knowledge of cooperative behavior in animals.

Mu-opioid receptor knockout on Foxp2-expressing neurons reduces aversion-resistant alcohol drinking.

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1).

Genes Regulate Purkinje Cell Diversity in Cerebellar Development and Evolution.

Mammalian cerebellar development is thought to be influenced by distinct Purkinje cell (PC) subtypes. However, the degree of PC heterogeneity and the molecular drivers of this diversity have remained unclear, hindering efforts to manipulate PC diversification and assess its role in cerebellar development. Here, we demonstrate the critical role of genes in cerebellar development by regulating PC diversification.

Development of methodology to support molecular endotype discovery from synovial fluid of individuals with knee osteoarthritis: The STEpUP OA consortium.

Objectives: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis.

Methods: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.

Cholinergic mu-opioid receptor deletion alters reward preference and aversion-resistance.

The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms.

Mu-opioid receptor knockout on Foxp2-expressing neurons reduces aversion-resistant alcohol drinking.

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1fl/fl).

Cholinergic mu-opioid receptor deletion alters reward preference and aversion-resistance.

Heavy alcohol use and binge drinking are important contributors to alcohol use disorder (AUD). The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors.

Tetracenomycin X sequesters peptidyl-tRNA during translation of QK motifs.

As antimicrobial resistance threatens our ability to treat common bacterial infections, new antibiotics with limited cross-resistance are urgently needed. In this regard, natural products that target the bacterial ribosome have the potential to be developed into potent drugs through structure-guided design, provided their mechanisms of action are well understood. Here we use inverse toeprinting coupled to next-generation sequencing to show that the aromatic polyketide tetracenomycin X primarily inhibits peptide bond formation between an incoming aminoacyl-tRNA and a terminal Gln-Lys (QK) motif in the nascent polypeptide.

Assembly mechanism and cryoEM structure of RecA recombination nucleofilaments from Streptococcus pneumoniae.

RecA-mediated homologous recombination (HR) is a key mechanism for genome maintenance and plasticity in bacteria. It proceeds through RecA assembly into a dynamic filament on ssDNA, the presynaptic filament, which mediates DNA homology search and ordered DNA strand exchange. Here, we combined structural, single molecule and biochemical approaches to characterize the ATP-dependent assembly mechanism of the presynaptic filament of RecA from Streptococcus pneumoniae (SpRecA), in comparison to the Escherichia coli RecA (EcRecA) paradigm.

Effects of early life stress paired with adolescent alcohol consumption on two-bottle choice alcohol drinking behaviors in mice.

Background: In humans, early life stress (ELS) is associated with an increased risk for developing both alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). We previously used an infant footshock model that produces stress-enhanced fear learning (SEFL) in rats and mice and increases aversion-resistant alcohol drinking in rats to explore this shared predisposition. The goal of the current study was to extend this model of comorbid PTSD and AUD to male and female C57BL/6J mice.

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data.

Objective: The FOURIER trial showed a benefit of the PCSK9 inhibitor evolocumab over placebo with respect to cardiovascular outcomes in patients with cardiovascular disease. However, we observed some inconsistencies between the information in the Clinical Study Report (CSR) and that in the 2017 primary trial results publication. We aimed to restore the mortality data in the FOURIER trial based on the information contained in the death narratives in the CSR.

The current state of the osteoarthritis drug development pipeline: a comprehensive narrative review of the present challenges and future opportunities.

In this narrative review article, we critically assess the current state of the osteoarthritis (OA) drug development pipeline. We discuss the current state-of-the-art in relation to the development and evaluation of candidate disease-modifying OA drugs (DMOADs) and the limitations associated with the tools and methodologies that are used to assess outcomes in OA clinical trials. We focus on the definition of DMOADs, highlight the need for an updated definition in the form of a consensus statement from all the major stakeholders, including academia, industry, regulatory agencies, and patient organizations, and provide a summary of the results of recent clinical trials of novel DMOAD candidates.

An open-label, single-arm trial of cryoneurolysis for improvements in pain, activities of daily living and quality of life in patients with symptomatic ankle osteoarthritis.

Objective: Cryoneurolysis, cold-induced reversible conduction block of peripheral nerves, is an effective treatment for reducing knee osteoarthritis (OA) symptoms and opioid use following knee arthroplasty. There are however, limited data concerning its use for ankle OA. Our aim was to assess clinically significant long-term symptomatic relief of ankle OA with cryoneurolysis.

A prebifurcated axillobifemoral polytetrafluoroethylene graft simplifies carotid to carotid to subclavian bypass.

The use of thoracic endovascular aortic repair for thoracic aortic disease will necessitate cervical debranching in cases involving the proximal arch. We have presented the case of a 57-year-old athletic woman who had developed a type A dissection that extended to the bilateral iliac arteries. After hemiarch repair, she underwent staged cervical debranching with carotid-carotid-subclavian bypass using a prebifurcated axillobifemoral graft and subsequent thoracic endovascular aortic repair.

Extra-Anatomic Bypass and Excision is Superior to Graft Salvage Attempts with Antibiotic Beads to Treat Vascular Graft Infections in the Groin.

Background: This study aimed to determine if conventional extra-anatomic bypass and graft removal versus aggressive attempts at graft preservation have better survival and limb salvage in patients with localized groin wound infections of vascular grafts.

Methods: We conducted a retrospective review of 53 consecutive patients with vascular graft infections presenting in the groin. Treatment groups consisted of group 1 (extra-anatomic bypass and graft excision, n = 22) and group 2 (initial graft preservation attempts with utilization of antibiotic beads, n = 31).

A genome-led study on the pathogenesis of Fusobacterium necrophorum infections.

Fusobacterium necrophorum causes a range of mild to life threatening infections and there is uncertainty in terms of diagnosis and treatment due to the lack of knowledge on their pathogenic mechanisms. This study characterised genomes of F. necrophorum to compare their virulence factors and investigate potential infection markers.

Impact of an Ultrasound Demonstration on Vascular Surgery Interest in Preclinical Medical Students.

Background: One strategy to address the impending shortage of vascular surgeons is to augment interest in the trainee pipeline. Endovascular procedures are unique to vascular surgery (VS) and endovascular simulations have proven effective at generating VS interest in the past. Like endovascular techniques, the use of ultrasound (US) testing in VS is unique among medical specialties.

Survival of primary ankle replacements: data from global joint registries.

Background: Ankle arthroplasty, commonly known as ankle replacement, is a surgical procedure for treating end-stage ankle osteoarthritis. Whilst evidence shows good clinical results after surgery, little is known of the long-term survival of ankle replacements and the need for ankle revision. Using more recent implant data and long-term data, there is now opportunity to examine at a population-level the survival rate for ankle implants, to examine between-country differences in ankle revision surgery, and to compare temporal trends in revision rates between countries.

Foot and ankle pain and risk of incident knee osteoarthritis and knee pain: Data from the Multicentre Osteoarthritis Study.

Objectives: To examine whether foot and/or ankle pain increases the risk of knee OA.

Design: We utilised longitudinal data from the Multicentre Osteoarthritis Study (MOST); a community-based cohort of risk factors for knee OA. Participants without frequent knee pain (clinic visit only) and radiographic knee OA (RKOA) at baseline and, with no evidence of inflammatory musculoskeletal disease and a history of knee-related surgery were followed for up to 84-months for incident outcomes; i) RKOA (Kellgren-Lawrence (KL) ≥2), ii) symptomatic RKOA (RKOA and frequent pain in the same knee) and iii) frequent knee pain only.

Recreational Physical Activity and Risk of Incident Knee Osteoarthritis: An International Meta-Analysis of Individual Participant-Level Data.

Objective: The effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions.

Methods: Data were acquired from 6 global, community-based cohorts of participants with and those without knee OA.

Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling.

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp.

Association between Markers of Synovial Inflammation, Matrix Turnover and Symptoms in Knee Osteoarthritis: A Cross-Sectional Study.

To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually.

Effect of Heeled Shoes on Joint Symptoms and Knee Osteoarthritis in Older Adults: A 5-Year Follow-Up Study.

Objective: Our aims were to examine the effects of heeled shoes on incident knee osteoarthritis (OA) and joint pain.

Methods: We used longitudinal data from the Chingford 1000 Women Study (Chingford Study), a prospective cohort of women aged 50 years or older. Participants with musculoskeletal disorders and/or a history of knee-related injury/surgery were excluded.