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Novel binary gene expression tools like the LexA-LexAop system could powerfully enhance studies of metabolism, development, and neurobiology in Drosophila. However, specific LexA drivers for neuroendocrine cells and many other developmentally relevant systems remain limited. In a unique high school biology course, we generated a LexA-based enhancer trap collection by transposon mobilization. The initial collection provides a source of novel LexA-based elements that permit targeted gene expression in the corpora cardiaca, cells central for metabolic homeostasis, and other neuroendocrine cell types. The collection further contains specific LexA drivers for stem cells and other enteric cells in the gut, and other developmentally relevant tissue types. We provide detailed analysis of nearly 100 new LexA lines, including molecular mapping of insertions, description of enhancer-driven reporter expression in larval tissues, and adult neuroendocrine cells, comparison with established enhancer trap collections and tissue specific RNAseq. Generation of this open-resource LexA collection facilitates neuroendocrine and developmental biology investigations, and shows how empowering secondary school science can achieve research and educational goals.

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD. Dysfunction in dorsal striatum, a brain region important for reward and habits, is linked to opioid use disorder (OUD). Here, authors delineate diverse cell populations in human dorsal striatum, revealing altered inflammatory and DNA damage signaling in OUD.

Opioid use disorder (OUD) and deaths from drug overdoses have reached unprecedented levels. Given the enormous impact of the opioid crisis on public health, a more thorough, in-depth understanding of the consequences of opioids on the brain is required to develop novel interventions and pharmacological therapeutics. In the brain, the effects of opioids are far reaching, from genes to cells, synapses, circuits, and ultimately behavior. Accumulating evidence implicates a primary role for the extracellular matrix (ECM) in opioid-induced plasticity of synapses and circuits, and the development of dependence and addiction to opioids. As a network of proteins and polysaccharides, including cell adhesion molecules, proteases, and perineuronal nets, the ECM is intimately involved in both the formation and structural support of synapses. In the human brain, recent findings support an association between altered ECM signaling and OUD, particularly within the cortical and striatal circuits involved in cognition, reward, and craving. Furthermore, the ECM signaling proteins, including matrix metalloproteinases and proteoglycans, are directly involved in opioid seeking, craving, and relapse behaviors in rodent opioid models. Both the impact of opioids on the ECM and the role of ECM signaling proteins in opioid use disorder, may, in part, depend on biological sex. Here, we highlight the current evidence supporting sex-specific roles for ECM signaling proteins in the brain and their associations with OUD. We emphasize knowledge gaps and future directions to further investigate the potential of the ECM as a therapeutic target for the treatment of OUD.

Key summary points Aim To explore the link between polypharmacy, psychotropic medications, and falls risk in a cohort of UK care home residents. Findings Polypharmacy and psychotropic drugs are predictive of falls in UK care home residents. Message Deprescribing interventions relating to psychotropic drugs should continue to be encouraged. Purpose Falls and polypharmacy are both common in care home residents. Deprescribing of medications in residents with increased falls risk is encouraged. Psychotropic medications are known to increase falls risk in older adults. These drugs are often used in care home residents for depression, anxiety, and behavioural and psychological symptoms of dementia. However, a few studies have explored the link between polypharmacy, psychotropic medications, and falls risk in care home residents. Methods This was a prospective cohort study of residents from 84 UK care homes. Data were collected from residents’ care records and medication administration records. Age, diagnoses, gender, number of medications, and number of psychotropic medications were collected at baseline and residents were monitored over three months for occurrence of falls. Logistic regression models were used to assess the effect of multiple medications and psychotropic medication on falls whilst adjusting for confounders. Results Of the 1655 participants, mean age 85 (SD 8.9) years, 67.9% female, 519 (31%) fell in 3 months. Both the total number of regular drugs prescribed and taking ≥ 1 regular psychotropic medication were independent risk factors for falling (adjusted odds ratio (OR) 1.06 (95% CI 1.03–1.09, p  < 0.01) and 1.39 (95% CI 1.10–1.76, p  < 0.01), respectively). The risk of falls was higher in those taking antidepressants ( p  < 0.01) and benzodiazepines ( p  < 0.01) but not antipsychotics ( p  > 0.05). Conclusion In UK care homes, number of medications and psychotropic medications (particularly antidepressants and benzodiazepines) predicted falls. This information can be used to inform prescribing and deprescribing decisions.

Agenesis of the left hepatic lobe is a rare anomaly described as the absence of liver tissue on the left side of the gallbladder fossa or falciform ligament. Here we report a case of agenesis of the left hepatic lobe identified during educational dissection of an 84-year-old male formalin-fixed cadaver. The gross anatomical characteristics, embryological origin, and clinical relevance of this rare variation are described in this report.

Gene expression plasticity can confer physiological plasticity in response to the environment. However, whether epigenetic marks contribute to the dynamics of gene expression is still not well described in most marine invertebrates. Here, we explored the extent and molecular basis of intra- and intergenerational plasticity in the purple sea urchin, Strongylocentrotus purpuratus, by examining relationships between changes in DNA methylation, transcription, and embryo spicule length. Adult urchins were conditioned in the lab for four months to treatments that represent upwelling (~1100μatm pCO2, 13 °C) and non-upwelling conditions (~500μatm pCO2, 17 °C). Embryos spawned from conditioned adults were reared in either the same adult treatment or the reciprocal condition. Maternal conditioning resulted in significantly differentially methylated CpG sites and differential gene expression in the larvae, despite no evidence of maternal effects on embryo spicule length. In contrast, conditions experienced during development resulted in significant differences in larval spicule length. Intragenerational plasticity in spicule length was strongly correlated to transcriptomic plasticity, despite low levels of intragenerational plasticity in CpG methylation. We find plasticity in DNA methylation and gene expression in response to different maternal environments and these changes have similarities across broad functional groups of genes; yet exhibit little overlap on a gene-by-gene basis. Our results suggest that different forms of environmentally induced plasticity are observable across different time scales and that DNA methylation dynamics may be uncoupled from fast transcriptional responses to the environment and whole organism traits. Overall, this study illuminates the extent to which environmental differences can induce both intra- and intergenerational phenotypic plasticity in a common kelp forest herbivore.

Objectives Refractory distributive shock (vasoplegia) has been treated with intravenous (IV) hydroxocobalamin (B12), but its use is poorly characterized. The objective of this study was to quantify the duration of hemodynamic improvement after B12 administration. Materials and methods This was a retrospective chart review of adult patients who received IV B12 while on vasopressors in the intensive care unit. Patients were divided into two groups: responders (≥10% decrease in baseline vasopressor requirements within 60 minutes of B12 administration) and non-responders. Results A total of 16 patients were included, and five (31%) met the 'responder' criteria. The median time to respond was 15 minutes, and the response was maintained for a median of 210 minutes. The baseline median norepinephrine equivalent (NEE) rate was 32.9 mcg/min in responders and 24.7 mcg/min in non-responders. Responders' NEE requirements decreased to 16.7 mcg/min after 15 minutes and 14.8 mcg/min after 60 minutes. All responders and 10 (91%) non-responders were mechanically ventilated; both groups were mostly male (60% and 91%) and had a median age of 54 years and 58 years, respectively. A total of 4 (80%) responders and 10 (91%) non-responders died while hospitalized. IV B12 was administered as 5 g over 15 minutes in all but two patients (one responder and one non-responder), who each received 5 g of B12 over 360 minutes. Conclusion Vasopressor requirements decreased rapidly in 31% of patients after B12 administration and remained so for a median of 210 minutes.

Bariatric surgery is associated with improved breast cancer (BC) outcomes, including greater immunotherapy effectiveness in a preclinical BC model. A potential mechanism of bariatric surgery–associated protection is the gut microbiota. Here, we demonstrate the dependency of improved immunotherapy response on the post–bariatric surgery gut microbiome via fecal microbiota transplantation (FMT). Response to αPD-1 immunotherapy was significantly improved following FMT from formerly obese bariatric surgery–treated mice. When stool from post–bariatric surgery patients was transplanted into recipient mice and compared to the patients’ presurgery transplants, postsurgery microbes significantly reduced tumor burden and doubled immunotherapy effectiveness. Microbes impact tumor burden through microbially derived metabolites, including branched-chain amino acids (BCAAs). Circulating BCAAs correlated significantly with natural killer T (NKT) cell content in the tumor microenvironment in donor mice after bariatric surgery and FMT recipients of donor cecal content after bariatric surgery compared with obese controls. BCAA supplementation replicated improved αPD-1 effectiveness in 2 BC models, supporting the role of BCAAs in increased immunotherapy effectiveness after bariatric surgery. Ex vivo exposure increased primary NKT cell expression of antitumor cytokines, demonstrating direct activation of NKT cells by BCAAs. Together, the findings suggest that reinvigorating antitumor immunity may depend on bariatric surgery–associated microbially derived metabolites, namely BCAAs.