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Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F0-F1-F2) to produce a heterogeneous F2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F0s (n = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F2s (n = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F2 behavior. In F0 and F2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (cis-expression quantitative trait loci or cis-eQTLs). These cis-eQTLs successfully predict bHR/bLR differential gene expression based on F0 genotype. Sixteen of these genes are associated with cis-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.

Pigment-dispersing factors (PDFs) are neuropeptides that play key roles in controlling the circadian rhythms in various insects, whereas their function remains elusive in other protostomes including tardigrades (water bears). Here we show that the three PDFs of the tardigrade Hypsibius exemplaris are co-localized in two pairs of inner lobe cells in the brain, whereas only one PDF occurs in four additional cerebral and two extracerebral cells. The axons of the inner lobe cells pass through the contralateral brain hemisphere, descend to the ventral nerve cord and terminate in two pairs of potential release sites in the posteriormost trunk ganglion. Using in vitro assays, we demonstrate that all three PDFs and their deorphanized receptor (PDFR) are functional. Widespread localization of PDFR suggests that tardigrade PDFs may act as multifunctional hormones and neuromodulators that control major functions including light detection, neural processing, locomotion, feeding, digestion, osmoregulation, growth, embryonic development and oogenesis/reproduction.

Introduction Emergency humanitarian situations can be caused by extreme weather events, natural disasters, civil conflicts, international wars, terrorism and pandemics, which threaten our health and compromise health systems worldwide. Pharmacists are the third-largest healthcare professional group globally and provide pharmaceutical care and advice to people in need. However, the training opportunities to prepare pharmacists to respond in emergency humanitarian areas are not well described and may be limited. This scoping review aims to understand the extent and type of evidence in relation to training and education activities to prepare future pharmacists for disaster management in humanitarian emergency situations.Methods and analysis We will analyse peer-reviewed literature relating to educational or training activities for pharmacists/pharmacy students in the delivery of pharmacy services in humanitarian emergency situations. Relevant medical subject headings and keywords will be used to search Ovid MEDLINE, Scopus, EMBASE, ERIC, Informit, Web of Science and CINAHL databases from inception to the end of July 2024. Hand searching of any key references identified will also be performed. The title and abstract of search results will be screened to identify articles eligible to be included for full review. Articles meeting the inclusion criteria will undergo data extraction, content analysis and synthesis of the evidence using NVivo qualitative analysis software. A narrative summary of key themes and concepts in the literature will be presented as results. An international panel of experts will be consulted to inform decision-making processes during the development and interpretation stages, and we propose a template for the incorporation of participatory/consultative methodology into the scoping review process.Ethics and dissemination Ethics approval is not required for this study protocol because the members of the expert panel consulted are researchers who are participating based on their professional skills. Findings will be disseminated via publication in a peer-reviewed journal and presentation at international conferences.

Pufferfish is common in marine, brackish and freshwater habitats in Bangladesh. Pufferfish poisoning sporadically occurs due to the consumption of toxic pufferfish throughout the country. Identification of pufferfish is challenging and/or misleading, based on only morphometric characteristics. A study was conducted for molecular characterization and phylogenetic analysis of Bangladeshi pufferfish using two markers, mitochondrial cytochrome c oxidase I (COI) and 16S ribosomal RNA (16S rRNA) genes. We aimed to generate DNA barcode sequences of pufferfish in Bangladesh waters, explore the differences and applicability of two gene fragments (16S rRNA and COI) in fish species identification, and establish a comprehensive barcoding reference database for pufferfish. A total of 36 barcode sequences (20 sequences of COI and 16 sequences of 16S rRNA) were obtained from 33 collected specimens representing seven species and five genera. The mean length of the sequences was 644 bp and 613 bp for COI and 16S, respectively. The average %GC content was 49.96 for COI which was higher compared to the 16S rRNA (46.30). The average Kimura two parameter (K2P) distances within species were found to be 0.29 ± 0.01 for COI and 0.70 ± 0.06 for 16S rRNA. The Neighbor-Joining (NJ) phylogenetic analysis of COI and 16S rRNA gene sequences revealed that the corresponding species were clustered together in the same clade. Results of cluster sequence analyses revealed seven Operational Taxonomic Units (OTUs). This study validates the utility of both COI and 16S rRNA as potential markers for identifying different puffer species. DNA-based identification of the remaining pufferfish species of Bangladesh, with multiple sequences and phylogenetic relationships remains to be established.

Opioid abuse and its negative effect have become a critical epidemic, putting our health and society in jeopardy. Opioids are effective treatment for pain, but at risk for developing associated health threatening impacts including the euphoria associated relapsing effects, persistent occurrence with addictive and withdrawal symptoms, and consequent respiratory depression and apnea. The opioid use disorder (OUD), represented as those recurring phases of symptoms, is initiated with mediation of opioid receptor signaling pathway and subsequent neurocircuitry transformation with homeostatic and motivational change. It has been imperative to establish modulatory mechanisms and alternative treatments to mitigate OUD. This review deals with central serotonin (5-HT) system as a cooperative mediator with OUD-related neural processing. We briefly introduce molecular base of opioid receptors and available research tools in mouse models and examine OUD-phase dependent circuit mechanisms, including pain, addiction, and respiratory depression. We interrogate the potential neural roles of 5-HT in OUD-related symptoms including 5-HT toxicity and pathophysiology and discuss potential availability of 5-HT-related agents as a neuromodulatory therapeutic interacting with opioid mediated neural mechanisms and the OUD-related symptoms.

Abstract Background Impact of baseline‐pool local impedance (BP‐LI) on the lesion size remains unclear. Methods Lesion size in the porcine left ventricular myocardium was evaluated using the STABLEPOINT™ catheter across various ablation settings and BP‐LIs (100, 140, and 180 ohms). Results A total of 184 lesions were created with different durations (15/30/60 s) at 30 watts or with different powers (30/40/50 W) for 15 s. Lesion depth became deeper (2.8/3.0/3.6 mm at 15 s; p = .007, 4.0/4.9/4.6 mm at 30 s; p = .004, and 5.9/5.5/5.2 mm at 60 s; p = .710) and lesion width wider (5.8/6.3/7.6 mm at 15 s; p = .002, 7.0/8.9/8.9 mm at 30 s; p

IntroductionCytomegalovirus (CMV) viremia remains a major contributor to clinical complications in solid organ transplant (SOT) patients, including organ injury, morbidity and mortality. Given their critical role in antiviral defense, CD8+ T cells are essential for protective immunity against CMV.MethodsUsing single-cell RNA sequencing, we investigated the transcriptional signatures and developmental lineages of CD8+ T cells in eight immunosuppressed kidney transplant recipients (KTRs) who received organs from CMV-seropositive donors. Results were validated in a cohort of 62 KTRs using immunophenotyping.ResultsOur data revealed a significant influence of CMV serostatus on transcriptional variance of CD8+ memory T cells, associating with the first principal component from a global analysis of CD8+ T cells (p =0.0406), forming a continuum with five principal differentiation trajectories driven by CMV primary infection or reactivation. Following CMV primary infection, CD8+ T cells were hallmarked by restrained effector-memory differentiation. CD8+ T cells during CMV reactivation diverged non-linearly into senescent-like cells with signatures of arrested cell cycle, diminished translational activity and downregulated ZNF683 and longitudinally expanding effector cells with robust cytotoxic potential and upregulated ZNF683, acting as a reservoir for long-lived effector cells supporting long-term protection. Notably, CD28lo KLRG1hi IL-7R (CD127)lo HLA-DRhi CD8+ T cells present prior to the detection of viremia in CMV-seropositive patients emerged as a key feature distinguishing patients who did or did not undergo CMV reactivation after prophylaxis discontinuation (p =0.0163). Frequencies of these cells were also positively correlated with CMV-stimulated secretion of IFN-γ (p =0.0494), TNF-α (p =0.0358), MIP-1α (p =0.0262), MIP-1β (p =0.0043).DiscussionThese results provide insights into the transcriptional regulation that influences the generation of CD8+ T cell immunity to CMV and may inform strategics for monitoring host immune response to CMV to better identify and introduce therapeutic intervention to patients at risk of developing clinically significant CMV viremia.

ObjectiveThis study aimed to determine and compare the tumor shrinkage rate and its durability by enfortumab vedotin treatment between primary urothelial carcinoma and metastatic organs.MethodsWe retrospectively evaluated the tumor shrinkage rate in 39 Japanese patients treated with enfortumab vedotin for advanced urothelial carcinoma. We also evaluated the periods of tumor shrinkage maintenance (the period when best response was maintained) and regrowth (the period from best response to tumor growth confirmation) between primary and metastatic organs.ResultsMeasurable metastatic organs included the lung in 17, lymph node in 22, liver in 6, and bone in 5 cases. Primary lesion was detected in 20 cases. The mean tumor shrinkage rates for lung, lymph node, liver, and bone metastases and primary sites were 21% (−212 to 100), 13% (−130 to 86), −8.5% (−158 to 85), −64% (−250 to 21), and 22% (−38 to 79), respectively. The tumor shrinkage was maintained for 5.9 (0.7–14) months in lung metastases, 8.3 (2.6–14.5) months in lymph node metastases, 3.6 months in liver metastases, 0.7 months in bone metastases, and 1.8 (0.7–5.4) months in primary sites, and the period of regrowth was 7.3 (2.2–19.4), 4.8 (2.0–8.9), 2.8, 6.5, and 2.5 (1.1–5.9) months, respectively.ConclusionsEnfortumab vedotin showed significant tumor shrinkage in the primary tumor, lung metastases, and lymph node metastases, whereas the durability of tumor shrinkage was limited in the primary tumor.

Abstract Nematic liquid crystals (NLCs), that is, fluids with optical anisotropy as well as electric‐ and magnetic‐field responsiveness, have been widely used in commercial liquid crystal displays. Recent advancements have extended the scope of NLC molecules to large calamitic π‐conjugated systems, which heralds prospects for novel applications that exploit their superior electronic or optical functionalities in, for example, electric field controlled fluorescence switch devices. However, NLC phases of such extended π‐systems usually flow only at high temperatures, which hampers device applications that operate around room temperature. Here, we show near‐room‐temperature NLCs of a π‐conjugated fluorophore by introducing a flexible cyclic structure into the mesogenic core. 3,8‐Bis(4‐propylphenyl)‐6,7‐dihydro‐5H‐benzo[7]annulene (DPB[7]‐C3) has a nematic phase in a significantly lower temperature range (52.6–160.4°C) than the DPB[7]‐C3 analog without flexible alkylene bridges, (E)‐4‐propyl‐4′‐(4‐propylstyryl)‐1,1′‐biphenyl (248–262°C). We attribute this large decrease in the phase transition temperature to large intramolecular conformational entropies that arise from the geometric change of the cyclic structure, which involves rotational motion of single biaryl‐bonds and bending motions along the long molecular axis in the thermal equilibrium state. The practical utility of these NLC molecules is demonstrated by preparing an electric‐field‐responsive large‐area fluorescent switch device with a sub‐millisecond response time from a mixture of 3,8‐bis(4‐alkylphenyl)‐6,7‐dihydro‐5H‐benzo[7]annulenes (DPB[7]‐Cns).

Objectives This qualitative study explored public and prescriber awareness of pharmaceutical pollution in the water environment and eco-directed sustainable prescribing (EDSP) as a mitigation strategy to reduce the environmental impact of prescribing in Scotland.Design Focus groups explored prescriber and public perceptions of the topic. Common questions were asked through semistructured facilitation. Focus groups were digitally recorded and transcribed verbatim using an artificial intelligence system, then anonymised and thematically analysed using NVivo software. Data were iteratively analysed using the one sheet of paper technique.Setting Public focus groups were held in-person (Inverness, Scotland, April 2023), and prescriber focus groups were held virtually (MS Teams, August 2023).Participants Nine public representatives and 17 NHS Scotland prescribers participated in one of four focus groups. Purposive and opportunistic sampling approaches were used to recruit participants through social media and other channels (ie, community groups, professional emails, general practitioner and hospital flyers). Prescriber representatives registered interest through an online survey to gather information about their professional background. Responses were reviewed to ensure representation of a mixture of medical backgrounds, experience, sectors and health boards.Results There is growing awareness among the public and healthcare professionals of pharmaceutical pollution in the environment, but further education is required on the drivers, potential effects and possible interventions. Suggestions for more sustainable healthcare included public health awareness campaigns, better provision for pharmacy take-back schemes, clear medicine/packaging labelling, regular medicines reviews and more considered patient-centred care. From the prescriber perspective, EDSP resonated well with current sustainability initiatives (eg, Realistic Medicine, switching to dry-powder inhalers), but barriers to EDSP included lack of knowledge, confidence, time and resources to implement changes. Although the public representatives were generally open to the concept of EDSP, this decision required weighing pros/cons considering personal health choices, information accessibility and transparency, and trust in and time with prescribers.Conclusions This study identified new insights from prescribers and the public related to the concept of, and barriers to, EDSP in Scotland, as well as perspectives regarding knowledge support tools and information communication. Cross-sector and transdisciplinary collaborative approaches are needed to address the challenges identified here. Nonetheless, EDSP merits further exploration in developing more sustainable, appropriate and effective healthcare which contributes to improved public and planetary health.

A 63-year-old Japanese housewife was admitted to our hospital because of hematuria and proteinuria lasting for 3 months. At the age of 59 years, she was diagnosed with neurosarcoidosis at another hospital, and she received oral glucocorticoid therapy for 1 year. Her serum angiotensin-converting enzyme (ACE) and 1, 25-dihydroxyvitamin D levels were elevated. Computed tomography showed lymphadenopathy of the tracheal bifurcation and diffuse nodular shadow in the lungs and liver. Renal biopsy findings were compatible with IgA nephropathy without noncaseating granulomas and glomerular galactose-deficient IgA1 (Gd-IgA1) was stained in mesangial area. Because of clinical suspicion of sarcoidosis, liver biopsy was also performed, which showed inflammation with multiple noncaseating granulomas. The patient was diagnosed with IgA nephropathy coincident with sarcoidosis. After oral administration of prednisolone, mild proteinuria persisted; however, serum creatinine level was normalized, hematuria disappeared, and serum ACE and 1, 25-dihydroxyvitamin D levels returned to normal. Although some patients with sarcoidosis occasionally present with glomerulonephritis, there have been few case reports of sarcoidosis with IgA nephropathy. This was the first case report in which glomerular Gd-IgA1 was identified in a patient with IgA nephropathy and sarcoidosis.

As far as the representation of deep moist convection is concerned, only two kinds of model physics are used at present: highly parameterized as in the conventional general circulation models (GCMs) and explicitly simulated as in the cloud-resolving models (CRMs). Ideally, these two kinds of model physics should be unified so that a continuous transition of model physics from one kind to the other takes place as the resolution changes. With such unification, the GCM can converge to a global CRM (GCRM) as the grid size is refined. This paper suggests two possible routes to achieve the unification. ROUTE I continues to follow the parameterization approach, but uses a unified parameterization that is applicable to any horizontal resolutions between those typically used by GCMs and CRMs. It is shown that a key to construct such a unified parameterization is to eliminate the assumption of small fractional area covered by convective clouds, which is commonly used in the conventional cumulus parameterizations either explicitly or implicitly. A preliminary design of the unified parameterization is presented, which demonstrates that such an assumption can be eliminated through a relatively minor modification of the existing mass-flux based parameterizations. Partial evaluations of the unified parameterization are also presented. ROUTE II follows the "multi-scale modeling framework (MMF)" approach, which takes advantage of explicit representation of deep moist convection and associated cloud-scale processes by CRMs. The Quasi-3-D (Q3-D) MMF is an attempt to broaden the applicability of MMF without necessarily using a fully three-dimensional CRM. This is accomplished using a network of cloud-resolving grids with large gaps. An outline of the Q3-D algorithm and highlights of preliminary results are reviewed.

Antimicrobial resistance (AMR) is a global threat to human health. Education on antibiotics is essential for AMR prevention, and training should be provided for undergraduate pharmacy students. This study evaluated the knowledge regarding antibiotic use and AMR among fourth-year Japanese pharmacy students and the effect of a lecture on treating infectious diseases with antibiotics had on their knowledge. A questionnaire survey was conducted, and the responses were recorded before and after participants attended the lecture. A small subset of the prelecture survey questions was used for the postlecture survey. From a total of 540 participants, 330 and 234 responses were collected before and after the lecture, respectively. In the prelecture survey, 39.4% of the participants incorrectly answered that antibiotics can effectively treat the common cold, 13.3% had taken leftover antibiotics, and 17.3% had taken antibiotics prescribed for their family members or others. Furthermore, the prelecture survey data showed that the mean number (± standard deviation) of correct answers across the eight questions on treatment and diagnosis of infectious diseases and antibiotics was 2.21 ± 1.64. However, in the postsurvey, this figure increased to 5.00 ± 1.82. Although the lecture improved their knowledge to some extent, the results suggested that fourth-year pharmacy students have inaccurate knowledge regarding the appropriate use of antibiotics and AMR. Therefore, it is necessary to improve early-year undergraduate pharmacy education on antibiotics in Japan.