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Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent member of the superfamily of voltage-gated potassium (Kv) channels, which expresses in heterotetramers with members of the KCNB (Kv2) family. The genetic variant Kv6.4-L360P has previously been linked to migraines, but their mode of action remains unknown. Here, we characterized the molecular characteristics of Kv6.4-L360P when co-expressed with Kv2.1. We found that Kv6.4-L360P almost completely abolishes Kv2 currents, and we propose that this mechanism in the trigeminal system, linked to the initiation of migraine, leads to the pathology. [ABSTRACT FROM AUTHOR]

The CernVM FileSystem (CVMFS) is widely used in High Throughput Computing to efficiently distributed experiment code. However, the standard CVMFS publishing tools are designed for a small group of people from each experiment to maintain common software, and the tools are not a good fit for publishing software from numerous users in each experiment. As a result, most user code, such as code to do specific physics analyses, is still sent with every job to the place the job is run. That process is relatively inefficient, especially when the user code is large. To overcome these limitations, we have built a CVMFS user code publication system. This publication system enables users to still submit their code with their jobs but the code is distributed and accessed through the standard CVMFS infrastructure. The user code is automatically deleted from CVMFS after a period of no use. Most of the software for the system is available as a single self-contained open source rpm called cvmfs-user-pub and is available for other deployments.

The FabrIc for Frontier Experiments (FIFE) project within the Fermilab Scientific Computing Division is charged with integrating offline computing components into a common computing stack for the non-LHC Fermilab experiments, supporting experiment offline computing, and consulting on new, novel workflows. We will discuss the general FIFE onboarding strategy, the upgrades and enhancements in the FIFE toolset, and plans for the coming year. These enhancements include: expansion of opportunistic computing resources (including GPU and high-performance computing resources) available to experiments; assistance with commissioning computing resources at European sites for individual experiments; StashCache repositories for experiments; enhanced job monitoring tools; and a custom workflow management service. Additionally we have completed the first phase of a Federated Identity Management system to make it easier for FIFE users to access Fermilab computing resources.

The OSG has long maintained a central accounting system called Gratia. It uses small probes on each computing and storage resource in order to collect resource usage. The probes report to a central collector which stores the usage in a database. The database is then queried to generate reports. As the OSG aged, the size of the database grew very large. It became too large for the database technology to efficiently query to generate detailed reports. The design of a replacement requires data storage that could be queried efficiently to generate multi-year reports. Additionally, it requires flexibilityto add new attributes to the collected data. In this paper we will describe updates to the GRACC architecture in the last 18 months. GRACC uses modern web technologies that were designed for large data storage, query, and visualization. That includes the open source database Elasticsearch, message broker software RabbitMQ, and Grafana and Kibana as data visualization platforms. It uses multiple agents that perform operations on the data to transform it for easier querying and summarization.

Organic cation transporters (OCTs) are membrane proteins that take up monoamines, cationic drugs and xenobiotics. We previously reported novel missense mutations of organic cation transporter 3 (OCT3, SLC22A3), some with drastically impacted transport capabilities compared to wildtype. For some variants, this was due to ER retention and subsequent degradation of the misfolded transporter. For other transporter families, it was previously shown that treatment of misfolded variants with pharmacological and chemical chaperones could restore transport function to a certain degree. To investigate two potentially ER-bound, misfolded variants (D340G and R348W), we employed confocal and biochemical analyses. In addition, radiotracer uptake assays were conducted to assess whether pre-treatment with chaperones could restore transporter function. We show that pre-treatment of cells with the chemical chaperone 4-PBA (4-phenyl butyric acid) leads to increased membrane expression of misfolded variants and is associated with increased transport capacity of D340G (8-fold) and R348W (1.5 times) compared to untreated variants. We herein present proof of principle that folding-deficient SLC22 transporter variants, in particular those of OCT3, are amenable to rescue by chaperones. These findings need to be extended to other SLC22 members with corroborated disease associations. [ABSTRACT FROM AUTHOR]

Context: Dexmedetomidine, an α2-agonist, has been studied widely as an adjuvant to local anesthetics in regional anesthesia techniques to enhance the quality and duration of analgesia (DOA). It was hypothesized that addition of dexmedetomidine 0.5 ug.kg‒1 to levobupivacaine would prolong the DOA. Aims: We aimed to evaluate the efficacy of dexmedetomidine as an adjuvant to levobupivacaine in supraclavicular brachial plexus block with respect to onset and duration of sensory and motor blockade, and duration of analgesia. Settings and Design: This was a prospective randomized double-blind study carried out at a tertiary hospital attached to medical college. Subjects and Methods: Sixty American Society of Anesthesiologists PS Class I and II patients aged between 18 and 60 years of either sex, undergoing elective upper-limb surgery lasting more than 30 min, were included in the study. They were randomly divided into two groups of thirty each to receive ultrasound-guided supraclavicular brachial plexus block. Group L was given nerve block with 20 mL of 0.25% levobupivacaine and 1 mL saline, and Group D received 20 mL of 0.25% levobupivacaine with 0.5 ug.kg‒1 of dexmedetomidine (diluted to volume of 1 mL). Onset time and duration of sensory and motor blockade, time to first rescue analgesia, and hemodynamic parameters were recorded. Statistical Analysis Used: Chi-square test for qualitative variables and Student's unpaired "t" test for continuous variables were used for statistical analysis. Results: The onset of sensory and motor blockade was 6.51 ± 0.77 min and 10.71 ± 0.34 min in Group D and 9.9 ± 0.45 and 15.93 ± 1.92 min in Group L, respectively (P < 0.005). DOA was 9.53 ± 0.29 h in Group D and 3.89 ± 0.30 h in Group L (P < 0.001). The duration of sensory and motor block was 9.14 ± 0.19 h and 8.55 ± 0.31 h in Group D and 6.15 ± 3.02 and 5.61 ± 2.98 h in Group L, respectively (P < 0.005). No adverse effects were observed in either of the groups. Conclusions: Addition of 0.5 ug.kg‒1 of dexmedetomidine to 20 mL 0.25% levobupivacaine in ultrasound guided (USG)-guided supraclavicular brachial plexus block shortens the onset time of sensory and motor blockade and prolongs duration of sensory and motor block and DOA. [ABSTRACT FROM AUTHOR]

The concentrative power of the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) is thought to be fueled by the transmembrane Na+ gradient, but it is conceivable that they can also tap other energy sources, for example, membrane voltage and/or the transmembrane K+ gradient. We have addressed this by recording uptake of endogenous substrates or the fluorescent substrate APP+(4-(4-dimethylamino)phenyl-1-methylpyridinium) under voltage control in cells expressing DAT, NET, or SERT. We have shown that DAT and NET differ from SERT in intracellular handling of K+. In DAT and NET, substrate uptake was voltage- dependent due to the transient nature of intracellular K+ binding, which precluded K+ antiport. SERT, however, antiports K+ and achieves voltage-independent transport. Thus, there is a trade-off between maintaining constant uptake and harvesting membrane potential for concentrative power, which we conclude to occur due to subtle differences in the kinetics of co-substrate ion binding in closely related transporters. [ABSTRACT FROM AUTHOR]

Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r . A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity., Competing Interests: CONFLICT OF INTEREST: The authors have no conflict of interest.

Human monkeypox virus (hMpoxV) is of zoonotic origin and is closely related to the once-dreaded smallpox virus. It is largely endemic to the African continent but has moved out of the endemic regions as sporadic clusters in the past 20 years, raising concerns worldwide. Human Mpox is characterized by a mild to severe, self-limiting infection, with mortality ranging from less than 1% to up to 10% during different outbreaks caused by different clades of MpoxV. Bushmeat hunting is one of the primary reasons for its transmission from animals to humans. Various international and national health regulatory bodies are closely monitoring the disease and have laid down guidelines to manage and prevent hMpox cases. Emergency Use Status has been granted to Tecovirimat and Brincidofovir to treat severe cases and vaccination with the smallpox vaccine is recommended for high-risk group individuals. Strategies to repurpose and discover novel therapeutics and vaccines to control the outbreak are being researched. The current Mpox outbreak that has mainly affected men as approximately 96% of all cases are reported in men, is probably the result of a complex intersection of various factors. This necessitates a strong One Health response coordination involving human, animal and environmental health institutions. This review is an attempt to provide an all-inclusive overview of the biology, history, epidemiology, pathophysiology, diagnosis and management of hMpox in context to the recent 2022-2023 multi-country outbreak which is termed by WHO a 'Public Health Emergency of International Concern (PHEIC)'.