Neurologic and Psychiatric Co-morbidity in Neuropsychiatry Training

Summary: Discusses a study on combined neuropsychiatry training for establishing competency in neuropsychiatry

T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones

Isolation of peptide-specific T-cell clones is highly desirable for determining the role of T-cells in human disease, as well as for the development of therapies and diagnostics. However, generation of monoclonal T-cells with the required specificity is challenging and time-consuming. Here we describe a library-based strategy for the simple parallel detection and isolation of multiple peptide-specific human T-cell clones from CD8+ or CD4+ polyclonal T-cell populations. T-cells were first amplified by CD3/CD28 microbeads in a 96U-well library format, prior to screening for desired peptide recognition. T-cells from peptide-reactive wells were then subjected to cytokine-mediated enrichment followed by single-cell cloning, with the entire process from sample to validated clone taking as little as 6 weeks. Overall, T-cell libraries represent an efficient and relatively rapid tool for the generation of peptide-specific T-cell clones, with applications shown here in infectious disease (Epstein–Barr virus, influenza A, and Ebola virus), autoimmunity (type 1 diabetes) and cancer

Neuroleptanalgesia for acute abdominal pain: a systematic review

Background: Acute abdominal pain (AAP) comprises up to 10% of all emergency department (ED) visits. Current pain management practice is moving toward multi-modal analgesia regimens that decrease opioid use. Objective: This project sought to determine whether, in patients with AAP (population), does administration of butyrophenone antipsychotics (intervention) compared to placebo, usual care, or opiates alone (comparisons) improve analgesia or decrease opiate consumption (outcomes)? Methods: A structured search was performed in Cochrane CENTRAL, CINAHL, Database of Abstracts of Reviews of Effects, Directory of Open Access Journals, Embase, IEEE-Xplorer, Latin American and Caribbean Health Sciences Literature, Magiran, PubMed, Scientific Information Database, Scopus, TÜBİTAK ULAKBİM, and Web of Science. Clinical trial registries (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and Australian New Zealand Clinical Trials Registry), relevant bibliographies, and conference proceedings were also searched. Searches were not limited by date, language, or publication status. Studies eligible for inclusion were prospective randomized clinical trials enrolling patients (age ≥18 years) with AAP treated in acute care environments (ED, intensive care unit, postoperative). The butyrophenone must have been administered either intravenously or intramuscularly. Comparison groups included placebo, opiate only, corticosteroids, non-steroidal anti-inflammatory drugs, or acetaminophen. Results: We identified 7,217 references. Six studies met inclusion criteria. One study assessed ED patients with AAP associated with gastroparesis, whereas five studies assessed patients with postoperative AAP: abdominal hysterectomy (n=4), sleeve gastrectomy (n=1). Three of four studies found improvements in pain intensity with butyrophenone use. Three of five studies reported no change in postoperative opiate consumption, while two reported a decrease. One ED study reported no change in patient satisfaction, while one postoperative study reported improved satisfaction scores. Both extrapyramidal side effects (n=3) and sedation (n=3) were reported as unchanged. Conclusion: Based on available evidence, we cannot draw a conclusion on the efficacy or benefit of neuroleptanalgesia in the management of patients with AAP. However, preliminary data suggest that it may improve analgesia and decrease opiate consumption

Peptide cargo tunes a network of correlated motions in human leukocyte antigens

Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug‐target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T‐cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T‐cell compartment. We have applied high‐pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide–HLA complexes. We find that different peptide sequences affect peptide–HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide‐binding interface, in a manner that could influence T‐cell antigen discrimination

Archival mitogenomes identify invasion by the Batrachochytrium dendrobatidis CAPE lineage caused an African amphibian extinction in the wild

Outbreaks of emerging infectious diseases are influenced by local biotic and abiotic factors, with host declines occurring when conditions favour the pathogen. Deterioration in the population of the microendemic Tanzanian Kihansi spray toad (Nectophrynoides asperginis) occurred after the construction of a hydropower dam, implicating habitat modification in this species decline. Population recovery followed habitat augmentation, however, a subsequent outbreak of chytridiomycosis caused by Batrachochytrium dendrobatidis (Bd) led to the spray toads extinction in the wild. We show using spatiotemporal surveillance and mitogenome assembly of Bd from archived toad mortalities that the outbreak was caused by invasion of the BdCAPE lineage and not the panzootic lineage BdGPL. Molecular dating reveals an emergence of BdCAPE across southern Africa overlapping with the timing of the spray toads extinction. That our post-outbreak surveillance of co-occurring amphibian species in the Udzungwa Mountains shows widespread infection by BdCAPE yet no signs of ill-health or decline suggests these other species can tolerate Bd when environments are stable. We conclude that, despite transient success in mitigating the impact caused by dams’ construction, invasion by BdCAPE caused the ultimate die-off that led to the extinction of the Kihansi spray toad

First Results for Solar Soft X-ray Irradiance Measurements from the Third Generation Miniature X-Ray Solar Spectrometer

Three generations of the Miniature X-ray Solar Spectrometer (MinXSS) have flown on small satellites with the goal "to explore the energy distribution of soft X-ray (SXR) emissions from the quiescent Sun, active regions, and during solar flares, and to model the impact on Earth's ionosphere and thermosphere". The primary science instrument is the Amptek X123 X-ray spectrometer that has improved with each generation of the MinXSS experiment. This third generation MinXSS-3 has higher energy resolution and larger effective area than its predecessors and is also known as the Dual-zone Aperture X-ray Solar Spectrometer (DAXSS). It was launched on the INSPIRESat-1 satellite on 2022 February 14, and INSPIRESat-1 has successfully completed its 6-month prime mission. The INSPIRESat-1 is in a dawn-dusk, Sun-Synchronous Orbit (SSO) and therefore has 24-hour coverage of the Sun during most of its mission so far. The rise of Solar Cycle 25 (SC-25) has been observed by DAXSS. This paper introduces the INSPIRESat-1 DAXSS solar SXR observations, and we focus the science results here on a solar occultation experiment and multiple flares on 2022 April 24. One key flare result is that the reduction of elemental abundances is greatest during the flare impulsive phase and thus highlighting the important role of chromospheric evaporation during flares to inject warmer plasma into the coronal loops. Furthermore, these results are suggestive that the amount of chromospheric evaporation is related to flare temperature and intensity.Comment: 43 pages including 19-page Appendix A, 8 figures, 7 table

Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors

Evidence indicates that autoimmunity can be triggered by virus-specific CD8+ T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8+ T-cell clones spanning different restriction elements and a range of epitope lengths. CPL scan data drove a protein database search limited to viruses that infect humans. Peptide sequences were ranked in order of likelihood of recognition. For all anti-viral CD8+ T-cell clones examined in this study, the index peptide was either the top-ranked sequence or ranked as one of the most likely sequences to be recognized. Thus, we demonstrate that anti-viral CD8+ T-cell clones are highly focused on their index peptide sequence and that ‘CPL-driven database searching’ can be used to identify the inciting virus-derived epitope for a given CD8+ T-cell clone. Moreover, to augment access to CPL-driven database searching, we have created a publicly accessible webtool. Application of these methodologies in the clinical setting may clarify the role of viral pathogens in the etiology of autoimmune diseases

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination