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DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

Monkeypox virus (MPXV) is an emerging zoonotic Orthopoxvirus causing mpox in humans, a disease similar to the eradicated smallpox (1). Since identification in a monkey in 1958 (2) and a [...]

For decades, the United Kingdom has maintained a stockpile of approximately 225 nuclear warheads—up to 120 of which are available for delivery by four Vanguard-class nuclear-powered ballistic missile submarines. The stockpile is now increasing. The United Kingdom is currently building a new class of Dreadnaught-class submarines and developing a new nuclear warhead. In addition, it is expected that the United Kingdom will eventually increase the size of its arsenal and that Royal Air Force (RAF) Lakenheath will regain a United States Air Force nuclear mission in the coming years. The Nuclear Notebook is researched and written by the staff of the Federation of American Scientists' Nuclear Information Project: director Hans M. Kristensen, associate director Matt Korda, and senior research associates Eliana Johns and Mackenzie Knight. To see all previous Nuclear Notebook columns in the Bulletin of the Atomic Scientists dating back to 1987, go to . [ABSTRACT FROM AUTHOR]

Abstract Background The accuracy of genomic prediction is partly determined by the size of the reference population. In Atlantic salmon breeding programs, four parallel populations often exist, thus offering the opportunity to increase the size of the reference set by combining these populations. By allowing a reduction in the number of records per population, multi-population prediction can potentially reduce cost and welfare issues related to the recording of traits, particularly for diseases. In this study, we evaluated the accuracy of multi- and across-population prediction of breeding values for resistance to amoebic gill disease (AGD) using all single nucleotide polymorphisms (SNPs) on a 55K chip or a selected subset of SNPs based on the signs of allele substitution effect estimates across populations, using both linear and nonlinear genomic prediction (GP) models in Atlantic salmon populations. In addition, we investigated genetic distance, genetic correlation estimated based on genomic relationships, and persistency of linkage disequilibrium (LD) phase across these populations. Results The genetic distance between populations ranged from 0.03 to 0.07, while the genetic correlation ranged from 0.19 to 0.99. Nonetheless, compared to within-population prediction, there was limited or no impact of combining populations for multi-population prediction across the various models used or when using the selected subset of SNPs. The estimates of across-population prediction accuracy were low and to some extent proportional to the genetic correlation estimates. The persistency of LD phase between adjacent markers across populations using all SNP data ranged from 0.51 to 0.65, indicating that LD is poorly conserved across the studied populations. Conclusions Our results show that a high genetic correlation and a high genetic relationship between populations do not guarantee a higher prediction accuracy from multi-population genomic prediction in Atlantic salmon.

Abstract We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10–7.67, Cox P = 2.63e−05) and PFS (HR = 3.72, 95% CI 2.06–6.73, Cox P = 1.38e−05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24–6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16–3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2–3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08–3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH.

Brain white matter is a dynamic environment that continuously adapts and reorganizes in response to stimuli and pathological changes. Glial cells, especially, play a key role in tissue repair, inflammation modulation, and neural recovery. The movements of glial cells and changes in their concentrations can influence the surrounding axon morphology. We introduce the White Matter Generator (WMG) tool to enable the study of how axon morphology is influenced through such dynamical processes, and how this, in turn, influences the diffusion-weighted MRI signal. This is made possible by allowing interactive changes to the configuration of the phantom generation throughout the optimization process. The phantoms can consist of myelinated axons, unmyelinated axons, and cell clusters, separated by extra-cellular space. Due to morphological flexibility and computational advantages during the optimization, the tool uses ellipsoids as building blocks for all structures; chains of ellipsoids for axons, and individual ellipsoids for cell clusters. After optimization, the ellipsoid representation can be converted to a mesh representation which can be employed in Monte-Carlo diffusion simulations. This offers an effective method for evaluating tissue microstructure models for diffusion-weighted MRI in controlled bio-mimicking white matter environments. Hence, the WMG offers valuable insights into white matter's adaptive nature and implications for diffusion-weighted MRI microstructure models, and thereby holds the potential to advance clinical diagnosis, treatment, and rehabilitation strategies for various neurological disorders and injuries.

Abstract Background Social anxiety disorder (SAD) most commonly develops in adolescence—a period of life that includes a transition to upper secondary school. The aim of this study is to investigate the extent to which social anxiety in adolescence is associated with the completion of upper secondary school and progression to higher education. Methods This longitudinal study includes 8,192 adolescents aged 13–19 years who participated in the Norwegian Young-HUNT 3 population-based study. Social anxiety is measured employing (1) diagnostic interview screening questions (interview) and (2) a self-reported symptom index (questionnaire). Notably, we define the cohorts based on these two methods. Using national educational data (2008–2019), we follow educational attainment among the cohorts until they turn 25 years of age. Results We found that adolescents who screened positive (SP) for SAD had a predicted probability of upper secondary school completion at 21 years of age that was 14% points lower than those who screened negative (SN). Further, differences remained when looking at completion rates at age 25 years. Moreover, predicted probabilities for completion were inversely associated with increasing levels of self-reported social anxiety symptoms. Similarly, the proportion of the completers of an academic program in the SP group that were enrolled in higher education by 25 years of age, were lower than for the SN group (87 vs. 92%). Conclusion Social anxiety in adolescence, both self-reported symptoms and diagnostic screening, has long-term negative impact on upper secondary school completion and to some extent enrollment to higher education.

During 1979–2022, Cameroon recorded 32 laboratory-confirmed mpox cases among 137 suspected mpox cases identified by the national surveillance network. The highest positivity rate occurred in 2022, indicating potential mpox re-emergence in Cameroon. Both clade I (n = 12) and clade II (n = 18) monkeypox virus (MPXV) were reported, a unique feature of mpox in Cameroon. The overall case-fatality ratio of 2.2% was associated with clade II. We found mpox occurred only in the forested southern part of the country, and MPXV phylogeographic structure revealed a clear geographic separation among concurrent circulating clades. Clade I originated from eastern regions close to neighboring mpox-endemic countries in Central Africa; clade II was prevalent in western regions close to West Africa. Our findings suggest that MPXV re-emerged after a 30-year lapse and might arise from different viral reservoirs unique to ecosystems in eastern and western rainforests of Cameroon.

Abstract Immune checkpoint inhibitors (ICI) improve overall survival in patients with metastatic urothelial cancer (mUC), but therapeutic success at the individual patient level varies significantly. Here we identify predictive markers of response, based on whole-genome DNA (n = 70) and RNA-sequencing (n = 41) of fresh metastatic biopsy samples, collected prior to treatment with pembrolizumab. We find that PD-L1 combined positivity score does not, whereas tumor mutational burden and APOBEC mutagenesis modestly predict response. In contrast, T cell-to-stroma enrichment (TSE) score, computed from gene expression signature data to capture the relative abundance of T cells and stromal cells, predicts response to immunotherapy with high accuracy. Patients with a positive and negative TSE score show progression free survival rates at 6 months of 67 and 0%, respectively. The abundance of T cells and stromal cells, as reflected by the TSE score is confirmed by immunofluorescence in tumor tissue, and its good performance in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS) validate the predictive power of the TSE score. In conclusion, the TSE score represents a clinically applicable metric that potentially supports the prospective selection of patients with mUC for ICI treatment.

India continues to modernize its nuclear arsenal, with at least four new weapon systems and several new delivery platforms under development to complement or replace existing nuclear-capable aircraft, land-based delivery systems, and sea-based systems. Several of these systems are nearing completion and will soon be fielded. We estimate that India may have produced enough military plutonium for 130 to 210 nuclear warheads but likely has produced only around 172, although the country's warhead stockpile is likely growing. The Nuclear Notebook is researched and written by the staff of the Federation of American Scientists' Nuclear Information Project: director Hans M. Kristensen, associate director Matt Korda, senior research associates Eliana Johns and Mackenzie Knight. To see all previous Nuclear Notebook columns in the Bulletin of the Atomic Scientists dating back to 1987, go to . [ABSTRACT FROM AUTHOR]

North Korea continues to modernize and grow its nuclear weapons arsenal. In this Nuclear Notebook, the authors cautiously estimate that North Korea may have produced enough fissile material to hypothetically build up to 90 nuclear warheads, but has likely assembled fewer than that—potentially around 50. To deliver the warheads, North Korea is enhancing and diversifying its missile force, most recently with new solid-fuel long-range strategic missiles, short-range tactical missiles, and sea-based missiles. The Nuclear Notebook is researched and written by the staff of the Federation of American Scientists' Nuclear Information Project: director Hans M. Kristensen, associate director Matt Korda, research associate Eliana Johns, and program associate Mackenzie Knight. To see all previous Nuclear Notebook columns in the Bulletin of the Atomic Scientists dating back to 1987, go to [ABSTRACT FROM AUTHOR]

IntroductionSubgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response.MethodsBinding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers.Results83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes.DiscussionSystematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.