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Abstract The Fourier harmonics, $$v_2$$ v 2 and $$v_3$$ v 3 of negative pions are measured at center-of-mass energy per nucleon pair of $$\sqrt{s_{\textrm{NN}}}$$ s NN = 17.3 GeV around midrapidity by the CERES/NA45 experiment at the CERN SPS in 0–30% central PbAu collisions with a mean centrality of 5.5%. The analysis is performed in two centrality bins as a function of the transverse momentum $$\mathrm {p_{\textrm{T}}}$$ p T from 0.05 GeV/c to more than 2 GeV/c. This is the first measurement of the $$v^{1/3}_{3}/v^{1/2}_{2}$$ v 3 1 / 3 / v 2 1 / 2 ratio as a function of transverse momentum at SPS energies, that reveals, independently of the hydrodynamic models, hydrodynamic behavior of the formed system. For $$\mathrm {p_{\textrm{T}}}$$ p T above 0.5 GeV/c, the ratio is nearly flat in accordance with the hydrodynamic prediction and as previously observed by the ATLAS and ALICE experiments at the much higher LHC energies. The results are also compared with the SMASH-vHLLE hybrid model predictions, as well as with the SMASH model applied alone.

Abstract Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson’s disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from a small cohort of post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating differentially expressed genes from three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified an association between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed an association with UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited an association with UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms.

Summary: Background: Healthcare workers in obstetric clinics may be exposed to airborne SARS-CoV-2 when treating patients with COVID-19. Method: In this study, performed during the midst of the pandemic, air samples were collected in delivery rooms during childbirth and analysed for SARS-CoV-2 RNA content. Result: Six of 28 samples collected inside delivery rooms were positive for SARS-CoV-2, but none in anterooms or corridors. Five of the six positive samples were from the same occasion. Discussion: This indicates that some patients could be major sources of exhaled virus, although the individual variation is large, and it is thus difficult to predict the risk of infection.

Abstract Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

Abstract Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology.

Abstract Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

Abstract Exhaled SARS-CoV-2-containing aerosols contributed significantly to the rapid and vast spread of covid-19. However, quantitative experimental data on the infectivity of such aerosols is missing. Here, we quantified emission rates of infectious viruses in exhaled aerosol from individuals within their first days after symptom onset from covid-19. Six aerosol samples from three individuals were culturable, of which five were successfully quantified using TCID50. The source strength of the three individuals was highest during singing, when they exhaled 4, 36, or 127 TCID50/s, respectively. Calculations with an indoor air transmission model showed that if an infected individual with this emission rate entered a room, a susceptible person would inhale an infectious dose within 6 to 37 min in a room with normal ventilation. Thus, our data show that exhaled aerosols from a single person can transmit covid-19 to others within minutes at normal indoor conditions.

Abstract Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer’s disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We perform comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We find an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically define a role for Appl in regulating autophagy through TGFβ signaling and document the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer’s disease.

ABSTRACT Objective We created WiTNNess as a hybrid prospective/cross‐sectional observational study to simulate a clinical trial for infantile‐onset TNNT1 myopathy. Our aims were to identify populations for future trial enrollment, rehearse outcome assessments, specify endpoints, and refine trial logistics. Methods Eligible participants had biallelic pathogenic variants of TNNT1 and infantile‐onset proximal weakness without confounding conditions. The primary endpoint was ventilator‐free survival. “Thriving” was a secondary endpoint defined as the ability to swallow and grow normally without non‐oral feeding support. Endpoints of gross motor function included independent sitting and standing as defined by the Word Health Organization, a novel TNNT1 abbreviated motor score, and video mapping of limb movement. We recorded adverse events, concomitant medications, and indices of organ function to serve as comparators of safety in future trials. Results Sixteen children were enrolled in the aggregate cohort (6 prospective, 10 cross‐sectional; median census age 2.3 years, range 0.5–13.8). Median ventilator‐free survival was 20.2 months and probability of death or permanent mechanical ventilation was 100% by age 60 months. All six children (100%) in the prospective arm failed to thrive by age 12 months. Only 2 of 16 (13%) children in the aggregate cohort sat independently and none stood alone. Novel exploratory motor assessments also proved informative. Laboratory and imaging data suggest that primary manifestations of TNNT1 deficiency are restricted to skeletal muscle. Interpretation WiTNNess allowed us to streamline and economize the collection of historical control data without compromising scientific rigor, and thereby establish a sound operational framework for future clinical trials.

Scaling up opioid agonist therapies (OAT) is the most effective strategy to control combined HIV and opioid epidemics, especially in Eastern Europe and Central Asia (EECA), where HIV incidence and mortality continue to increase. Patient concerns about OAT, however, have undermined scale-up. The objective of this study is to understand Ukrainian opioid use disorder patient preferences about OAT to guide the development of an evidence-informed decision aid for clinical decision-making. We conducted a conjoint-based choice (CBC) survey. Participants were asked to about their preferences relating to 7 attributes of OAT (cost, dosing frequency, concerns about withdrawal symptoms, adverse side effects, improvements in quality of life, precipitation of withdrawal and legislative requirements to be registered as a drug dependent person) and 20 attribute levels for receiving OAT under differing potential treatment constraints. Data were analyzed using Hierarchical Bayesian models. Using respondent-driven sampling and random sampling, we recruited 2,028 people who inject drugs with opioid use disorder. Relative importance (RIS) and partial-worth utility scores (PWUS) were used to assess preferences for attributes and thresholds within each attribute. Cost and dosing frequency were the most important attributes (RIS = 39.2% and RIS = 25.2%, respectively) to potential patients, followed by concerns about withdrawal symptoms (RIS = 10.8%), adverse side effects (RIS = 9.0%), quality-of-life improvement (RIS = 7.5%), precipitation of euphoria (5.2%) and requirement to be registered as a drug- dependent person (RIS = 3.1%). The monthly cost-threshold for willingness-to-pay was 1,900 UAH ($70 USD). In Ukraine, where both governmental and private OAT clinics have emerged and provide markedly different delivery strategies, preferences are mostly driven by out-of-pocket expenses, despite many patients being willing to pay for OAT. Programmatic demands (flexibility and ease of acquiring medications) remain an important consideration while for a minority, clinical concerns about withdrawal symptoms, adverse side effects and OAT impact on life play a smaller role.

This article analyzes the talmudic story of the first encounter between Rav and Shmuel (b. Shabbat 108a). It focuses on the structural difficulties of the plot, particularly the relationship between Ravs interview at the beginning of the story and the aggressive medical treatment he undergoes at the end. A new interpretation of Shmuel's request of his student Karna to 'sniff Ravs jar' can solve these problems. The request is here understood as a play on words, which concretizes the metaphorical idiom. This interpretation enables a new reading of the entire story, as one that centers on the relationship between metaphor and reality and, by extension, between the Torah and the body of the immigrant sage., In literary works as in everyday speech, metaphor functions on the rhetorical level; it serves as an illustrative tool, a 'figure of speech,' in the interaction between narrator and reader. [...]

Abstract Subseasonal forecasting—predicting temperature and precipitation 2 to 6 weeks ahead—is critical for effective water allocation, wildfire management, and drought and flood mitigation. Recent international research efforts have advanced the subseasonal capabilities of operational dynamical models, yet temperature and precipitation prediction skills remain poor, partly due to stubborn errors in representing atmospheric dynamics and physics inside dynamical models. Here, to counter these errors, we introduce an adaptive bias correction (ABC) method that combines state-of-the-art dynamical forecasts with observations using machine learning. We show that, when applied to the leading subseasonal model from the European Centre for Medium-Range Weather Forecasts (ECMWF), ABC improves temperature forecasting skill by 60–90% (over baseline skills of 0.18–0.25) and precipitation forecasting skill by 40–69% (over baseline skills of 0.11–0.15) in the contiguous U.S. We couple these performance improvements with a practical workflow to explain ABC skill gains and identify higher-skill windows of opportunity based on specific climate conditions.

Dengue virus (DENV) poses a significant threat to global health, infecting approximately 390 million people annually. This virus comprises four serotypes capable of causing severe disease. Genetic analyses are crucial for understanding the epidemiology, evolution, and spread of DENV. Although previous studies have focused on the envelope protein-coding (E) gene, only a few primers can efficiently detect and amplify the viral genes from multiple endemic countries simultaneously. In this study, we designed degenerate primer pairs for each DENV serotype to amplify and sequence the entire E gene, using globally representative sequences for each serotype. These primers were validated using DENV isolates from various Asian countries and demonstrated broad-spectrum detection capabilities and high-quality sequences. The primers provide effective tools for genetic analysis in the regions affected by dengue, aiding strain identification and epidemiological studies during outbreaks.

Objective. The aim of the present study was to assess insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP3) as markers of insulin resistance in patients with prediabetes and type 2 diabetes mellitus (TDM2).

Measurement(s) Protein expression Technology Type(s) Mass Spectrometry Factor Type(s) genetically distinct human cell lines Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location United States

AIM: To analyse the macular vascularisation changes analysed using optical coherence tomography angiography (OCTA) after successful rhegmatogenous retinal detachment (RRD) repair by comparing gas vs silicone oil and macula-on vs macula-off. METHODS: This retrospective data collection included 77 eyes with RRD that underwent pars plana vitrectomy (PPV) and gas or silicone oil tamponade. We performed an OCTA during the postoperative control between 6 and 24mo after the last surgery and evaluated the main parameters measured by OCTA: foveal avascular zone (FAZ) and parafoveolar vascular density (PVD) in the superficial capillary plexus. The patients were divided into four groups: RRD with macular involvement treated with gas tamponade, RRD without macular involvement treated with gas tamponade, RRD with macular involvement treated with silicone oil tamponade and RRD without macular involvement treated with silicone oil tamponade. A one-way ANOVA test combined with post hoc Bonferroni corrections compared FAZ sizes and PVD in all four groups. RESULTS: The FAZ size was statistically significantly larger in eyes with RRD involving the macula than in those not involving it (P=0.005). There was no statistically significant difference in the FAZ sizes of the eyes treated with silicone oil tamponade compared to those treated with gas tamponade (P=0.54). There was no statistically significant difference in the PVD comparing all four groups. CONCLUSION: Despite the known risks associated with silicone oil, our findings suggest that the type of tamponade used during PPV to treat an RRD has no significant effect on the future integrity of the PVD or the size of the FAZ in the superficial capillary plexus as measured by OCTA.

Here the authors evaluate single cell gene expression from mouse and human Huntington’s disease brains, finding incomplete oligodendrocyte maturation and pathways involved. Treating mice with thiamine/biotin ameliorates molecular pathology.

Abstract Background The 2021 American College of Rheumatology (ACR) rheumatoid arthritis (RA) guideline considers the specific context of the United States which differs from that of Saudi Arabia in many aspects that may impact recommendations. The objective of this project was to adapt a set of prioritized recommendations from the 2021 ACR guideline for the treatment of rheumatoid arthritis RA for the context of Saudi Arabia, by the Saudi Society for Rheumatology (SSR). Methods The process followed the GRADE-ADOLOPMENT methodology, and the reporting adhered to the RIGHT-Ad@pt checklist. Working groups included a coordination group and a 19-member panel representing different stakeholder groups. The Evidence to Decision (EtD) tables included evidence on health effects from the source guideline and contextual information from the Saudi setting. Results The panel prioritized and adapted five recommendations from the source guideline. The process led to modifying two out of the five prioritized recommendations, all listed here. In naive patients with low disease activity, methotrexate (MTX) is conditionally recommended over sulfasalazine (SSZ) (modified direction); hydroxychloroquine (HCQ) is conditionally recommended over SSZ (unmodified). Initiation of csDMARDs with short-term glucocorticoids is conditionally recommended over csDMARDs alone in naive patients with moderate to high disease activity (modified direction). Switch to subcutaneous MTX is conditionally recommended over addition/switch to alternative DMARD(s) in patients taking oral MTX who are not at target (unmodified). Discontinuation of MTX is conditionally recommended over gradual discontinuation of the bDMARD or tsDMARD for patients taking MTX plus a bDMARD or tsDMARD who wish to discontinue a DMARD (unmodified). Conclusion Rheumatologists practicing in Saudi Arabia can use the adoloped recommendations generated by this project while adopting the rest of the recommendations from the 2021 ACR guidelines.