VarNMF: Non-negative Probabilistic Factorization with Source Variation.

Motivation: Non-negative Matrix Factorization (NMF) is a powerful tool often applied to genomic data, to identify non-negative latent components that constitute linearly mixed samples. It is useful when the observed signal combines contributions from multiple sources, such as cell types in bulk measurements of heterogeneous tissue. NMF accounts for two types of variation between samples-disparities in the proportions of sources and observation noise.

[AI-BASED HEALTH AND BIOLOGICAL SCIENCES: AN OPPORTUNITY FOR ISRAELI LEADERSHIP].

Artificial Intelligence (AI) has become a key tool for the acceleration of scientific discovery, from accelerated drug discovery through automatic-robotic lab to the discovery of new materials that can help reduce air pollution. Israel is blessed with a unique combination of strong expertise in health and biological sciences, as well as advanced AI technologies. Hence, Israel can potentially become a leader in AI based biomedical scientific discovery.

Can placing posters increase awareness to pediatric obesity in a Pediatric Emergency Department?

Background: Identification and addressing of pediatric obesity are the first steps in its management, and Pediatric Emergency Department (PED) visits have a potential to increase its awareness. The main aim of this study was to examine if posters placed in the PED alerting to obesity increased its documentation.

Methods: The design of this paper is that of an interventional study which took place at a large tertiary PED during May-August 2022.

Molecular mechanisms underlying the modulation of T-cell proliferation and cytotoxicity by immobilized CCL21 and ICAM1.

Background: Adoptive cancer immunotherapy, using engineered T-cells, expressing chimeric antigen receptor or autologous tumor infiltrating lymphocytes became, in recent years, a major therapeutic approach for diverse types of cancer. However, despite the transformative potential of adoptive cancer immunotherapy, this field still faces major challenges, manifested by the apparent decline of the cytotoxic capacity of effector CD8 T cells upon their expansion. To address these challenges, we have developed an ex vivo "synthetic immune niche" (SIN), composed of immobilized CCL21 and ICAM1, which synergistically induce an efficient expansion of antigen-specific CD8 T cells while retaining, and even enhancing their cytotoxic potency.

SLAM-Drop-seq reveals mRNA kinetic rates throughout the cell cycle.

RNA abundance is tightly regulated in eukaryotic cells by modulating the kinetic rates of RNA production, processing, and degradation. To date, little is known about time‐dependent kinetic rates during dynamic processes. Here, we present SLAM‐Drop‐seq, a method that combines RNA metabolic labeling and alkylation of modified nucleotides in methanol‐fixed cells with droplet‐based sequencing to detect newly synthesized and preexisting mRNAs in single cells.

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma.

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas.

Bacterial Infections and Clinical Outcomes Among Febrile Infants up to 90 Days Old With SARS-CoV-2 Infection: A Multicenter Cohort Study.

We present a large, multicenter, cohort study that aimed to assess bacterial infection rates among febrile infants up to 90 days old presenting to the pediatric emergency department with severe acute respiratory syndrome coronavirus 2 infection during 2021-2022 throughout successive variant waves. Overall, 417 febrile infants were included. Twenty-six infants (6.

Viral infection reveals hidden sharing of TCR CDR3 sequences between individuals.

The T cell receptor is generated by a process of random and imprecise somatic recombination. The number of possible T cell receptors which this process can produce is enormous, greatly exceeding the number of T cells in an individual. Thus, the likelihood of identical TCRs being observed in multiple individuals (public TCRs) might be expected to be very low.

Elevated cfDNA after exercise is derived primarily from mature polymorphonuclear neutrophils, with a minor contribution of cardiomyocytes.

Strenuous physical exercise causes a massive elevation in the concentration of circulating cell-free DNA (cfDNA), which correlates with effort intensity and duration. The cellular sources and physiological drivers of this phenomenon are unknown. Using methylation patterns of cfDNA and associated histones, we show that cfDNA in exercise originates mostly in extramedullary polymorphonuclear neutrophils.

The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC.

Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined.

Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT.

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality.

Modulating the proliferative and cytotoxic properties of patient-derived TIL by a synthetic immune niche of immobilized CCL21 and ICAM1.

A major challenge in developing an effective adoptive cancer immunotherapy is the generation of tumor-reactive cells in sufficient numbers and with enhanced cytotoxic potential. It was recently demonstrated that culturing of activated murine CD8+ T-cells on a "Synthetic Immune Niche" (SIN), consisting of immobilized CCL21 and ICAM-1, enhances T-cell expansion, increases their cytotoxicity against cultured cancer cells and suppresses tumor growth . In the study reported here, we have tested the effect of the CCL21+ICAM1 SIN, on the expansion and cytotoxic phenotype of Tumor Infiltrating Lymphocytes (TIL) from melanoma patients, following activation with immobilized anti-CD3/CD28 stimulation, or commercial activation beads.

Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes.

Unlabelled: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions.

Quantifying changes in the T cell receptor repertoire during thymic development.

One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood.

From pseudo to real-time dynamics of T cell thymic differentiation.

Numerous methods have recently emerged for ordering single cells along developmental trajectories. However, accurate depiction of developmental dynamics can only be achieved after rescaling the trajectory according to the relative time spent at each developmental point. We formulate a model which estimates local cell densities and fluxes, and incorporates cell division and apoptosis rates, to infer the real-time dimension of the developmental trajectory.

Obesity screening in the pediatric emergency department - A missed opportunity?

Objectives: There is a low rate of body mass index measurements and obesity screening in primary pediatric care. Pediatric emergency department (PED) visits, with their large volumes and routine weight measurements, provide a unique opportunity to identify and address obesity. The study objectives were to examine the rate of addressing obesity in the PED and to identify its predicting factors.

Conserved degronome features governing quality control associated proteolysis.

The eukaryotic proteome undergoes constant surveillance by quality control systems that either sequester, refold, or eliminate aberrant proteins by ubiquitin-dependent mechanisms. Ubiquitin-conjugation necessitates the recognition of degradation determinants, termed degrons, by their cognate E3 ubiquitin-protein ligases. To learn about the distinctive properties of quality control degrons, we performed an unbiased peptidome stability screen in yeast.

A hierarchy of selection pressures determines the organization of the T cell receptor repertoire.

We systematically examine the receptor repertoire in T cell subsets in young, adult, and LCMV-infected mice. Somatic recombination generates diversity, resulting in the limited overlap between nucleotide sequences of different repertoires even within the same individual. However, statistical features of the repertoire, quantified by the V gene and CDR3 k-mer frequency distributions, are highly conserved.

Triage performance in adolescent patients with SARS-CoV-2 infection in Israel.

Objective: The aim of this study was to assess the performance of the Pediatric Canadian Triage and Acuity Scale (PaedCTAS) in adolescent patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods: A time-series study was conducted in the Emergency Departments (EDs) of 17 public hospitals during the Delta (B.1.

Transcription feedback dynamics in the wake of cytoplasmic mRNA degradation shutdown.

In the last decade, multiple studies demonstrated that cells maintain a balance of mRNA production and degradation, but the mechanisms by which cells implement this balance remain unknown. Here, we monitored cells' total and recently-transcribed mRNA profiles immediately following an acute depletion of Xrn1-the main 5'-3' mRNA exonuclease-which was previously implicated in balancing mRNA levels. We captured the detailed dynamics of the adaptation to rapid degradation of Xrn1 and observed a significant accumulation of mRNA, followed by a delayed global reduction in transcription and a gradual return to baseline mRNA levels.

Dissemination and Use of Point-of-Care Ultrasound by Pediatricians in Europe: A Research in European Pediatric Emergency Medicine Network Collaborative Survey.

Objective: We surveyed the dissemination and use of point-of-care ultrasound (POCUS), physician training levels, and barriers and limitations to use of POCUS among pediatricians and pediatric emergency medicine (PEM) physicians across Europe and Israel.

Methods: A questionnaire was distributed through the PEM section of the European Society for Emergency Medicine and the Research in European Pediatric Emergency Medicine Network.

Results: A total of 581 physicians from 22 countries fully completed the questionnaire.

Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.