The early-life gut microbiome and vaccine efficacy

Vaccines are one of the greatest successes of public health, preventing millions of cases of disease and death in children each year. However, the efficacy of many vaccines can vary greatly between infants from geographically and socioeconomically distinct locations. Differences in the composition of the intestinal microbiome have emerged as one of the main factors that can account for variations in immunisation outcomes. In this Review, we assess the influence of the gut microbiota upon early life immunity, focusing on two important members of the microbiota with health-promoting and immunomodulatory properties: Bifidobacterium and Bacteroides. Additionally, we discuss their immune stimulatory microbial properties, interactions with the host, and their effect on vaccine responses and efficacy in infants. We also provide an overview of current microbiota-based approaches to enhance vaccine outcomes, and describe novel microbe-derived components that could lead to safer, more effective vaccines and vaccine adjuvants

Public Health in Pharmacy Practice: A Casebook 2nd Edition

This casebook, now in its second edition, is a collaboration of over 90 individuals with expertise and training in public health pharmacy. A total of 54 chapters are presented, covering a broad array of topics relevant to pharmacy applications of public health. These topics include, but are not limited to, cross-cultural care, health literacy and disparities, infectious disease, health promotion and disease prevention, medication safety, structural racism, advocacy/policy analysis, chronic disease, women’s health, rural health, travel medicine and more. The book is designed to allow educators/students to choose chapters of interest as they feel suited, as each chapter is independent from the others. Each chapter contains learning objectives and an introduction to the topic, followed by a case and questions. The chapter closes with commentary from the authors and patient-oriented considerations for the topic at hand.https://knightscholar.geneseo.edu/oer-ost/1026/thumbnail.jp

Optimal Hypercontractivity for Fermi Fields and Related Non-Commutative Integration

Optimal hypercontractivity bounds for the fermion oscillator semigroup are obtained. These are the fermion analogs of the optimal hypercontractivity bounds for the boson oscillator semigroup obtained by Nelson. In the process, several results of independent interest in the theory of non-commutative integration are established. {}.Comment: 18 p., princeton/ecel/7-12-9

Retrotransposons Are the Major Contributors to the Expansion of the \u3ci\u3eDrosophila ananassae\u3c/i\u3e Muller F Element

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (\u3e18.7 Mb) in D. ananassae. To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae. Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5′ ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains

Advanced Large Area Plastic Scintillator Project (ALPS): Final Report

The advanced Large-Area Plastic Scintillator (ALPS) Project at Pacific Northwest National Laboratory investigated possible technological avenues for substantially advancing the state-of-the-art in gamma-ray detection via large-area plastic scintillators. The three predominant themes of these investigations comprised the following: * Maximizing light collection efficiency from a single large-area sheet of plastic scintillator, and optimizing hardware event trigger definition to retain detection efficiency while exploiting the power of coincidence to suppress single-PMT "dark current" background; * Utilizing anti-Compton vetoing and supplementary spectral information from a co-located secondary, or "Back" detector, to both (1) minimize Compton background in the low-energy portion of the "Front" scintillator's pulse-height spectrum, and (2) sharpen the statistical accuracy of the front detector's low-energy response prediction as impelmented in suitable energy-windowing algorithms; and * Investigating alternative materials to enhance the intrinsic gamma-ray detection efficiency of plastic-based sensors

Coordination by Cdc42 of actin, contractility, and adhesion for melanoblast movement in mouse skin

YesThe individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually associated with fast mesenchymal motility, Cdc42 knockout melanoblasts migrated slowly and inefficiently in the epidermis, with nearly static pseudopods. Although much of the basic actin machinery was intact, Cdc42 null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics.Cancer Research UK (to L.M.M. [A17196], R.H.I. [A19257], and S.W.G.T.) and NIH grants P01-GM103723 and P41-EB002025 (to K.M.H.). N.R.P. is supported by a Pancreatic Cancer Research Fund grant (to L.M.M.). Funding to Prof. Rottner by the Deutsche Forschungsgemeinschaft (grant RO2414/3-2)

Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis

Anatomy of STEM Teaching in American Universities: A Snapshot from a Large-Scale Observation Study

National and local initiatives focused on the transformation of STEM teaching in higher education have multiplied over the last decade. These initiatives often focus on measuring change in instructional practices, but it is difficult to monitor such change without a national picture of STEM educational practices, especially as characterized by common observational instruments. We characterized a snapshot of this landscape by conducting the first large scale observation-based study. We found that lecturing was prominent throughout the undergraduate STEM curriculum, even in classrooms with infrastructure designed to support active learning, indicating that further work is required to reform STEM education. Additionally, we established that STEM faculty’s instructional practices can vary substantially within a course, invalidating the commonly-used teaching evaluations based on a one-time observation

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485