Stimulated Muscle Contractions Regulate Membrane-Bound and Soluble TLR4 to Prevent LPS-Induced Signaling and Myotube Atrophy in Skeletal Muscle Cells

Toll-like receptor 4 (TLR4) activation by lipopolysaccharides (LPS) contributes to chronic inflammation and causes upregulation of muscle atrophy signaling pathways. Exercise can suppress LPS/TLR4 axis activation by reducing the expression of TLR4 on immune cells. It is unknown how this regulation occurs, and it is not clear how exercise affects TLR4 on skeletal muscle. PURPOSE: To uncover the nature and mechanisms by which exercise affects TLR4 expression and intracellular signaling using cell culture models and human experiments. METHODS: C2C12 myotubes were subjected to electrical pulse stimulation (EPS) with and without subsequent treatment with 500 ng/mL lipopolysaccharide (LPS) along with corresponding control conditions. To investigate the effect of muscle contraction on the regulation of TLR4 in-vivo, we analyzed PBMC and serum samples from eight recreationally active men that completed 60-minutes of cycling at a moderate intensity (65% of VO2max). RESULTS: In-vitro, LPS decreased membrane-bound TLR4, increased TLR4 signaling (decreased inhibitor of κBα), and induced myotube atrophy. However, stimulated muscle contractions decreased membrane-bound TLR4, increased soluble TLR4 (sTLR4), and prevented LPS-induced signaling and myotube atrophy. In human participants, a single bout of moderate-intensity exercise decreased membrane-bound TLR4 on PBMCs and increased serum-borne sTLR4. CONCLUSION: These experiments support exercise may exert a novel anti-catabolic/ anti-inflammatory effect by increasing sTLR4 and decreasing TLR4 expressed on the muscle membrane. These results could help improve interventions for conditions associated with TLR4-mediated inflammation and muscle atrophy, such as diabetes, sarcopenia, and cancer cachexia

Fluorescent Risedronate Analogues Reveal Bisphosphonate Uptake by Bone Marrow Monocytes and Localization Around Osteocytes In Vivo

Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647–labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Researc

Search for rare or forbidden decays of the D0 meson

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D0→h'−h−ℓ'+ℓ+ and D0→h'−h+ℓ'±ℓ∓, where h and h′ represent a K or π meson and ℓ and ℓ′ an electron or muon. The analysis is based on 468 fb−1 of e+e− annihilation data collected at or close to the Υ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0–30.6)×10−7. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.publishedVersio

Light meson spectroscopy from Dalitz plot analyses of ηc decays to η0 K+K− , η0 π + π − , and ηπ + π − produced in two-photon interactions

We study the processes γγ→ηc→η′K+K−, η′π+π−, and ηπ+π− using a data sample of 519  fb−1 recorded with the BABAR detector operating at the SLAC PEP-II asymmetric-energy e+e− collider at center-of-mass energies at and near the Υ(nS) (n=2, 3, 4) resonances. This is the first observation of the decay ηc→η′K+K− and we measure the branching fraction Γ(ηc→η′K+K−)/(Γ(ηc→η′π+π−)=0.644±0.039stat±0.032sys. Significant interference is observed between γγ→ηc→ηπ+π− and the nonresonant two-photon process γγ→ηπ+π−. A Dalitz plot analysis is performed of ηc decays to η′K+K−, η′π+π−, and ηπ+π−. Combined with our previous analysis of ηc→K¯Kπ, we measure the K∗0(1430) parameters and the ratio between its η′K and πK couplings. The decay ηc→η′π+π− is dominated by the f0(2100) resonance, also observed in J/ψ radiative decays. A new a0(1700)→ηπ resonance is observed in the ηc→ηπ+π− channel. We also compare ηc decays to η and η′ final states in association with scalar mesons as they relate to the identification of the scalar glueball.publishedVersio

Measurements of the absolute branching fractions of B± →k±Xc c

A study of the two-body decays B±→Xc¯cK±, where Xc¯c refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424 fb−1. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B+→X(3872)K+ at the 3σ level. The absolute branching fraction B[B+→X(3872)K+]=[2.1±0.6(stat)±0.3(syst)]×10−4 is measured for the first time. It follows that B[X(3872)→J/ψπ+π−]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.publishedVersio

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

The somatic genomic landscape of glioblastoma

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer