Notes

Reaction to Powell et 's., "Do Assistive hearing aid devices Prevent Drops? Discourse upon Study From the country's Nutrition and health Exam Survey".
Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.Oxygen isotope speleothem records exhibit coherent variability over the pan-Asian summer monsoon (AM) region. The hydroclimatic representation of these oxygen isotope records for the AM, however, has remained poorly understood. Here, combining an isotope-enabled Earth system model in transient experiments with proxy records, we show that the widespread AM δ18Oc signal during the last deglaciation (20 to 11 thousand years ago) is accompanied by a continental-scale, coherent hydroclimate footprint, with spatially opposite signs in rainfall. This footprint is generated as a dynamically coherent response of the AM system primarily to meltwater forcing and secondarily to insolation forcing and is further reinforced by atmospheric teleconnection. Hence, widespread δ18Op depletion in the AM region is accompanied by a northward migration of the westerly jet and enhanced southwesterly monsoon wind, as well as increased rainfall from South Asia (India) to northern China but decreased rainfall in southeast China.Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.Combination immunotherapy is promising to overcome the limited objective response rates of immune checkpoint blockade (ICB) therapy. Here, a tumor immunological phenotype (TIP) gene signature and high-throughput sequencing-based high-throughput screening (HTS2) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature distinguishing "cold" tumors from "hot" tumors. After screening thousands of compounds, we identified that aurora kinase inhibitors (AKIs) could reprogram the expression pattern of TIP genes in triple-negative breast cancer (TNBC) cells. AKIs treatments up-regulate expression of chemokine genes CXCL10 and CXCL11 through inhibiting aurora kinase A (AURKA)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, which promotes effective T cells infiltrating into tumor microenvironment and improves anti-programmed cell death 1 (PD-1) efficacy in preclinical models. Our study established a novel strategy to discover combination immunotherapy compounds and suggested the therapeutic potential of combining AKIs with ICB for the treatment of TNBC.One of the most intriguing questions in vertebrate evolution is how tetrapods gained the ability to walk on land. Although many hypotheses have been proposed, few have been rigorously tested using the fossil record. Here, we build three-dimensional musculoskeletal models of the pectoral appendage in Eusthenopteron, Acanthostega, and Pederpes and quantitatively examine changes in forelimb function across the fin-to-limb transition. Through comparison with extant fishes and tetrapods, we show that early tetrapods share a suite of characters including restricted mobility in humerus long-axis rotation, increased muscular leverage for humeral retraction, but not depression/adduction, and increased mobility in elbow flexion-extension. ZX703 chemical structure We infer that the earliest steps in tetrapod forelimb evolution were related to limb-substrate interactions, whereas specializations for weight support appeared later. Together, these results suggest that competing selective pressures for aquatic and terrestrial environments produced a unique, ancestral "early tetrapod" forelimb locomotor mode unlike that of any extant animal.Despite intensive research, the role of metabolism in bacterial sporulation remains poorly understood. Here, we demonstrate that Bacillus subtilis sporulation entails a marked metabolic differentiation of the two cells comprising the sporangium the forespore, which becomes the dormant spore, and the mother cell, which dies as sporulation completes. Our data provide evidence that metabolic precursor biosynthesis becomes restricted to the mother cell and that the forespore becomes reliant on mother cell-derived metabolites for protein synthesis. We further show that arginine is trafficked between the two cells and that proposed proteinaceous channels mediate small-molecule intercellular transport. Thus, sporulation entails the profound metabolic reprogramming of the forespore, which is depleted of key metabolic enzymes and must import metabolites from the mother cell. Together, our results provide a bacterial example analogous to progeny nurturing.
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