Rothsteensen4060

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.The mathematical foundation of quantum mechanics is built on linear algebra, while the application of nonlinear operators can lead to outstanding discoveries under some circumstances, such as the prediction of positron, a direct outcome of the Dirac equation which stems from the square-root of the Klein-Gordon equation. In this article, we propose a model of square-root higher-order Weyl semimetal (SHOWS) by inheriting features from its parent Hamiltonians. It is found that the SHOWS hosts both "Fermi-arc" surface and hinge states that respectively connect the projection of the Weyl points on the side surface and arris. We theoretically construct and experimentally observe the exotic SHOWS state in three-dimensional (3D) stacked electric circuits with honeycomb-kagome hybridizations and double-helix interlayer couplings. Our results open the door for realizing the square-root topology in 3D solid-state platforms.Continuous mechanical work output can be generated by using combustion engines and electric motors, as well as actuators, through on/off control via external stimuli. Solar energy has been used to generate electricity and heat in human daily life; however, the direct conversion of solar energy to continuous mechanical work has not been realized. In this work, a solar engine is developed using an oscillating actuator, which is realized through an alternating volume decrease of each side of a polypropylene/carbon black polymer film induced by photothermal-derived solvent evaporation. The anisotropic solvent evaporation and fast gradient diffusion in the polymer film sustains oscillating bending actuation under the illumination of divergent light. This light-driven oscillator shows excellent oscillation performance, excellent loading capability, and high energy conversion efficiency, and it can never stop with solvent supply. The oscillator can cyclically lift up a load and output work, exhibiting a maximum specific work of 30.9 × 10-5 J g-1 and a maximum specific power of 15.4 × 10-5 W g-1 under infrared light. This work can inspire the development of autonomous devices and provide a design strategy for solar engines.Molecular understanding of osteogenic differentiation (OD) of human bone marrow-derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications for cancer. We report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4-deficient hBMSCs remain as stalled progenitors. Remarkably, incubation of RNF4-deficient hBMSCs in conditioned media of differentiating hBMSCs restored OD. Transcriptional analysis of RNF4-dependent gene signatures identified two secreted factors that act downstream of RNF4 promoting OD (1) BMP6 and (2) the BMP6 co-receptor, RGMb (Dragon). Indeed, knockdown of either RGMb or BMP6 in hBMSCs halted OD, while only the combined co-addition of purified RGMb and BMP6 proteins to RNF4-deficient hBMSCs fully restored OD. Moreover, we found that the RNF4-RGMb-BMP6 axis is essential for survival and tumorigenicity of osteosarcoma and therapy-resistant melanoma cells. Importantly, patient-derived sarcomas such as osteosarcoma, Ewing sarcoma, liposarcomas, and leiomyosarcomas exhibit high levels of RNF4 and BMP6, which are associated with reduced patient survival. Overall, we discovered that the RNF4~BMP6~RGMb axis is required for both OD and tumorigenesis.Sarcomas include cancer stem cells, but how these cells contribute to local and metastatic relapse is largely unknown. We previously showed the pro-tumor functions of calpain-6 in sarcoma stem cells. Here, we use an osteosarcoma cell model, osteosarcoma tissues and transcriptomic data from human tumors to study gene patterns associated with calpain-6 expression or suppression. Calpain-6 modulates the expression of Hippo pathway genes and stabilizes the hippo effector YAP. It also modulates the vesicular trafficking of β-catenin degradation complexes. Calpain-6 expression is associated with genes of the G2M phase of the cell cycle, supports G2M-related YAP activities and up-regulated genes controlling mitosis in sarcoma stem cells and tissues. In mouse models of bone sarcoma, most tumor cells expressed calpain-6 during the early steps of tumor out-growth. YAP inhibition prevented the neoformation of primary tumors and metastases but had no effect on already developed tumors. It could even accelerate lung metastasis associated with large bone tumors by affecting tumor-associated inflammation in the host tissues. Our results highlight a specific mechanism involving YAP transcriptional activity in cancer stem cells that is crucial during the early steps of tumor and metastasis outgrowth and that could be targeted to prevent sarcoma relapse.Because of their small size, the recently developed CRISPR-Cas12f nucleases can be effectively packaged into adeno-associated viruses for gene therapy. However, a systematic evaluation of the editing outcomes of CRISPR-Cas12f is lacking. In this study, we apply a high-throughput sequencing method to comprehensively assess the editing efficiency, specificity, and safety of four Cas12f proteins in parallel with that of Cas9 and two Cas12a proteins at multiple genomic sites. Cas12f nucleases achieve robust cleavage at most of the tested sites and mainly produce deletional fragments. In contrast, Cas9 and Cas12a show relatively higher editing efficiency at the vast majority of the tested sites. However, the off-target hotspots identified in the Cas9- and Cas12a-edited cells are negligibly detected in the Cas12f-edited cells. Moreover, compared to Cas9 and Cas12a nucleases, Cas12f nucleases reduce the levels of chromosomal translocations, large deletions, and integrated vectors by 2- to 3-fold. Therefore, our findings confirm the editing capacity of Cas12f and reveal the ability of this nuclease family to preserve genome integrity during genome editing.Parkinson's disease (PD) remains a significant unmet clinical need. Gut dysbiosis stands as a PD pathologic source and therapeutic target. Here, we assessed the role of the gut-brain axis in PD pathology and treatment. Adult transgenic (Tg) α-synuclein-overexpressing mice served as subjects and were randomly assigned to either transplantation of vehicle or human umbilical cord blood-derived stem cells and plasma. Behavioral and immunohistochemical assays evaluated the functional outcomes following transplantation. Tg mice displayed typical motor and gut motility deficits, elevated α-synuclein levels, and dopaminergic depletion, accompanied by gut dysbiosis characterized by upregulation of microbiota and cytokines associated with inflammation in the gut and the brain. In contrast, transplanted Tg mice displayed amelioration of motor deficits, improved sparing of nigral dopaminergic neurons, and downregulation of α-synuclein and inflammatory-relevant microbiota and cytokines in both gut and brain. Parallel in vitro studies revealed that cultured dopaminergic SH-SY5Y cells exposed to homogenates of Tg mouse-derived dysbiotic gut exhibited significantly reduced cell viability and elevated inflammatory signals compared to wild-type mouse-derived gut homogenates. Moreover, treatment with human umbilical cord blood-derived stem cells and plasma improved cell viability and decreased inflammation in dysbiotic gut-exposed SH-SY5Y cells. Intravenous transplantation of human umbilical cord blood-derived stem/progenitor cells and plasma reduced inflammatory microbiota and cytokine, and dampened α-synuclein overload in the gut and the brain of adult α-synuclein-overexpressing Tg mice. Our findings advance the gut-brain axis as a key pathological origin, as well as a robust therapeutic target for PD.An effective malaria vaccine remains a global health priority and vaccine immunogens which prevent transmission of the parasite will have important roles in multi-component vaccines. One of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut. Indeed, antibodies which bind Pfs48/45 can prevent transmission if ingested with the parasite as part of the mosquito bloodmeal. Here we present the structure of full-length Pfs48/45, showing its three domains to form a dynamic, planar, triangular arrangement. We reveal where transmission-blocking and non-blocking antibodies bind on Pfs48/45. Finally, we demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. selleck compound Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.