Clausencastaneda9116

There are increasing efforts to engineer functional compartments that mimic cellular behaviours from the bottom-up. One behaviour that is receiving particular attention is motility, due to its biotechnological potential and ubiquity in living systems. Many existing platforms make use of the Marangoni effect to achieve motion in water/oil (w/o) droplet systems. However, most of these systems are unsuitable for biological applications due to biocompatibility issues caused by the presence of oil phases. Here we report a biocompatible all aqueous (w/w) PEG/dextran Pickering-like emulsion system consisting of liposome-stabilised cell-sized droplets, where the stability can be easily tuned by adjusting liposome composition and concentration. We demonstrate that the compartments are capable of negative chemotaxis these droplets can respond to a PEG/dextran polymer gradient through directional motion down to the gradient. The biocompatibility, motility and partitioning abilities of this droplet system offers new directions to pursue research in motion-related biological processes.Hepatocellular carcinoma (HCC) is one of the most common cancers with an insidious onset, strong invasiveness, insensitivity to chemotherapy, and poor prognosis, thus makes clinical treatment challenging. The mechanisms require further elucidation for developing novel therapies and targeting drug resistance. Here, we observed high Shc3 expression in patients with chemoresistant and recurrent HCCs. Shc3 overexpression induced a significant increase in MDR1/P-glycoprotein expression, whereas Shc3 knockdown impaired this expression. Cucurbitacin I in vivo Further, Shc3 inhibition significantly restored HCC cell sensitivity to doxorubicin and sorafenib. Mechanistically, Shc3 interacted with β-catenin, inhibited destruction complex stability, promoted β-catenin release, and dampened β-catenin ubiquitination. Shc3 bound β-catenin and facilitated its nuclear translocation, prompting the β-catenin/TCF pathway to elevate MDR1 transcription. β-catenin blockage abolished the discrepancy in drug resistance between Shc3-depleted HCC cells and control cells, which further validating that β-catenin is required for Shc3-mediated liver chemotherapy. We also determined the effect of Shc3 on the sensitivity of HCC to chemotherapy in vivo. Collectively, this study provides a potential strategy to target these pathways concurrently with systemic chemotherapy that can improve the clinical treatment of HCC.Climate change poses a significant threat to global biodiversity, but freshwater fishes have been largely ignored in climate change assessments. Here, we assess threats of future flow and water temperature extremes to ~11,500 riverine fish species. In a 3.2 °C warmer world (no further emission cuts after current governments' pledges for 2030), 36% of the species have over half of their present-day geographic range exposed to climatic extremes beyond current levels. Threats are largest in tropical and sub-arid regions and increases in maximum water temperature are more threatening than changes in flow extremes. In comparison, 9% of the species are projected to have more than half of their present-day geographic range threatened in a 2 °C warmer world, which further reduces to 4% of the species if warming is limited to 1.5 °C. Our results highlight the need to intensify (inter)national commitments to limit global warming if freshwater biodiversity is to be safeguarded.T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients' prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling.