Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/ß-catenin signaling.

Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSCs maintain the balance between activation and quiescence remains largely unknown. Herein, we found that Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) is required for the expansion of phenotypic HSCs in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from CLPs. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSCs revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with ß-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease of the active ß- catenin (non-phosphorylated) that interrupted the Wnt/ß-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role of Ppm1b in regulating HSC homeostasis via Wnt/ß-catenin pathway.

Ambient γ-Rays-Mediated Noble-Metal Deposition on Defect-Rich Manganese Oxide for Glycerol-Assisted H2 Evolution at Industrial-Level Current Density.

Developing novel synthesis technologies is crucial to expanding bifunctional electrocatalysts for energy-saving hydrogen production. Herein, we report an ambient and controllable γ-ray radiation reduction to synthesize a series of noble metal nanoparticles anchored on defect-rich manganese oxides (M@MnO2-x , M=Ru, Pt, Pd, Ir) for glycerol-assisted H2 evolution. Benefiting from the strong penetrability of γ-rays, nanoparticles and defect supports are formed simultaneously and bridged by metal-oxygen bonds, guaranteeing structural stability and active site exposure. The special Ru-O-Mn bonds activate the Ru and Mn sites in Ru@MnO2-x through strong interfacial coordination, driving glycerol electrolysis at low overpotential. Furthermore, only a low cell voltage of 1.68 V is required to achieve 0.5 A cm-2 in a continuous-flow electrolyzer system along with excellent stability. In situ spectroscopic analysis reveals that the strong interfacial coordination in Ru@MnO2-x balances the competitive adsorption of glycerol and OH* on the catalyst surface. Theoretical calculations further demonstrate that the defect-rich MnO2 support promotes the dissociation of H2 O, while the defect-regulated Ru sites promote deprotonation and hydrogen desorption, synergistically enhancing glycerol-assisted hydrogen production.

Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies.

Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca2+ binding and luminal Ca2+-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl-]ER and [K+]ER and ER morphology and regulates ER Ca2+ homeostasis, including internal Ca2+ release and steady-state [Ca2+]ER. ALS-associated mutant forms of CLCC1 increase steady-state [Cl-]ER and impair ER Ca2+ homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies.

Prognostic value of neutrophil to lymphocyte ratio in gastric cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The neutrophil to lymphocyte ratio (NLR) is a cost-effective and easily identifiable inflammatory biomarker that has been shown to be closely associated with tumor prognosis and predict survival in patients with multiple malignancies. However, the predictive value of NLR in patients with gastric cancer (GC) treated with immune checkpoint inhibitors (ICIs) has not been fully explored. Therefore, we conducted a meta-analysis to explore the potential of NLR as a predictor of survival in this population. Methods: We systematically searched the PubMed, Cochrane Library, and EMBASE databases from inception to the present for observational researches on NLR and its relationship with progression or survival in GC patients receiving ICIs. To assess the prognostic significance of NLR on overall survival (OS) or progression-free survival (PFS), we used fixed or random-effect models to derive and combine hazard ratios (HRs) with 95% confidence intervals (CIs). We also examined the relationship between NLR and treatment efficacy by calculating relative risks (RRs) with 95% CIs for objective response rate (ORR) and disease control rate (DCR) in patients with GC receiving ICIs. Results: Nine studies of 806 patients were eligible. OS and PFS data were obtained from 9 and 5 studies, respectively. In nine studies, NLR was associated with poor survival, the pooled HR was 1.98 (95% CI 1.67- 2.35, p < 0.001), indicating a significant association between high NLR and worse OS. We conducted subgroup analyses based on study characteristics to confirm the robustness of our findings. A relationship between NLR and PFS were reported in five studies with a HR of 1.49 (95% CI 0.99- 2.23, p = 0.056), which was not significantly associated. Pooling four studies that examined the correlation between NLR and ORR/DCR in GC patients, we observed a significant correlation between NLR and ORR (RR = 0.51, p = 0.003), but no significant correlation between NLR and DCR (RR = 0.48, p = 0.111). Conclusion: In summary, this meta-analysis indicates that increased NLR is significantly linked to worse OS in patients with GC receiving ICIs. In addition, lowering NLR can improve ORR. Thus, NLR can serve as a predictor for prognosis and treatment response in GC patients treated with ICIs. Nevertheless, further high-quality prospective studies are required to verify our findings in the future.

Prioritizing risk genes as novel stratification biomarkers for acute monocytic leukemia by integrative analysis.

Acute myeloid leukemia (AML) is a blood cancer with high heterogeneity and stratified as M0-M7 subtypes in the French-American-British (FAB) diagnosis system. Improved diagnosis with leverage of key molecular inputs will assist precisive medicine. Through deep-analyzing the transcriptomic data and mutations of AML, we report that a modern clustering algorithm, t-distributed Stochastic Neighbor Embedding (t-SNE), successfully demarcates M2, M3 and M5 territories while M4 bias to M5 and M0 & M1 bias to M2, consistent with the traditional FAB classification. Combining with mutation profiles, the results show that top recurrent AML mutations were unbiasedly allocated into M2 and M5 territories, indicating the t-SNE instructed transcriptomic stratification profoundly outperforms mutation profiling in the FAB system. Further functional data mining prioritizes several myeloid-specific genes as potential regulators of AML progression and treatment by Venetoclax, a BCL2 inhibitor. Among them two encode membrane proteins, LILRB4 and LRRC25, which could be utilized as cell surface biomarkers for monocytic AML or for innovative immuno-therapy candidates in future. In summary, our deep functional data-mining analysis warrants several unappreciated immune signaling-encoding genes as novel diagnostic biomarkers and potential therapeutic targets.

Attitudes Toward the Global Allocation of Chinese COVID-19 Vaccines: Cross-sectional Online Survey of Adults Living in China.

BACKGROUND: COVID-19 vaccines are in short supply worldwide. China was among the first countries to pledge supplies of the COVID-19 vaccine as a global public product, and to date, the country has provided more than 600 million vaccines to more than 200 countries and regions with low COVID-19 vaccination rates. Understanding the public's attitude in China toward the global distribution of COVID-19 vaccines could inform global and national decisions, policies, and debates. OBJECTIVE: The aim of this study was to determine the attitudes of adults living in China regarding the global allocation of COVID-19 vaccines developed in China and how these attitudes vary across provinces and by sociodemographic characteristics. METHODS: We conducted a cross-sectional online survey among adults registered with the survey company KuRunData. The survey asked participants 31 questions about their attitudes regarding the global allocation of COVID-19 vaccines developed in China. We disaggregated responses by province and sociodemographic characteristics. All analyses used survey sampling weights. RESULTS: A total of 10,000 participants completed the questionnaire. Participants generally favored providing COVID-19 vaccines to foreign countries before fulfilling domestic needs (75.6%, 95% CI 74.6%-76.5%). Women (3778/4921, 76.8%; odds ratio 1.18, 95% CI 1.07-1.32; P=.002) and those living in rural areas (3123/4065, 76.8%; odds ratio 1.13, 95% CI 1.01-1.27; P=.03) were especially likely to hold this opinion. Most respondents preferred providing financial support through international platforms rather than directly offering support to individual countries (72.1%, 95% CI 71%-73.1%), while for vaccine products they preferred direct provision to relevant countries instead of via a delivery platform such as COVAX (77.3%, 95% CI 76.3%-78.2%). CONCLUSIONS: Among our survey sample, we found that adults are generally supportive of the international distribution of COVID-19 vaccines, which may encourage policy makers to support and implement the distribution of COVID-19 vaccines developed in China worldwide. Conducting similar surveys in other countries could help align policy makers' actions on COVID-19 vaccine distribution with the preferences of their constituencies.