An analysis of bicycle accidents with respect to spatial heterogeneity.

Bicycles are an eco-friendly mode of transportation, and in the capital city of South Korea, Seoul, efforts are being made to encourage citizens to use bicycles. However, without appropriate safety measures, these efforts can lead to an increase in bicycle-related traffic accidents. To promote bicycle usage while ensuring safety, this study identified various factors that influence bicycle accidents. Data were utilized that had not been properly considered in previous bicycle accident-related studies, including slope and the level of public transportation services. By considering the factors influencing bicycle traffic accidents, various models were constructed, and through comparisons of statistical indicators, the optimal model was selected geographically weighted negative binomial regression. Ultimately, three significant conclusions to ensure bicycle safety were drawn. First, across all areas of Seoul, an increase in road slope leads to a decrease in bicycle-related accidents. Furthermore, for certain Traffic Analysis Zones (TAZs), as the number of local buses (or neighborhood/community buses) increases, the bicycle traffic volume decreases, resulting in a reduction in bicycle accidents. Lastly, for some TAZs, an increase in bicycle lanes to be installed into the roadway was associated with an increase in bicycle accidents.

Low-Index Facet Polyhedron-Shaped Binary Cerium Titanium Oxide for High-Voltage Aqueous Zinc-Vanadium Redox Flow Batteries.

Aqueous zinc-vanadium hybrid redox flow battery systems are an efficient strategy to address the problems of low voltage and high cost of conventional all-vanadium redox flow batteries. However, the low electrochemical activity of carbon-based electrodes toward a vanadium redox reaction limits the performance of redox flow batteries. In this study, polyhedral binary cerium titanium oxide (Ce2/3TiO3, CTO) is synthesized using molten salt synthesis. CTO is fabricated by adjusting the temperature and composition. Notably, the prepared CTO obtained at 1000 °C shows the highest catalytic activity for a VO2+/VO2+ redox reaction. Further, CTO is prepared as a composite electrocatalyst and applied to a high-voltage aqueous zinc-vanadium redox flow battery. The cell adopts an alkali zinc electrolyte containing a Zn/[Zn(OH)4]2- redox pair and exhibits a high operating voltage of 2.26 V. Remarkably, a zinc-vanadium redox flow battery using the composite electrocatalyst exhibits a high energy density of 42.68 Wh L-1 at 20 mA cm-2 and an initial voltage efficiency of 90.3%. The excellent cell performance is attributed to structural defects caused by A-site deficiency in the perovskite oxide structure as well as oxygen vacancies resulting from the low valence state of the metal ion, which enhance the catalytic activity of the vanadium ions.

Coupling the effects of extreme temperature and air pollution on non-accidental mortality in Rencheng, China.

Background: Extreme temperatures and air pollution have raised widespread concerns about their impact on population health. Aim: To explore the quantitative exposure risks of high/low temperatures and types of air pollutants on the health of various populations in urban areas in China, this study assessed the effects of temperature and air pollutants on daily non-accidental deaths in Rencheng District, Jining City, China from 2019 to 2021. Methods: A combination of Poisson regression models and distributed lag non-linear models was used to examine the relationships between temperature, air pollutants, and daily non-accidental deaths. We found that temperature and air pollutants had a significant non-linear effect on non-accidental mortality. Both high and low temperatures had a noticeable impact on non-accidental deaths, with heat effects occurring immediately and lasting 2-3 days, while cold effects lasted for 6-12 days. The relative risks of non-accidental deaths from PM2.5, NO2, and SO2 were highest in winter and lowest in autumn. The relative risk of non-accidental deaths from O3 was highest in spring, with no significant variations in other seasons. Older adults (≥75) and outdoor workers were at the greatest risk from temperature and air pollutant exposure. Conclusions/interpretation: Exposure to extreme temperatures and air pollutants in the Rencheng District was associated with an increased mortality rate. Under the influence of climate change, it is necessary for policymakers to take measures to reduce the risk of non-accidental deaths among residents.

Controllable Carbon Felt Etching by Binary Nickel Bismuth Cluster for Vanadium-Manganese Redox Flow Batteries.

Various redox couples have been reported to increase the energy density and reduce the price of redox flow batteries (RFBs). Among them, the vanadium electrolyte is mainly used due to its high solubility, but electrode modification is still necessary due to its low reversibility and sluggish kinetics. Also, an incompatible ion exchange membrane with redox-active species leads to self-discharge referred to as crossover. Here, we report a V/Mn RFB using an anion exchange membrane (AEM) for crossover mitigation and etched carbon felt by nickel-bismuth (NB-ECF) for the vanadium anolyte. The NB-ECF significantly enhances the reversibility and kinetics of the V2+/V3+ redox reaction, attributed to inhibited irreversible hydrogen evolution by the Bi catalyst and increased carboxyl groups by nickel (etching and NiO catalyst). Notably, the V/Mn cell employed in the NB-ECF maintains a high energy efficiency of 85.7% during 50 cycles without capacity degradation at a current density of 20 mA cm-2, which is attributed to a synergistic effect of crossover mitigation and facilitated V2+/V3+ redox reaction. This study demonstrates the novel electrocatalyst design of carbon felt using two metal species.

Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia.

BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3 mimetics in AML. Insensitivity to BH3 mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux, which acts as a prosurvival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3 mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML. SIGNIFICANCE: AML remains one of the most difficult-to-treat blood cancers. BH3 mimetics represent a promising therapeutic approach to eliminate AML blasts by activating the apoptotic pathway. Enhanced mitochondrial clearance drives resistance to BH3 mimetics and predicts poor prognosis. Reverting excessive mitophagy can halt BH3-mimetic resistance in AML. This article is highlighted in the In This Issue feature, p. 1501.

Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.

Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.

A High Voltage Aqueous Zinc-Vanadium Redox Flow Battery with Bimodal Tin and Copper Clusters by a Continuous-Flow Electrometallic Synthesis.

Aqueous zinc-based redox flow batteries are promising large-scale energy storage applications due to their low cost, high safety, and environmental friendliness. However, the zinc dendritic growth has depressed the cycle performance, stability, and efficiency, hindering the commercialization of the zinc-based redox flow batteries. We fabricate the carbon felt modified with bimodal sized tin and copper clusters (SCCF) with the electrometallic synthesis in a continuous-flow cell. The SCCF electrode provides a larger zinc nucleation area and lower overpotential than pristine carbon felt, which is ascribed to the well-controlled interfacial interaction of bimodal tin and copper particle clusters by suppressing unwanted alloy formation. The zinc symmetric flow battery and the zinc-based hybrid redox flow battery show the improved zinc plating and stripping efficiency. The SCCF electrode exhibits 75% improved cycling stability compared to the pristine carbon felt electrode in the zinc symmetric flow battery. Notably, the high-voltage aqueous zinc-vanadium redox flow battery demonstrates a high average cell voltage of 2.31 V at 40 mA cm-2, showing a Coulombic efficiency of 99.9% and an energy efficiency of 87.6% for 100 cycles. We introduce a facile strategy to suppress the zinc dendritic growth, enhancing the performance of the zinc-based redox flow batteries.

Recent Progress in High-voltage Aqueous Zinc-based Hybrid Redox Flow Batteries.

The energy density of redox flow batteries (RFBs) is generally affected by the standard electrode potential and the solubility of the redox active species. These crucial factors are closely related to the solvent in which the active materials are dissolved. Aqueous RFBs have been widely studied due to their excellent reaction kinetics and high solubility of the redox couple in aqueous media. However, the low voltage of conventional aqueous RFBs has hindered them from being candidates for practical applications. Recently, high-voltage aqueous RFBs are implemented based on the low negative potential of the Zn/[Zn(OH)4 ]2- reaction in an alkaline solution. Here, we review recent progress in the design of high energy density RFBs in both aqueous and non-aqueous electrolytes, notably focusing on the Zn/MnO2 hybrid RFBs in detail. Furthermore, strategies for inhibiting zinc dendritic growth and stabilizing manganese redox couple in the RFBs system are discussed.

NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.

B cell progenitor acute lymphoblastic leukemia (B-ALL) treatment has been revolutionized by T cell-based immunotherapies-including chimeric antigen receptor T cell therapy (CAR-T) and the bispecific T cell engager therapeutic, blinatumomab-targeting surface glycoprotein CD19. Unfortunately, many patients with B-ALL will fail immunotherapy due to 'antigen escape'-the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. In the present study, we utilized a genome-wide CRISPR-Cas9 screening approach to identify modulators of CD19 abundance on human B-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 messenger RNA polyadenylation and stability. NUDT21 deletion in B-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human B-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify new CD19 modulators in human B-ALL.

Material design and surface chemistry for advanced rechargeable zinc-air batteries.

Zinc-air batteries (ZABs) have been considered as a next-generation battery system with high energy density and abundant resources. However, the sluggish multi-step reaction of the oxygen is the main obstacle for the practical application of ZABs. Therefore, bifunctional electrocatalysts with high stability and activity for the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) are greatly required to promote the catalytic reaction. In this review, we first explain the reaction mechanism of the ZABs, mainly focusing on multiple oxygen intermediates. Then, the latest studies on bifunctional electrocatalysts for the air cathodes and their progress of the ZABs are discussed with following aspects: platinum group metal, metal-free, transition metal, and metal compound-derived electrocatalysts. Finally, we highlight the advanced ZAB systems with the design of the full-temperature range operation, the all-solid-state, and the newly reported non-alkaline electrolyte, summarizing the remaining challenges and requirements of the future research directions.

Estimation of Relative Risk of Mortality and Economic Burden Attributable to High Temperature in Wuhan, China.

In the context of climate change, most of the global regions are facing the threat of high temperature. Influenced by tropical cyclones in the western North Pacific Ocean, high temperatures are more likely to occur in central China, and the economic losses caused by heat are in urgent need of quantification to form the basis for health decisions. In order to study the economic burden of high temperature on the health of Wuhan residents between 2013 and 2019, we employed meta-analysis and the value of statistical life (VSL) approach to calculate the relative risk of high temperature health endpoints, the number of premature deaths, and the corresponding economic losses in Wuhan City, China. The results suggested that the pooled estimates of relative risk of death from high temperature health endpoints was 1.26 [95% confidence interval (CI): 1.15, 1.39]. The average number of premature deaths caused by high temperature was estimated to be 77,369 (95% CI: 48,906-105,198) during 2013-2019, and the induced economic losses were 156.1 billion RMB (95% CI: 92.28-211.40 billion RMB), accounting for 1.81% (95% CI: 1.14-2.45%) of Wuhan's annual GDP in the seven-year period. It can be seen that high temperature drives an increase in the premature deaths, and the influence of high temperature on human health results in an economic burden on the health system and population in Wuhan City. It is necessary for the decision-makers to take measures to reduce the risk of premature death and the proportion of economic loss of residents under the impacts of climate change.

Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor.

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

Synthetic Rashba spin-orbit system using a silicon metal-oxide semiconductor.

The spin-orbit interaction (SOI), mainly manifesting itself in heavy elements and compound materials, has been attracting much attention as a means of manipulating and/or converting a spin degree of freedom. Here, we show that a Si metal-oxide- semiconductor (MOS) heterostructure possesses Rashba-type SOI, although Si is a light element and has lattice inversion symmetry resulting in inherently negligible SOI in bulk form. When a strong gate electric field is applied to the Si MOS, we observe spin lifetime anisotropy of propagating spins in the Si through the formation of an emergent effective magnetic field due to the SOI. Furthermore, the Rashba parameter α in the system increases linearly up to 9.8 × 10-16 eV m for a gate electric field of 0.5 V nm-1; that is, it is gate tuneable and the spin splitting of 0.6 µeV is relatively large. Our finding establishes a family of spin-orbit systems.

A Systems Biology Approach to Identifying a Master Regulator That Can Transform the Fast Growing Cellular State to a Slowly Growing One in Early Colorectal Cancer Development Model.

Colorectal cancer (CRC) has been most extensively studied for characterizing genetic mutations along its development. However, we still have a poor understanding of CRC initiation due to limited measures of its observation and analysis. If we can unveil CRC initiation events, we might identify novel prognostic markers and therapeutic targets for early cancer detection and prevention. To tackle this problem, we establish the early CRC development model and perform transcriptome analysis of its single cell RNA-sequencing data. Interestingly, we find two subtypes, fast growing vs. slowly growing populations of distinct growth rate and gene signatures, and identify CCDC85B as a master regulator that can transform the cellular state of fast growing subtype cells into that of slowly growing subtype cells. We further validate this by in vitro experiments and suggest CCDC85B as a novel potential therapeutic target that may prevent malignant CRC development by suppressing stemness and uncontrolled cell proliferation.

Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

Cotargeting BET proteins overcomes resistance arising from PI3K/mTOR blockade-induced protumorigenic senescence in colorectal cancer.

Therapeutics targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal-regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence-associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra-terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC.

Network Inference Analysis Identifies SETDB1 as a Key Regulator for Reverting Colorectal Cancer Cells into Differentiated Normal-Like Cells.

Cancer cells exhibit properties of cells in a less differentiated state than the adjacent normal cells in the tissue. We explored whether cancer cells can be converted to a differentiated normal-like state by restoring the gene regulatory network (GRN) of normal cells. Here, we report that colorectal cancer cells exhibit a range of developmental states from embryonic and intestinal stem-like cells to differentiated normal-like cells. To identify the transcription factors (TF) that commit stem-like colorectal cancer cells into a differentiated normal-like state, we reconstructed GRNs of normal colon mucosa and identified core TFs (CDX2, ELF3, HNF4G, PPARG, and VDR) that govern the cellular state. We further found that SET Domain Bifurcated 1 (SETDB1), a histone H3 lysine 9-specific methyltransferase, hinders the function of the identified TFs. SETDB1 depletion effectively converts stem-like colorectal cancer cells into postmitotic cells and restores normal morphology in patient-derived colorectal cancer organoids. RNA-sequencing analyses revealed that SETDB1 depletion recapitulates global gene expression profiles of normal differentiated cells by restoring the transcriptional activity of core TFs on their target genes. IMPLICATIONS: Our study provides insights into the molecular regulatory mechanism underlying the developmental hierarchy of colorectal cancer and suggests that induction of a postmitotic state may be a therapeutic alternative to destruction of cancer cells.

Systems analysis identifies potential target genes to overcome cetuximab resistance in colorectal cancer cells.

Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild-type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these five genes can increase CTX sensitivity in KRAS WT cells. Interestingly, we further found that GNB5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation.

Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes.

Human resistin is a cytokine that induces low-grade inflammation by stimulating monocytes. Resistin-mediated chronic inflammation can lead to obesity, atherosclerosis, and other cardiometabolic diseases. Nevertheless, the receptor for human resistin has not been clarified. Here, we identified adenylyl cyclase-associated protein 1 (CAP1) as a functional receptor for human resistin and clarified its intracellular signaling pathway to modulate inflammatory action of monocytes. We found that human resistin directly binds to CAP1 in monocytes and upregulates cyclic AMP (cAMP) concentration, protein kinase A (PKA) activity, and NF-κB-related transcription of inflammatory cytokines. Overexpression of CAP1 in monocytes enhanced the resistin-induced increased activity of the cAMP-dependent signaling. Moreover, CAP1-overexpressed monocytes aggravated adipose tissue inflammation in transgenic mice that express human resistin from their monocytes. In contrast, suppression of CAP1 expression abrogated the resistin-mediated inflammatory activity both in vitro and in vivo. Therefore, CAP1 is the bona fide receptor for resistin leading to inflammation in humans.