C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis.

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.

Global, regional and national trends and impacts of natural floods, 1990-2022.

Objective: To assess global, regional and national trends in the impact of floods from 1990 to 2022 and determine factors influencing flood-related deaths. Methods: We used data on flood disasters from the International Disaster Database for 1990-2022 from 168 countries. We calculated the annual percentage change to estimate trends in the rates of people affected and killed by floods by study period, World Health Organization (WHO) region, country income level and flood type. We used multivariable logistic regression analysis to assess the factors associated with death from floods. Findings: From 1990 to 2022, 4713 floods were recorded in 168 countries, which affected > 3.2 billion people, caused 218 353 deaths and were responsible for more than 1.3 trillion United States dollars of economic losses. The WHO Western Pacific Region had the most people affected by floods (> 2.0 billion), accounting for 63.19% (2 024 599 380/3 203 944 965) of all affected populations. The South-East Asia Region had the most deaths (71 713, 32.84%). The African and Eastern Mediterranean Regions had the highest number of people affected and killed by floods per 100 000 population in 2022. The odds of floods causing more than 50 deaths were significantly higher in low-income countries (adjusted odds ratio: 14.34; 95% confidence interval: 7.46 to 30.04) compared with high-income countries. Numbers of people affected and mortality due to floods declined over time. Conclusion: Despite the decreases in populations affected and deaths, floods still have a serious impact on people and economies globally, particularly in lower-income countries. Action is needed to improve disaster risk management and flood mitigation.

Discovery of highly potent PARP7 inhibitors for cancer immunotherapy.

PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 µM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents.

TRPC4 aggravates hypoxic pulmonary hypertension by promoting pulmonary endothelial cell apoptosis.

Pulmonary hypertension (PH) is a devastating disease that lacks effective treatment options and is characterized by severe pulmonary vascular remodeling. Pulmonary arterial endothelial cell (PAEC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension. Canonical transient receptor potential (TRPC) channels, a family of Ca2+-permeable channels, play an important role in various diseases. However, the effect and mechanism of TRPCs on PH development have not been fully elucidated. Among the TRPC family members, TRPC4 expression was markedly upregulated in PAECs from hypoxia combined with SU5416 (HySu)-induced PH mice and monocrotaline (MCT)-treated PH rats, as well as in hypoxia-exposed PAECs, suggesting that TRPC4 in PAECs may participate in the occurrence and development of PH. In this study, we aimed to investigate whether TRPC4 in PAECs has an aggravating effect on PH and elucidate the molecular mechanisms. We observed that hypoxia treatment promoted PAEC apoptosis through a caspase-12/endoplasmic reticulum stress (ERS)-dependent pathway. Knockdown of TRPC4 attenuated hypoxia-induced apoptosis and caspase-3/caspase-12 activity in PAECs. Accordingly, adeno-associated virus (AAV) serotype 6-mediated pulmonary endothelial TRPC4 silencing (AAV6-Tie-shRNA-TRPC4) or TRPC4 antagonist suppressed PH progression as evidenced by reduced right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, PAEC apoptosis and reactive oxygen species (ROS) production. Mechanistically, unbiased RNA sequencing (RNA-seq) suggested that TRPC4 deficiency suppressed the expression of the proapoptotic protein sushi domain containing 2 (Susd2) in hypoxia-exposed mouse PAECs. Moreover, TRPC4 activated hypoxia-induced PAEC apoptosis by promoting Susd2 expression. Therefore, inhibiting TRPC4 ameliorated PAEC apoptosis and hypoxic PH in animals by repressing Susd2 signaling, which may serve as a therapeutic target for the management of PH.

Design and Asymmetric Control of Orientational Chirality by Using the Combination of C(sp2)-C(sp) Levers and Achiral N-Protecting Group.

New chiral targets of orientational chirality have been designed and asymmetrically synthesized by taking advantage of N-sulfinyl imine-directed nucleophilic addition/oxidation, Suzuki-Miyaura, and Sonogashira cross-coupling reactions. Orientation of single isomers has been selectively controlled by using aryl/alkynyl levers [C(sp2)-C(sp) axis] and tBuSO2- protecting group on nitrogen as proven by X-ray diffraction analysis. The key structural characteristic of resulting orientational products is shown by remote through-space blocking manner. Seventeen examples of multi-step synthesis were obtained with modest to good chemical yields and complete orientational selectivity.

Association of temperature and precipitation with malaria incidence in 57 countries and territories from 2000 to 2019: A worldwide observational study.

Background: The transmission of malaria is known to be affected by climatic factors. However, existing studies on the impact of temperature and precipitation on malaria incidence offer no clear-cut conclusions, and there is a lack of research on a global scale. We aimed to estimate the association of temperature and precipitation with malaria incidence globally from 2000 to 2019. Methods: We used meteorological data from the National Centers for Environmental Information and malaria incidence data from the Global Burden of Disease Study 2019 to calculate effect sizes through quasi-Poisson generalised linear models while controlling for confounders. Results: 231.4 million malaria cases occurred worldwide in 2019. National annual average temperature and precipitation were associated with malaria incidence, with an increase in the age-standardised incidence rate (ASIR) of 2.01% (95% confidence interval (CI) = 2.00, 2.02) and 6.04% (95% CI = 6.00, 6.09) following one unit increase of national annual average temperature and precipitation. In subgroup analysis, we found that malaria incidence in Asian countries was most affected by temperature, while the incidence in African countries was most affected by precipitation (P < 0.05). Stratified by age, children under five were most affected by both temperature and precipitation (P < 0.05). We additionally found that the impact of the national annual average temperature on malaria incidence increased over time (P < 0.05). Conclusions: We advocate for a comprehensive approach to malaria prevention, focussed on addressing the impact of climate factors through international collaboration, adaptive measures, and targeted interventions for vulnerable populations.

LiNAC100 contributes to linalool biosynthesis by directly regulating LiLiS in Lilium 'Siberia'.

MAIN CONCLUSION: The transcription factor LiNAC100 has a novel function of regulating floral fragrance by directly regulating linalool synthase gene LiLiS. Lilium 'Siberia', an Oriental hybrid, is renowned as both a cut flower and garden plant, prized for its color and fragrance. The fragrance comprises volatile organic compounds (VOCs), primarily monoterpenes found in the plant. While the primary terpene synthases in Lilium 'Siberia' were identified, the transcriptional regulation of these terpene synthase (TPS) genes remains unclear. Thus, understanding the regulatory mechanisms of monoterpene biosynthesis is crucial for breeding flower fragrance, thereby improving ornamental and commercial values. In this study, we isolated a nuclear-localized LiNAC100 transcription factor from Lilium 'Siberia'. The virus-induced gene silencing (VIGS) of LiNAC100 was found to down-regulate the expression of linalool synthase gene (LiLiS) and significantly inhibit linalool synthesis. Conversely, transient overexpression of LiNAC100 produced opposite effects. Additionally, yeast one-hybrid and dual-luciferase assays confirmed that LiNAC100 directly activates LiLiS expression. Our findings reveal that LiNAC100 plays a key role in monoterpene biosynthesis in Lilium 'Siberia', promoting linalool synthesis through the activation of LiLiS expression. These results offer insights into the molecular mechanisms of terpene biosynthesis in Lilium 'Siberia' and open avenues for biotechnological enhancement of floral scent.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Advanced strategies in high-throughput droplet screening for enzyme engineering.

Enzymes, as biocatalysts, play a cumulatively important role in environmental purification and industrial production of chemicals and pharmaceuticals. However, natural enzymes are limited by their physiological properties in practice, which need to be modified driven by requirements. Screening and isolating certain enzyme variants or ideal industrial strains with high yielding of target product enzymes is one of the main directions of enzyme engineering research. Droplet-based high-throughput screening (DHTS) technology employs massive monodisperse emulsion droplets as microreactors to achieve single strain encapsulation, as well as continuous monitoring for the inside mutant library. It can effectively sort out strains or enzymes with desired characteristics, offering a throughput of 108 events per hour. Much of the early literature focused on screening various engineered strains or designing signalling sorting strategies based on DHTS technology. However, the field of enzyme engineering lacks a comprehensive overview of advanced methods for microfluidic droplets and their cutting-edge developments in generation and manipulation. This review emphasizes the advanced strategies and frontiers of microfluidic droplet generation and manipulation facilitating enzyme engineering development. We also introduce design for various screening signals that cooperate with DHTS and devote to enzyme engineering.

Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

PARP7 plays a crucial role in cancer immunity. The inhibition of PARP7 has shown potential in boosting the immune response against cancer, making it an attractive target for cancer immunotherapy. Herein, we employed a rigid constraint strategy (reduction in molecular flexibility) to design and synthesize a series of novel indazole-7-carboxamide derivatives based on the structure of RBN-2397. Among these derivatives, (S)-XY-05 was identified as the most promising PARP7 inhibitor (IC50: 4.5 nM). Additionally, (S)-XY-05 showed enhanced selectivity toward PARP7 and improved pharmacokinetic properties (oral bioavailability: 94.60%) compared with RBN-2397 (oral bioavailability: 25.67%). In the CT26 syngeneic mouse model, monotherapy with (S)-XY-05 displayed a strong antitumor effect (TGI: 83%) by activating T-cell-mediated immunity within the tumor microenvironment. Collectively, we confirmed that (S)-XY-05 has profound effects on tumor immunity, which paves the way for future studies of PARP7 inhibitors that could be utilized in cancer immunotherapy.

Expansion of YALIcloneHR toolkit for Yarrowia lipolytica combined with Golden Gate and CRISPR technology.

Metabolic Engineering of yeast is a critical approach to improving the production capacity of cell factories. To obtain genetically stable recombinant strains, the exogenous DNA is preferred to be integrated into the genome. Previously, we developed a Golden Gate toolkit YALIcloneNHEJ, which could be used as an efficient modular cloning toolkit for the random integration of multigene pathways through the innate non-homologous end-joining repair mechanisms of Yarrowia lipolytica. We expanded the toolkit by designing additional building blocks of homologous arms and using CRISPR technology. The reconstructed toolkit was thus entitled YALIcloneHR and designed for gene-specific knockout and integration. To verify the effectiveness of the system, the gene PEX10 was selected as the target for the knockout. This system was subsequently applied for the arachidonic acid production, and the reconstructed strain can accumulate 4.8% of arachidonic acid. The toolkit will expand gene editing technology in Y. lipolytica, which would help produce other chemicals derived from acetyl-CoA in the future.

Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

Development and validation of prediction models for poor sleep quality among older adults in the post-COVID-19 pandemic era.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) has a significant impact on sleep quality. However, the effects on sleep quality in the post-COVID-19 pandemic era remain unclear, and there is a lack of a screening tool for Chinese older adults. This study aimed to understand the prevalence of poor sleep quality and determine sensitive variables to develop an effective prediction model for screening sleep problems during infectious diseases outbreaks. MATERIALS AND METHODS: The Peking University Health Cohort included 10,156 participants enrolled from April to May 2023. The Pittsburgh Sleep Quality Index (PSQI) scale was used to assess sleep quality. The data were randomly divided into a training-testing cohort (n = 7109, 70%) and an independent validation cohort (n = 3027, 30%). Five prediction models with 10-fold cross validation including the Least Absolute Shrinkage and Selection Operator (LASSO), Stochastic Volatility Model (SVM), Random Forest (RF), Artificial Neural Network (ANN), and XGBoost model based on the area under curve (AUC) were used to develop and validate predictors. RESULTS: The prevalence of poor sleep quality (PSQI >7) was 30.69% (3117/10,156). Among the generated models, the LASSO model outperformed SVM (AUC 0.579), RF (AUC 0.626), ANN (AUC 0.615) and XGBoost (AUC 0.606), with an AUC of 0.7. Finally, a total of 12 variables related to sleep quality were used as parameters in the prediction models. These variables included age, gender, ethnicity, educational level, residence, marital status, history of chronic diseases, SARS-CoV-2 infection, COVID-19 vaccination, social support, depressive symptoms, and cognitive impairment among older adults during the post-COVID-19 pandemic. The nomogram illustrated that depressive symptoms contributed the most to the prediction of poor sleep quality, followed by age and residence. CONCLUSIONS: This nomogram, based on twelve-variable, could potentially serve as a practical and reliable tool for early identification of poor sleep quality among older adults during the post-pandemic period.

The poor sleep quality (PSQI >7) was still prevalent among older adults during the post-COVID-19 pandemic.The LASSO model was the best model to predict poor sleep quality among older adults, compared with SVM, RF, ANN and XGBoost.This prediction model, based on twelve variables, may potentially serve as a practical and reliable tool for the early identification of poor sleep quality among older adults during the post-pandemic period.

Pandemic Fatigue and Vaccine Hesitancy among People Who Have Recovered from COVID-19 Infection in the Post-Pandemic Era: Cross-Sectional Study in China.

At present, the COVID-19 pandemic is still ongoing globally and the virus is constantly mutating. The herd immunity barrier established by past infections or vaccinations is gradually weakening and reinfections are occurring. To evaluate the pandemic fatigue and vaccine hesitancy among people who have recovered from COVID-19 in the post-pandemic era, we conducted an anonymous cross-sectional survey study in China from 4 July to 11 August 2023, nearly 6 months after the last large-scale nationwide infection. Basic sociodemographic characteristics, health-related factors (smoking, drinking, and chronic disease history), COVID-19 vaccination history, and self-reported long COVID were obtained as potential covariates. A series of logistic regression models were performed to examine the association between pandemic fatigue and vaccine hesitancy toward the next dose of COVID-19 vaccines via crude relative risks (cORs) and adjusted relative risks (aORs) with 95% CIs. According to our results, of the 2942 participants, 1242 (42.2%) were hesitant (unwilling or not sure) to receive the next dose of COVID-19 vaccines. The average score on the Pandemic Fatigue Scale was 21.67 ± 8.86, in which the scores of all items in the vaccine-hesitant group were significantly higher than those in the vaccine-accepting group. Additionally, the higher the pandemic fatigue level among people who have recovered from COVID-19, the more likely they were to be hesitant to receive the next dose of the COVID-19 vaccines (moderate: aOR = 2.94, 95% CI: 2.46-3.53; high: aOR = 6.88, 95% CI: 5.49-8.64). Overall, more than 40% of the recovered participants were unwilling or uncertain about the next vaccine dose, with varying degrees of pandemic fatigue. Pandemic fatigue is a potentially relevant factor for vaccine hesitancy and may hinder the translation of vaccination intention into behavior. Considering the ongoing reinfection situation, implementing a health education plan to reduce pandemic fatigue and prioritizing vaccination issues for people who have recovered from COVID-19 may be key to promoting the reduction of the COVID-19 disease burden and ensuring the health and well-being of the population.

3, 3'-diindolylmethane, a natural aryl hydrocarbon receptor agonist, alleviates ulcerative colitis by enhancing "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.

BACKGROUND: Aryl hydrocarbon receptor (AhR) plays an important role in the occurrence and development of ulcerative colitis (UC). In this study, the effect and mechanism of 3, 3'-diindolylmethane (DIM), the classical AhR agonist, on UC was investigated from the angle of recovering the balance of Th17/Treg. METHODS: The in vivo colitis model was established in mice by using dextran sulfate sodium, and CD4+ T cells were used to simulate the in vitro differentiation of Treg and Th17 cells. The proportions and related factors of Th17 and Treg cells were measured using flow cytometry, Q-PCR and western blotting. The glycolysis was evaluated by examining the glucose uptake, glucose consumption and lactate production using kits or immunofluorescence. The activation of AhR was detected by western blotting and the XRE-luciferase reporter gene. The co-immunoprecipitation, transfection or other methods were selected to investigate and identify the signaling molecular pathway. RESULTS: DIM significantly attenuated symptoms of colitis mice by rebuilding the balance of Th17/Treg in anoxic colons. In hypoxia, a more potent promotion of Treg differentiation was showed by DIM relative to normoxia, and siFoxp3 prevented DIM-suppressed Th17 differentiation. DIM repressed the excessive glycolysis in hypoxia evidenced by down-regulated glucose uptake, lactate production, Glut1 and HK2 levels. Interestingly, IL-10, the function-related factor of Treg cells, showed the feedback effect of DIM-suppressed glycolysis. Besides, 2-deoxy-D-glucose, HK2 plasmid and IL-10 antibody prevented increase of DIM on the expression of Foxp3 at the transcriptional level and subsequent Treg differentiation through the lactate-STAT3 pathway, and reasons for the direct improvement of DIM on Foxp3 protein was attributed to promoting the formation of HIF-1α/TIP60 complexes as well as subsequent acetylation and protein stability. Finally, AhR dependence and mechanisms for DIM-improved Treg differentiation in vitro and in vivo were well confirmed by using plasmids or inhibitors. CONCLUSIONS: DIM enhances activation of AhR and subsequent "glycolysis-lactate-STAT3″ and TIP60 signals-mediated Treg differentiation.

Study on the Mechanism of Ru-Catalyzed Cyclization of Aromatic Amides with Allylphosphine Oxides.

The mechanism of Ru-catalyzed cyclization of aromatic amides with allylphosphine oxides is studied by density functional theory calculation (DFT). The results show that, first, a 5-membered Ru ring intermediate is formed by N-H and C-H diprotons via the concerted metalation-deprotonation mechanism (CMD) and then the allylphosphine oxide is inserted through the ring-extending reaction to form a 7-membered ring intermediate. Next, reduction elimination is followed via intramolecular hydrogen transfer isomerization. At last, with the assistance of acetic acid, Ru (II) → Ru (IV) → Ru (II) complexes occur from the 7-membered Ru ring intermediate, and the final product is formed by reduction elimination and protonation reaction, while the catalyst is released to participate in the next cycle.

Trends in the Baidu Index in Search Activity Related to Mpox at Geographical and Economic Levels and Associated Factors in China: National Longitudinal Analysis.

BACKGROUND: Research assessing trends in online search activity related to mpox in China is scarce. OBJECTIVE: We aimed to provide evidence for an overview of online information searching during an infectious disease outbreak by analyzing trends in online search activity related to mpox at geographical and economic levels in China and explore influencing factors. METHODS: We used the Baidu index to present online search activity related to mpox from May 19 to September 19, 2022. Segmented interrupted time-series analysis was used to estimate trends in online search activity. Factors influencing these trends were analyzed using a general linear regression (GLM) model. We calculated the concentration index to measure economic-related inequality in online search activity and related trends. RESULTS: Online search activity was highest on the day the first imported case of mpox appeared in Chongqing compared to 3 other cutoff time points. After the day of the first imported mpox case in Taiwan, the declaration of a public health emergency of international concern, the first imported mpox case in Hong Kong, and the first imported mpox case in Chongqing, national online search activity increased by 0.642%, 1.035%, 1.199%, and 2.023%, respectively. The eastern regions had higher increases than the central and western regions. Across 31 provinces, municipalities, and autonomous regions, the top 3 areas with higher increases were Beijing, Shanghai, and Tianjin at 3 time points, with the exception of the day of the first imported mpox case in Chongqing (Chongqing replaced Tianjin on that day). When AIDS incidence increased by 1 per 100,000 people, there was an increase after the day of the first imported mpox case in Chongqing of 36.22% (95% CI 3.29%-69.15%; P=.04) after controlling for other covariates. Online search activity (concentration index=0.18; P<.001) was more concentrated among populations with a higher economic status. Unlike the central area, the eastern (concentration index=0.234; P<.001) and western areas (concentration index=0.047; P=.04) had significant economic-related disparities (P for difference <.001) in online search activity. The overall concentration index of changes in online search activity became lower over time. CONCLUSIONS: Regions with a higher economic level showed more interest in mpox, especially Beijing and Shanghai. After the day of the first imported mpox case in Chongqing, changes in online search activity were affected by AIDS incidence rate. Economic-related disparities in changes in online search activity became lower over time. It would be desirable to construct a reliable information source in regions with a higher economic level and higher AIDS incidence rate and promote public knowledge in regions with a lower economic level in China, especially after important public events.

Bile acids promote the development of HCC by activating inflammasome.

BACKGROUND: Hepatocellular carcinoma (HCC) is associated with chronic inflammation caused by different factors; especially, the interaction of inflammatory pathways and bile acids (BAs) can affect hepatocyte proliferation, death, and regeneration, but whether BAs promote HCC progression through inflammatory pathways and the mechanisms is still unclear. METHODS AND RESULTS: By examining cancer and tumor-adjacent tissue BA levels and genes associated with BA homeostasis in 37 HCC patients, we found that total bile acids (TBAs) were decreased by 36% and varying degrees of changes in factors regulating BA homeostasis (p < 0.05). In addition, we found that BA homeostasis was disturbed in diethylnitrosamine-induced HCC mouse models, and TBA was correlated with inflammasome activation during HCC progression (6-24 W) (p < 0.05). Similarly, the inflammasome and chenodeoxycholic acid (CDCA) content were suppressed in cholestasis model mice (Mrp2-deficient mice) (p < 0.05). In vitro, CDCA significantly promoted the malignant transformation of hepatocytes (p < 0.001), activated the inflammasome by triggering the release of mitochondrial reactive oxygen species and mitochondrial DNA, and ultimately induced pyroptosis. Furthermore, we found that CDCA has a targeted binding effect with HO-1 through molecular docking and Cellular Thermal Shift Assay experiments. CONCLUSIONS: In conclusion, we found that CDCA can trigger the excessive accumulation of mitochondrial reactive oxygen species by targeting HO-1 to promote the activation of the inflammasome and ultimately promote the progression of HCC. Our study provides a novel mechanism by which BAs promote HCC by activating the inflammasome and establishes the important role of BA homeostasis imbalance in the progression of HCC from the aspect of inflammation.

Incidence and mortality trends of neglected tropical diseases and malaria in China and ASEAN countries from 1990 to 2019 and its association with the socio-demographic index.

BACKGROUND: People in China and the countries in the Association of Southeast Asian Nations (ASEAN) are affected by neglected tropical diseases and malaria (NTDM). In this study, we aimed to assess the current status and trends of NTDM burden from 1990 to 2019 in China and ASEAN countries, and also explore the association of NTDM burden with socio-demographic index (SDI). METHODS: The data from the Global Burden of Diseases Study 2019 (GBD 2019) results were used. Absolute incidence and death number, and age-standardized incidence and mortality rate (ASIR and ASMR) of NTDM in China and ASEAN were extracted. The estimated annual percentage change (EAPC) and join-point regression in the rates quantified the trends. Nonlinear regression (second order polynomial) was used to explore the association between SDI and ASRs. RESULTS: The ASIR of NTDM increased in China, Philippines, Singapore and Brunei, at a speed of an average 4.15% (95% CI 3.83-4.47%), 2.15% (1.68-2.63%), 1.03% (0.63-1.43%), and 0.88% (0.60-1.17%) per year. Uptrends of ASIR of NTDM in recent years were found in China (2014-2017, APC = 10.4%), Laos (2005-2013, APC = 3.9%), Malaysia (2010-2015, APC = 4.3%), Philippines (2015-2019, APC = 4.2%), Thailand (2015-2019, APC = 2.4%), and Vietnam (2014-2017, APC = 3.2%, all P < 0.05). Children < 5 had relatively low incidences but unexpectedly high mortality rates of NTDM in most ASEAN countries. Both incidence and mortality rates of NTDM were higher in older people. ASIR and ASMR of NTDM had a U-shaped association with SDI. CONCLUSIONS: The burden of NTDM in China and ASEAN countries was still huge and affects vulnerable and impoverished populations' livelihoods, including children under the age of 5 and people aged 60 and older. Facing with the large burden and complex situation of NTDM in China and ASEAN countries, regional cooperating strategies are needed to reduce the burden of NTDM, so as to achieve the goal of elimination in the world.

Association between inequalities in human resources for health and all cause and cause specific mortality in 172 countries and territories, 1990-2019: observational study.

OBJECTIVE: To explore inequalities in human resources for health (HRH) in relation to all cause and cause specific mortality globally in 1990-2019. DESIGN: Observational study. SETTING: 172 countries and territories. DATA SOURCES: Databases of the Global Burden of Disease Study 2019, United Nations Statistics, and Our World in Data. MAIN OUTCOME MEASURES: The main outcome was age standardized all cause mortality per 100 000 population in relation to HRH density per 10 000 population, and secondary outcome was age standardized cause specific mortality. The Lorenz curve and the concentration index (CCI) were used to assess trends and inequalities in HRH. RESULTS: Globally, the total HRH density per 10 000 population increased, from 56.0 in 1990 to 142.5 in 2019, whereas age standardized all cause mortality per 100 000 population decreased, from 995.5 in 1990 to 743.8 in 2019. The Lorenz curve lay below the equality line and CCI was 0.43 (P<0.05), indicating that the health workforce was more concentrated among countries and territories ranked high on the human development index. The CCI for HRH was stable, at about 0.42-0.43 between 1990 and 2001 and continued to decline (narrowed inequality), from 0.43 in 2001 to 0.38 in 2019 (P<0.001). In the multivariable generalized estimating equation model, a negative association was found between total HRH level and all cause mortality, with the highest levels of HRH as reference (low: incidence risk ratio 1.15, 95% confidence interval 1.00 to 1.32; middle: 1.14, 1.01 to 1.29; high: 1.18, 1.08 to 1.28). A negative association between total HRH density and mortality rate was more pronounced for some types of cause specific mortality, including neglected tropical diseases and malaria, enteric infections, maternal and neonatal disorders, and diabetes and kidney diseases. The risk of death was more likely to be higher in people from countries and territories with a lower density of doctors, dentistry staff, pharmaceutical staff, aides and emergency medical workers, optometrists, psychologists, personal care workers, physiotherapists, and radiographers. CONCLUSIONS: Inequalities in HRH have been decreasing over the past 30 years globally but persist. All cause mortality and most types of cause specific mortality were relatively higher in countries and territories with a limited health workforce, especially for several specific HRH types among priority diseases. The findings highlight the importance of strengthening political commitment to develop equity oriented health workforce policies, expanding health financing, and implementing targeted measures to reduce deaths related to inadequate HRH to achieve universal health coverage by 2030.