Synthesis and Antiosteoporotic Characterization of Diselenyl Maleimides: Discovery of a Potent Agent for the Treatment of Osteoporosis by Targeting RANKL.

To discover new osteoclast-targeting antiosteoporosis agents, we identified forty-six diselenyl maleimides, which were efficiently prepared using a novel, simple, and metal-free method at room temperature in a short reaction time. Among them, 3k showed the most marked inhibition of osteoclast differentiation with an IC50 value of 0.36 ± 0.03 µM. Moreover, 3k significantly suppressed RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes expression in vitro. Mechanistic studies revealed that 3k remarkably blocked the RANKL-induced mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways. In ovariectomized mice, intragastric administration of 3k significantly alleviated bone loss, exhibiting an effect similar to that of alendronate. Surface plasmon resonance assay and microscale thermophoresis assay results suggested that RANKL might be a potential molecular target for 3k. Collectively, the findings presented above provided a novel candidate for further development of bone antiresorptive drugs that target RANKL.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

Oncogenic-tsRNA: A novel diagnostic and therapeutic molecule for cancer clinic.

tsRNA (tRNA-derived small RNA) is derived from mature tRNA or precursor tRNA (pre-tRNAs). It is lately found that tsRNA's aberrant expression is associated with tumor occurrence and development, it may be used a molecule of diagnosis and therapy. Based on the cleavage position of pre-tRNAs or mature tRNAs, tsRNAs are classified into two categories: tRNA-derived fragments (tRFs) and tRNA halves (also named tiRNAs or tRHs). tsRNAs display more stability within cells, tissues, and peripheral blood than other small non-coding RNAs (sncRNAs), and play a role of stable entities that function in various biological contexts, thus, they may serve as functional molecules in human disease. Recently, tsRNAs have been found in a large number of tumors including such as lung cancer, breast cancer, gastric cancer, colorectal cancer, liver cancer, and prostate cancer. Although the biological function of tsRNAs is still poorly understood, increasing evidences have indicated that tsRNAs have a great significance and potential in early tumor screening and diagnosis, therapeutic targets and application, and prognosis. In the present review, we mainly describe tsRNAs in tumors and their potential clinical value in early screening and diagnosis, therapeutic targets and application, and prognosis, it provides theoretical support and guidance for further revealing the therapeutic potential of tsRNAs in tumor.

Cryptococcosis in wait-listed liver transplant candidates: Prevalence, manifestations, and risk factors.

BACKGROUND: Liver cirrhosis compromises immunity against cryptococcosis, and liver transplant recipients tend to develop the disease earlier after transplantation, possibly due to unrecognized pretransplant infection. We assessed the prevalence and characteristics of cryptococcosis among liver transplant candidates and whether pre-transplant cryptococcal antigen (CrAg) can detect the disease before transplantation. METHODS: We retrospectively included liver transplant candidates in a tertiary hospital during 2017-2022. Serum CrAg and pulmonary computed tomography were incorporated in routine transplant evaluation. Other investigations were done if indicated. Cryptococcosis was diagnosed by positive culture or CrAg. Risk factors for cryptococcosis were also assessed. RESULTS: Of the 377 candidates with a median MELD-Na score of 18, 84.4% had hepatitis B virus (HBV) infection. Cryptococcosis was diagnosed in 10 (2.6%) candidates, by CrAg in 6, culture in 2, or both in 2. Only 3 had fever, and 3 were asymptomatic; 7 had pulmonary cryptococcosis. Of the 10 candidates with cryptococcosis, one underwent transplantation after 143-day antifungals. Of the 87 candidates undergoing liver transplantation, one (1.2%) recipient developed cryptococcosis 14 days post-transplant with negative CrAg three weeks before transplantation. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis (odds ratio 4.4, 95% confidence interval 1.2-16.5, p = 0.03) after the adjustment of MELD-Na score. CONCLUSIONS: The prevalence of cryptococcosis was 2.6% among our liver transplant candidates and CrAg detected 80% of the cases. Disease presentation was mild and pulmonary disease predominated. HBsAg-positive chronic HBV infection with HBV DNA loads <2000 IU/mL was significantly associated with cryptococcosis.

Autophagy in benign prostatic hyperplasia: insights and therapeutic potential.

Autophagy is a cellular homeostatic mechanism characterized by cyclic degradation. It plays an essential role in maintaining cellular quality and survival by eliminating dysfunctional cellular components. This process is pivotal in various pathophysiological processes. Benign prostatic hyperplasia (BPH) is a common urological disorder in middle-aged and elderly men. It frequently presents as lower urinary tract symptoms due to an increase in epithelial and stromal cells surrounding the prostatic urethra. The precise pathogenesis of BPH is complex. In recent years, research on autophagy in BPH has gained significant momentum, with accumulating evidence indicating its crucial role in the onset and progression of the disease. This review aims to outline the various roles of autophagy in BPH and elucidate potential therapeutic strategies targeting autophagy for managing BPH.

Single vs. multi-slice assessments of in vivo placental T2∗ measurements.

INTRODUCTION: Placental health is vital for maternal and fetal well-being, and placental T2∗ has been suggested to identify in vivo placental dysfunction prior to delivery. However, ideal regions of interest to best inform functional assessments of the placenta remain unknown. The aim of this study is to compare global and slice-wise measures of in-vivo placental T2∗ assessments. METHODS: This prospective study recruited pregnant people with singleton pregnancies between December 2017 and February 2022.3D multi-echo RF-spoiled gradient echo sequences were acquired, and placental T2∗ values were derived from global and slice-wise approaches. Statistical analyses included Pearson correlation coefficients, concordance correlation coefficients (CCC), intraclass correlation coefficients (ICC), and Bland-Altman analyses. RESULTS: Of 115 participants (mean gestational age, 29.25 ± 5.05 weeks), 68 were healthy controls, and 47 were high-risk pregnancies. Global and slice-wise placental T2∗ assessments for the entire cohort showed no significant difference nor for individual subgroups (healthy controls or high-risk). Pearson correlation values ranged between 0.88 and 0.99 for mean global and slice-wise placental T2∗. CCC analyses ranged from 0.88 to 0.99 for mean T2∗, and ICC analyses ranged between 0.88 and 0.99 for mean T2∗, showing a strong agreement between measurements. Bland-Altman analyses depicted T2∗ differences across coverage methods, and groups resided within the 95 % limits of agreement. DISCUSSION: Single-slice placental assessments offer robust, comparable T2∗ values to global assessments, with the added benefit of reducing post-processing time and SAR exposure. This supports slice-wise approaches as valid alternatives for assessing placental health in various pregnancies.

Harnessing Spatiotemporal-Specific Tumorous Exosome Dynamics: Ultra-Sensitive Lanthanide Luminescence Detection Strategy Enabled by Exosomal Membrane Engineering for Melanoma Immunotherapy Monitoring.

Focused on the newly secreted tumorous exosomes during melanoma immunotherapy, this work has pioneered an ultra-sensitive spatiotemporal-specific exosome detection strategy, leveraging advanced exosomal membrane engineering techniques. The proposed strategy harnesses the power of amplified lanthanide luminescence signals on these exosomes, enabling precise and real-time monitoring of the efficacy of melanoma immunotherapy. The methodology comprises two pivotal steps. Initially, Ac4ManNAz-associated metabolic labeling is employed to evolve azide groups onto the membranes of newly secreted exosomes with remarkable selectivity. These azide groups serve as versatile clickable artificial tags, enabling the precise identification of melanoma exosomes emerging during immunotherapy. Subsequently, lanthanide-nanoparticle-functionalized polymer chains are controllably grafted onto the exosome surfaces through click chemistry and in situ Fenton-RAFT polymerization, serving as robust signal amplifiers. When integrated with time-resolved fluorescence detection, this strategy yields detection signals with an exceptionally high signal-to-noise ratio, enabling ultra-sensitive detection of PD-L1 antigen expression levels on the spatiotemporal-specific exosomes. The detection strategy boasts a wide linear concentration range spanning from 1.7 × 104 to 1.7 × 109 particles/mL, with a remarkable theoretical detection limit of 1.28 × 103 particles/mL. The remarkable enhancements in detection sensitivity and accuracy facilitate the evaluation of the efficacy of immunotherapeutic interventions in the mouse B16 melanoma model, notably revealing a substantial disparity in PD-L1 levels between immunotherapy-treated and untreated groups (P < 0.01) and further emphasizing the cumulative therapeutic effect that intensifies with repeated treatments (P < 0.001).

Glutathione-Disrupting Nanotherapeutics Potentiate Ferroptosis for Treating Luminal Androgen Receptor-Positive Triple-Negative Breast Cancer.

The refractory luminal androgen receptor (LAR) subtype of triple-negative breast cancer (TNBC) patients is challenged by significant resistance to neoadjuvant chemotherapy and increased immunosuppression. Regarding the distinct upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in LAR TNBC tumors, we herein designed a GSH-depleting phospholipid derivative (BPP) and propose a BPP-based nanotherapeutics of RSL-3 (GDNS), aiming to deplete intracellular GSH and repress GPX4 activity, thereby potentiating ferroptosis for treating LAR-subtype TNBC. GDNS treatment drastically downregulated the expression of GSH and GPX4, resulting in a 33.88-fold enhancement of lipid peroxidation and significant relief of immunosuppression in the 4T1 TNBC model. Moreover, GDNS and its combination with antibody against programed cell death protein 1 (antiPD-1) retarded tumor growth and produced 2.83-fold prolongation of survival in the LAR-positive TNBC model. Therefore, the GSH-disrupting GDNS represents an encouraging strategy to potentiate ferroptosis for treating refractory LAR-subtype TNBC.

Altitude characteristics in the response of rain-on-snow flood risk to future climate change in a high-latitude water tower.

Global warming is profoundly impacting snowmelt runoff processes in seasonal freeze-thaw zones, thereby altering the risk of rain-on-snow (ROS) floods. These changes not only affect the frequency of floods but also alter the allocation of water resources, which has implications for agriculture and other key economic sectors. While these risks present a significant threat to our lives and economies, the risk of ROS floods triggered by climate change has not received the attention it deserves. Therefore, we chose Changbai Mountain, a water tower in a high-latitude cold zone, as a typical study area. The semi-distributed hydrological model SWAT is coupled with CMIP6 meteorological data, and four shared socioeconomic pathways (SSP126, SSP245, SSP370, and SSP585) are selected after bias correction, thus quantifying the impacts of climate change on hydrological processes in the Changbai Mountain region as well as future evolution of the ROS flood risk. The results indicate that: (1) Under future climate change scenarios, snowmelt in most areas of the Changbai Mountains decreases. The annual average snowmelt under SSP126, SSP245, SSP370, and SSP585 is projected to be 148.65 mm, 135.63 mm, 123.44 mm, and 116.5 mm, respectively. The onset of snowmelt is projected to advance in the future. Specifically, in the Songhua River (SR) and Yalu River (YR) regions, the start of snowmelt is expected to advance by 1-11 days. Spatially, significant reductions in snowmelt were observed in both the central part of the watershed and the lower reaches of the river under SSP585 scenario. (2) In 2021-2060, the frequency of ROS floods decreases sequentially for different scenarios, with SSP 126 > SSP 245 > SSP 370 > SSP 585. The frequency increments of ROS floods in the source area for the four scenarios were 0.12 days/year, 0.1 d/yr, 0.13 days/year, and 0.15 days/year, respectively. The frequency of high-elevation ROS events increases in the YR in the low emission scenario. Conversely, in high emission scenarios, YR high-elevation ROS events will only increase in 2061-2100. This phenomenon is more pronounced in the Tumen River (TR), where floods become more frequent with increasing elevation.

Syntheses, Structural Analyses, and Properties of Condensed Arenes with Multihelicity.

A C1-symmetric hexapole helicene (HH) and a C3-symmetric dodecapole helicene (DH) were prepared, and their three-dimensional structures were verified by X-ray crystallography and density functional theory calculations. The molecular geometries and local helical configurations of their most stable diastereomers were correctly predicted by arranging suitable conformations of the peripheral aryl rings. Importantly, the outermost three [5]helicenes with a consistent configuration in DH were observed to increase the thermostability, enantiomerization barrier (ΔH⧧ = 40.5 kcal/mol), specific rotation ([α]24D = -4228°) and absorption dissymmetry factor (gabs = 1.35 × 10-3 at 453 nm).

Risks of infectious disease hospitalisations in the aftermath of tropical cyclones: a multi-country time-series study.

BACKGROUND: The proportion of intense tropical cyclones is expected to increase in a changing climate. However, there is currently no consistent and comprehensive assessment of infectious disease risk following tropical cyclone exposure across countries and over decades. We aimed to explore the tropical cyclone-associated hospitalisation risks and burden for cause-specific infectious diseases on a multi-country scale. METHODS: Hospitalisation records for infectious diseases were collected from six countries and territories (Canada, South Korea, New Zealand, Taiwan, Thailand, and Viet Nam) during various periods between 2000 and 2019. The days with tropical cyclone-associated maximum sustained windspeeds of 34 knots or higher derived from a parametric wind field model were considered as tropical cyclone exposure days. The association of monthly infectious diseases hospitalisations and tropical cyclone exposure days was first examined at location level using a distributed lag non-linear quasi-Poisson regression model, and then pooled using a random-effects meta-analysis. The tropical cyclone-attributable number and fraction of infectious disease hospitalisations were also calculated. FINDINGS: Overall, 2·2 million people who were hospitalised for infectious diseases in 179 locations that had at least one tropical cyclone exposure day in the six countries and territories were included in the analysis. The elevated hospitalisation risks for infectious diseases associated with tropical cyclones tended to dissipate 2 months after the tropical cyclone exposure. Overall, each additional tropical cyclone day was associated with a 9% (cumulative relative risk 1·09 [95% CI 1·05-1·14]) increase in hospitalisations for all-cause infectious diseases, 13% (1·13 [1·05-1·21]) for intestinal infectious diseases, 14% (1·14 [1·05-1·23]) for sepsis, and 22% (1·22 [1·03-1·46]) for dengue during the 2 months after a tropical cyclone. Associations of tropical cyclones with hospitalisations for tuberculosis and malaria were not significant. In total, 0·72% (95% CI 0·40-1·01) of the hospitalisations for all-cause infectious diseases, 0·33% (0·15-0·49) for intestinal infectious diseases, 1·31% (0·57-1·95) for sepsis, and 0·63% (0·10-1·04) for dengue were attributable to tropical cyclone exposures. The attributable burdens were higher among young populations (aged ≤19 years) and male individuals compared with their counterparts, especially for intestinal infectious diseases. The heterogeneous spatiotemporal pattern was further revealed at the country and territory level-tropical cyclone-attributable fractions showed a decreasing trend in South Korea during the study period but an increasing trend in Viet Nam, Taiwan, and New Zealand. INTERPRETATION: Tropical cyclones were associated with persistent elevated hospitalisation risks of infectious diseases (particularly sepsis and intestinal infectious diseases). Targeted interventions should be formulated for different populations, regions, and causes of infectious diseases based on evidence on tropical cyclone epidemiology to respond to the increasing risk and burden. FUNDING: Australian Research Council, Australian National Health, and Medical Research Council.

Potential-driven structural distortion in cobalt phthalocyanine for electrocatalytic CO2/CO reduction towards methanol.

Cobalt phthalocyanine immobilized on carbon nanotube has demonstrated appreciable selectivity and activity for methanol synthesis in electrocatalytic CO2/CO reduction. However, discrepancies in methanol production selectivity and activity between CO2 and CO reduction have been observed, leading to inconclusive mechanisms for methanol production in this system. Here, we discover that the interaction between cobalt phthalocyanine molecules and defects on carbon nanotube substrate plays a key role in methanol production during CO2/CO electroreduction. Through detailed operando X-ray absorption and infrared spectroscopies, we find that upon application of cathodic potential, this interaction induces the transformation of the planar CoN4 center in cobalt phthalocyanine to an out-of-plane distorted configuration. Consequently, this potential induced structural change promotes the transformation of linearly bonded *CO at the CoN4 center to bridge *CO, thereby facilitating methanol production. Overall, these comprehensive mechanistic investigations and the outstanding performance (methanol partial current density over 150 mA cm-2) provide valuable insights in guiding the activity and selectivity of immobilized cobalt phthalocyanine for methanol production in CO2/CO reduction.

Aqueous extract of Descuraniae Semen attenuates lipopolysaccharide-induced inflammation by inhibiting ER stress and WNK4-SPAK-NKCC1 pathway.

Sepsis causes systemic inflammatory responses and acute lung injury (ALI). Despite modern treatments, sepsis-related ALI mortality remains high. Aqueous extract of Descuraniae Semen (AEDS) exerts anti-endoplasmic reticulum (ER) stress, antioxidant and anti-inflammatory effects. AEDS alleviates inflammation and oedema in ALI. Sodium-potassium-chloride co-transporter isoform 1 (NKCC1) is essential for regulating alveolar fluid and is important in ALI. The NKCC1 activity is regulated by upstream with-no-lysine kinase-4 (WNK4) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). This study aimed to investigate the effects of AEDS on lipopolysaccharide (LPS)-induced ALI model in A549 cells, considering the regulation of ER stress, WNK4-SPAK-NKCC1 cascades, inflammation and apoptosis. Cell viability was investigated by the CCK-8 assay. The expressions of the proteins were assessed by immunoblotting analysis assays. The levels of pro-inflammatory cytokines were determined by ELISA. The expression of cytoplasmic Ca2+ in A549 cells was determined using Fluo-4 AM. AEDS attenuates LPS-induced inflammation, which is associated with increased pro-inflammatory cytokine expression and activation of the WNK4-SPAK-NKCC1 pathway. AEDS inhibits the WNK4-SPAK-NKCC1 pathway by regulating of Bcl-2, IP3R and intracellular Ca2+. WNK4 expression levels are significantly higher in the WNK4-overexpressed transfected A549 cells and significantly decrease after AEDS treatment. AEDS attenuates LPS-induced inflammation by inhibiting the WNK4-SPAK-NKCC1 cascade. Therefore, AEDS is regarded as a potential therapeutic agent for ALI.

The association of adverse birth outcomes with flood exposure before and during pregnancy in Australia: a cohort study.

BACKGROUND: Exposure to floods might increase the risks of adverse birth outcomes. However, the current evidence is scarce, inconsistent, and has knowledge gaps. This study aims to estimate the associations of flood exposure before and during pregnancy with adverse birth outcomes and to identify susceptible exposure windows and effect modifiers. METHODS: In this cohort study, we obtained all the birth records occurring in Greater Sydney, Australia, from Jan 1, 2001, to Dec 31, 2020, from the New South Wales Midwives Data Collection and in the Brisbane metropolitan region, Australia, from Jan 1, 1995, to Dec 31, 2014, from the Queensland Health Perinatal Data Collection. For each birth, residential address and historical flood information from the Dartmouth Flood Observatory were used to estimate the numbers of days with floods during five exposure windows (Pre-1 was defined as 13-24 weeks before the last menstrual period [LMP], Pre-2 was 0-12 weeks before the LMP, trimester 1 [Tri-1] was 0-12 weeks after the LMP, trimester 2 [Tri-2] was 13-28 weeks after the LMP, and trimester 3 [Tri-3] was ≥29 weeks after the LMP). We estimated the hazard ratios (HRs) of adverse birth outcomes (preterm births, stillbirths, term low birthweight [TLBW], and small for gestational age [SGA]) associated with flood exposures in the five exposure windows using Cox proportional hazards regression models. FINDINGS: 1 338 314 birth records were included in our analyses, which included 91 851 (6·9%) preterm births, 9831 (0·7%) stillbirths, 25 567 (1·9%) TLBW, and 108 658 (8·1%) SGA. Flood exposure in Pre-1 was associated with increased risks of TLBW (HR 1·06 [95% CI 1·01-1·12]) and SGA (1·04 [1·01-1·06]); flood exposure during Tri-1 was associated with increased risks of preterm births (1·03 [1·002-1·05]), stillbirth (1·11 [1·03-1·20]), and SGA (1·03 [1·01-1·06]). In contrast, flood exposures during Pre-2 and Tri-3 were associated with reduced risks. INTERPRETATION: Exposures to floods in Pre-1 and Tri-1 are both associated with increased risks of adverse birth outcomes, and the risks increase with a higher exposure. Upon planning for conception and prenatal care, individuals and health practitioners should raise awareness of the increased risks of adverse birth outcomes after experiencing floods. FUNDING: The Australian Research Council and the Australian National Health and Medical Research Council.

Comprehensive review of indicators and techniques for optical mapping of intracellular calcium ions.

Calcium ions (Ca2+) play crucial roles in almost every cellular process, making the detection of changes in intracellular Ca2+ essential to understanding cell function. The fluorescence indicator method has garnered widespread application due to its exceptional sensitivity, rapid analysis, cost-effectiveness, and user-friendly nature. It has successfully delineated the spatial and temporal dynamics of Ca2+ signaling across diverse cell types. However, it is vital to understand that different indicators have varying levels of accuracy, sensitivity, and stability, making choosing the right inspection method crucial. As optical detection technologies advance, they continually broaden the horizons of scientific inquiry. This primer offers a systematic synthesis of the current fluorescence indicators and optical imaging modalities utilized for the detection of intracellular Ca2+. It elucidates their practical applications and inherent limitations, serving as an essential reference for researchers seeking to identify the most suitable detection methodologies for their calcium-centric investigations.

The level of discomfort during the use of different circuits of the mechanical ventilator.

Objectives: Endotracheal tube (ETT) intubation is a life-saving procedure in patients with respiratory failure. However, the presence of an ETT can cause significant discomfort. A tracheostomy tube is used to administer a mechanical ventilator, resulting in a more stable airway and fewer serious injuries. Noninvasive ventilators (NIPPVs) administer ventilation through masks and must be tightly fixed to the face. ETT, tracheostomy, and NIPPV are the most common methods of ventilator maintenance. However, these interventions often cause discomfort to patients. This study aimed to compare discomfort associated with ETT, tracheostomy, and NIPPV. Materials and Methods: Forty-nine conscious patients with postextubation NIPPV and eight conscious patients who underwent postextubation tracheotomy were evaluated for discomfort. A questionnaire survey on discomfort was performed before and after NIPPV or tracheostomy. These patients reported their level of discomfort on a visual analog scale. Results: The levels of sore throat, nasal pain, body pain, activity limitation, respiratory discomfort, oral discomfort, difficulty coughing sputum, worry about respiratory tube disconnection, back pain, anxiety, worry about long-term admission, sleep disturbance, and general discomfort during ETT intubation were higher than during tracheostomy or NIPPV (all P < 0.05). The mean level of discomfort was approximately 5-6 points (moderate) in patients with ETT and 2-3 points (mild) in patients with NIPPV or tracheostomy. Conclusion: The level of discomfort was higher in patients who underwent ETT intubation than in those who underwent NIPPV or tracheostomy. However, the level of discomfort was similar between the patients with NIPPV and those who underwent tracheostomy.

Short-term ozone exposure and cancer mortality in Brazil: A nationwide case-crossover study.

Exposure to ambient ozone (O3) is linked to increased mortality risks from various diseases, but epidemiological investigations delving into its potential implications for cancer mortality are limited. We aimed to examine the association between short-term O3 exposure and site-specific cancer mortality and investigate vulnerable subgroups in Brazil. In total 3,459,826 cancer death records from 5570 Brazilian municipalities between 2000 and 2019, were included. Municipal average daily O3 concentration was calculated from a global estimation at 0.25°×0.25° spatial resolution. The time-stratified case-crossover design was applied to assess the O3-cancer mortality association. Subgroup analyses by age, sex, season, time-period, region, urban hierarchy, climate classification, quantiles of GDP per capita and illiteracy rates were performed. A linear and non-threshold exposure-response relationship was observed for short-term exposure to O3 with cancer mortality, with a 1.00% (95% CI: 0.79%-1.20%) increase in all-cancer mortality risks for each 10-µg/m3 increment of three-day average O3. Kidney cancer was most strongly with O3 exposure, followed by cancers of the prostate, stomach, breast, lymphoma, brain and lung. The associated cancer risks were relatively higher in the warm season and in southern Brazil, with a decreasing trend over time. When restricting O3 concentration to the national minimum value during 2000-2019, a total of 147,074 (116,690-177,451) cancer deaths could be avoided in Brazil, which included 17,836 (7014-28,653) lung cancer deaths. Notably, these associations persisted despite observed adaptation within the Brazilian population, highlighting the need for a focus on incorporating specific measures to mitigate O3 exposure into cancer care recommendations.

Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).