Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

Cu-Pd bimetal-decorated siloxene nanosheets for semi-hydrogenation of acetylene.

Metallic Pd has been proved highly promising when paired with Cu for industrially important acetylene semi-hydrogenation. Herein, we demonstrate that high-surface-area siloxene can feasibly enable alloying between Pd and Cu via room-temperature reduction with Si-H bonds. Unprecedentedly small Cu nanoparticles with isolated Pd were in situ loaded on siloxene, addressing the core problem of low selectivity of Pd and low activity of Cu. This devised structure outclassed the traditional impregnated SiO2 in every aspect of the catalytic performance for the semi-hydrogenation of acetylene under industry conditions, with a 91% acetylene conversion and an impressive 93% selectivity to ethylene at 200 °C, and showed long-term stability with negligible activity decay at this harsh temperature. This work provides new insights for the design of economic bimetallic loaded catalysts for balancing the activity-selectivity dilemma, demonstrating the viability of siloxene as both a synthetic reagent and a carrier material for efficient catalysis.

In vitro batch fermentation demonstrates variations in the regulation of gut microbiota and metabolic functions by ß-glucans of differing structures.

The gut microbiota is widely acknowledged as a crucial factor in regulating host health. The structure of dietary fibers determines changes in the gut microbiota and metabolic differences resulting from their fermentation, which in turn affect gut microbe-related health effects. ß-Glucan (BG) is a widely accessible dietary fiber to humans, and its structural characteristics vary depending on the source. However, the interactions between different structural BGs and gut microbiota remain unclear. This study used an in vitro fermentation model to investigate the effects of BG on gut microbiota, and microbiomics and metabolomics techniques to explore the relationship between the structure of BG, bacterial communities, and metabolic profiles. The four sources of BG (barley, yeast, algae, and microbial fermentation) contained different types and proportions of glycosidic bonds, which differentially altered the bacterial community. The BG from algal sources, which contained only ß(1 â†’ 4) glycosidic bonds, was the least metabolized by the gut microbiota and caused limited metabolic changes. The other three BGs contain more diverse glycosidic bonds and can be degraded by bacteria from multiple genera, causing a wider range of metabolic changes. This work also suggested potential synergistic degradation relationships between gut bacteria based on BG. Overall, this study deepens the structural characterization-microbial-functional understanding of BGs and provides theoretical support for the development of gut microbiota-targeted foods.

Impact of intraoperative dexmedetomidine on postoperative delirium and pro-inflammatory cytokine levels in elderly patients undergoing thoracolumbar compression fracture surgery: A prospective, randomized, placebo-controlled clinical trial.

BACKGROUND: This study evaluates the efficacy of dexmedetomidine (DEX) in reducing postoperative delirium (POD) and modulating pro-inflammatory cytokines in elderly patients undergoing thoracolumbar compression fracture surgery. METHODS: In this randomized, double-blind, placebo-controlled trial conducted from October 2022 to January 2023 at Anting Hospital in Shanghai, 218 elderly patients were randomized into DEX (n = 110) and normal saline (NS, n = 108) groups. The DEX group received 0.5 µg/kg/h DEX, and delirium incidence was assessed using the Confusion Assessment Method (CAM) on days 1 to 3 post-surgery. Levels of interleukins IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured pre-operation (T0) and on postoperative days 1 (T1) and 3 (T3). Preoperative (T0) and postoperative day 1 (T1) cerebrospinal fluid (CSF) samples were treated with varying concentrations of olanzapine or DEX to observe their regulatory effects on the expression of Phospho-ERK1/2 and Phospho-JNK. RESULTS: Dexmedetomidine significantly lowered the incidence of POD to 18.2%, compared to 30.6% in the NS group (P = .033). While all patients showed an initial increase in cytokine levels after surgery, by T3, IL-6 and TNF-α levels notably decreased in the DEX group, with no significant change in IL-1ß levels across groups. The adverse events rate was similar between groups, demonstrating the safety of DEX in this population. In postoperative CSF samples, treatment with 0.5 mM DEX significantly downregulated Phospho-JNK and upregulated Phospho-ERK1/2 expression, demonstrating a dose-dependent modulation of inflammatory responses. CONCLUSION: Dexmedetomidine is effective in reducing early POD in elderly patients post-thoracolumbar compression fracture surgery. It also decreases IL-6 and TNF-α levels, indicating its potential in managing postoperative inflammatory responses. Treatment with 0.5 mM DEX significantly modulated Phospho-ERK1/2 and Phospho-JNK expressions in postoperative CSF samples, indicating a dose-dependent effect on reducing inflammation. This study contributes to understanding DEX's role in improving postoperative outcomes in elderly patients.

Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

Spin Crossover in [Fe(qsal-5-Brq)2]+ Complexes with a Quinoline-Substituted Qsal Ligand.

Using a quinoline substituted Qsal ligand, Hqsal-5-Brq (Hqsal-5-Brq = N-(5-bromo-8-quinolyl)salicylaldimine), four FeIII complexes, [Fe(qsal-5-Brq)2]A·CH3OH (Y = NO3- (1NO3), BF4- (2BF4), PF6- (3PF6), OTf- (4OTf), were prepared and characterized. Structure analysis revealed that complex 2BF4 contained two species (2BF4(P1̅) and 2BF4(C2/c)). In these compounds except 3PF6, the [Fe(qsal-5-Brq)2]+ cations form 1D chains through π-π interactions and other weak interactions. Adjacent chains are connected to form the 2D "Chain Layer" structures and 3D structures through various supramolecular interactions. For 3PF6, a "Dimer Chain" structure is formed from the loosely connected dimers. Magnetic studies revealed that compounds 1NO3 and 2BF4(P1̅) displayed abrupt hysteretic SCO with the transition temperature T1/2↓ = 235 K, T1/2↑ = 240 K for 1NO3 and T1/2↓ = 230 K, T1/2↑ = 235 K for 2BF4(P1̅), while compounds 3PF6 and 4OTf are in the HS state. Desolvation of the complexes significantly modifies their SCO properties: the desolvated 1NO3 and 2BF4 show a gradual SCO, desolvated 3PF6 undergoes a two-step SCO, and desolvated 4OTf exhibits a hysteretic transition. Overall, this work reported the FeIII-SCO complexes of the quinoline-substituted Hqsal ligand and highlighted the potential of these ligands for the development of interesting FeIII-SCO materials.

Integrating single-cell and multi-omic approaches reveals Euphorbiae Humifusae Herba-dependent mitochondrial dysfunction in non-small-cell lung cancer.

Euphorbiae Humifusae Herba (EHH) is a pivotal therapeutic agent with diverse pharmacological effects. However, a substantial gap exists in understanding its pharmacological properties and anti-tumour mechanisms. This study aimed to address this gap by exploring EHH's pharmacological properties, identifying NSCLC therapy-associated protein targets, and elucidating how EHH induces mitochondrial disruption in NSCLC cells, offering insights into novel NSCLC treatment strategies. String database was utilized to explore protein-protein interactions. Subsequently, single-cell analysis and multi-omics further unveiled the impact of EHH-targeted genes on the immune microenvironment of NSCLC, as well as their influence on immunotherapeutic responses. Finally, both in vivo and in vitro experiments elucidated the anti-tumour mechanisms of EHH, specifically through the assessment of mitochondrial ROS levels and alterations in mitochondrial membrane potential. EHH exerts its influence through engagement with a cluster of 10 genes, including the apoptotic gene CASP3. This regulatory impact on the immune milieu within NSCLC holds promise as an indicator for predicting responses to immunotherapy. Besides, EHH demonstrated the capability to induce mitochondrial ROS generation and perturbations in mitochondrial membrane potential in NSCLC cells, ultimately leading to mitochondrial dysfunction and consequent apoptosis of tumour cells. EHH induces mitochondrial disruption in NSCLC cells, leading to cell apoptosis to inhibit the progress of NSCLC.

Association of accelerated aging with the incidence risk of Cardiometabolic diseases in people with severe mental illnesses: A prospective analysis in UK Biobank.

Cardiometabolic diseases (CMDs) comorbidities among people with severe mental illnesses (SMI) are associated with a high healthcare burden and premature mortality. This study aims to evaluate whether biological aging has an interaction with SMI on incident CMDs, and to examine the association of four biological aging indicators with CMDs incidence in this population. Data were sourced from the UK Biobank, a large prospective cohort study. Four indicators were used to assess biological aging including frailty phenotype, frailty index, KDM-biological age acceleration and phenotypic age acceleration. Cox proportional hazards regression models were used to examine the associations. We observed higher prevalence of frailty and accelerated biological age with SMI than those without SMI. Further analysis found significant interaction effect of pre-frailty and SMI (PPre-frail*SMI=0.005) as well as biological age acceleration and SMI (PQ3 (>P75)*SMI=0.038). 14.7 % of the participants with SMI developed CMDs during the follow-up. Compared with non-frail participants, those with frailty (frailty phenotype: HR=1.68, 95 % CI: 1.50, 1.88, P < 0.001; frailty index: HR=2.44, 95 % CI: 2.11-2.81, P < 0.001) and biological age acceleration (KDM-biological age acceleration (Q3): HR=1.91, 95 % CI: 1.74, 2.11, P < 0.001; phenotypic age acceleration (Q3): HR=2.07, 95 % CI: 1.86, 2.30, P < 0.001) had a significantly higher risk of CMDs in the adjusted model. A series of sensitivity analyses were conducted to illustrate the robustness of the findings. These findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI.

Synthesis of isothiocyanato alkyl sulfides from alkenes using KSCN and DMTSM.

A method for the synthesis of isothiocyanato alkyl sulfides from KSCN and DMTSM under metal-free conditions has been developed. The features of this reaction are low-cost, readily accessible starting materials and the use of KSCN as nucleophiles for C-NCS bond formation. Alkenes with various substituted groups react smoothly and the desired products are obtained in moderate to good yields.

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.

BACKGROUND: There is a clear demand for innovative therapeutics for bipolar disorder (BD). METHODS: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. RESULTS: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. CONCLUSIONS: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

Synthesis and Evaluation of Novel 68Ga-Labeled [D-Phe6,Leu13ψThz14]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [68Ga]Ga-TacsBOMB2 ([68Ga]Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13ψThz14-NH2), which showed a minimal pancreas uptake in a preclinical mouse model. In this study, we synthesized four derivatives with unnatural amino acid substitutions (Tle10-derived Ga-LW01158, NMe-His12-derived Ga-LW01160, α-Me-Trp8- and Tle10-derived Ga-LW01186, and Tle10- and N-Me-Gly11-derived Ga-LW02002) and evaluated their potential for detecting GRPR-expressing tumors with positron emission tomography (PET). The binding affinities (Ki(GRPR)) of Ga-LW01158, Ga-LW01160, Ga-LW01186, and Ga-LW02002 were 5.11 ± 0.47, 187 ± 17.8, 6.94 ± 0.95, and 11.0 ± 0.39 nM, respectively. [68Ga]Ga-LW01158, [68Ga]Ga-LW01186, and [68Ga]Ga-LW02002 enabled clear visualization of subcutaneously implanted human prostate cancer PC-3 tumor xenografts in mice in PET images. Ex vivo biodistribution studies showed that [68Ga]Ga-LW01158 had the highest tumor uptake (11.2 ± 0.65 %ID/g) and good tumor-to-background uptake ratios at 1 h post-injection. Comparable in vivo stabilities were observed for [68Ga]Ga-LW01158, [68Ga]Ga-LW01186, and [68Ga]Ga-LW02002 (76.5-80.7% remaining intact in mouse plasma at 15 min post-injection). In summary, the Tle10 substitution, either alone or combined with α-Me-Trp8 or NMe-Gly11 substitution, in Ga-TacsBOMB2 generates derivatives that retained good GRPR binding affinity and in vivo stability. With good tumor uptake and tumor-to-background imaging contrast, [68Ga]Ga-LW01158 is promising for detecting GRPR-expressing lesions with PET.

Preclinical evaluation of MC1R targeting theranostic pair [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH.

BACKGROUND: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (149Tb, 152Tb, 155Tb, 161Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving 155Tb- and 161Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma. METHODS: 155Tb was produced via proton induced spallation of Ta targets using the isotope separation and acceleration facility at TRIUMF with isotope separation on-line (ISAC/ISOL). The radiolabeling characteristics of crown-αMSH with 155Tb and/or 161Tb were evaluated by concentration-dependence radiolabeling studies, and radio-HPLC stability studies. LogD7.4 measurements were obtained for [161Tb]Tb-crown-αMSH. Competitive binding assays were undertaken to determine the inhibition constant for [natTb]Tb-crown-αMSH in B16-F10 cells. Pre-clinical biodistribution and SPECT/CT imaging studies of 155Tb and 161Tb labeled crown-αMSH were undertaken in male C57Bl/6 J mice bearing B16-F10 melanoma tumors to evaluate tumor specific uptake and imaging potential for each radionuclide. RESULTS: Quantitative radiolabeling of crown-αMSH with [155Tb]Tb3+ and [161Tb]Tb3+ was demonstrated under mild conditions (RT, 10 min) and low chelator concentrations; achieving high molar activities (23-29 MBq/nmol). Radio-HPLC studies showed [161Tb]Tb-crown-αMSH maintains excellent radiochemical purity in human serum, while gradual metabolic degradation is observed in mouse serum. Competitive binding assays showed the high affinity of [natTb]Tb-crown-αMSH toward MC1R. Two different methods for preparation of the [155Tb]Tb-crown-αMSH radiotracer were investigated and the impacts on the biodistribution profile in tumor bearing mice is compared. Preclinical in vivo studies of 155Tb- and 161Tb- labeled crown-αMSH were performed in parallel, in mice bearing B16-F10 tumors; where the biodistribution results showed similar tumor specific uptake (6.06-7.44 %IA/g at 2 h pi) and very low uptake in nontarget organs. These results were further corroborated through a series of single-photon emission computed tomography (SPECT) studies, with [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH showing comparable uptake profiles and excellent image contrast. CONCLUSIONS: Collectively, our studies highlight the promising characteristics of [155Tb]Tb-crown-αMSH and [161Tb]Tb-crown-αMSH as theranostic pair for nuclear imaging (155Tb) and radionuclide therapy (161Tb).

Analysis of the key genes of Lactobacillus reuteri strains involved in the protection against alcohol-induced intestinal barrier damage.

Gastrointestinal inflammation and intestinal barrier function have important effects on human health. Alcohol, an important foodborne hazard factor, damages the intestinal barrier, increasing the risk of disease. Lactobacillus reuteri strains have been reported to reduce gastrointestinal inflammation and strengthen the intestinal barrier. In this study, we selected three anti-inflammatory L. reuteri strains to evaluate their role in the protection of the intestinal barrier and their immunomodulatory activity in a mouse model of gradient alcohol intake. Among the three strains tested (FSCDJY33M3, FGSZY33L6, and FCQHCL8L6), L. reuteri FSCDJY33M3 was found to protect the intestinal barrier most effectively, possibly due to its ability to reduce the expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) and increase the expression of tight junction proteins (occludin, claudin-3). Genomic analysis suggested that the protective effects of L. reuteri FSCDJY33M3 may be related to functional genes and glycoside hydrolases associated with energy production and conversion, amino acid transport and metabolism, carbohydrate transport and metabolism, and DNA replication, recombination, and repair. These genes include COG2856, COG1804, COG2071, and COG1061, which encode adenine deaminase, acyl-CoA transferases, glutamine amidotransferase, RNA helicase, and glycoside hydrolases, including GH13_20, GH53, and GH70. Our results identified functional genes that may be related to protection against alcohol-induced intestinal barrier damage, which might be useful for screening lactic acid bacterial strains that can protect the intestinal barrier.

Enhancing m6A modification of lncRNA through METTL3 and RBM15 to promote malignant progression in bladder cancer.

Objective: Bladder cancer is one of the most prominent malignancies affecting the urinary tract, characterized by a poor prognosis. Our previous research has underscored the pivotal role of m6A methylation in the progression of bladder cancer. Nevertheless, the precise relationship between N6-methyladenosine (m6A) regulation of long non-coding RNA (lncRNA) and bladder cancer remains elusive. Methods: This study harnessed sequencing data and clinical records from 408 bladder cancer patients in the TCGA database. Employing R software, we conducted bioinformatics analysis to establish an m6A-lncRNA co-expression network. Analyzing the differences between high and low-risk groups, particularly at the immunological level, and subsequently investigating the primary regulatory factors of these lncRNA, validating the findings through experiments, and exploring their specific cellular functions. Results: We identified 50 m6A-related lncRNA with prognostic significance through univariate Cox regression analysis. In parallel, we employed a LASSO-Cox regression model to pinpoint 11 lncRNA and calculate risk scores for bladder cancer patients. Based on the median risk score, patients were categorized into low-risk and high-risk groups. The high-risk cohort exhibited notably lower survival rates than their low-risk counterparts. Further analysis pointed to RBM15 and METTL3 as potential master regulators of these m6A-lncRNA. Experimental findings also shed light on the upregulated expression of METTlL3 and RBM15 in bladder cancer, where they contributed to the malignant progression of tumors. The experimental findings demonstrated a significant upregulation of METTL3 and RBM15 in bladder cancer specimens, implicating their contributory role in the oncogenic progression. Knockdown of METTL3 and RBM15 resulted in a marked attenuation of tumor cell proliferation, invasion, and migration, which was concomitant with a downregulation in the cellular m6A methylation status. Moreover, these results revealed that RBM15 and METTL3 function in a synergistic capacity, positing their involvement in cancer promotion via the upregulation of m6A modifications in long non-coding RNAs. Additionally, this study successfully developed an N-methyl-N-nitrosourea (MNU)-induced rat model of in situ bladder carcinoma, confirming the elevated expression of RBM15 and METTL3, which paralleled the overexpression of m6A-related- lncRNAs observed in bladder cancer cell lines. This congruence underscores the potential utility of these molecular markers in in vivo models that mirror human malignancies. Conclusion: This study not only offers novel molecular targets,but also enriches the research on m6A modification in bladder cancer, thereby facilitating its clinical translation.

Association of air pollution with incidence of elderly-onset seborrheic dermatitis: A prospective cohort study in UK Biobank.

BACKGROUND: Elderly-onset seborrheic dermatitis (SD) seriously affects the quality of life. However, associations between air pollution exposures and elderly-onset SD incidence have not been elucidated. OBJECTIVES: Investigate air pollution's role in the incidence of elderly-onset SD. METHODS: We engaged a prospective cohort analysis utilizing the UK Biobank database. Exposure data for specific air pollutants (PM2.5, PM2.5-10, NOX, NO2, and PM10) spanning various years was incorporated. Through a composite air pollution score constructed from five pollutants and employing Cox proportional hazards models, the relationship between pollution and SD was delineated. RESULTS: Our examination of 193,995 participants identified 3,363 SD cases. Higher concentrations of specific pollutants, particularly in the upper quartile (Q4), were significantly linked to an elevated SD risk. Notably, PM2.5, PM10, NO2, and NOX exhibited hazard ratios of 1.11, 1.15, 1.22, and 1.15, respectively. The correlation was further solidified with a positive association between air pollution score increments and SD onset. Intriguingly, this association was accentuated in certain demographics, including younger males, the socioeconomically deprived, smokers, daily alcohol consumers, and those engaging in regular physical activity. CONCLUSIONS: Our findings revealed that air pollution exposures were associated with elderly-onset SD incidence. These results emphasize the importance of preventing environmental exposures to the risk of SD development.

Desorption Characteristics of CH4-C2H6 Mixed Gas in Heavy Hydrocarbon-Rich Coal Seams.

The gas desorption characteristics of coal are closely related to the gas content of the coal seam. The gas in heavy hydrocarbon-rich coal seams contains CH4 and C2H6 heavy hydrocarbons. However, most current research on the gas desorption characteristics of coal seams focuses on CH4 analysis, ignoring the influence of the C2H6 heavy hydrocarbon gas. To accurately determine the gas content of a heavy hydrocarbon-rich coal seam, methods based on CH4 analysis are inadequate and the desorption characteristics of CH4-C2H6 mixed gas must be clarified. This work experimentally and theoretically studies the desorption characteristics of single-component gas and CH4-C2H6 mixed gas from coal samples. The results show that increasing the adsorption-equilibrium pressure was found to increase the desorption quantity and desorption speed of single-component gas and increase the desorption quantity, desorption ratio, and diffusion coefficient of mixed gas. Under the same adsorption-equilibrium pressure, the desorption quantity and rate of single-component CH4 gas exceeded those of C2H6. The quantity and speed of mixed gas desorption increased with rising CH4 concentration and decreased with rising C2H6 concentration. The change in the mixed gas concentration during desorption reflects the distribution characteristics of light hydrocarbon components on the outer surface and heavy hydrocarbon components on the inner surface of coal. From the desorption characteristics of mixed gas, desorption models of mixed gas were obtained at different concentrations, laying a theoretical foundation for accurate determinations of gas contents in heavy hydrocarbon-rich coal seams.

Global patterns of human-wildlife spatial associations and implications for differentiating conservation strategies.

Understanding the global patterns of human and wildlife spatial associations is essential for pragmatic conservation implementation, yet analytical foundations and indicator-based assessments that would further this understanding are lacking. We integrated the global distributions of 30,664 terrestrial vertebrates and human pressures to map human-nature index (HNI) categories that indicate the extent and intensity of human-wildlife interactions. Along the 2 dimensions of biodiversity and human activity, the HNI allowed placement of terrestrial areas worldwide in one of 4 HNI categories: anthropic (human-dominated areas), wildlife-dominated (little human influence and rich in wildlife), co-occurring (substantial presence of humans and wildlife), and harsh-environment (limited presence of humans and wildlife) areas. The HNI varied considerably among taxonomic groups, and the leading driver of HNI was global climate patterns. Co-occurring regions were the most prevalent (35.9%), and wildlife-dominated and anthropic regions encompassed 26.45% and 6.50% of land area, respectively. Our results highlight the necessity for customizing conservation strategies to regions based on human-wildlife spatial associations and the distribution of existing protected area networks. Human activity and biodiversity should be integrated for complementary strategies to support conservation toward ambitious and pragmatic 30×30 goals.

Patrones globales de las asociaciones espaciales entre humanos y fauna y las implicaciones para la diferenciación de las estrategias de conservación Resumen Es esencial entender los patrones globales de asociaciones entre humanos y fauna para la implementación pragmática de la conservación. Aun así, son muy pocos los fundamentos analíticos y las evaluaciones basadas en indicadores que incrementarían este conocimiento. Integramos la distribución global de 30,664 vertebrados terrestres y presiones humanas para mapear las categorías del índice de naturaleza humana (INH) que indican la extensión e intensidad de las interacciones humano­fauna. El INH permitió la colocación de áreas terrestres en todo el mundo en las dos dimensiones de la biodiversidad y las actividades humanas dentro de una de las cuatro categorías del INH: áreas antrópicas (dominadas por humanos), dominadas por fauna (poca influencia humana y rica en fauna), co­ocurrentes (presencia sustancial de humanos y fauna) y de ambiente severo (presencia limitada de humanos y fauna). El INH varió considerablemente entre los taxones, y el factor principal fueron los patrones climáticos mundiales. Las regiones co­ocurrentes fueron las más frecuentes (35.9%) las regiones antrópicas y dominadas por fauna englobaron el 26.45% y 6.50% del área terrestre respectivamente. Nuestros resultados enfatizan la necesidad de personalizar las estrategias de conservación acorde a la región con base en las asociaciones espaciales entre humanos y fauna y la distribución de las redes existentes de áreas protegidas. La actividad humana y la biodiversidad deberían estar integradas para las estrategias complementarias para respaldar a la conservación hacia los objetivos ambiciosos y pragmáticos de 30 para el 30.

Development of TSHR-CAR NK-92 cells for Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) is the predominant type of thyroid cancer, with some patients experiencing relapse, distant metastases, or refractoriness, revealing limited treatment options. Chimeric antigen receptor (CAR)-modified Natural Killer (NK) cells are revolutionary therapeutic agents effective against various resistant cancers. Thyroid-stimulating hormone receptor (TSHR) expression in DTC provides a unique tumor-specific target for CAR therapy. Here, we developed an innovative strategy for treating DTC using modified NK-92 cells armed with a TSHR-targeted CAR. The modified cells showed enhanced cytotoxicity against TSHR-positive DTC cell lines and exhibited elevated degranulation and cytokine release. After undergoing irradiation, the cells effectively halted their proliferative capacity while maintaining potent targeted killing ability. Transfer of these irradiation-treated cells into NSG mice with DTC tumors resulted in profound tumor suppression. NK-92 cells modified with TSHR-CAR offer a promising, off-the-shelf option for advancing DTC immunotherapy.

Anisotropic Damage Mechanism of Coal Seam Water Injection with Multiphase Coupling.

After coal seam water injection, coal mechanical properties will change with brittleness weakening and plasticity enhancement. Aiming at the problem of coal damage caused by the coal seam water injection process, based on nonlinear pore elasticity theory and continuum damage theory, a nonlinear pore elastic damage model considering anisotropic characteristics is proposed to calculate and analyze the gas-liquid-solid multiphase coupling effect with the fully coupled finite element method during the coal seam water injection process. The research results indicate that the wetting radius of calculated results by the model agrees well with the in situ test results, and the relative errors are less than 10%. Water saturation and induced damage of the coal body in the parallel bedding direction are greater than that in the vertical bedding direction during the coal seam water injection process, which exhibits significant anisotropic characteristics. With the increasing water injection time, the induced damage of the coal body also increases near the water injection hole. Considering the inherent permeability arising with damage, it has a significant impact on both water saturation and induced damage, which also indicates that there is a strong interaction between water saturation and induced damage. The theoretical model reveals the coal damage mechanism of gas-liquid-solid multiphase coupling after coal seam water injection and provides a theoretical prediction of coal containing water characteristics in engineering practice.