Depressive symptom mediates the association between the number of chronic diseases and cognitive impairment: a multi-center cross-sectional study based on community older adults.

Objective: The purpose of this study was to understand the relationship between the multiple chronic conditions (MCC), mental health and cognitive function of older adults in the community, and to propose a hypothesis that depressive symptom mediate the number of chronic diseases and cognitive impairment in older adults. Method: Participants aged 65 years and older from 35 communities in 14 cities in Guangxi, China were recruited. The residents' depressive symptom (PHQ-9) and cognitive status (AD-8) were evaluated, Chi-square test was used to explore the effects of different socio-demographic characteristics on depressive symptom and cognitive impairment. Pearson correlation analysis and the process model 4 were used to explore the relationship between the number of chronic diseases, depressive symptom and cognitive impairment. Result: A total of 11,582 older adults were included in our analysis. The rate of MCC reaching 26.53%. Hypertension combined with diabetes accounts for the highest proportion of two chronic diseases (13.2%). Among the combination of three chronic diseases, the highest incidence of coexisting hypertension combined with cervical/lumbar spondylosis, and rheumatoid arthritis (7.1%). In this study, depression symptoms accounted for 12.9% of older adults aged 65 and above, and cognitive impairment accounted for 27.4%. Female, older age, reside in urban areas, lower educational levels, no spouse, live alone, and MCC were risk factors for depressive symptom and cognitive impairment in older adults (P<0.05). Depressive symptom had a mediating effect in the number of chronic diseases and cognitive impairment, and the mediating effect (1.109) accounted for 44.13% of the total effect (0.247). Conclusion: The mental health of the older adult needs to be taken seriously, and improving depressive symptom can reduce the occurrence of cognitive impairment in older patients with MCC to a certain extent.

Self-Harm and Suicide Rates Before and After an Early Intervention Program for Patients With First-Episode Schizophrenia.

Importance: Evidence on the association of early intervention services (EISs) with self-harm and suicide among patients with first-episode schizophrenia (FES) at older than 25 years is lacking. Objective: To examine changes in self-harm and suicide rates among patients with FES before and after the implementation of an EIS program. Design, Setting, and Participants: This population-based cohort study conducted among 37 040 patients aged 15 to 64 years with FES between January 1, 2001, and March 31, 2020, used electronic medical records from the Hong Kong Clinical Data Analysis and Reporting System. All patients were followed up from the first diagnosis of schizophrenia (the index date) until the date of their death or the end of the study period (March 31, 2021), whichever came first. Statistical analysis was performed from July to November 2023. Exposure: The EIS extended the Early Assessment Service for Young People With Early Psychosis (EASY) program from patients aged 15 to 25 years to those aged 15 to 64 years (EASY Plus). The exposure was the implementation of the EASY Plus program in April 2011. The exposure period was defined as between April 2012 and March 2021 for the 1-year-time-lag analysis. Main Outcomes and Measures: The outcomes were monthly rates of self-harm and suicide among patients with FES before and after the implementation of the EASY Plus program. Interrupted time series analysis was used for the main analysis. Results: This study included 37 040 patients with FES (mean [SD] age at onset, 39 [12] years; 82.6% older than 25 years; 53.0% female patients). The 1-year-time-lag analysis found an immediate decrease in self-harm rates among patients aged 26 to 44 years (rate ratio [RR], 0.77 [95% CI, 0.59-1.00]) and 45 to 64 years (RR, 0.70 [95% CI, 0.49-1.00]) and among male patients (RR, 0.71 [95% CI, 0.56-0.91]). A significant long-term decrease in self-harm rates was found for all patients with FES (patients aged 15-25 years: RR, 0.98 [95% CI, 0.97-1.00]; patients aged 26-44 years: RR, 0.98 [95% CI, 0.97-0.99]; patients aged 45-64 years: RR, 0.97 [95% CI, 0.96-0.98]). Suicide rates decreased immediately after the implementation of the EASY Plus program among patients aged 15 to 25 years (RR, 0.33 [95% CI, 0.14-0.77]) and 26 to 44 years (RR, 0.38 [95% CI, 0.20-0.73]). Compared with the counterfactual scenario, the EASY Plus program might have led to 6302 fewer self-harm episodes among patients aged 26 to 44 years. Conclusions and Relevance: This cohort study of the EASY Plus program suggests that the extended EIS was associated with reduced self-harm and suicide rates among all patients with FES, including those older than 25 years. These findings emphasize the importance of developing tailored interventions for patients across all age ranges to maximize the benefits of EISs.

Science development study for the Atacama Large Aperture Submillimeter Telescope (AtLAST): Solar and stellar observations.

Observations at (sub-)millimeter wavelengths offer a complementary perspective on our Sun and other stars, offering significant insights into both the thermal and magnetic composition of their chromospheres. Despite the fundamental progress in (sub-)millimeter observations of the Sun, some important aspects require diagnostic capabilities that are not offered by existing observatories. In particular, simultaneously observations of the radiation continuum across an extended frequency range would facilitate the mapping of different layers and thus ultimately the 3D structure of the solar atmosphere. Mapping large regions on the Sun or even the whole solar disk at a very high temporal cadence would be crucial for systematically detecting and following the temporal evolution of flares, while synoptic observations, i.e., daily maps, over periods of years would provide an unprecedented view of the solar activity cycle in this wavelength regime. As our Sun is a fundamental reference for studying the atmospheres of active main sequence stars, observing the Sun and other stars with the same instrument would unlock the enormous diagnostic potential for understanding stellar activity and its impact on exoplanets. The Atacama Large Aperture Submillimeter Telescope (AtLAST), a single-dish telescope with 50m aperture proposed to be built in the Atacama desert in Chile, would be able to provide these observational capabilities. Equipped with a large number of detector elements for probing the radiation continuum across a wide frequency range, AtLAST would address a wide range of scientific topics including the thermal structure and heating of the solar chromosphere, flares and prominences, and the solar activity cycle. In this white paper, the key science cases and their technical requirements for AtLAST are discussed.

Observations of our Sun and other stars at wavelengths of around one millimeter, i.e. in the range between infrared and radio waves, present a valuable complementary perspective. Despite significant technological advancements, certain critical aspects necessitate diagnostic capabilities not offered by current observatories. The proposed Atacama Large Aperture Submillimeter Telescope (AtLAST), featuring a 50-meter aperture and slated for construction at a high altitude in Chile's Atacama desert, promises to address these observational needs. Equipped with novel detectors that would cover a wide frequency range, AtLAST could unlock a plethora of scientific studies contributing to a better understanding of our host star. Simultaneous observations over a broad frequency range at rapid succession would enable the imaging of different layers of the Sun, thus elucidating the three-dimensional thermal and magnetic structure of the solar atmosphere and providing important clues for many long-standing central questions such as how the outermost layers of the Sun are heated to very high temperatures, the nature of large-scale structures like prominences, and how flares and coronal mass ejections, i.e. enormous eruptions, are produced. The latter is of particular interest to modern society due to the potentially devastating impact on the technological infrastructure we depend on today. Another unique possibility would be to study the Sun's long-term evolution in this wavelength range, which would yield important insights into its activity cycle. Moreover, the Sun serves as a fundamental reference for other stars as, due to its proximity, it is the only star that can be investigated in such detail. The results for the Sun would therefore have direct implications for understanding other stars and their impact on exoplanets. This article outlines the key scientific objectives and technical requirements for solar observations with AtLAST.

Time-course swRNA-seq uncovers a hierarchical gene regulatory network in controlling the response-repair-remodeling after wounding.

Wounding initiates intricate responses crucial for tissue repair and regeneration. Yet, the gene regulatory networks governing wound healing remain poorly understood. Here, employing single-worm RNA sequencing (swRNA-seq) across 12 time-points, we delineated a three-stage wound repair process in C. elegans: response, repair, and remodeling. Integrating diverse datasets, we constructed a dynamic regulatory network comprising 241 transcription regulators and their inferred targets. We identified potentially seven autoregulatory TFs and five cross-autoregulatory loops involving pqm-1 and jun-1. We revealed that TFs might interact with chromatin factors and form TF-TF combinatory modules via intrinsically disordered regions to enhance response robustness. We experimentally validated six regulators functioning in transcriptional and translocation-dependent manners. Notably, nhr-76, daf-16, nhr-84, and oef-1 are potentially required for efficient repair, while elt-2 may act as an inhibitor. These findings elucidate transcriptional responses and hierarchical regulatory networks during C. elegans wound repair, shedding light on mechanisms underlying tissue repair and regeneration.

A Segmented Iterative Learning Scheme-Based Distributed Fault Estimation for Switched Interconnected Nonlinear Systems.

In this article, a distributed fault estimation (DFE) approach for switched interconnected nonlinear systems (SINSs) with time delays and external disturbances is proposed using a novel segmented iterative learning scheme (SILS). First, through the utilization of interrelated information among subsystems, a distributed iterative learning observer is developed to enhance the accuracy of fault estimation results, which can realize the fault estimation of all subsystems under time delays and external disturbances. Simultaneously, to facilitate rapid fault information tracking and significantly reduce sensitivity to interference, a new SILS-based fault estimation law is constructed by combining the idea of segmented design with the method of variable gain. Then, an assessment of the convergence of the established fault estimation methodology is conducted, and the configurations of observer gain matrices and iterative learning gain matrices are duly accomplished. Finally, simulation results are showcased to demonstrate the superiority and feasibility of the developed fault estimation approach.

Impact of COVID-19 pandemic on depression incidence and healthcare service use among patients with depression: an interrupted time-series analysis from a 9-year population-based study.

BACKGROUND: Most studies on the impact of the COVID-19 pandemic on depression burden focused on the earlier pandemic phase specific to lockdowns, but the longer-term impact of the pandemic is less well-studied. In this population-based cohort study, we examined the short-term and long-term impacts of COVID-19 on depression incidence and healthcare service use among patients with depression. METHODS: Using the territory-wide electronic medical records in Hong Kong, we identified all patients aged ≥ 10 years with new diagnoses of depression from 2014 to 2022. We performed an interrupted time-series (ITS) analysis to examine changes in incidence of medically attended depression before and during the pandemic. We then divided all patients into nine cohorts based on year of depression incidence and studied their initial and ongoing service use patterns until the end of 2022. We applied generalized linear modeling to compare the rates of healthcare service use in the year of diagnosis between patients newly diagnosed before and during the pandemic. A separate ITS analysis explored the pandemic impact on the ongoing service use among prevalent patients with depression. RESULTS: We found an immediate increase in depression incidence (RR = 1.21, 95% CI: 1.10-1.33, p < 0.001) in the population after the pandemic began with non-significant slope change, suggesting a sustained effect until the end of 2022. Subgroup analysis showed that the increases in incidence were significant among adults and the older population, but not adolescents. Depression patients newly diagnosed during the pandemic used 11% fewer resources than the pre-pandemic patients in the first diagnosis year. Pre-existing depression patients also had an immediate decrease of 16% in overall all-cause service use since the pandemic, with a positive slope change indicating a gradual rebound over a 3-year period. CONCLUSIONS: During the pandemic, service provision for depression was suboptimal in the face of increased demand generated by the increasing depression incidence during the COVID-19 pandemic. Our findings indicate the need to improve mental health resource planning preparedness for future public health crises.

Incidence of mental health diagnoses during the COVID-19 pandemic: a multinational network study.

AIMS: Population-wide restrictions during the COVID-19 pandemic may create barriers to mental health diagnosis. This study aims to examine changes in the number of incident cases and the incidence rates of mental health diagnoses during the COVID-19 pandemic. METHODS: By using electronic health records from France, Germany, Italy, South Korea and the UK and claims data from the US, this study conducted interrupted time-series analyses to compare the monthly incident cases and the incidence of depressive disorders, anxiety disorders, alcohol misuse or dependence, substance misuse or dependence, bipolar disorders, personality disorders and psychoses diagnoses before (January 2017 to February 2020) and after (April 2020 to the latest available date of each database [up to November 2021]) the introduction of COVID-related restrictions. RESULTS: A total of 629,712,954 individuals were enrolled across nine databases. Following the introduction of restrictions, an immediate decline was observed in the number of incident cases of all mental health diagnoses in the US (rate ratios (RRs) ranged from 0.005 to 0.677) and in the incidence of all conditions in France, Germany, Italy and the US (RRs ranged from 0.002 to 0.422). In the UK, significant reductions were only observed in common mental illnesses. The number of incident cases and the incidence began to return to or exceed pre-pandemic levels in most countries from mid-2020 through 2021. CONCLUSIONS: Healthcare providers should be prepared to deliver service adaptations to mitigate burdens directly or indirectly caused by delays in the diagnosis and treatment of mental health conditions.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Effects of Tannic Acid Supplementation of a High-Carbohydrate Diet on the Growth, Serum Biochemical Parameters, Antioxidant Capacity, Digestive Enzyme Activity, and Liver and Intestinal Health of Largemouth Bass, Micropterus salmoides.

We investigated the effects of dietary tannic acid (TA) supplementation of a high-carbohydrate diet on growth, feed utilization, whole-body proximate composition, serum biochemical indicators, antioxidant capacity, digestive enzyme activity, and liver and intestinal health of juvenile largemouth bass, Micropterus salmoides (initial mean weight: 8.08 ± 0.08 g). Five diets were prepared, including a positive control (dietary carbohydrate level, 16%, LC0), a negative control (dietary carbohydrate level, 21%, HC0), and three TA-supplementation diets based on the negative control diet with TA addition at 200, 400, and 800 mg/kg, respectively. After 8 weeks of feeding, the results showed that compared with the LC0 diet, 400-800 mg/kg dietary TA significantly improved the survival rate of largemouth bass (P < 0.05) while significantly reducing its weight-gain rate and specific growth rate (P < 0.05). Compared with the HC0 diet, 400 mg/kg dietary TA significantly increased serum catalase activity (P < 0.05), and significantly decreased serum malondialdehyde, liver glycogen, lightness (L ∗), and yellowness (b ∗) (P < 0.05). Moreover, compared with the HC0 diet, 200-400 mg/kg dietary TA effectively improved the vacuolation of hepatocytes caused by the high-carbohydrate diet and reduced the occurrence of intestinal epithelial cell vacuolation and necrosis. In turn, 800 mg/kg dietary TA significantly inhibited protease activity in the pyloric caecum and intestine (P < 0.05). In conclusion, dietary supplementation with TA inhibited protease activity, which resulted in decreased growth performance in largemouth bass. However, it was also found that 200-400 mg/kg TA enhanced the antioxidant capacity of largemouth bass in the case of the high-carbohydrate diet, reduced liver glycogen levels, and improved liver and intestinal health. Finally, it should be noted that, when the dietary TA level exceeded 800 mg/kg, TA appeared to play a pro-oxidation role in the liver, which may cause oxidative stress in the liver.

Palladium/Norbornene Cooperative Catalysis Bifunctionalization: Acylation/Cyanation of Aryl Iodides by Cleaving C-CN Bond of Aryl Acyl Nitrile.

A palladium/norbornene catalyzed two-component coupling process involving acylation/cyanation of aryl iodides is reported. In this work, aryl acyl nitrile compounds are cleverly selected to provide both nitrile and acyl sources by palladium-catalyzed cleavage of the C-CN bond as both an electrophilic reagent and a termination reagent. This is the first example of C-CN bond cleavage bifunctionalization of aryl iodides. After a series of important NBE derivatives are screened, the products resulting from the bifunctionalization of aryl iodides are smoothly obtained. This strategy has a wide range of substrates and good functional group compatibility. Moreover, this synthetic protocol demonstrated a good application for the synthesis of diverse O,N,C-substituted isoindolinones.

[Effects of Organic Fertilizer of Kitchen Waste on Soil Microbial Activity and Function].

Changes in soil microbial activity and ecological function can be used to assess the level of soil fertility and the stability of ecosystems. To assess the fertility and safety of organic fertilizer of kitchen waste (OFK), soils containing 0% (CK), 1%, 3%, and 5% OFK were cultured, and the physical, chemical, and microbial properties of the soils were measured dynamically with routine agrochemical analysis measures and amplicon sequencing. The results showed that compared with those in CK, the contents of organic matter, available phosphorus, available potassium, NH4+-N, and NO3--N in soils with OFK increased by 23.80%-35.13%, 13.29%-29.72%, 16.91%-39.37%, 164.7%-340.2%, and 28.56%-32.71%, respectively. The activities of hydrolases related to the cycle of carbon, nitrogen, and phosphorus (α-glucosidase, leucine aminopeptidase, acid phosphatase, etc.) were also significantly higher than those of the CK treatment. OFK stimulated the growth of soil microorganisms and increased the carbon content of the microbial biomass. The amplicon sequencing analysis found that the microbial community structures of different treatments were significantly different at both the class and genus levels. In addition, it was found that the abundance of beneficial microbes in the soils with OFK increased, whereas pathogenic microbes decreased. RDA results confirmed that soil properties (including soil pH, organic matter, available nutrients, and microbial biomass) had a significant impact on microbial community structure. The results of investing bacterial community based on PICRUSt and FAPROTAX revealed that the function of the soil bacterial community was similar in the four treatments, but OFK supply significantly improved the microbial carbon utilization and metabolic ability. Moreover, by using the FUNGuild software, we found that the application of OFK increased the proportion of saprotroph-symbiotroph and symbiotroph and stimulated the growth of ectomycorrhizal fungi-undefined saprophytic fungi but inhibited plant and animal pathogenic fungi in soil. These results implied that OFK could promote the establishment of symbiotic relationships and inhibit the growth of pathogenic fungi. In summary, OFK could improve soil fertility and hydrolase activity, stimulate the growth of beneficial microorganisms, and defend against pathogens, indicating a promising use as safe and efficient organic fertilizer.

Bioinformatic analysis of wheat defensin gene family and function verification of candidate genes.

Plant defensins are widely distributed in the leaves, fruits, roots, stems, seeds, and tubers. Research shows that defensin in plants play a significant role in physiological metabolism, growth and development. Plant defensins can kill and suppress a variety of pathogenic bacteria. In this study, we understand the phylogenetic relationships, protein characterization, chromosomal localization, promoter and gene structural features of the TaPDFs family through sequence alignment and conserved protein structural domain analysis. A total of 73 PDF gene members in wheat, 15 PDF genes in maize, and 11 PDF genes in rice were identified. A total of 35, 65, and 34 PDF gene members were identified in the genomes of Ae. tauschii, T. urartu, and T. dicoccoides, respectively. TaPDF4.9 and TaPDF2.15 were constructed into pART27 vector with YFP by homologous recombination for subcellular localization analysis. Subcellular localization results showed that TaPDF4.9 and TaPDF2.15 were basically located in the cell membrane and cytoplasm, and TaPDF4.9 was also located in the nucleus. TaPDF4.9 and TaPDF2.15 could inhibit the infection of Phytophthora infestans strain '88069'. The results suggest that TaPDFs may be able to improve disease resistance. The study of wheat defensins will be beneficial for improving wheat yield and provides a theoretical basis for research on resistance to wheat diseases.

[Hydrochemical Characteristics and Control Factors of Surface Water and Groundwater in Huainan Coal Mine Area].

To clarify the hydrochemical characteristics and control factors of surface and underground water in Huainan mining area, 115 groups of groundwater and 30 groups of surface water samples were collected, and the hydrogeochemical characteristics of surface water and groundwater in Huainan mining area were analyzed. Additionally, the hydrochemistry evolution law was discussed by comprehensively using mathematical statistics, the Piper triangular diagram, Gibbs diagram, mineral stability field diagram, and ion ratio relationship, etc. The results showed that the groundwater and surface water in the study area were weakly alkaline, the dominant anion was HCO3-, and the dominant cations were Ca+ and Na+. The hydrochemical types of groundwater and surface water were dominated by HCO3-Ca type and HCO3-Ca·Na·Mg type, respectively. The hydrochemical composition of groundwater and surface water was mainly controlled by rock weathering, as well as by alternating adsorption of cations and evaporation concentration. Silicate and carbonate minerals were mainly dissolved in the water-rock interaction. The main ions such as Ca2+, Mg2+, and HCO3- came from the dissolution of carbonate rocks. The Cl-, SO42-, NO3-, and Ca2+ were affected by exogenous inputs caused by human activities. The chemical components of groundwater and surface water in Huainan coal mining area were affected by water-rock interactions and human activities, and groundwater was greatly affected by human activities.

Synthetic High-Density Lipoprotein-Based Nanomedicine to Silence SOCS1 in Tumor Microenvironment and Trigger Antitumor Immunity against Glioma.

Immunotherapies have shed light on the treatment of many cancers, but have not improved the outcomes of glioma (GBM). Here, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) was associated with the GBM-associated immunosuppression and developed a multifunctional nanomedicine, which silenced SOCS1 in the tumor microenvironment (TME) of GBM and triggered strong antitumor immunity against GBM. Synthetic high-density lipoprotein (sHDL) was selected as the nanocarrier and a peptide was used to facilitate the blood-brain-barrier (BBB) penetration. The nanocarrier was loaded with a small interfering RNA (siRNA), a peptide, and an adjuvant to trigger antitumor immunity. The nanomedicine concentrated on the TME in vivo, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. Our work provides an alternative strategy to simultaneously target and modulate the TME in GBM patients and points to an avenue for enhancing the efficacy of immunotherapeutics.

Study of the mass balance, biotransformation and safety of [14C]SHR8554, a novel µ-opioid receptor injection, in healthy Chinese subjects.

Background: SHR8554 is a novel µ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects. Methods: A single 1 mg/41.3 µCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatography-tandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection. Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed. Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20220450.

Association between cumulative exposure periods of flupentixol or any antipsychotics and risk of lung cancer.

BACKGROUND: Preclinical evidence suggests that certain antipsychotic medications may inhibit the development of lung cancer. This study aims to investigate the association between incident lung cancer and different cumulative exposure periods of flupentixol or any antipsychotics. METHODS: Using electronic health records from the Hospital Authority in Hong Kong, this nested case-control study included case participants aged 18 years or older with newly diagnosed lung cancer after initiating antipsychotics between January 1, 2003, and August 31, 2022. Each case was matched to up to ten controls of the same sex and age, who were also antipsychotic users. Multivariable conditional logistic regression models were conducted to quantify the association between lung cancer and different cumulative exposure times of flupentixol (0-365 days [ref]; 366-1825 days; 1826+ days) and any antipsychotics (1-365 days [ref]; 366-1825 days; 1826+ days), separately. RESULTS: Here we show that among 6435 cases and 64,348 matched controls, 64.06% are males, and 52.98% are aged 65-84 years. Compared to patients with less than 365 days of exposure, those with 366-1825 days of exposure to flupentixol (OR = 0.65 [95% CI, 0.47-0.91]) and any antipsychotics (0.42 [0.38-0.45]) have a lower risk of lung cancer. A decreased risk is observed in patients who have 1826+ days of cumulative use of any antipsychotics (0.54 [0.47-0.60]). CONCLUSIONS: A reduced risk of lung cancer is observed in patients with more than one year of exposure to flupentixol or any antipsychotics. Further research on the association between lung cancer and other antipsychotic agents is warranted.

Antipsychotic drugs are mainly used to treat mental illnesses. Certain antipsychotic medications, such as flupentixol, may help protect patients against lung cancer. Here, we investigated whether prolonged use of flupentixol or other antipsychotics could reduce the occurrence of lung cancer among antipsychotic users. We demonstrated that a smaller proportion of patients with one to five years and more than five years of exposure to any antipsychotics develop lung cancer compared to those with less than one year of exposure. Specifically, for flupentixol, we observed a smaller proportion of patients with one to five years of exposure develop lung cancer compared to those with less than one year. To substantiate our current findings, further studies examining other populations and specific antipsychotic agents are necessary for developing effective lung cancer prevention strategies among this high-risk population.

Targeted genome mining for microbial antitumor agents acting through DNA intercalation.

Microbial natural products have been one of the most important sources for drug development. In the current postgenomic era, sequence-driven approaches for natural product discovery are becoming increasingly popular. Here, we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities. Our method employs uvrA-like genes as genetic markers, which have been identified in the biosynthetic gene clusters (BGCs) of several chemotherapeutic drugs of microbial origin and confer self-resistance to the corresponding producers. Through systematic genomic analysis of gifted actinobacteria genera, identification of uvrA-like gene-containing BGCs, and targeted isolation of products from a BGC prioritized for metabolic analysis, we identified a new tetracycline-type DNA intercalator timmycins. Our results thus provide a new genome mining strategy for the efficient discovery of antitumor agents acting through DNA intercalation.

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.

ETHNOPHARMACOLOGICAL RELEVANCE: Salidroside (SAL), a phenolic natural product present in Rhodiola rosea, are commonly used in the treatment of various ischemic-hypoxic diseases, including intestinal ischemia-reperfusion (IR) injury. However, their efficacy and potential mechanisms in the treatment of intestinal IR injury have not been investigated. OBJECTIVE: The objective of the present study is to investigate the pharmacological mechanism of action of SAL on intestinal IR injury using a network pharmacology approach combined with experimental validation. METHODS: In the present study, we used the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and analysis platform and Comparative Toxicogenomics Database (CTD) to predict possible target genes of SAL, collected relevant target genes of intestinal IR injury from GeneCards and DisGenet websites, and collected summary data to screen common target genes. Then, the protein-protein interaction (PPI) target network was constructed and analyzed by STRING database and Cytoscape 3.8.2 with the above intersecting genes. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed and the component-target-pathway network was constructed, followed by the use of molecular docking and molecular dynamic simulation to verify the possible binding conformation between SAL and candidate targets to further explore the potential targets of SAL in the treatment of intestinal IR injury. Finally, an in vivo model of mouse superior mesenteric artery ligation was established to assess the anti-intestinal IR injury effect of SAL by assessing histopathological changes in mouse small intestine by HE staining, detecting inflammatory factor expression by ELISA kit, and detecting the expression of key protein targets by Western blotting. RESULTS: A total of 166 SAL target genes and 1740 disease-related targets were retrieved, and 88 overlapping proteins were obtained as potential therapeutic targets. The pathway enrichment analysis revealed that the pharmacological effects of SAL on intestinal IR injury were anti-hypoxic, anti-inflammatory and metabolic pathway related, and the molecular docking and molecular dynamic simulation results showed that the core bioactive components had good binding affinity for TXNIP and AMPK, and the immunoblotting results indicated that the expression levels of TXNIP and AMPK in the small intestinal tissues of mice in the drug-treated group compared with the model group were significantly changed. CONCLUSION: SAL may target AMPK and TXNIP domains to act as a therapeutic agent for intestinal IR. These findings comprehensively reveal the potential therapeutic targets for SAL against intestinal IR and provide theoretical basis for the clinical application of SAL in the treatment of intestinal IR.

Identifying a prognostic model and screening of potential natural compounds for acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is one of the most common hematologic malignancies with a poor prognosis and high recurrence rate. The discovery of new predictive models and therapeutic agents plays a crucial role. Methods: The differentially expressed gene that was explicitly highly expressed in The Cancer Genome Atlas (TCGA) and GSE9476 transcriptome databases were screened and included in the least absolute shrinkage and selection operator (LASSO) regression model to derive risk coefficients and build a risk score model. Functional enrichment analysis was conducted on the screened hub genes to explore the potential mechanisms. Subsequently, critical genes were incorporated into a nomogram model based on risk scores to analyze prognostic value. Finally, this study combined network pharmacology to find potential natural compounds for hub genes and used molecular docking to verify the binding ability of molecular structures to natural compounds to explore drug development for possible efficacy in AML. Results: A total of 33 highly expressed genes may be associated with poor prognosis of AML patients. After LASSO and multivariate Cox regression analysis of 33 critical genes, Rho-related BTB domain containing 2 (RHOBTB2), phospholipase A2 (PLA2G4A), interleukin-2 receptor-α (IL2RA), cysteine and glycine-rich protein 1 (CSRP1), and olfactomedin-like 2A (OLFML2A) were found to played a significant role in the prognosis of AML patients. CSRP1 and OLFML2A were independent prognostic factors of AML. The predictive power of these 5 hub genes in combination with clinical features was better than clinical data alone in predicting AML in the column line graphs and had better predictive value at 1, 3, and 5 years. Finally, through network pharmacology and molecular docking, this study found that diosgenin in Guadi docked well with PLA2G4A, beta-sitosterol in Fangji docked well with IL2RA, and OLFML2A docked well with 3,4-di-O-caffeoylquinic acid in Beiliujinu. Conclusions: The predictive model of RHOBTB2, PLA2G4A, IL2RA, CSRP1, and OLFML2A combined with clinical features can better guide the prognosis of AML. In addition, the stable docking of PLA2G4A, IL2RA, and OLFML2A with natural compounds may provide new options for treating AML.

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability.

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.