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Antipsychotic drug treatment for schizophrenia (SZ) can alter brain structure and function, but it is unclear if specific regional changes are associated with treatment outcome. Therefore, we examined the effects of antipsychotic drug treatment on regional grey matter (GM) density, white matter (WM) density, and functional connectivity (FC) as well as associations between regional changes and treatment efficacy. SZ patients (n = 163) and health controls (HCs) (n = 131) were examined by structural magnetic resonance imaging (sMRI) at baseline, and a subset of SZ patients (n = 77) were re-examined after 8 weeks of second-generation antipsychotic treatment to assess changes in regional GM and WM density. In addition, 88 SZ patients and 81 HCs were examined by resting-state functional MRI (rs-fMRI) at baseline and the patients were re-examined post-treatment to examine FC changes. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were applied to measure psychiatric symptoms and cognitive impairments in SZ. SZ patients were then stratified into response and non-response groups according to PANSS score change (≥50 % decrease or

Objective: We examined the relationships between infants’ growth trajectories and prenatal exposure to air pollution, which is still under-investigated. Methods: A birth cohort study was constructed using medical records of pregnant women and infants born between 2015 and 2019 in Foshan, China. Using satellite-based spatial-temporal models, prenatal exposure to air pollutants including particulate matter with an aerodynamic dimension of < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) was assessed at each woman's residence. Latent class growth modeling was used to identify trajectories of physical (body length and weight) growth and neurodevelopment, which were repeatedly measured within 1 year after birth. Logistic regression models were used to investigate the associations between prenatal exposure to air pollution and the risks of growth disorders, adjusting for an array of potential confounders. Results: We identified two growth trajectories for body length [normal: 3829 (93%); retardation: 288 (7%)], three for weight [normal: 2475 (59.6%); retardation: 390 (9.4%); overgrowth: 1287 (31%)], and two for neurodevelopment [normal: 956 (66.1%); retardation: 491 (33.9%)]. For exposure over whole pregnancy, SO2 was associated with an increased risk of body length retardation (OR for per 1 µg/m3 increment: 1.09, 95%CI: 1.01–1.17); PM2.5 (OR: 1.05, 95%CI: 1.03–1.07), SO2 (OR: 1.15, 95%CI: 1.08–1.22), and NO2 (OR: 1.05, 95%CI: 1.03–1.07) were positively associated with neurodevelopmental retardation. Such associations appeared stronger for exposures over the first and second trimesters. No significant associations were detected for weight growth. Conclusions: Maternal exposure to air pollution during pregnancy was associated with higher risks of impairments in both physical growth, particularly body length, and neurodevelopment.

Background and Hypothesis: Schizophrenia (SZ) patients display significant structural brain abnormalities; nevertheless, the genetic mechanisms regulating cortical anatomical variations and their correlation with the disease phenotype are still ambiguous. Study Design: We characterized anatomical variation using a surface-based method derived from structural magnetic resonance imaging of patients with SZ and age- and sex-matched healthy controls (HCs). Partial least-squares regression was performed across cortex regions between anatomical variation and average transcriptional profiles of SZ risk genes and all qualified genes from the Allen Human Brain Atlas. The morphological features of each brain region were correlated to symptomology variables in patients with SZ using partial correlation analysis. Study Results: A total of 203 SZ and 201 HCs were included in the final analysis. We observed significant variation of 55 regions of cortical thickness, 23 regions of volume, 7 regions of area, and 55 regions of local gyrification index (LGI) between SZ and HC groups. Expression profiles of 4 SZ risk genes and 96 genes from all qualified genes showed a correlation to anatomical variability, however, after multiple comparisons, the correlations were no longer significant. LGI variability in multiple frontal subregions was associated with specific symptoms of SZ, whereas cognitive function involving attention/vigilance was linked to LGI variability across nine brain regions. Conclusions: Cortical anatomical variation of patients with schizophrenia is associated with gene transcriptome profiles as well as clinical phenotypes.

Summary: Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency with high mortality, so identifying modifiable risk factors of AAD is of great public health significance. The associations of non-optimal temperature and temperature variability with AAD onset and the disease burden have not been fully understood. Methods: We conducted a time-stratified case-crossover study using a nationwide registry dataset from 1,868 hospitals in 313 Chinese cities. Conditional logistic regression and distributed lag models were used to investigate associations of temperature and temperature changes between neighboring days (TCN) with the hourly AAD onset and calculate the attributable fractions. We also evaluated the heterogeneity of the associations. Findings: A total of 40,270 eligible AAD cases were included. The exposure-response curves for temperature and TCN with AAD onset risk were both inverse and approximately linear. The risks were present on the concurrent hour (for temperature) or day (for TCN) and lasted for almost 1 day. The cumulative relative risks of AAD were 1.027 and 1.026 per 1°C lower temperature and temperature decline between neighboring days, respectively. The associations were significant during the non-heating period, but were not present during the heating period in cities with central heating. 23.13% of AAD cases nationwide were attributable to low temperature and 1.58% were attributable to temperature decline from the previous day. Interpretation: This is the largest nationwide study demonstrating robust associations of low temperature and temperature decline with AAD onset. We, for the first time, calculated the corresponding disease burden and further showed that central heating may be a modifier for temperature-related AAD risk and burden. Funding: This work was supported by the National Natural Science Foundation of China (92043301 and 92143301), Shanghai International Science and Technology Partnership Project (No. 21230780200), the Medical Research Council-UK (MR/R013349/1), and the Natural Environment Research Council UK (NE/R009384/1).

Summary: Background: The associations of ambient temperature with acute myocardial infarction (AMI) have seldom been examined based on the time of symptom onset. Methods: We conducted a time-stratified case-crossover study among 1,046,773 eligible AMI patients from 2,093 hospitals in 324 Chinese cities from January 1, 2015 to June 30, 2021, after excluding those transferred from other hospitals or having not reported the time of symptom onset. Hourly exposure to ambient temperature was calculated as multiple moving 24-h averages (days) before hourly onset of AMI symptoms. Conditional logistic regression and distributed lag non-linear models with a duration of 0–21 days were used to estimate the cumulative associations of non-optimum temperature with AMI onset and the corresponding disease burden nationally. Subgroup analyses by region and period were conducted. Specifically, cities with and without centralized heating system were classified into heating and non-heating regions, respectively. The whole year in heating region was divided into heating and non-heating periods based on the duration of centralized heating in each city. Findings: Almost monotonically increasing risks were observed for both overall AMI and its two subtypes when ambient temperature declined. The effects of extremely low temperature occurred immediately on the concurrent day, and lasted up to almost 3 weeks. The excess risks of AMI onset associated with non-optimum ambient temperatures were observed during the whole year in the non-heating region and non-heating period in the heating region, but not during heating period. Specifically, odds ratios of AMI onset associated with extremely low temperature cumulated over 0–21 days were 1.24 (95% CI: 1.13–1.37), 1.46 (95% CI: 1.20–1.76), and 1.62 (95% CI: 1.46–1.81) in the heating region during non-heating period, in the non-heating region during winter and non-winter period, respectively. The heat effects on AMI onset were very modest and transient. Totally, 13.26% of AMI cases could be attributable to non-optimum temperatures nationally. The burden of AMI attributable to non-optimum temperature was much smaller in heating region than in non-heating region. Somewhat stronger effects were observed in females and patients aged older than 65. Interpretation: This nationwide study provided robust evidence that non-optimum ambient temperature may significantly trigger AMI onset, and for the first time estimated the disease burden after accounting for spatial and seasonal heterogeneity. Centralized heating might substantially mitigate AMI burden due to non-optimum temperature. Funding: Shanghai International Science and Technology Partnership Project, National Natural Science Foundation of China, Talent Training Program of Zhongshan Hospital, Fudan University.

Probiotics have been widely used in aquaculture and may serve as a potential alternative to antibiotics. Diverse sources of probiotics have different effects on the host, and the application of native probiotics isolated from target fish may play a better role. This study was conducted to evaluate the probiotic potential of the bacteria isolated from the gut of common carp (Cyprinus carpio L.). Based on morphological, 16 S rRNA sequencing and whole-genome sequencing analysis, an isolated strain that simultaneously produces protease, mannanase, amylase, and cellulose was identified as Bacillus velezensis R-71003. This strain showed antagonistic activity against various pathogens. Further studies showed that B. velezensis R-71003 was susceptible to ampicillin, gentamicin, penicillin G, erythromycin, chloramphenicol, amikacin, cefamezin, sulfamethoxazole, ciprofloxacin and norfloxacin. Additionally, B. velezensis R-71003 met the safety criteria based on safety evaluation results, such as haemolytic activity and biosafety tests in common carp. Moreover, B. velezensis R7–1003 was resistant to low pH (2) and higher bile salt concentration (0.3 %) and showed higher viability ability after high temperature exposure (60, 70, and 80 °C), as well as higher auto-aggregation and cell-surface hydrophobicity. In addition, the challenge test showed that B. velezensis R-71003 significantly increased the survival rate of common carp after challenged with Aeromonas hydrophila. Finally, the growth-promoting effects of sodium gluconate on B. velezensis R-71003 were evaluated. The results indicated that a low concentration of sodium gluconate could promote the growth of B. velezensis R-71003 and increase the expression levels of dnaA and yabD. Whole-genome analysis revealed that genome contains genes related to the biosynthesis of antibacterial substances, digestive enzymes, amino acids and vitamins, as well as stress resistance. The results collectively suggest that B. velezensis R-71003 exhibited good probiotic potential, and its combined application with sodium gluconate may be used to improve the health status of aquatic animals.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Functional deficits in schizophrenia (SZ) are observed prior to the onset of psychosis and differ at different stages of SZ. However, there is a paucity of studies focused on adolescent first-episode SZ (AOS), adult first-episode SZ (AFES), and adult chronic SZ (CHSZ). In this study, we investigated regional activity and corresponding functional connectivity alterations that have aimed to compare the three disease stages simultaneously. The subjects comprised 49 patients with AOS, 57 patients with AFES, 51 patients with CHSZ, 41 adolescent healthy controls, and 138 adult healthy controls. We compared regional homogeneity (ReHo) between patients at each disease stage with matched healthy controls. We focused on the shared brain regions that showed significant differences between SZ patients at the three different disease stages and healthy controls. Further analysis was conducted to explore whether the patterns of the whole brain functional connectivity alterations were similar. The putamen and medial frontal gyrus (MFG) showed consistently abnormal patterns in AOS, AFES, and CHSZ. Commonly decreased ReHo values in the MFG and increased ReHo values in the bilateral putamen were found in AOS, AFES, and CHSZ. Functional connectivity of MFG remained common abnormality in different SZ stage. In conclusion, ReHo abnormalities in the MFG and the putamen may be common abnormal patterns of brain function in the three different stages of SZ. The vmPFC-dlPFC FC abnormality common occurs in adolescence and adulthood.. This study may provide a more comprehensive understanding of the neurodevelopmental abnormality across the AOS, AFES, and CHSZ.

Ionic liquids (ILs) are widely used for their physical and chemical properties. Toxicological assessments of ILs could help to avoid their threat to human health, but these are rarely reported, and no assessments of IL neurotoxicity in mammals have been performed. Here, we aimed to evaluate the neurotoxicity of chronic 1-octyl-3-methylimidazolium hexafluorophosphate ([C8mim][PF6]) (0, 1 mg/kg) exposure during development on rats. Our results indicated that chronic exposure to low-dose ([C8mim][PF6]) induces behavioural abnormalities, including cognitive deficits, social communication disorders, and sensory gating function impairment. Moreover, rats subjected to chronic ([C8mim][PF6]) exposure showed hypofunction of glutamatergic excitatory synapses, including increased expression of NMDA receptor subunits, increased density and immaturity of dendritic spines, and increased expression of PSD95. Additionally, ([C8mim][PF6]) exposure resulted in hippocampal-specific inflammatory activation, indicated by increased levels of proinflammatory factors, elevated nuclear localisation of NF-κB, and activation of microglia and astrocytes. In conclusion, chronic exposure to low-dose ([C8mim][PF6]) induced neurotoxicity, including damage to glutamatergic excitatory synapses and inflammatory activation, which may illuminate the associated behavioural abnormalities. The results presented here may be helpful for the safe use of ILs in the future.

Heavy metal cadmium (Cd) pollution is a serious problem affecting the sustainable development of aquaculture and the safety of aquatic foods. Research about the use of probiotics to attenuate toxic damage caused by Cd2+ in aquatic animals has received widespread attention. Bacillus coagulans (B. coagulans), a kind of probiotics commonly used in aquaculture, has been shown to adsorb Cd2+ both in vivo and vitro. Here, we aimed to determine the effects of B. coagulans on Cd2+ bioaccumulation, gut barrier function, oxidative stress and gut microbiota in common carp following Cd2+ exposure. The fish were exposure to Cd2+ at 0 and 0.5 mg/L and/or fed a B. coagulans-containing diet at 107, 108 and 109 CFU/g for 8 weeks. The results indicated that B. coagulans can maintain gut barrier function in Cd2+-exposed fish by reducing Cd2+ bioaccumulation, increasing the mRNA levels of tight junction protein genes (occludin, claudin-2 and zonula occludens-1), and decreasing the levels of diamine oxidase and D-lactic acid. In addition, B. coagulans could relieve oxidative stress in Cd2+-exposed fish by restoring the activities of glutathione peroxidase, catalase and superoxide dismutase. Moreover, Cd2+ exposure decreased the intestinal microbiota diversity and changed the intestinal microbiota compositions in common carp. However, supplementation with B. coagulans could reverse the altered intestinal microbiota diversity and composition after Cd2+ exposure, decrease the abundance of some pathogens (Shewanella and Vibrio), and increase the abundance of probiotics (Bacillus and Lactobacillus). These results indicate that B. coagulans may serve as a potential antidote for alleviating Cd2+ toxicity.

ABSTRACT: Oxidative stress is a frequent concern in the breeding of laying hens, and limit the healthy development of poultry. Dexamethasone (DXM) has been demonstrated to induce oxidative stress. Conversely, betaine is an alkaloid with a potent antioxidant activity. The study was designed to investigate the ameliorative effect of betaine on DXM-induced oxidative stress in laying hens. The results revealed that DXM treatment significantly decreased laying rate, shell strength, albumen height, Haugh unit, egg weight, folk weight and albumen weight, alongside increased malondialdehyde (MDA) and decreased total antioxidant capacity (T-AOC) in serum and liver (P < 0.05). In contrast, dietary betaine addition reversed those parameters mentioned above (P < 0.05). Hepatic RNA-seq analysis showed that there existed 110 up- and 88 down-regulated genes in DXM group when compared with the control. Meanwhile there were 117 upregulation and 169 downregulation genes in BT group when compared with DXM group. Besides, we found that dietary betaine addition significantly down-regulated cell adhesion molecules, glycerolipid metabolism and glycolysis gluconeogenesis pathways. In addition, a total of 44 and 94 differential metabolites were identified respectively from Con vs. DXM and DXM vs BT. More importantly, dietary betaine addition significantly increased the levels of pantothenic acid, gamma-Aminobutyric acid, equol and choline, all of which were related to antioxidant and anti-inflammatory properties. Furthermore, gut microbiota analysis indicated that the Chao and Observed_species indexes were remarkably higher in BT group (P

ABSTRACT: The hyperplasia and hypertrophy of preadipocytes were closely related to lipid deposition in animals. Butyric acid was reported to be involved in lipid metabolism. The aim of the current study was to investigate the effect of butyric acid on the proliferation and differentiation of the immortalized chicken preadipocyte 2 (ICP2). ICP2 were treated respectively with 12mM butyric acid for 48h in proliferation trial and 4mM butyric acid plus 200 μM oleic acid for 3 d in differentiation trial. For the proliferation trial, RNA-seq analysis revealed that 2039 genes were significantly up-regulated and 780 genes were significantly down-regulated with 12 mM butyric acid after 48 h treatment. Concurrently, Cell cycle, DNA replication and p53 signaling pathways were down-regulated in Butyric acid group. More importantly, 12 mM butyric acid restrained the expression of cell proliferation genes such as PCNA, CDK1 and CDK2 in Butyric acid group (P < 0.05), and the protein expression levels of PCNA and CDK1 were also significantly decreased (P < 0.05). The Oil red staining revealed a fewer presence of red fat droplets in ICP2 following treatment with 4 mM butyric acid, accompanied by decreased levels of total cholesterol (TC) and triglycerides (TG). RNA-seq analysis shown that the number of up and down-regulated genes were 2095 and 1042 respectively in OAB group (oleic acid+butyric acid) when compared with OA group (oleic acid). Meanwhile the AMPK signaling pathway, FOXO signaling pathway and focal adhesion were significantly enriched in OAB group. Additionally, 4 mM butyric acid inhibited the expression of lipid differentiation genes including FABP4, C/EBPα, PPARγ and LPL in OAB group (P < 0.05), as well as lipogenesis proteins such as FABP4, C/EBP-α and PPARγ (P < 0.05). In conclusion, 12 mM butyric acid effectively inhibited the proliferation of ICP2 by slowing down cell cycle progression, while 4 mM butyric acid alleviated lipid deposition by reducing the production of lipid droplets through inhibiting the expression of lipid differentiation marker genes and proteins.

Abstracts: Objective: Diabetic kidney disease (DKD) is a common complication of diabetes mellitus. The pathophysiological changes in platelet function and the hypercoagulable state associated with DKD are closely linked to inflammatory processes. Poecilobdella manillensis (PM), a type of leech known for its anticoagulant and antithrombotic properties, has the potential to modulate the inflammatory response in DKD. This study aims to investigate the effect of freeze-dried powder of PM on improving inflammatory injury in rat glomerular mesangial cells and to explore its underlying mechanism. Methods: Lipopolysaccharide (LPS) stimulated HBZY-1 rat mesangial cells to establish an in vitro DKD inflammation model. After the intervention with the water extract of freeze-dried powder of PM (FDPM), cell viability, NO content, and the levels of inflammatory factors such as IL-1β, IL-18, and TNF-α were assessed. Finally, utilizing transcriptomics technology, RT-qPCR, and Western blot methods, the mechanism by which FDPM improves inflammatory injury in rat glomerular mesangial cells was explored and preliminarily validated. Results: FDPM effectively enhances cell viability and inhibits the production of NO and related inflammatory factors. Transcriptomic analysis suggests that FDPM may exert these effects by regulating the TXNIP/NLRP3 signaling pathway. The mRNA and protein expressions of TXNIP, NLRP3, and MCP-1 in the model cells were reversed by FDPM. Conclusion: FDPM may improve the micro-inflammatory state of DKD and slow the progression of the disease by regulating the TXNIP/NLRP3 signaling pathway. This study provides a scientific basis for the clinical application of PM DKD treatment.

As widely used energy-absorbing protective materials, the application of aluminum foam sandwich (AFS) panels remains constrained by the inherently low mechanical properties of the foam core. The incorporation of copper-coated carbon fibers (Cf) has proven to be effective in improving the mechanical properties of aluminum foam. Yet, the understanding of its foaming process and microstructure is still limited. In this work, AFS and Cf/AFS were fabricated by the packing rolling powder metallurgy method. The foaming behavior of AFS and Cf/AFS during elevated temperatures was in situ observed using synchrotron radiation X-ray imaging technology to investigate the effect of Cf on bubble nucleation, growth, and foam stability. Furthermore, the macroscopic pore size distribution, microscopic microstructure, and compressive mechanical properties of AFS and Cf/AFS were analyzed. The results showed that the existence of Cf greatly increases the nucleation rate, improves the foaming stability, and prevents the formation of localized abnormally large bubbles during the early nucleation and growth process. Meanwhile, Cf/AFS exhibited finer pore diameters and fewer pore defects than AFS. The distribution of Cf with excellent wettability along the pore wall prevented liquid film rupture and reduced coalescence. The compression experiment indicated that, in comparison to AFS, the compressive strength and energy absorption capacity of Cf/AFS have increased by approximately 40.6% and 84.8%, respectively.

RNA-binding motif protein 10 (RBM10) has a tumor suppressor role in multiple cancers. Combining Oncomine database results with tissue samples, Western blot analysis showed that RBM10 was significantly lower in lung adenocarcinoma (LUAD) than in adjacent normal tissues. Moreover, KM analysis revealed that the group with higher RBM10 expression in LUAD correlated with better overall survival (OS). Luciferase reporter assay revealed that an important tumor-promotive miRNA, miR-224-5p, was directly bound to the 3′UTR of RBM10, resulting in inhibition of RBM10 expression, and promoted LUAD progression both in vitro and in vivo. Mechanistically, we found that miR-224-5p directly targeted RBM10 to inhibit p53 expression during LUAD progression. Meanwhile, p53 affected RBM10 expression through p53/miR-224-5p axis. Our study identified RBM10 as a key tumor suppressor in the proliferation and metastasis of LUAD. The findings provide a novel mechanism involving a feedback loop of miR-224-5p/RBM10/p53 regulated tumor progression in LUAD, which may help with the design of more effective LUAD treatments.

ABSTRACT: Excess abdominal fat reduces carcass yield and feed conversion ratio, thereby resulting in significant economic losses in the poultry industry. Our previous study demonstrated that dietary addition of folic acid reduced fat deposition and changed gut microbiota and short-chain fatty acid. However, whether folic acid regulating abdominal fat deposition was mediated by gut microbiota was unclear. A total of 210 one-day-old broiler chickens were divided into 3 groups including the control (CON), folic acid (FA), and fecal microbiota transplantation (FMT) groups. From 14th day, broiler chickens in CON and FA groups were given perfusion administration with 1 mL diluent daily, while 1 mL fecal microbiota transplantation suspension from FA group prepared before was perfusion in FMT group receiving control diets. The result showed that abdominal fat percentage was significantly lower in FA and FMT groups when compared with CON group (P < 0.05). Morphology analysis revealed that the villus height of jejunum and ileum were significantly higher in FMT group (P < 0.05), and the villus height of jejunum was also significantly higher in FA group (P < 0.05), while the diameter and cross-sectional area (CSA) of adipocytes were significantly decreased in FA and FMT groups when compared with CON group (P < 0.05). Western blot results indicated that the expression levels of FOXO1 and PLIN1 in FMT group were significantly increased (P < 0.05), whereas the expression levels of PPARγ, C/EBPα, and FABP4 were significantly decreased (P < 0.05). Additionally, the Chao1, Observed-species, Shannon and Simpson indexes in FA and FMT groups were significantly higher (P < 0.05), but the microbiota were similar between FMT and FA groups (P < 0.05). LEfSe analysis determined that Lactobacillus, Clostridium and Dehalobacterium were found to be predominant in FA group, while Oscillospira, Shigella, and Streptococcus were the dominant microflora in FMT group. Furthermore, these cecal microbiota were mostly involved in infectious disease, cellular community prokaryotes, cell motility and signal transduction in FA group (P < 0.05), whereas functional capacities involved in signal transduction, cell motility, infectious disease and environment adaptation were enriched significantly of cecal microbiota in FMT group (P < 0.05). In summary, both fecal microbiota transplantation from the broiler chickens of dietary added folic acid and dietary folic acid addition effectively reduced abdominal fat deposition, indicating that the regulatory effect of folic acid on abdominal fat deposition was mediated partly by gut microbiota in broiler chickens.

Summary: Background: The impact of previous vaccination on protective immunity, duration, and immune imprinting in the context of BA.5-XBB.1.9.1 reinfection remains unknown. Methods: Based on a 2-year longitudinal cohort from vaccination, BA.5 infection and XBB reinfection, several immune effectors, including neutralizing antibodies (Nabs), antibody-dependent cellular cytotoxicity (ADCC), virus-specific T cell immunity were measured to investigate the impact of previous vaccination on host immunity induced by BA.5 breakthrough infection and BA.5-XBB.1.9.1 reinfection. Findings: In absence of BA.5 Nabs, plasma collected 3 months after receiving three doses of inactivated vaccine (I-I-I) showed high ADCC that protected hACE2-K18 mice from fatality and significantly reduced viral load in the lungs and brain upon BA.5 challenge, compared to plasma collected 12 months after I-I-I. Nabs against XBB.1.9.1 induced by BA.5 breakthrough infection were low at day 14 and decreased to a GMT of 10 at 4 months and 28% (9/32) had GMT ≤4, among whom 67% (6/9) were reinfected with XBB.1.9.1 within 1 month. However, 63% (20/32) were not reinfected with XBB.1.9.1 at 5 months post BA.5 infection. Interestingly, XBB.1.9.1 reinfection increased Nabs against XBB.1.9.1 by 24.5-fold at 14 days post-reinfection, which was much higher than that against BA.5 (7.3-fold) and WT (4.5-fold), indicating an immune imprinting shifting from WT to XBB antigenic side. Interpretation: Overall, I-I-I can provide protection against BA.5 infection and elicit rapid immune response upon BA.5 infection. Furthermore, BA.5 breakthrough infection effectively protects against XBB.1.9.1 lasting more than 5 months, and XBB.1.9.1 reinfection results in immune imprinting shifting from WT antigen induced by previous vaccination to the new XBB.1.9.1 antigen. These findings strongly suggest that future vaccines should target variant strain antigens, replacing prototype strain antigens. Funding: This study was supported by R&D Program of Guangzhou National Laboratory (SRPG23-005), National Key Research and Development Program of China (2022YFC2604104, 2019YFC0810900), S&T Program of Guangzhou Laboratory (SRPG22-006), and National Natural Science Foundation of China (81971485, 82271801, 81970038), Emergency Key Program of Guangzhou Laboratory (EKPG21-30-3), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA-2020013), and State Key Laboratory of Respiratory Disease (J19112006202304).

Streets comprise a major area of urban land use and connect built areas to one another. However, the role of streetscapes for maintaining urban plant diversity remains poorly understood. In this study, urban street vegetation was investigated in Oulu, Finland, and Yokohama, Japan, to explore how species richness and composition of plant communities change among different street habitat types, including road-verge grass beds, asphalted surfaces, stone pavements, curbside gaps, wall bases, street shrubbery, and tree bases. All plant species were recorded separately for different street habitat types along a maximum of 500 m of street sections. The gamma diversity of each habitat type and the contributions of native and exotic species were evaluated based on species accumulation curves. Plant species composition was examined using non-metric multidimensional scaling and Venn diagrams. A total of 145 and 273 species were recorded in Oulu and Yokohama, respectively. In Oulu, native species contributed more to the total diversity across habitat types, whereas in Yokohama, we observed similar contributions of native and exotic species to the total diversity. There was a large overlap in species occurrence among different habitat types in Oulu, where the road-verge grass beds included over 90 % of the total diversity, and all species present in asphalted habitats. Road verge grass beds in Oulu and street shrubbery in Yokohama include a large number of unique species, implying that these species have adapted to the environment in each habitat. Thus, streetscape vegetation includes a mixture of common urban species and some unique species depending on habitat type, which is often overlooked as a part of the spontaneous plant diversity across streetscapes. We propose that diverse street habitats, including both gray and green surfaces, support diverse plant species and may thereby create biodiverse urban streetscapes.

Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.

ABSTRACT: Excess abdominal fat is a common phenomenon in broiler chickens. Gut microbiota could regulate lipid metabolism through their effects on short-chain fatty acids (SCFAs) production. This study was conducted to investigate the potential relationship between abdominal fat development and cecal microorganism populations. Abdominal fat and cecum contents were collected at 3, 7, 14, 21, 28, 35, and 42 d of age. The results showed that abdominal fat weight increased with age. The abdominal fat percentage was higher between 7 and 21 d of age than at 3 d (P < 0.05), and it increased again at 28 to 42 d (P < 0.05). Morphological analysis showed that adipocyte diameter and cross-sectional area (CSA) increased significantly after 14 d of age (P < 0.05). Moreover, gut microbiota analysis indicated that the Chao1 and Shannon indices were higher between 14 and 28 d than at 3 d of age (P < 0.05). Furthermore, LEfse analysis revealed that Faecalibacterium, Anaerotruncus, Anaeroplasma, Subdoligranulum, and Clostridium emerged to become dominant at 14 d. A greater abundance of Bacteroides, Ruminococcus, Dehalobacterium, and Lactobacillus were determined at 28 d when compared with 14 d of age. Parabacteroides, Ochrobactrum, Lactobacillus, Blautia, Alistipes, Dehalobacterium, Odoribacter, and Suuterella were found to be predominant at 42 d. PICRUSt analysis revealed that amino acid metabolism, lipid metabolism, and terpenoids and polyketides metabolism were elevated at 14 d; the immune and digestive systems were significantly developed at 28 d. In addition, cecum propionic acid and butyric acid contents gradually increased (P < 0.05), while the isobutyric acid contents gradually decreased with advancing age (P < 0.05). Correlation analysis among SCFAs, differential genera and abdominal fat suggested that Coprobacillus, Shigella, and Butyricicoccus had negative correlations with propionic acid, butyric acid, and abdominal fat weight, but positive correlations with isobutyric acid. Isobutyric acid was identified as being negatively associated with abdominal fat weight, while the reverse was found for propionic acid and butyric acid. In conclusion, abdominal fat development is correlated with the emergence of specific microbes and d 14 may be a pivotal age for establishing this relationship.

Carboxylesterase (CarE) was considered as important phase-I detoxifying enzymes which participated in detoxification of different types of insecticides. Up-regulation of CarE genes has been proved playing a major role in insecticide resistance in many pest insects, but its involvement in resistance to insecticides in Plutella xylostella has been rarely reported. In this study, a CarE cDNA named PxαE8 was identified in P. xylostella, which has an open reading frame of 1 599 nucleotides and putatively encodes 532 amino acids. The investigation of spatial expression profiles of PxαE8 revealed that it was expressed in all developmental stages, especially in larvae and adults. The body part/tissue-specific expression profiles showed that the PxαE8 mainly expressed in fat body, malpighian tubule and hemolymph of larvae. Further, the relative expression of PxαE8 in two multi-resistant field populations, Hainan (HN) and Guangdong (GD) populations, was found 24.4- and 15.5-fold higher than that in susceptible population, respectively. Knockdown of PxαE8 by RNA interference dramatically increased the mortalities of larvae of HN population treated with LC50 of beta-cypermethrin and phoxim by 25.3 and 18.3%, respectively. These results suggested that up-regulation of PxαE8 was involved in resistance to both beta-cypermethrin and phoxim in P. xylostella, which shed light on further understanding of molecular mechanisms of multi-insecticide-resistance in P. xylostella and other pest insects.

ABSTRACT: Fatty liver syndrome (FLS) is a kind of nutritional metabolic disease in laying hens. Revealing FLS pathogenesis during the early period is what really makes sense for the prevention or nutritional regulation strategies. In the study, 9 healthy or naturally occurring early FLS birds were screened based on visual inspection, liver index and morphologic analysis. Liver and fresh cecal content samples were collected. Then transcriptomic and 16S rRNA technologies are applied to investigate hepatic transcriptome and cecum microbiota composition. Unpaired Student t test and some omics methods were used for statistical analysis. Results showed higher liver weight and index were found in FLS group; morphologic analysis indicated that there existed more lipid droplets in the liver of birds with FLS. Based on DESeq2 analysis, there were 229 up- and 487 down-regulated genes in the FLS group, among which most genes related to de novo fatty acid synthesis were up-regulated such as acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and ELOVL fatty acid elongase 6 (ELOVL6). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that pathways associated with lipid metabolism and liver damage were affected. 16S rRNA sequencing analysis of cecum microbiota showed that there was a significant difference between the Con and FLS groups. LEfSe analysis revealed that the relative abundance of Coprococcus, Odoribacter, Collinsella, Turicibacter, YRC22, Enterococcus, Shigella, and Bifidobacterium were down-regulated in the FLS group, whereas the abundance of Bacteroides, Mucispirillum, Butyricicoccus, Campylobacter, Akkermansia, and Clostridium were up-regulated. The KEGG enrichment from differential microbiota suggested that some metabolism-related functions were altered to some extent. Taken together, during the developmental of early fatty liver of laying hens, lipogenesis was enhanced, whereas abnormal metabolism occurs not only in lipid transportation but also in hydrolysis, which caused structural damage to the liver organ. Moreover, the dysbiosis of the cecum microbiota occurred. All of these serve as targets or provide theoretical references for the development of probiotics for fatty liver prevention in laying hens.

ABSTRACT: The liver undergoes a slow process for lipid deposition during chick embryonic period. However, the underlying physiological and molecular mechanisms are still unclear. Therefore, the aim of the current study was to reveal the epigenetic mechanism of hepatic transcriptional reprogramming changes based on the integration analysis of RNA-seq and H3K27ac labeled CUT&Tag. Results showed that lipid contents increased gradually with the embryonic age (E) 11, E15, and E19 based on morphological analysis of Hematoxylin-eosin and Oil Red O staining as well as total triglyceride and cholesterol detection. The hepatic protein level of SREBP-1c was higher in E19 when compared with that in E11 and E15, while H3K27ac and H3K4me2 levels declined from E11 to E19. Differential expression genes (DEGs) among these 3 embryonic ages were determined by transcriptome analysis. A total of 107 and 46 genes were gradually upregulated and downregulated respectively with the embryonic age. Meanwhile, differential H3K27ac occupancy in chromatin was investigated. But the integration analysis of RNA-seq and CUT&Tag data showed that the overlap genes were less between DEGs and target genes of differential peaks in the promoter regions. Further, some KEGG pathways enriched from target genes of typical enhancer were overlapped with those from DEGs in transcriptome analysis such as insulin, FoxO, MAPK signaling pathways which were related to lipid metabolism. DNA motif analysis identify 8 and 10 transcription factors (TFs) based on up and down differential peaks individually among E11, E15, and E19 stages where 7 TFs were overlapped including COUP-TFII, FOXM1, FOXA1, HNF4A, RXR, ERRA, FOXA2. These results indicated that H3K27ac histone modification is involved in the transcriptional reprogramming regulation during embryonic development, which could recruit TFs binding to mediate differential enhancer activation. Differential activated enhancer impels dynamic transcriptional reprogramming towards lipid metabolism to promote the occurrence of special phenotype of hepatic lipid deposition.

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

Background: The aim of this study was to analyze the association of molecular subtype concordance and disease outcome in patients with synchronous bilateral breast cancer (SBBC) and metachronous breast cancer (MBBC). Patients and methods: Patients diagnosed with SBBC or MBBC in the Surveillance, Epidemiology, and End Results (SEER) database or Comprehensive Breast Health Center (CBHC) Ruijin Hospital, Shanghai were retrospectively reviewed and included. Clinicopathologic features, molecular subtype status concordance, and prognosis were compared in patients with SBBC and MBBC. Other prognostic factors for breast cancer-specific survival (BCSS) and overall survival (OS) were also identified for bilateral breast cancer patients. Results: Totally, 3395 and 115 patients were included from the SEER and Ruijin CBHC cohorts. Molecular subtype concordance rate was higher in the SBBC group compared to MBBC in both SEER cohort (75.8% vs 57.7%, p

Myocardial infarction (MI) is a myocardial injury caused by coronary thrombosis or persistent ischemia and hypoxia. Due to its high morbidity and mortality, a safer and more effective treatment strategy is urgently needed. Daming capsule (DMC), a hypolipidemic drug, reportedly exerts cardioprotective effects in clinical and basic research, although its protective mechanism remains unknown. To investigate the mechanism underlying DMC-mediated improvement of cardiac function post-MI, C57/BL6 mice subjected to coronary artery ligation were administered DMC for 4 weeks. Our data demonstrated that DMC significantly improved cardiac structure and function compared to the saline group. Moreover, DMC inhibited inflammatory response and oxidative stress and improved mitochondrial structure and function in MI mice and hypoxia-stressed cardiomyocytes. Next, our research proved that DMC increased the expression of mitophagy receptor NLRX1. Interestingly, with the administration of DMC and siNLRX1, NLRX1 expression, mitochondria and lysosome colocalization, and mitochondrial membrane potential decreased, while mitochondrial ROS accumulation increased, suggesting that DMC promoted mitophagy to improve mitochondrial function via NLRX1 regulation. Further analysis showed that DMC activated the SIRT1/AMPK signaling pathway in vivo and in vitro. Our data showed that SIRT1 knockdown downregulated NLRX1 expression, leading to structural damage and functional impairment in mitochondria, as well as increased oxidative stress, inflammatory response, and decreased cardiac function in MI mice. Collectively, our findings reveal that DMC improves cardiac function post-MI by increasing mitophagy and inhibiting oxidative stress and inflammotory response in cardiomyocytes through the SIRT1/AMPK signaling pathway.

Environmental or occupational exposure of Cadmium (Cd) is concerned to be a threat to human health. The kidney is main target of Cd accumulation, which increases the risk of renal cell carcinoma (RCC). In addition, low content of Cd had been determined in kidney cancer, however, the roles of presence of Cd in renal tumors progression are still unclear. The present study is proposed to determine the effect of low-dose Cd exposure on the renal cancer cells and aimed to clarify the underlying mechanisms. The cell viability, cytotoxicity, and the migratory effect of low-dose Cd on the renal cancer cells were detected. Moreover, the roles of reactive oxygen species (ROS), Ca2+, and cyclic AMP (cAMP)/protein kinase A (PKA)-cyclooxygenase2 (COX2) signaling, as well as COX2 catalytic product prostaglandin E2 (PGE2) on cell migration and invasion were identified. Our results suggested that low dose Cd exposure promoted migration of renal cancer Caki-1 cells, which was not dependent on Cd-induced ROS and intracellular Ca2+ levels. Cd exposure induced cAMP/PKA-COX2, which mediated cell migration and invasion, and decreased expressions of epithelial-mesenchymal transition (EMT) marker, E-cadherin, but increased expressions of N-cadherin and Vimentin. Moreover, Cd-induced secretion of PGE2 feedback on activation of cAMP/PKA-COX2 signaling, also promoted EMT, migration and invasion of renal cancer Caki-1 cells. This study might contribute to understanding of the mechanism of Cd-induce progression of renal cancer and future studies on the prevention and therapy of renal cell carcinomas.

Background/aims: Acute myocardial infarction (AMI) is a major clinical manifestation of ischemic heart disease and represents a significant cause of morbidity and mortality. However, key regulators in the pathogenesis of ischemic heart disease remain controversial. The present study was designed to investigate the involvement of miR-200a and its related mechanism in AMI. Methods: Left coronary artery (LCA) ligation was conducted to induce an AMI mouse model. The infarct size was measured by TTC staining. H2O2 was used to induce an AMI model in vitro. miR-200a mimics, anti-miR-200a antisense oligodeoxyribonucleotides (AMO-200a), as well as corresponding negative controls were transfected into cardiomyocytes to observe the effect of miR-200a. Flow cytometry was used to detect cell apoptosis. Real-time PCR, immunofluorescence and western blot assays were used to evaluate gene expression at RNA or protein levels, respectively. Results: Apoptosis was activated in AMI models. The expression of miR-200a was upregulated both in the peri-infarcted region of mice myocardium and H2O2-treated cardiomyocytes. The co-administration of AMO-200a decreased the number of apoptosis cells and altered the expression of apoptosis related proteins. Interestingly, bioinformatics analysis results revealed that miR-200a could bind to the 3′-untranslated regions (3’-UTR) of Fus mRNA. In addition, the expression of Fus was downregulated in the AMI mouse models and in H2O2-treated cardiomyocytes. The alteration of miR-200a negatively regulated Fus expression in cardiomyocytes. Also, the protective effect of AMO-200a was observed through its regulation of Fus. Conclusion: MiR-200a-dependent apoptosis signaling pathway plays an important role in the pathogenesis of AMI injury and could be an exciting potential therapeutic target.

Liver cancer is a heterogeneous disease characterized by poor responses to standard therapies and therefore unfavourable clinical outcomes. Understanding the characteristics of liver cancer and developing novel therapeutic strategies are imperative. Ferroptosis, a type of programmed cell death induced by lipid peroxidation, has emerged as a potential target for treatment. Naringenin, a natural compound that modulates lipid metabolism by targeting AMPK, shows promise in enhancing the efficacy of ferroptosis inducers. In this study, we utilized liver cancer cell lines and xenograft mice to explore the synergistic effects of naringenin in combination with ferroptosis inducers, examining both phenotypic outcomes and molecular mechanisms. Our study results indicate that the use of naringenin at non-toxic doses to hepatocytes can significantly enhance the anticancer effects of ferroptosis inducers (erastin, RSL3, and sorafenib). The combination index method confirmed a synergistic effect between naringenin and ferroptosis inducers. In comparison to naringenin or ferroptosis inducers alone, the combined therapy caused more robust lipid peroxidation and hence more severe ferroptotic damage to cancer cells. The inhibition of aerobic glycolysis mediated by the AMPK-PGC1α signalling axis is the key to naringenin's effect on reducing ferroptosis resistance in liver cancer, and the synergistic cytotoxic effect of naringenin and ferroptosis inducers on cancer cells was reversed after pretreatment with an AMPK inhibitor or a PGC1α inhibitor. Taken together, these findings suggest that naringenin could boost cancer cell sensitivity to ferroptosis inducers, which has potential clinical translational value.