Alzheimer's disease biomarker burden in primary motor cortices is associated with poorer dexterity performance.

INTRODUCTION: Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices. METHODS: A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance. RESULTS: Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants. DISCUSSION: Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention. HIGHLIGHTS: Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments.

Ketogenic Diets Alter the Gut Microbiome, Resulting in Decreased Susceptibility to and Cognitive Impairment in Rats with Pilocarpine-Induced Status Epilepticus.

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated.

Microplastics in Hong Kong's marine waters: Impact of rainfall and Pearl River discharge.

This study provided a systematic investigation of microplastics in Hong Kong's surface marine waters during the pandemic from 2019 to 2021. Microplastics (2.07 ± 4.00 particles/m3) exhibited significant temporal variations with higher abundance in the wet season, without a consistent trend after the mandatory mask-wearing requirement was announced. The impact of pandemic restrictions on microplastic distribution was found to be relatively minor. However, significant correlations between microplastic abundances and rainfall highlighted the substantial contribution of local emissions through surface runoff. Notably, sites in closer proximity to the Pearl River Delta exhibited higher microplastic abundances, indicating their association with emission sources. The influence of rainfall and adverse weather on marine microplastic loads demonstrated different sensitivities among various locations but can generally last for one month. These results revealed the impact of seasonal rainfall on coastal microplastics and emphasized the need for efforts to reduce microplastic discharge from land-based sources.

Elevated Serum Copper, Zinc, Selenium, and Lowered α-Klotho Associations: Findings from NHANES 2011-2016 Dataset.

The α-Klotho is crucial for human health and longevity. However, the relationship between trace elements and α-Klotho levels needs further investigation. We aimed to explore the relationship between serum levels of selenium (Se), copper (Cu), and zinc (Zn), and serum α-Klotho levels. We analyzed 2138 samples from the 2011-2016 National Health and Nutrition Examination Survey, and the weighted linear regression, WQS, and qgcomp models were utilized to evaluate the effects of these elements on serum α-Klotho levels, individually and combined. A negative correlation was observed between serum Cu concentration and serum α-Klotho levels (ß = - 0.128, 95% CI - 0.196, - 0.059), with each increase in Cu concentration grade showing a gradual decrease in serum α-Klotho levels (Ptrend = 0.002). The WQS model exhibited a negative correlation between the combined effect of Se, Cu, and Zn and serum α-Klotho levels (ß = - 0.035, 95%CI - 0.060, - 0.010), consistently in males (ß = - 0.038 (- 0.059, - 0.017)) and in the 40-49 age group (ß = - 0.059, 95% CI - 0.119, - 0.012). The qgcomp model mirrored these findings, showing a negative correlation in the combined effect index of Se, Cu, and Zn with serum α-Klotho levels (ß = - 0.027, 95% CI - 0.047, - 0.006), consistent in females (ß = - 0.032, 95% CI - 0.061, - 0.004) and in individuals with BMI ≥ 25 (ß = - 0.030, 95% CI - 0.054, - 0.006), and in the 40-49 age group (ß = - 0.047, 95% CI - 0.088, - 0.006). Elevated serum Cu levels may be associated with lower serum α-Klotho levels. The combined effect of serum Se, Cu, and Zn shows a negative correlation with serum α-Klotho levels, with Cu contributing the most. Our findings provide significant insights into assessing the role of trace nutrients in maintaining human health.

An in-situ polymerization strategy for gel polymer electrolyte Si||Ni-rich lithium-ion batteries.

Coupling the Si-based anodes with nickel-rich LiNixMnyCo1-x-yO2 cathodes (x ≥ 0.8) in the energy-dense cell prototype suffers from the mechanical instability of the Li-Si alloys, cathode collapse upon the high-voltage cycling, as well as the severe leakage current at elevated temperatures. More seriously, the cathode-to-anode cross-talk effect of transitional metal aggravates the depletion of the active Li reservoir. To reconcile the cation utilization degree, stress dissipation, and extreme temperature tolerance of the Si-based anode||NMC prototype, we propose a gel polymer electrolyte to reinforce the mechanical integrity of Si anode and chelate with the transitional cations towards the stabilized interfacial property. As coupling the conformal gel polymer electrolyte encapsulation with the spatial arranged Si anode and NMC811 cathode, the 2.7 Ah pouch-format cell could achieve the high energy density of 325.9 Wh kg-1 (based on the whole pouch cell), 88.7% capacity retention for 2000 cycles, self-extinguish property as well as a wide temperature tolerance. Therefore, this proposed polymerization strategy provides a leap toward the secured Li batteries.

Association between COVID-19 and the Risk of Vascular Dementia: A Mendelian Randomisation Study of the Potential Cognitive Sequela of COVID-19.

A growing body of observational studies and Mendelian Randomisation analyses suggest an increased risk of Alzheimer's disease and dementia following COVID-19 infection. However, evidence on the potential association between COVID-19 and vascular dementia, which is plausible given the vascular complications of COVID-19 infection, is still limited. In this study, we conducted a two-sample Mendelian Randomisation analysis to examine the potential causal relationship between COVID-19 phenotypes and the risk of vascular dementia, using summary data from large-scale GWASs. The two-sample Mendelian Randomisation analysis did not detect any significant associations of COVID-19 infection, COVID-19 hospitalisation, or critical COVID-19 with the risk of vascular dementia, with weighted average ß values of -0.29 (95% CI: -0.84, 0.26; p = 0.301), -0.12 (95% CI: -0.36, 0.13; p = 0.345), and -0.07 (95% CI: -0.23, 0.09; p = 0.374), respectively. Our findings do not support the hypothesis that vascular dementia is one of the long-term sequelae of COVID-19.

Study on Changes in Gut Microbiota and Microbiability in Rabbits at Different Developmental Stages.

This study used feces from 0-day-old (36 rabbits), 10-day-old (119 rabbits), and 60-day-old (119 rabbits) offspring rabbits and their corresponding female rabbits (36 rabbits) as experimental materials. Using 16s rRNA sequencing, the study analyzed the types and changes of gut microbiota in rabbits at different growth and development stages, as well as the correlation between gut microbiota composition and the weight of 60-day-old rabbits. All experimental rabbits were placed in the same rabbit shed. Juvenile rabbits were fed solid feed at 18 days of age and weaned at 35 days of age. In addition to identifying the dominant bacterial phyla of gut microbiota in rabbits at different age stages, it was found that the abundance of Clostridium tertium and Clostridium paraputrificum in all suckling rabbits (10-day-old) was significantly higher than that in rabbits fed with whole feed (60-day-old) (p < 0.05), while the abundance of Gram-negative bacterium cTPY13 was significantly lower (p < 0.05). In addition, Fast Expected Maximum Microbial Source Tracing (FEAST) analysis showed that the contribution of female rabbits' gut microbiota to the colonization of offspring rabbits' gut microbiota was significantly higher than that of unrelated rabbits' gut microbiota (p < 0.05). The contribution of female rabbits' gut microbiota to the colonization of gut microbiota in 0-day-old rabbits was significantly higher than that to the colonization of gut microbiota in the 10- and 60-day-old rabbits (p < 0.05). Finally, the correlation between gut microbiota composition and body weight of 60-day-old rabbits was analyzed based on a mixed linear model, and six ASVs significantly affecting body weight were screened. The above results provide important theoretical and practical guidance for maintaining gut health, improving growth and development performance, and feeding formulation in rabbits.

Using a Leroux-prior-based conditional autoregression-based strategy to map the short-term association between temperature and bacillary dysentery and its attributable burden in China.

Background: In China, bacillary dysentery (BD) is the third most frequently reported infectious disease, with the greatest annual incidence rate of 38.03 cases per 10,000 person-years. It is well acknowledged that temperature is associated with BD and the previous studies of temperature-BD association in different provinces of China present a considerable heterogeneity, which may lead to an inaccurate estimation for a region-specific association and incorrect attributable burdens. Meanwhile, the common methods for multi-city studies, such as stratified strategy and meta-analysis, have their own limitations in handling the heterogeneity. Therefore, it is necessary to adopt an appropriate method considering the spatial autocorrelation to accurately characterize the spatial distribution of temperature-BD association and obtain its attributable burden in 31 provinces of China. Methods: A novel three-stage strategy was adopted. In the first stage, we used the generalized additive model (GAM) model to independently estimate the province-specific association between monthly average temperature (MAT) and BD. In the second stage, the Leroux-prior-based conditional autoregression (LCAR) was used to spatially smooth the association and characterize its spatial distribution. In the third stage, we calculate the attribute BD cases based on a more accurate estimation of association. Results: The smoothed association curves generally show a higher relative risk with a higher MAT, but some of them have an inverted "V" shape. Meanwhile, the spatial distribution of association indicates that western provinces have a higher relative risk of MAT than eastern provinces with 0.695 and 0.645 on average, respectively. The maximum and minimum total attributable number of cases are 224,257 in Beijing and 88,906 in Hainan, respectively. The average values of each province in the eastern, western, and central areas are approximately 40,991, 42,025, and 26,947, respectively. Conclusion: Based on the LCAR-based three-stage strategy, we can obtain a more accurate spatial distribution of temperature-BD association and attributable BD cases. Furthermore, the results can help relevant institutions to prevent and control the epidemic of BD efficiently.

Tomato Pectin Ameliorated Hepatic Steatosis in High-Fat-Diet Mice by Modulating Gut Microbiota and Bile Acid Metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health issue. Changes in the gut microbiota structure and composition are closely related to host pathophysiology processes. Pectin is associated with several beneficial health effects. In the present study, we aimed at investigating the effect of tomato pectin (TP) on hepatic steatosis and exploring the underlying mechanisms by focusing on the regulation of the gut microbiota-bile acid axis. Our results showed that TP attenuated high-fat diet (HFD)-induced liver steatosis and inflammation. TP administration increased the diversity of gut microbiota, enhancing the abundance of beneficial bacteria and suppressing the abundance of harmful or conditional pathogenic bacteria. Further antibiotic-caused microbiome depletion confirmed that the anti-NAFLD activities of TP were dependent on the regulation of gut microbiota. Besides, TP intervention affected feces bile acid metabolism and caused significant changes in functional conjugated bile acids, which in turn inhibited the ileum FXR/FGF15 signaling, leading to stimulation of the hepatic bile acid (BA) production. Furthermore, TP treatment accelerated BA excretion, promoted BA transportation, inhibited BA reabsorption, and facilitated cholesterol efflux to relieve HFD-induced hyperlipidemia. These findings provide a potential dietary intervention strategy for TP against NAFLD via modulation of cross-talk between BAs and gut bacteria.

Revitalizing liver function in mice with liver failure through transplantation of 3D-bioprinted liver with expanded primary hepatocytes.

The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.

The miR7125-MdARF1 module enhances the resistance of apple to Colletotrichum gloeosporioides by promoting lignin synthesis in response to salicylic acid signalling.

Apple is an important cash crop in China, and it is susceptible to fungal infections that have deleterious effects on its yield. Apple bitter rot caused by Colletorichum gloeosporioides is one of the most severe fungal diseases of apple. Salicylic acid (SA) is a key signalling molecule in the plant disease resistance signalling pathways. Lignin synthesis also plays a key role in conferring disease resistance. However, few studies have clarified the relationship between the SA disease resistance signalling pathway and the lignin disease resistance pathway in apple. MdMYB46 has previously been shown to promote lignin accumulation in apple and enhance salt and osmotic stress tolerance. Here, we investigated the relationship between MdMYB46 and biological stress; we found that MdMYB46 overexpression enhances the resistance of apple to C. gloeosporioides. We also identified MdARF1, a transcription factor upstream of MdMYB46, via yeast library screening and determined that MdARF1 was regulated by miR7125 through psRNATarget prediction. This regulatory relationship was confirmed through LUC and qRT-PCR experiments, demonstrating that miR7125 negatively regulates MdARF1. Analysis of the miR7125 promoter revealed that miR7125 responds to SA signals. The accumulation of SA level will result in the decrease of miR7125 expression level. In sum, the results of our study provide novel insights into the molecular mechanisms underlying the resistance of apple to C. gloeosporioides and reveal a new pathway that enhances lignin accumulation in apple in response to SA signals. These findings provide valuable information for future studies aimed at breeding apple for disease resistance.

Association between influenza vaccination and one-year all-cause and cardiovascular mortality risk: A self-controlled case series and matched case-control study.

Debates surrounding the efficacy of influenza vaccination for survival benefits persist, and there is a lack of data regarding its duration of protection. A self-controlled case series (SCCS) and a 1:4 matched case-control study were conducted using the National Health Interview Survey (NHIS) and public-use mortality data from 2005 to 2018 in the United States. The SCCS study identified participants who received influenza vaccination within 12 months before the survey and subsequently died within 1 year of postvaccination. The matched case-control study paired participants who died during the influenza season at the time of survey with four survivors. Among 1167 participants in the SCCS study, there was a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality within 29-196 days of postvaccination. The greatest protection was observed during days 29-56 (all-cause mortality: RI: 0.19; 95% CI: 0.12-0.29; cardiovascular mortality: RI: 0.28; 95% CI: 0.14-0.56). Among 626 cases and 2504 controls included in the matched case-control study, influenza vaccination was associated with a reduction in all-cause mortality (OR: 0.74, 95% CI: 0.60-0.92) and cardiovascular mortality (OR: 0.64, 95% CI: 0.44-0.93) during the influenza season. This study highlights the importance of influenza vaccination in reducing the risks of all-cause and cardiovascular mortality, with effects lasting for approximately 6 months.

Diet shapes the metabolite profile in the intact human ileum, which affects PYY release.

The human ileum contains a high density of enteroendocrine L-cells, which release the appetite-suppressing hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in response to food intake. Recent evidence highlighted the potential role of food structures in PYY release, but the link between food structures, ileal metabolites, and appetite hormone release remains unclear owing to limited access to intact human ileum. In a randomized crossover trial (ISRCTN11327221; isrctn.com), we investigated the role of human ileum in GLP-1 and PYY release by giving healthy volunteers diets differing in fiber and food structure: high-fiber (intact or disrupted food structures) or low-fiber disrupted food structures. We used nasoenteric tubes to sample chyme from the intact distal ileum lumina of humans in the fasted state and every 60 min for 480 min postprandially. We demonstrate the highly dynamic, wide-ranging molecular environment of the ileum over time, with a substantial decrease in ileum bacterial numbers and bacterial metabolites after food intake. We also show that high-fiber diets, independent of food structure, increased PYY release compared with a low-fiber diet during 0 to 240 min postprandially. High-fiber diets also increased ileal stachyose, and a disrupted high-fiber diet increased certain ileal amino acids. Treatment of human ileal organoids with ileal fluids or an amino acid and stachyose mixture stimulated PYY expression in a similar profile to blood PYY concentrations, confirming the role of ileal metabolites in PYY release. Our study demonstrates the diet-induced changes over time in the metabolite environment of intact human ileum, which play a role in PYY release.

A bacterial ghost vaccine against Aeromonas salmonicida infection in turbot (Scophthalmus maximus).

Aeromonas salmonicida is one of the most prevalent pathogens that causes huge economic losses to aquaculture. Effective vaccination is the first choice for preventing infection. Bacterial ghost (BG), an empty bacterial shell devoid of cytoplasm, is a promising vaccine antigen with distinct advantages. Herein, we established strategies for producing a substantial yield of A. salmonicida ghost (ASG) and investigated the immune-protective properties of it. As a result, 2.84 mg/ml NaOH was discovered to be capable of inducing considerable amounts of ASG. Furthermore, the ASG vaccine elicited adaptive immunity in turbots after rapid activation of innate immunity. Even though formalin-killed cells (FKC) produced a few more antibodies than ASG, ASG ultimately provided a much stronger immune protection effect because it strengthened cellular immunity, with a relative percentage survival (RPS) of 50.1% compared to FKC. These findings demonstrated that ASG effectively activated cell-mediated immunity, which helped get rid of microorganisms inside cells. Therefore, this study presented novel perspectives for future research on furunculosis vaccine products based on ASG as an antigen.

Analysis of Clinical Efficacy and Quality of Life of Braun Anastomosis in Gastrointestinal Reconstruction in Totally Laparoscopic Distal Gastrectomy: A Single-Center Retrospective Study.

OBJECTIVE: This study aimed to compare the clinical efficacy and quality of life of B-IIB (Billroth-II with Braun anastomosis) and B-II (Billroth-II anastomosis) in the alimentary tract reconstruction postoperative totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. METHODS: From February 2016 to January 2022, 158 patients underwent totally laparoscopic distal gastrectomy and D2 lymphadenectomy in Northern Jiangsu People's Hospital, with Billroth-II with Braun anastomosis for 93 patients and Billroth-II anastomosis for 65 patients. The patients' data were collected prospectively and reviewed retrospectively. RESULTS: In this study, the post-op hospital stay of B-IIB group were shorter than B-II group (12.70 ± 3.08 days in the B-IIB group versus 14.12 ± 4.90 days in the B-II group, p < 0.05) and the first post-op flatus time of the B-IIB group were shorter than B-II group (3.49 ± 1.02 days versus 4.08 ± 1.85 days, p < 0.05). Two groups did differ significantly in hemoglobin on postoperative 3 months, albumin at 3 months after operation, and serum sodium on postoperative 3 days and 3 months (p < 0.05), and the B-IIB had an advantage; the complications incidence (Clavien-Dindo grade II or even a higher grade) of the B-IIB group and B-II group were 10.75% and 29.23%, respectively. There being a statistical difference between the two groups. The B-IIB group and the B-II group both had different degrees of weight loss at 3 months after operation compared with preoperative weight. The weight of B-IIB group was 4.04 ± 1.33 kg, which was less than B-II group (8.08 ± 1.47 kg). The difference was statistically significant (p < 0.05). According to the PGSAS (Postgastrectomy Syndrome Assessment Scale), the score of the B-IIB group is lower than that of the B-II group for esophageal reflux gastritis, dyspepsia, and dumping syndrome group (1.84 ± 0.92 VS 2.15 ± 0.85, P = 0.031; 1.86 ± 1.10 VS 2.22 ± 0.91, P = 0.034; 1.98 ± 1.06 VS 2.32 ± 0.94, P = 0.037, respectively). CONCLUSION: Totally laparoscopic distal gastrectomy with Billroth-II Braun reconstruction is a safe and technically feasible method for gastric cancer patients, which can reduce the incidence of postoperative reflux esophagitis and dumping syndrome. Compared with Billroth-II reconstruction, it has advantages in maintaining postoperative nutritional status and electrolyte balance and improving quality of life.

Structure-activity relationships of the intramolecular disulphide bonds in LEAP2, an antimicrobial peptide from Acrossocheilus fasciatus.

BACKGROUND: The liver-expressed antimicrobial peptide 2 (LEAP2) plays a pivotal role in the host's immune response against pathogenic microorganisms. Numerous such antimicrobial peptides have recently been shown to mitigate infection risk in fish, and studying those harboured by the economically important fish Acrossocheilus fasciatus is imperative for enhancing its immune responses against pathogenic microorganisms. In this study, we cloned and sequenced LEAP2 cDNA from A. fasciatus to examine its expression in immune tissues and investigate the structure-activity relationships of its intramolecular disulphide bonds. RESULTS: The predicted amino acid sequence of A. fasciatus LEAP2 was found to include a signal peptide, pro-domain, and mature peptide. Sequence analysis indicated that A. fasciatus LEAP2 is a member of the fish LEAP2A cluster and is closely related to Cyprinus carpio LEAP2A. A. fasciatus LEAP2 transcripts were expressed in various tissues, with the head kidney exhibiting the highest mRNA levels. Upon exposure to Aeromonas hydrophila infection, LEAP2 expression was significantly upregulated in the liver, head kidney, and spleen. A mature peptide of A. fasciatus LEAP2, consisting of two disulphide bonds (Af-LEAP2-cys), and a linear form of the LEAP2 mature peptide (Af-LEAP2) were chemically synthesised. The circular dichroism spectroscopy result shows differences between the secondary structures of Af-LEAP2 and Af-LEAP2-cys, with a lower proportion of alpha helix and a higher proportion of random coil in Af-LEAP2. Af-LEAP2 exhibited potent antimicrobial activity against most tested bacteria, including Acinetobacter guillouiae, Pseudomonas aeruginosa, Staphylococcus saprophyticus, and Staphylococcus warneri. In contrast, Af-LEAP2-cys demonstrated weak or no antibacterial activity against the tested bacteria. Af-LEAP2 had a disruptive effect on bacterial cell membrane integrity, whereas Af-LEAP2-cys did not exhibit this effect. Additionally, neither Af-LEAP2 nor Af-LEAP2-cys displayed any observable ability to hydrolyse the genomic DNA of P. aeruginosa. CONCLUSIONS: Our study provides clear evidence that linear LEAP2 exhibits better antibacterial activity than oxidised LEAP2, thereby confirming, for the first time, this phenomenon in fish.

A predictive study of the efficacy of transcutaneous auricular vagus nerve stimulation in the treatment of major depressive disorder: An fMRI-based machine learning analysis.

BACKGROUND: In order to improve taVNS efficacy, the usage of fMRI to explore the predictive neuroimaging markers would be beneficial for screening the appropriate MDD population before treatment. METHODS: A total of 86 MDD patients were recruited in this study, and all subjects were conducted with the clinical scales and resting-state functional magnetic resonance imaging (fMRI) scan before and after 8 weeks' taVNS treatment. A two-stage feature selection strategy combining Machine Learning and Statistical was used to screen out the critical brain functional connections (FC) that were significantly associated with efficacy prediction, then the efficacy prediction model was constructed for taVNS treating MDD. Finally, the model was validated by separated the responding and non-responding patients. RESULTS: This study showed that taVNS produced promising clinical efficacy in the treatment of mild and moderate MDD. Eleven FCs were selected out and were found to be associated with the cortico-striatal-pallidum-thalamic loop, the hippocampus and cerebellum and the HAMD-17 scores. The prediction model was created based on these FCs for the efficacy prediction of taVNS treatment. The R-square of the conducted regression model for predicting HAMD-17 reduction rate is 0.44, and the AUC for classifying the responding and non-responding patients is 0.856. CONCLUSION: The study demonstrates the validity and feasibility of combining neuroimaging and machine learning techniques to predict the efficacy of taVNS on MDD, and provides an effective solution for personalized and precise treatment for MDD.

Efficacy and safety of immune checkpoint inhibitors in solid tumor patients combined with chronic coronary syndromes or its risk factor: a nationwide multicenter cohort study.

BACKGROUND: Although, immune checkpoint inhibitors (ICIs) have been widely applied in the therapy of malignant tumors, the efficacy and safety of ICIs in patients with tumors and pre-existing CAD, especially chronic coronary syndromes (CCS) or their risk factors (CRF), is not well identified. METHODS: This was a nationwide multicenter observational study that enrolled participants who diagnosed with solid tumors and received ICIs therapy. The main efficacy indicators were progression-free survival (PFS) and overall survival (OS), followed by objective response rate (ORR) and disease control rate (DCR). Safety was assessed by describing treatment-related adverse events (TRAEs) during ICIs therapy evaluated by the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). RESULTS: In the current research, we retrospectively analyzed the data of 551 patients diagnosed with solid tumors and received ICIs therapy, and these patients were divided into CCS/CRF group and non-CCS/CRF group. Patients with CCS/CRF had more favorable PFS and OS than patients without CCS/CRF (P < 0.001) and the pre-existing CCS/CRF was a protective factor for survival. The ORR (51.8% vs. 39.1%) and DCR (95.8% vs. 89.2%) were higher in CCS/CRF group than in non-CCS/CRF group (P = 0.003, P = 0.006). In this study, there was no significant difference in treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), between the two groups. CONCLUSIONS: We concluded that ICIs appear to have better efficacy in malignant solid tumor patients with pre-existing CCS/CRF and are not accompanied by more serious irAEs.

Cystathionine γ-lyase-derived H2S negatively regulates thymic egress via allosteric inhibition of sphingosine-1-phosphate lyase.

Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H2S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H2S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H2S. In addition, the CSE-generated H2S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H2S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C203XC205 redox motif adjacent to the enzyme's active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H2S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.