The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.

Microbial communities such as those residing in the human gut are highly diverse and complex, and many with important implications for health and diseases. The effects and functions of these microbial communities are determined not only by their species compositions and diversities but also by the dynamic intra- and inter-cellular states at the transcriptional level. Powerful and scalable technologies capable of acquiring single-microbe-resolution RNA sequencing information in order to achieve a comprehensive understanding of complex microbial communities together with their hosts are therefore utterly needed. Here we report the development and utilization of a droplet-based smRNA-seq (single-microbe RNA sequencing) method capable of identifying large species varieties in human samples, which we name smRandom-seq2. Together with a triple-module computational pipeline designed for the bacteria and bacteriophage sequencing data by smRandom-seq2 in four human gut samples, we established a single-cell level bacterial transcriptional landscape of human gut microbiome, which included 29,742 single microbes and 329 unique species. Distinct adaptive response states among species in Prevotella and Roseburia genera and intrinsic adaptive strategy heterogeneity in Phascolarctobacterium succinatutens were uncovered. Additionally, we identified hundreds of novel host-phage transcriptional activity associations in the human gut microbiome. Our results indicated that smRandom-seq2 is a high-throughput and high-resolution smRNA-seq technique that is highly adaptable to complex microbial communities in real-world situations and promises new perspectives in the understanding of human microbiomes.
Humans ; Gastrointestinal Microbiome/genetics* ; Bacteriophages/physiology* ; High-Throughput Nucleotide Sequencing ; Sequence Analysis, RNA/methods* ; Bacteria/virology*

Attention deficit hyperactivity disorder is a common neurodevelopmental disorder characterized by persistent attention deficit, hyperactivity, and impulsive behaviors that are not consistent with developmental age.Academic and vocational difficulties, social exclusion, and delinquent behaviors are manifested in daily life.It is also commonly accompanied by psychiatric problems.At the same time, mental problems are common, and the overall quality of life is greatly affected, placing a heavy burden on society as well as the family.International attention deficit hyperactivity disorder experts have developed a common and comprehensive International Classification of Functioning, Disability and Health core set of classifications for assessing individual functioning in attention deficit hyperactivity disorder.

Objective This study used resting-state functional magnetic resonance imaging(rs-fMRI)to investigate the changes of local brain regional homogeneity in patients with depression and childhood maltreatment,and we calculated the relationship between altered ReHo values and the severity of childhood maltreatment.Methods 25 patients with depression and childhood maltreatment,25 patients with depression without childhood maltreatment,and 25 age,gender,and education-matched healthy controls were prospectively enrolled.All subjects underwent resting-state functional magnetic resonance imaging and ReHo analysis.One-way analysis of variance was used to compare the group differences,along with multiple comparison correction.Pearson correlation analysis was used to explore the relationship between region ReHo values with clinical scales.Results Compared with the group of depression without childhood maltreatment,the abnormal brain regions of depression with childhood maltreatment are mainly located in the dorsolateral prefrontal cortex,cerebellum,parietal gyrus,and precentral gyrus.The ReHo values of depression with childhood maltreatment in the left cerebellum and the left dorsolateral prefrontal cortex are correlated with the severity of childhood maltreatment.Conclusions Depression with childhood mal-treatment is associated with changes in local spontaneous brain activity,which are correlated with the severity of childhood maltreatment.The brain changes in the dorsolateral prefrontal cortex and cerebellum may explain the neurobiological mechanisms of depression with childhood maltreatment.

Objective:To investigate the efficacy and adverse reactions of moderately hypofractionated intensity modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) for locally advanced prostate cancer (LAPC).Methods:This study retrospectively analyzed the medical records of 40 LAPC patients who were admitted in The Second Hospital of Dalian Medical University during 2014-2020. The planning gross target volume (PGTV) dose for prostate gland and seminal vesicle gland was 64.8-70.0 Gy/25-28 f, 2.4-2.8 Gy/f and the dose of PGTVnd in 20 cases with positive pelvic lymph nodes was 60.0-64.4 Gy/25-28 f, 2.3-2.4 Gy/f. The dose of planning target volume (PTV) for the drainage area of pelvic lymph nodes was 45.0-50.4 Gy/25-28 f. The enrolled patients were treated with long-term ADT, including neoadjuvant, simultaneous, and adjuvant therapies. The efficacy and adverse reactions were evaluated. The prognostic factors affecting the biochemical failure-free survival (BFFS) were analyzed.Results:The median follow-up time was 31 months. The 2- and 3-year overall survival (OS) rates were 100% and 96.9%, respectively. The 1-, 2-, and 3-year BFFS rates were 90%, 76.8% and 72%, respectively. The 1-, 2-, and 3-year distant metastasis-free survival (DMFS) rates were 92.2%, 82.8% and 75.1%, respectively. Gleason (GS) score ( χ2=10.00, P < 0.05) and adjacent tissue invasion ( χ2=8.85, P<0.05) were prognostic factors related to BFFS for LAPC. Adjacent tissue invasion and GS 9-10 were independent poor prognostic factors. The incidence of acute urinary adverse reaction and rectal injury (grade≥2) was 7.5% and 20%, respectively. The incidence of late urinary adverse reaction and rectal injury (grade≥2) was 12.5% and 17.5%, respectively. Adverse reactions at grade 3-4 did not occur. Conclusions:The moderately hypofractionated IMRT combined with ADT is feasible for LAPC treatment, achieving satisfactory survival effects. 70 Gy/25-28 f, 2.5-2.8 Gy/f is a safe and effective moderate hypofraction scheme. Adjacent tissue invasion and GS score are prognostic factors related to BFFS for LAPC.

H 1-antihistamines are widely used in the treatment of various allergic diseases, but there are still many challenges in the safe and rational use of H 1-antihistamines in pediatrics, and there is a lack of guidance on the prescription review of H 1-antihistamines for children.In this paper, suggestions are put forward from the indications, dosage, route of administration, pathophysiological characteristics of children with individual difference and drug interactions, so as to provide reference for clinicians and pharmacists.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Objective:To evaluate the impact of artificial intelligence (AI) system on the diagnosis rate of precancerous state of gastric cancer.Methods:A single center self-controlled study was conducted under the premise that such factors were controlled as mainframe and model of the endoscope, operating doctor, season and climate, and pathology was taken as the gold standard. The diagnosis rate of precancerous state of gastric cancer, including atrophic gastritis (AG) and intestinal metaplasia (IM) in traditional gastroscopy (from September 1, 2019 to November 30, 2019) and AI assisted endoscopy (from September 1, 2020 to November 15, 2020) in the Eighth Hospital of Wuhan was statistically analyzed and compared, and the subgroup analysis was conducted according to the seniority of doctors.Results:Compared with traditional gastroscopy, AI system could significantly improve the diagnosis rate of AG [13.3% (38/286) VS 7.4% (24/323), χ2=5.689, P=0.017] and IM [33.9% (97/286) VS 26.0% (84/323), χ2=4.544, P=0.033]. For the junior doctors (less than 5 years of endoscopic experience), AI system had a more significant effect on the diagnosis rate of AG [11.9% (22/185) VS 5.8% (11/189), χ2=4.284, P=0.038] and IM [30.3% (56/185) VS 20.6% (39/189), χ2=4.580, P=0.032]. For the senior doctors (more than 10 years of endoscopic experience), although the diagnosis rate of AG and IM increased slightly, the difference was not statistically significant. Conclusion:AI system shows the potential to improve the diagnosis rate of precancerous state of gastric cancer, especially for junior endoscopists, and to reduce missed diagnosis of early gastric cancer.

Antipyretic-analgesics are currently one of the most prescribed drugs in children.The clinical application of antipyretic-analgesics for children in our country still have irrational phenomenon, which affects the therapeutic effect and even poses hidden dangers to the safety of children.In this paper, suggestions were put forward from the indications, dosage form/route, dosage suitability, pathophysiological characteristics of children with individual differences and drug interactions in the symptomatic treatment of febrile children, so as to provide reference for the general pharmacists when conducting prescription review.

Background The increasing threats of air pollution and extreme weather have been widely recognized in recent years in China, but their individual and joint effects on cardio-cerebrovascular mortality are unclear. Objective This study aims to investigate the individual effects of and potential interactions between oxidant pollutants and ambient temperature on cardio-cerebrovascular mortality risks. Methods We collected daily data on death counts of cardio-cerebrovascular diseases, concentrations of ambient air pollutants, and meteorological parameters in Guangzhou, Chinabetween 1 January 2006 and 31 December 2016. A generalized additive model with a Poisson distribution was conducted to assess the associations of oxidant pollutants and ambient temperature with cardio-cerebrovascular mortality risks. Bivariate response surface models and stratified analyses were further adopted to qualitatively and quantitatively examine the potential interactions between oxidant pollutants and ambient temperature on cardio-cerebrovascular mortality risks. Results During the study period, the daily averages were 60.3 μg·m⁻³ for ozone (O₃), 50.9 μg·m⁻³ for combined atmospheric oxidant capacity (O_x), 32.5 μg·m⁻³ for nitrogen dioxide (NO₂), and 22.3℃ for ambient temperature. The average daily death counts of coronary and stroke diseases were 20 and 15, respectively. Per 10 μg·m⁻³ increment in O₃, O_x, and NO₂ were associated with increased coronary mortality risks (excess risk, ER) of 1.26% (95%CI: 0.79%-1.74%), 1.61% (95%CI: 0.99%-2.23%), and 1.33% (95%CI: 0.59%-2.07%), and with increased stroke mortality risks of 1.56% (95%CI: 1.04%-2.09%), 2.30% (95%CI: 1.60%-3.01%), and 2.93% (95%CI: 2.07%-3.79%) over cumulative lags of 2-5 days, respectively. The exposure-response relationships between ambient temperature and coronary and stroke mortality risks exhibited an inverse "J" shape, with the minimum mortality at temperatures of 25.7℃ for coronary disease and 27.3℃ for stroke. Our results further showed potentially synergic effects of higher temperatures and higher levels of O₃ and O_x exposures on coronary mortality risks, and the relative ER due to interactions was 0.103 (95%CI: 0.028-0.178) for O₃ and 0.079 (95%CI: 0.004-0.154) for O_x. We didn't find evidence of an interaction between oxidant pollutants and low temperature. Conclusion Short-term exposures to oxidant pollutants are associated with increased cardio-cerebrovascular mortality risks, and the interactive effects of high temperature and oxidant pollutants are synergistic in relation to cardio-cerebrovascular mortality risks.