BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(...BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.展开更多
Ferroptosis plays a key role in aggravating the progression of spinal cord injury(SCI),but the specific mechanism remains unknown.In this study,we constructed a rat model of T10 SCI using a modified Allen method.We id...Ferroptosis plays a key role in aggravating the progression of spinal cord injury(SCI),but the specific mechanism remains unknown.In this study,we constructed a rat model of T10 SCI using a modified Allen method.We identified 48,44,and 27 ferroptosis genes that were differentially expressed at 1,3,and 7 days after SCI induction.Compared with the sham group and other SCI subgroups,the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower.These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression.Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI:STAT3,JUN,TLR4,ATF3,HMOX1,MAPK1,MAPK9,PTGS2,VEGFA,and RELA.Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3,JUN,TLR4,ATF3,HMOX1,PTGS2,and RELA mRNA levels were up-regulated and VEGFA,MAPK1 and MAPK9 mRNA levels were down-regulated.Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI.We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs,10 miRNAs,and 12 genes.Our results help further the understanding of the mechanism underlying ferroptosis in SCI.展开更多
AIM To measure the leptin levels in patients with diarrheapredominant irritable bowel syndrome(IBS-D) and analyze the relationship of leptin with clinical features, visceral sensitivity, mast cells, and nerve fibers. ...AIM To measure the leptin levels in patients with diarrheapredominant irritable bowel syndrome(IBS-D) and analyze the relationship of leptin with clinical features, visceral sensitivity, mast cells, and nerve fibers. METHODS Forty-two patients with IBS-D fulfilling the Rome Ⅲ criteria and 20 age-and sex-matched healthy controls underwent clinical and psychological evaluations using validated questionnaires(including IBS Symptom Severity Scale, IBS-specific Quality of Life, Hamilton Anxiety Scale, and Hamilton Depression Scale), along with colonoscopy, colonic mucosal biopsy, and visceral sensitivity testing. Serum leptin levels were assayed using enzyme-linked immunosorbent assay. Mucosal leptin expression and localization were evaluated using immunohistochemistry and immunofluorescence.Mucosal leptin m RNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction. Mast cell counts and activation rates were investigated by toluidine blue staining. Correlation analyses between these parameters were performed.RESULTS There were no statistically significant differences in age, gender, or body mass index between the IBS-D group and the control group. The median IBS Symptom Severity Scale score in the IBS-D group was 225.0(range, 100-475). IBS-D patients had significantly increased anxiety [IBS-D: median, 6.5; interquartile range(IQR), 3.3; control: median, 2.0; IQR, 2.0; P < 0.001] and depression(IBS-D: median, 7.0; IQR, 3.0; control: median, 3.0; IQR, 2.0; P < 0.001) scores. IBS-D patients had significantly lower first sensation threshold(IBS-D: median, 50.6; IQR, 25.9; control: median, 80.5; IQR, 18.6; P < 0.001), defecation sensation threshold(IBS-D: median, 91.5; IQR, 29.3; control: median, 155.0; IQR, 21.1; P < 0.001) and maximum tolerable threshold(IBS-D: median, 163.2; IQR, 71.2; control: median, 226.2; IQR, 39.3; P < 0.001). Mucosal leptin expression, as reflected by integrated optical density(IBS-D: median, 4424.71; IQR, 4533.63; control: median, 933.65; IQR, 888.10; P < 0.001), leptin mR NA expression(IBS-D: median, 1.1226; IQR, 1.6351; control: median, 0.8947; IQR, 0.4595; P = 0.009), and mast cell activation rate(IBS-D: median, 71.2%; IQR, 12.9%; control group: median, 59.4%; IQR, 18.88%; P < 0.001) were significantly increased in IBS-D patients. The colocalization of leptin and leptin receptors was observed on mast cells and PGP9.5-positive nerve fibers in the intestinal mucosa. Also, leptin expression was positively correlated with anxiety, depression, and the mast cell activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold during visceral sensitivity testing(adjusted P < 0.0038).CONCLUSION Increased levels of mucosal leptin may interact with mast cells and the nervous system to contribute to the pathogenesis of IBS-D.展开更多
Tremendous amount of data are being generated and saved in many complex engineering and social systems every day.It is significant and feasible to utilize the big data to make better decisions by machine learning tech...Tremendous amount of data are being generated and saved in many complex engineering and social systems every day.It is significant and feasible to utilize the big data to make better decisions by machine learning techniques. In this paper, we focus on batch reinforcement learning(RL) algorithms for discounted Markov decision processes(MDPs) with large discrete or continuous state spaces, aiming to learn the best possible policy given a fixed amount of training data. The batch RL algorithms with handcrafted feature representations work well for low-dimensional MDPs. However, for many real-world RL tasks which often involve high-dimensional state spaces, it is difficult and even infeasible to use feature engineering methods to design features for value function approximation. To cope with high-dimensional RL problems, the desire to obtain data-driven features has led to a lot of works in incorporating feature selection and feature learning into traditional batch RL algorithms. In this paper, we provide a comprehensive survey on automatic feature selection and unsupervised feature learning for high-dimensional batch RL. Moreover, we present recent theoretical developments on applying statistical learning to establish finite-sample error bounds for batch RL algorithms based on weighted Lpnorms. Finally, we derive some future directions in the research of RL algorithms, theories and applications.展开更多
基金Supported by the National Key Technology Support Program during "12th Five-Year Plan"Period of China,No.2014BAI08B00the Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008
文摘BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.
基金supported by National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100Tianjin Key Research and Development Plan,Key Projects for Science and Technology Support,No.19YFZCSY00660(both to SQF)。
文摘Ferroptosis plays a key role in aggravating the progression of spinal cord injury(SCI),but the specific mechanism remains unknown.In this study,we constructed a rat model of T10 SCI using a modified Allen method.We identified 48,44,and 27 ferroptosis genes that were differentially expressed at 1,3,and 7 days after SCI induction.Compared with the sham group and other SCI subgroups,the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower.These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression.Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI:STAT3,JUN,TLR4,ATF3,HMOX1,MAPK1,MAPK9,PTGS2,VEGFA,and RELA.Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3,JUN,TLR4,ATF3,HMOX1,PTGS2,and RELA mRNA levels were up-regulated and VEGFA,MAPK1 and MAPK9 mRNA levels were down-regulated.Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI.We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs,10 miRNAs,and 12 genes.Our results help further the understanding of the mechanism underlying ferroptosis in SCI.
基金Supported by National key Technology Support Program during the"12th Five-Year Plan"Period of China,No.2014BAI08B02
文摘AIM To measure the leptin levels in patients with diarrheapredominant irritable bowel syndrome(IBS-D) and analyze the relationship of leptin with clinical features, visceral sensitivity, mast cells, and nerve fibers. METHODS Forty-two patients with IBS-D fulfilling the Rome Ⅲ criteria and 20 age-and sex-matched healthy controls underwent clinical and psychological evaluations using validated questionnaires(including IBS Symptom Severity Scale, IBS-specific Quality of Life, Hamilton Anxiety Scale, and Hamilton Depression Scale), along with colonoscopy, colonic mucosal biopsy, and visceral sensitivity testing. Serum leptin levels were assayed using enzyme-linked immunosorbent assay. Mucosal leptin expression and localization were evaluated using immunohistochemistry and immunofluorescence.Mucosal leptin m RNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction. Mast cell counts and activation rates were investigated by toluidine blue staining. Correlation analyses between these parameters were performed.RESULTS There were no statistically significant differences in age, gender, or body mass index between the IBS-D group and the control group. The median IBS Symptom Severity Scale score in the IBS-D group was 225.0(range, 100-475). IBS-D patients had significantly increased anxiety [IBS-D: median, 6.5; interquartile range(IQR), 3.3; control: median, 2.0; IQR, 2.0; P < 0.001] and depression(IBS-D: median, 7.0; IQR, 3.0; control: median, 3.0; IQR, 2.0; P < 0.001) scores. IBS-D patients had significantly lower first sensation threshold(IBS-D: median, 50.6; IQR, 25.9; control: median, 80.5; IQR, 18.6; P < 0.001), defecation sensation threshold(IBS-D: median, 91.5; IQR, 29.3; control: median, 155.0; IQR, 21.1; P < 0.001) and maximum tolerable threshold(IBS-D: median, 163.2; IQR, 71.2; control: median, 226.2; IQR, 39.3; P < 0.001). Mucosal leptin expression, as reflected by integrated optical density(IBS-D: median, 4424.71; IQR, 4533.63; control: median, 933.65; IQR, 888.10; P < 0.001), leptin mR NA expression(IBS-D: median, 1.1226; IQR, 1.6351; control: median, 0.8947; IQR, 0.4595; P = 0.009), and mast cell activation rate(IBS-D: median, 71.2%; IQR, 12.9%; control group: median, 59.4%; IQR, 18.88%; P < 0.001) were significantly increased in IBS-D patients. The colocalization of leptin and leptin receptors was observed on mast cells and PGP9.5-positive nerve fibers in the intestinal mucosa. Also, leptin expression was positively correlated with anxiety, depression, and the mast cell activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold during visceral sensitivity testing(adjusted P < 0.0038).CONCLUSION Increased levels of mucosal leptin may interact with mast cells and the nervous system to contribute to the pathogenesis of IBS-D.
基金supported by National Natural Science Foundation of China(Nos.61034002,61233001 and 61273140)
文摘Tremendous amount of data are being generated and saved in many complex engineering and social systems every day.It is significant and feasible to utilize the big data to make better decisions by machine learning techniques. In this paper, we focus on batch reinforcement learning(RL) algorithms for discounted Markov decision processes(MDPs) with large discrete or continuous state spaces, aiming to learn the best possible policy given a fixed amount of training data. The batch RL algorithms with handcrafted feature representations work well for low-dimensional MDPs. However, for many real-world RL tasks which often involve high-dimensional state spaces, it is difficult and even infeasible to use feature engineering methods to design features for value function approximation. To cope with high-dimensional RL problems, the desire to obtain data-driven features has led to a lot of works in incorporating feature selection and feature learning into traditional batch RL algorithms. In this paper, we provide a comprehensive survey on automatic feature selection and unsupervised feature learning for high-dimensional batch RL. Moreover, we present recent theoretical developments on applying statistical learning to establish finite-sample error bounds for batch RL algorithms based on weighted Lpnorms. Finally, we derive some future directions in the research of RL algorithms, theories and applications.
