Background: Cross-country skiing(XCS) racing, a popular international winter sport, is complex and challenging from physical, technical, and tactical perspectives. Despite the vast amount of research focusing on this ...Background: Cross-country skiing(XCS) racing, a popular international winter sport, is complex and challenging from physical, technical, and tactical perspectives. Despite the vast amount of research focusing on this sport, no review has yet addressed the pacing strategies of elite XCS racers or the factors that influence their performance. The aim was to review the scientific literature in an attempt to determine the effects of pacing strategy on the performance of elite XCS racers.Methods: Four electronic databases were searched using relevant subject headings and keywords. Only original research articles published in peerreviewed journals and the English language and addressing performance, biomechanics, physiology, and anthropometry of XCS racers were reviewed.Results: All 27 included articles applied correlative designs to study the effectiveness of different pacing strategies. None of the articles involved the use of an experimental design. Furthermore, potential changes in external conditions(e.g., weather, ski properties) were not taken into consideration. A comparable number of studies focused on the skating or classical technique. In most cases, positive pacing was observed, with certain indications that higher-level athletes and those with more endurance and strength utilized a more even pacing strategy. The ability to achieve and maintain a long cycle length on all types of terrain was an important determinant of performance in all of the included studies, which was not the case for cycle rate. In general, uphill performance was closely related to overall race performance, with uphill performance being most closely correlated to the success of female skiers and performance on flat terrain being more important for male skiers. Moreover, pacing was coupled to the selection and distribution of technique during a race, with faster skiers employing more double poling and kick double poling,less diagonal stride, and more V2(double dance) than V1(single dance) skating across a race.Conclusion: We propose that skiers at all levels can improve their performance with more specific training in techniques(i.e., maintaining long cycles without compromising cycle rate and selecting appropriate techniques) in combination with training for endurance and more strength. Furthermore, we would advise less experienced skiers and/or those with lower levels of performance to apply a more even pacing strategy rather than a positive one(i.e., starting the race too fast).展开更多
AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow ...AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 m L/min·g in males and 0.51 ± 0.03 m L/min·g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 μm and 80 ± 3 μm respectively. After 60 min the mucus thickness increased to 113 ± 3 μm in males and 121 ± 3 μm in females with no statistically significant difference seen between the sexes. Following oestrogen administration(0.1 followed by 1 μg/kg·min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline(P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 m L/min·100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 m L/min·100 g in females(P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM)(0.06 ± 0.07) and females(0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP(P = 0.14).CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.展开更多
Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment o...Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.展开更多
Primarily driven by an increasingly sedentary lifestyle and hypercaloric nutritionally imbalanced diets,non-alcoholic fatty liver disease(NAFLD)has emerged as the most prevalent liver disease in the US and Europe.NAFL...Primarily driven by an increasingly sedentary lifestyle and hypercaloric nutritionally imbalanced diets,non-alcoholic fatty liver disease(NAFLD)has emerged as the most prevalent liver disease in the US and Europe.NAFLD constitutes an umbrella term that includes a spectrum of disease from non-alcoholic fatty liver(NAFL)to non-alcoholic steatohepatitis(NASH),NASH fibrosis and NASH cirrhosis that are all characterized by≥5%of all hepatocytes being steatotic in patients with little alcohol intake and no apparent alternative causes.展开更多
Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes an...Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.展开更多
Forces acting on the skeleton could be divided into those originating from gravitational loading and those originating from muscle loading. Flat bones in a non-weight-baring segment of the skeleton probably experience...Forces acting on the skeleton could be divided into those originating from gravitational loading and those originating from muscle loading. Flat bones in a non-weight-baring segment of the skeleton probably experience forces mostly generated by muscle contractions. One purpose of muscle contractions is to generate blood flow within skeletal tissues. The present study aimed to investigate the pulsatile patellar bone blood flow after low and high intensity leg extension exercises. Forty-two healthy individuals volunteered for the study. Dynamic isotonic one leg extension/flexion exercises were performed in a leg extension machine. Randomly, the exercises were performed with the left or right leg with either 10 repetition maximum (10 RM) continuously without any resting periods (high intensity muscle work), or 20 RM with a 2 second rest between contractions (low intensity muscle work). The work load, expressed in kilograms totally lifted, was identical in both legs. The pulsatile patellar blood flow was recorded continuously using a photoplethysmographic technique. Blood pressure was measured continuously during muscle work by a non-invasive method (Finapress). The patellar pulsatile bone blood flow increased significantly more after high intensity muscle work (61%) compared to the same work load performed using a lower intensity (22%), p = 0.000073. Systolic blood pressure changed equally during and after both interventions. Post-exercise bone hyperaemia appears to be correlated to the intensity of muscle contractions in the muscle compartment attached to the bone.展开更多
The muscle RING-finger protein-1 (MuRFl) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRFl gene transcription participa...The muscle RING-finger protein-1 (MuRFl) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRFl gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRFl gene point mutations have been found to generate protein aggregate myopathies defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRFl turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUM01 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASy/4. SUMOylation takes place at lysine 238 localized at the second coiled-coil protein domain that is required for efficient substrate interaction for polyubiquitination. We provided evidence that SUMOylation is essential for MuRFl nuclear translocation and its mitochondria accumulation is enhanced in hyper? glycemic conditions delivering a stabilization of the overall SUMOylated proteins in cultured myocytes. Thus, our findings add this SUM01 post-translational modification as a new concept to understand muscle disorders related to the defect in MuRFl activity.展开更多
Recently, the arguments raised by Gang and Jing have been published in Chinese Journal of Integrative Medicine, concerning the randomized controlled trial （RCT） of our team published in JAMA. The conclusions of Gang...Recently, the arguments raised by Gang and Jing have been published in Chinese Journal of Integrative Medicine, concerning the randomized controlled trial （RCT） of our team published in JAMA. The conclusions of Gang and Jingo） result not only from misunderstanding of the aims of our study,） but also a lack of basic knowledge for the design of RCT and the limitations on the content, and hence the length, of the primary outcome article in high-impact journals （i.e. 2,500 words and a total of 5 figures/tables in JAMA）. We will address their main critiques point by point below.展开更多
At the 2022 Winter Olympics in Beijing,the XC skiing,biathlon and nordic combined events will be held at altitudes of~1700 m above sea level,possibly in cold environmental conditions and while requiring adjustment to ...At the 2022 Winter Olympics in Beijing,the XC skiing,biathlon and nordic combined events will be held at altitudes of~1700 m above sea level,possibly in cold environmental conditions and while requiring adjustment to several time zones.However,the ongoing COVID-19 pandemic may lead to sub-optimal preparations.The current commentary provides the following evidence-based recommendations for the Olympic preparations:make sure to have extensive experience of training(>60 days annually)and competition at or above the altitude of competition(~1700 m),to optimize and individualize your strategies for acclimatization and competition.In preparing for the Olympics,10-14 days at~1700 m seems to optimize performance at this altitude effectively.An alternative strategy involves two-three weeks of training at>2000 m,followed by 7-10 days of tapering off at~1700 m.During each of the last 3 or 4 days prior to departure,shift your sleeping and eating schedule by 0.5-1 h towards the time zone in Beijing.In addition,we recommend that you arrive in Beijing one day earlier for each hour change in time zone,followed by appropriate timing of exposure to daylight,meals,social contacts,and naps,in combination with a gradual increase in training load.Optimize your own individual procedures for warming-up,as well as for maintaining body temperature during the period between the warm-up and competition,effective treatment of asthma(if necessary)and pacing at~1700 m with cold ambient temperatures.Although we hope that these recommendations will be helpful in preparing for the Beijing Olympics in 2022,there is a clear need for more solid evidence gained through new sophisticated experiments and observational studies.展开更多
Chronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide.Chronic inflammation is characterized by persistent,low-grade inflammation and is increased in the agin...Chronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide.Chronic inflammation is characterized by persistent,low-grade inflammation and is increased in the aging population.Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation.However,in chronic inflammation,the role of neutrophils is less well understood and has been described as either beneficial or detrimental,causing tissue damage and enhancing the immune response.Emerging evidence suggests that neutrophils are important players in several chronic diseases,such as atherosclerosis,diabetes mellitus,nonalcoholic fatty liver disease and autoimmune disorders.This review will highlight the interaction of neutrophils with other cells in the context of chronic inflammation,the contribution of neutrophils to selected chronic inflammatory diseases,and possible future therapeutic strategies.展开更多
Excessive release of neutrophil extracellular traps(NETs)is associated with disease severity and contributes to tissue injury,followed by severe organ damage.Pharmacological or genetic inhibition of NET release reduce...Excessive release of neutrophil extracellular traps(NETs)is associated with disease severity and contributes to tissue injury,followed by severe organ damage.Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models,indicating that NETs are potential therapeutic targets.Here,we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody(tACPA)has broad therapeutic potential.Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology,including inflammatory arthritis(IA),pulmonary fibrosis,inflammatory bowel disease and sepsis.We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention,whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects.Because citrullinated histones are generated during NET release,we investigated the ability of tACPA to inhibit NET formation.tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli.Moreover,tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo,which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA.To our knowledge,we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases,as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.展开更多
文摘Background: Cross-country skiing(XCS) racing, a popular international winter sport, is complex and challenging from physical, technical, and tactical perspectives. Despite the vast amount of research focusing on this sport, no review has yet addressed the pacing strategies of elite XCS racers or the factors that influence their performance. The aim was to review the scientific literature in an attempt to determine the effects of pacing strategy on the performance of elite XCS racers.Methods: Four electronic databases were searched using relevant subject headings and keywords. Only original research articles published in peerreviewed journals and the English language and addressing performance, biomechanics, physiology, and anthropometry of XCS racers were reviewed.Results: All 27 included articles applied correlative designs to study the effectiveness of different pacing strategies. None of the articles involved the use of an experimental design. Furthermore, potential changes in external conditions(e.g., weather, ski properties) were not taken into consideration. A comparable number of studies focused on the skating or classical technique. In most cases, positive pacing was observed, with certain indications that higher-level athletes and those with more endurance and strength utilized a more even pacing strategy. The ability to achieve and maintain a long cycle length on all types of terrain was an important determinant of performance in all of the included studies, which was not the case for cycle rate. In general, uphill performance was closely related to overall race performance, with uphill performance being most closely correlated to the success of female skiers and performance on flat terrain being more important for male skiers. Moreover, pacing was coupled to the selection and distribution of technique during a race, with faster skiers employing more double poling and kick double poling,less diagonal stride, and more V2(double dance) than V1(single dance) skating across a race.Conclusion: We propose that skiers at all levels can improve their performance with more specific training in techniques(i.e., maintaining long cycles without compromising cycle rate and selecting appropriate techniques) in combination with training for endurance and more strength. Furthermore, we would advise less experienced skiers and/or those with lower levels of performance to apply a more even pacing strategy rather than a positive one(i.e., starting the race too fast).
文摘AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 m L/min·g in males and 0.51 ± 0.03 m L/min·g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 μm and 80 ± 3 μm respectively. After 60 min the mucus thickness increased to 113 ± 3 μm in males and 121 ± 3 μm in females with no statistically significant difference seen between the sexes. Following oestrogen administration(0.1 followed by 1 μg/kg·min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline(P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 m L/min·100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 m L/min·100 g in females(P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM)(0.06 ± 0.07) and females(0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP(P = 0.14).CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.
基金supported by the China Scholarship Council(to YW)the Swedish Research Council,No.2018-02601(to MS)+7 种基金the Alzheimer Foundation,No.AF-980695(to MS)the Stockholm County Council,No.RS2020-0731(to MS)the Foundation of Old Servants(to MS)the Gun and Bertil Stohne Foundation(to MS)the?hlén Foundation,No.233055(to MS)The Swedish Fund for Research without Animal Experiments(to MS)the Swedish Dementia Foundation(to MS)the Brain foundation,No.FO2022-0131(to MS)。
文摘Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.
基金supported by the National key Research and Development Program of China (2019YFC1709500)the National Collaboration Project of Critical Illness by Integrating Chinese Medicine and Western Medicine+8 种基金the Project of Heilongjiang Province Innovation Team “Tou Yan”the Yi-Xun Liu and Xiao-Ke Wu Academician Workstationthe Innovation Team of Reproductive Technique with Integrative Chinese Medicine and Western Medicine in Xuzhou City, ChinaHeilongjiang University of Chinese Medicine from the National Clinical Trial BaseHeilongjiang Provincial Clinical Research Center for Ovary Diseasesthe Research Grant Council (T13-602/21-N, C5045-20EF, and 14122021)Food and Health Bureau in Hong Kong, China (06171026)supported by a National Health and Medical Research Council (NHMRC) Investigator grant (GNT1176437)travel support from Merck.
基金funded by the Swedish Research Council(Nos.2019-01837 and 2021-02801)by the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking(EUbOPEN No.875510)and by the Robert Bosch Stiftung,Stuttgart,Germany.
文摘Primarily driven by an increasingly sedentary lifestyle and hypercaloric nutritionally imbalanced diets,non-alcoholic fatty liver disease(NAFLD)has emerged as the most prevalent liver disease in the US and Europe.NAFLD constitutes an umbrella term that includes a spectrum of disease from non-alcoholic fatty liver(NAFL)to non-alcoholic steatohepatitis(NASH),NASH fibrosis and NASH cirrhosis that are all characterized by≥5%of all hepatocytes being steatotic in patients with little alcohol intake and no apparent alternative causes.
基金supported by grants of U01CA175315 and R01GM113888 from the U.S.National Institutes of Health(NIH)supported by grants of ES006694 and ES007091 from NIH+8 种基金supported by grants of ES021800,ES020522,and ES005022 from NIHsupported by the Robert Bosch Foundation,Stuttgart,Germanysupported by grants of ES023438 and DK083952 from NIHsupported by grant of R01HL122593 from NIH and the Searle Scholars Program,USAsupported by grant of R01ES025708 from NIHsupported by grants of CA098468 and T32DK007737 from NIHsupported by grants of R01DK33765 and R01ES024421 from NIHsupported by grants of R01DK104656,R01DK080440,R01ES025909,R21AA022482,and R21AA024935 from NIH,grant of 1I01BX002634 from VA Merit Award,USA,grant of No.81572443 from National Natural Science Foundation of China,and grant of P30 DK34989 from Yale Liver Center,USAsupported by grants of R01ES019487,R01GM087367,and R01GM118367 from NIH
文摘Variations in drug metabolism may alter drug efficacy and cause toxicity;better understanding of the mechanisms and risks shall help to practice precision medicine.At the 21 st International Symposium on Microsomes and Drug Oxidations held in Davis,California,USA,in October 2-6,2016,a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity,and discussed potential implications to personalized medications.A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption,distribution,metabolism,and excretion(ADME) and drug response.Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented.In addition,the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed.These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.
文摘Forces acting on the skeleton could be divided into those originating from gravitational loading and those originating from muscle loading. Flat bones in a non-weight-baring segment of the skeleton probably experience forces mostly generated by muscle contractions. One purpose of muscle contractions is to generate blood flow within skeletal tissues. The present study aimed to investigate the pulsatile patellar bone blood flow after low and high intensity leg extension exercises. Forty-two healthy individuals volunteered for the study. Dynamic isotonic one leg extension/flexion exercises were performed in a leg extension machine. Randomly, the exercises were performed with the left or right leg with either 10 repetition maximum (10 RM) continuously without any resting periods (high intensity muscle work), or 20 RM with a 2 second rest between contractions (low intensity muscle work). The work load, expressed in kilograms totally lifted, was identical in both legs. The pulsatile patellar blood flow was recorded continuously using a photoplethysmographic technique. Blood pressure was measured continuously during muscle work by a non-invasive method (Finapress). The patellar pulsatile bone blood flow increased significantly more after high intensity muscle work (61%) compared to the same work load performed using a lower intensity (22%), p = 0.000073. Systolic blood pressure changed equally during and after both interventions. Post-exercise bone hyperaemia appears to be correlated to the intensity of muscle contractions in the muscle compartment attached to the bone.
基金Swedish Research Council 2013- 3074 (Vetenskapsradet) and Erik och Edith Fernstroms foundation 2012 to S.G., G.H., and A.V.N., COST Proteostasis (BM1307- 040917-087135) to S.G. and A.V.N., Taishan Scholar's program to G.T., the National Natural Science Foundation of China (31671139 to M.J. and 31771284 to G.T.)Natural Science Foundation of Shandong Province, China (ZR2016)L026) to G.T., and the Key Research and Development Plan of Shandong Province (2017GSF18103) to MJ. G.H. is partially supported by KID Karolinska Institutet (C333802033)+2 种基金Also financial support from Ake Wiberg Foundation (Ml4-0127)Magnus Bergvall Foundation (2015-01200, 2016-01675)Carl Trygger Foun dation (CST 15:57) to S.B.L. are ack no wledged.
文摘The muscle RING-finger protein-1 (MuRFl) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRFl gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRFl gene point mutations have been found to generate protein aggregate myopathies defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRFl turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUM01 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASy/4. SUMOylation takes place at lysine 238 localized at the second coiled-coil protein domain that is required for efficient substrate interaction for polyubiquitination. We provided evidence that SUMOylation is essential for MuRFl nuclear translocation and its mitochondria accumulation is enhanced in hyper? glycemic conditions delivering a stabilization of the overall SUMOylated proteins in cultured myocytes. Thus, our findings add this SUM01 post-translational modification as a new concept to understand muscle disorders related to the defect in MuRFl activity.
文摘Recently, the arguments raised by Gang and Jing have been published in Chinese Journal of Integrative Medicine, concerning the randomized controlled trial （RCT） of our team published in JAMA. The conclusions of Gang and Jingo） result not only from misunderstanding of the aims of our study,） but also a lack of basic knowledge for the design of RCT and the limitations on the content, and hence the length, of the primary outcome article in high-impact journals （i.e. 2,500 words and a total of 5 figures/tables in JAMA）. We will address their main critiques point by point below.
文摘At the 2022 Winter Olympics in Beijing,the XC skiing,biathlon and nordic combined events will be held at altitudes of~1700 m above sea level,possibly in cold environmental conditions and while requiring adjustment to several time zones.However,the ongoing COVID-19 pandemic may lead to sub-optimal preparations.The current commentary provides the following evidence-based recommendations for the Olympic preparations:make sure to have extensive experience of training(>60 days annually)and competition at or above the altitude of competition(~1700 m),to optimize and individualize your strategies for acclimatization and competition.In preparing for the Olympics,10-14 days at~1700 m seems to optimize performance at this altitude effectively.An alternative strategy involves two-three weeks of training at>2000 m,followed by 7-10 days of tapering off at~1700 m.During each of the last 3 or 4 days prior to departure,shift your sleeping and eating schedule by 0.5-1 h towards the time zone in Beijing.In addition,we recommend that you arrive in Beijing one day earlier for each hour change in time zone,followed by appropriate timing of exposure to daylight,meals,social contacts,and naps,in combination with a gradual increase in training load.Optimize your own individual procedures for warming-up,as well as for maintaining body temperature during the period between the warm-up and competition,effective treatment of asthma(if necessary)and pacing at~1700 m with cold ambient temperatures.Although we hope that these recommendations will be helpful in preparing for the Beijing Olympics in 2022,there is a clear need for more solid evidence gained through new sophisticated experiments and observational studies.
基金Open Access funding enabled and organized by Projekt DEAL。
文摘Chronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide.Chronic inflammation is characterized by persistent,low-grade inflammation and is increased in the aging population.Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation.However,in chronic inflammation,the role of neutrophils is less well understood and has been described as either beneficial or detrimental,causing tissue damage and enhancing the immune response.Emerging evidence suggests that neutrophils are important players in several chronic diseases,such as atherosclerosis,diabetes mellitus,nonalcoholic fatty liver disease and autoimmune disorders.This review will highlight the interaction of neutrophils with other cells in the context of chronic inflammation,the contribution of neutrophils to selected chronic inflammatory diseases,and possible future therapeutic strategies.
基金Feasibility grants from the Dutch government(MTVLA15144 and NITLS14050).
文摘Excessive release of neutrophil extracellular traps(NETs)is associated with disease severity and contributes to tissue injury,followed by severe organ damage.Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models,indicating that NETs are potential therapeutic targets.Here,we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody(tACPA)has broad therapeutic potential.Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology,including inflammatory arthritis(IA),pulmonary fibrosis,inflammatory bowel disease and sepsis.We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention,whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects.Because citrullinated histones are generated during NET release,we investigated the ability of tACPA to inhibit NET formation.tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli.Moreover,tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo,which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA.To our knowledge,we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases,as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
