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the role of inflammasomes in human diseases and their potential as therapeutic targets

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Signal transduction and targeted therapy 2024年第2期9卷 479-508页

作者： Jing Yao keenan Sterling Zhe Wang Yun Zhang Weihong Song the National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053China townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Key Laboratory of Neurodegenerative Diseases Ministry of EducationBeijingP.R.China Zhejiang Clinical Research Center for Mental Disorders Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325000China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000China

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response.Each inflammasome complex has three major components:an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC.Inflammasome formation typically occurs in response to infectious agents or cellular damage.the active inflammasome then triggers caspase-1 activation,followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death.Aberrant inflammasome activation and activity contribute to the development of diabetes,cancer,and several cardiovascular and neurodegenerative disorders.As a result,recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation,as well as the potential of targeting inflammasomes to treat various diseases.Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies.therefore,understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies.In this article,we provide a summary of the biological and pathological roles of inflammasomes in health and disease.We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

关键词： inflam therapeutic potential

Do Systemic Infections Contribute to the Pathogenesis of Dementia?

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Neuroscience Bulletin 2022年第3期38卷 331-333页

作者： keenan Sterling Mengen Xing Weihong Song townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouverBCV6T 1Z3Canada Institute of Aging Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and Kangning HospitalThe Second Affiliated Hospital and Yuying Children’s HospitalWenzhou Medical UniversityWenzhou325035China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou325000China

With over 50 million people currently living with dementia and numbers expected to double every twenty years,the world is currently facing a dementia epidemic.Nevertheless,a poor understanding of the etiology of dementia has resulted in the inability to develop any successful disease-modifying treatment.Over the past year,several researchers have highlighted the role of systemic infections in increasing the risk of developing dementia.these findings are particularly troubling given the ongoing coronavirus 19(COVID-19)pandemic,adding yet another cause for concern over the long-term impact of COVID-19 on the public’s mental health.

关键词： adding etiology finding

Amyloidβ-based therapy for Alzheimer’s disease:challenges,successes and future

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Signal transduction and targeted therapy 2023年第7期8卷 3374-3399页

作者： Yun Zhang Huaqiu Chen Ran Li keenan Sterling Weihong Song National Clinical Research Center for Geriatric Disorders Xuanwu HospitalCapital Medical UniversityBeijingChina the Second Affiliated Hospital and Yuying Children’s Hospital Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceWenzhou Medical UniversityWenzhouZhejiangChina townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouverBC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiangChina

Amyloidβprotein(Aβ)is the main component of neuritic plaques in Alzheimer’s disease(AD),and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression.Aβhas been the prime target for the development of AD therapy.However,the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course.

关键词： Alzheimer Aβ clinical

Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential

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translational Neurodegeneration 2022年第1期11卷 883-916页

作者： Lina Gao Yun Zhang keenan Sterling Weihong Song Shandong Collaborative Innovation Center for Diagnosis Treatment and Behavioral Interventions of Mental DisordersInstitute of Mental HealthCollege of PharmacyJining Medical UniversityJining 272067ShandongChina townsend Family Laboratories Department of PsychiatryThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada National Clinical Research Center for Geriatric Disorders Xuanwu HospitalCapital Medical UniversityBeijing 100053China Institute of Aging Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalWenzhou Medical UniversityWenzhou 325000ZhejiangChina Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou 325001ZhejiangChina.

Synaptic abnormalities are a cardinal feature of Alzheimer’s disease(AD)that are known to arise as the disease progresses.A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloidβ(Aβ)and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD.Brain-derived neurotrophic factors(BDNFs)play an important role in maintaining synaptic plasticity in learning and memory.Considering AD as a synaptic disorder,BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD.Although depletion of BDNF has been linked with Aβaccumulation,tau phosphorylation,neuroinflammation and neuronal apoptosis,the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown.Here,we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling.We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.

关键词： Brain-derived neurotrophic factor Alzheimer’s disease Amyloidβprotein tau protein Neuroinflammation Neuronal apoptosis

Heritability of Heart Rate Response to Arousals in twins

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Heritability of Heart Rate Response to Arousals in Twins

Heritability of Heart Rate Response to Arousals in twins

中国睡眠研究会第十届全国学术年会

作者： Xiaoling Gao Ali Azarbarzin Brendan t.keenan Michele Ostrowski Frances M.Pack Bethany Staley Greg Maislin Allan I.Pack Magdy Younes Samuel t.Kuna Department of Medicine and Center for Sleep and Circadian Neurobiology University of Pennsylvania Department of Respiration The Second Hospital of Shanxi Medical University Division of Sleep Medicine Brigham and Women’s Hospital and Harvard Medical School Sleep Disorders Centre University of Manitoba

Objectives: to determine if the large and highly reproducible interindividual differences in arousal intensity and heart rate response to arousal（ΔHR） during non-REM sleep are heritable.Methods: Polysomnograms of 55 monozygotic（14 male and 41 female pairs） and 36 dizygotic（15 male and 21 female pairs） same-sex twin pairs were analyzed.Arousals were scored using the 2012 American Academy of Sleep Medicine criteria.Arousal intensity was scaled（between 0 and 9） using an automatic algorithm based on the change in electroencephalogram time and frequency characteristics.the ΔHR was determined at each arousal.We calculated average arousal duration,average arousal intensity,average overall ΔHR,average ΔHR at a given arousal intensity,slope of ΔHR per arousal intensity,and arousal intensity threshold of ΔHR.Results: the intraclass correlations among monozygotic and dizygotic twin pairs were 0.663 and 0.146,respectively,for average arousal intensity,and 0.449 and 0,respectively,for arousal intensity threshold of ΔHR controlling for age,sex,and race.these values imply large broad sense heritability（H2） for these traits.this evidence was confirmed by a robust maximum likelihood-based variance components estimation approach,with an additive genetic heritability of 0.64（95% confidence interval: 0.48 to 0.80） for average arousal intensity and a combined additive and dominance genetic heritability and of 0.46（0.25 to 0.68） for arousal intensity threshold of ΔHR.Results also suggested significant additive genetic effects for average arousal duration,ΔHR at arousal intensity scale 4 and the overall average ΔHR.Conclusion: Genetic factors explain a significant fraction of the phenotypic variability for average arousal intensity and arousal intensity threshold of ΔHR.Results suggest that the duration of arousals and specific average ΔHR values may also be heritable traits.

关键词： polysomnogram monozygotic dizygotic

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Heritability of Heart Rate Response to Arousals in Twins

Clinical classification of symptomatic heterotopic pancreas of the stomach and duodenum:A case series and systematic literature review

中国睡眠研究会第九届学术年会

作者： Xiaoling Gao Ali Azarbarzin Brendan t.keenan Michele Ostrowski Frances M.Pack Bethany Staley Greg Maislin Allan I.Pack Magdy Younes Samuel t.Kuna Department of Medicine and Center for Sleep and Circadian Neurobiology University of Pennsylvania Department of Respiration The second Hospital of Shanxi Medical University Sleep Disorders Centre University of Manitoba

Study Objectives:to determine if the large and highly reproducible inter-individual differences in heart rate(HR) response to arousals during non-REM sleep arise from a heritable trait.Design:Post-hoc analysis of polysomnograms of same-sex monozygotic and dizygotic twin pairs.Setting:Academic medical center and Research and Development Laboratory(YRt Limited).Participants:55 monozygotic(mean[±SD]age 29.2±6.9 years;14 male and 41 female pairs) and 36dizygotic(mean age 26.217.5 years;15 male and 21 female pairs) twin pairs with a normal polysomnogram.Interventions:None Measurements and Results:Arousals were scored using the 2007 American Academy of Sleep Medicine criteria.Arousal intensity was scaled(between 0 and 9) using an automatic algorithm based on the change in EEG time and frequency characteristics and a training data set.Heart rate response to arousal(AHR) was determined and averaged at each arousal intensity per subject.We calculated the average arousal duration,average arousal intensity,average AHR,AHR at a given arousal intensity,rate of AHR per arousal intensity,and arousal intensity threshold of AHR.Using the classical approach to assess broad sense heritability(h),the arousal intensity threshold of AHR(h=0.94) and average arousal intensity(h=1.05) showed the strongest evidence for heritability after age and sex adjustment.Evidence was supported by a maximum likelihood based variance components estimation approach,with h(95%CI) estimates of 0.38(0.13,0.62) for arousal intensity threshold of AHR and 0.64(0.48,0.80) for average arousal intensity.this approach also suggested significant additive genetic effects for the number of arousals,average arousal duration,and the average AHR.Conclusion:Genetic factors explain a significant fraction of the phenotypic variability for the threshold of AHR to arousal and average arousal intensity.Results also suggest that the number and duration of arousals and the average AHR may be heritable traits.

关键词：

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World Journal of Gastroenterology 2022年第14期28卷 1455-1478页

作者： Michael t Le Compte Brandon Mason keenan J Robbins Motoyo Yano Deyali Chatterjee Ryan C Fields Steven M Strasberg William G Hawkins Department of Surgical Oncology University of North CarolinaRaleighNC 27608United States Department of Radiology Stillwater Medical CenterStillwaterOK 74074United States Department of General Surgery Washington University St.LouisSt.LouisMO 63110-8109United States Department of Radiology Mayo ClinicPhoenixAZ 8505United States Department of Pathology and Immunology MD Anderson Cancer CenterHoustonTX 77030United States Department of Surgical Oncology Washington University School of MedicineSt.LouisMO 63110-8109United States Section of Hepatobiliary-Pancreatic and GI Surgery Washington University St.LouisSt.LouisMO 63110United States

BACKGROUND Heterotopic pancreas(HP)is an aberrant anatomic malformation that occurs most commonly in the upper gastrointestinal tract.While the majority of heterotopic pancreatic lesions are asymptomatic,many manifest severe clinical symptoms which require surgical or endoscopic intervention.Understanding of the clinical manifestations and symptoms of HP is limited due to the lack of large volume studies in the literature.the purpose of this study is to review symptomatic cases at a single center and compare these to a systematic review of the literature in order to characterize common clinical manifestations and treatment of this disease.AIM to classify the common clinical manifestations of heterotopic pancreas.MEtHODS A retrospective review was conducted of pathologic samples containing heterotopic pancreas from 2000-2018.Review was limited to HP of the upper gastrointestinal tract due to the frequency of presentation in this location.Symptomatic patients were identified from review of the medical records and clinical symptoms were tabulated.these were compared to a systematic review of the literature utilizing Pub Med and Embase searches for papers pertaining to heterotopic pancreas.Publications describing symptomatic presentation of HP were selected for review.Information including demographics,symptoms,presentation and treatment were compiled and analyzed.RESULtS twenty-nine patient were identified with HP at a single center,with six of these identified has having clinical symptoms.Clinical manifestations included,gastrointestinal bleeding,gastric ulceration with/without perforation,pancreatitis,and gastric outlet obstruction.Systemic review of the literature yielded 232 publications detailing symptomatic cases with only 20 studies describing ten or more patients.Single and multi-patient studies were combined to form a cohort of 934 symptomatic patients.the majority of patients presented with abdominal pain(67%)combined with one of the following clinical categories:(1)Dyspepsia,(n=445,48%);(2)Pancreatitis(n=

关键词： Heterotopic pancreas Ectopic pancreas Aberrant pancreas Pancreatic rest Groove pancreatitis

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从洋中脊到俯冲带的快速转换

矿物岩石地球化学通报 2017年第1期36卷 91-91页

作者： keenan t E Encarnación J Buchwaldt R Fernandez D Mattinson J Rasozanamparany C Luetkemeyer P B 夏群科

板块俯冲是地球上最基本的也是最明显的板块构造过程,但是新的俯冲带从哪里形成以及如何形成,目前都还没有很好的地质限定。海洋扩张中心虽然是板块构造系统中最薄弱的部分之一,但是由于新形成的海洋岩石圈的浮力作用,以前都认为它不容... 详细信息

板块俯冲是地球上最基本的也是最明显的板块构造过程,但是新的俯冲带从哪里形成以及如何形成,目前都还没有很好的地质限定。海洋扩张中心虽然是板块构造系统中最薄弱的部分之一,但是由于新形成的海洋岩石圈的浮力作用,以前都认为它不容易参与俯冲。

关键词：俯冲带圣路易斯大学板块构造浮力作用洋中脊岩石圈板块俯冲扩张中心变质作用力学性质

A study of real-world micrograph data quality and machine learning model robustness

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npj Computational Materials 2021年第1期7卷 1463-1473页

作者： Xiaoting Zhong Brian Gallagher keenan Eves Emily Robertson t.Nathan Mundhenk t.Yong-Jin Han Materials Science Division Lawrence Livermore National LaboratoryLivermoreCAUSA Center for Applied Scientific Computing Lawrence Livermore National LaboratoryLivermoreCAUSA Defense technologies Engineering Division Lawrence Livermore National LaboratoryLivermoreCAUSA Computational Engineering Division Lawrence Livermore National LaboratoryLivermoreCAUSA

Machine-learning(ML)techniques hold the potential of enabling efficient quantitative micrograph analysis,but the robustness of ML models with respect to real-world micrograph quality variations has not been carefully evaluated.We collected thousands of scanning electron microscopy(SEM)micrographs for molecular solid materials,in which image pixel intensities vary due to both the microstructure content and microscope instrument conditions.We then built ML models to predict the ultimate compressive strength(UCS)of consolidated molecular solids,by encoding micrographs with different image feature descriptors and training a random forest regressor,and by training an end-to-end deep-learning(DL)model.Results show that instrument-induced pixel intensity signals can affect ML model predictions in a consistently negative way.As a remedy,we explored intensity normalization techniques.It is seen that intensity normalization helps to improve micrograph data quality and ML model robustness,but microscope-induced intensity variations can be difficult to eliminate.

关键词： instrument image eliminate