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Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

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Neural Regeneration Research 2025年第6期20卷 1711-1712页

作者： Haoqi Sun Shiqian Shen Robert j.thomas M.Brandon Westover Can Zhang Department of Neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Center for Translational Pain Research Department of AnesthesiaCritical Care and Pain MedicineMassachusetis General HospitalHarvard Medical SchoolBostonMAUSA Division of Pulmonary Critical Care and Sleep MedicineDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Genetics and Aging Research Unit McCance Center for Brain HealthMass General Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

关键词： Alzheimer inflammation hypothesis

Outcomes of critically ill children with pre-existing mental health conditions

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Pediatric Investigation 2024年第2期8卷 108-116页

作者： Conrad Krawiec Morgan Cash Gary Ceneviva Zizhong Tian Shouhao Zhou Neal j.thomas Department of Pediatrics Pediatric Critical Care MedicinePenn State Hershey Children's HospitalPennsylvaniaUSA Department of Public Health Sciences Division of Biostatistics and BioinformaticsPennsylvania State University College of MedicinePennsylvaniaUSA Department of Public Health_Sciences Pennsylvania State University College of MedicinePennsylvaniaUSA

Importance:Critically ill children with pre-existing mental health conditions may have an increased risk of poor health ***:We aimed to evaluate if pre-existing mental health conditions in critically ill pediatric patients would be associated with worse clinical outcomes,compared to children with no documented mental health ***:This retrospective observational cohort study utilized the TriNetX electronic health record database of critically ill subjects aged 12-18 *** were analyzed for demographics,pre-existing conditions,diagnostic,medication,procedural codes,and ***:From a dataset of 102027 critically ill children,we analyzed 1999 subjects(284[14.2%]with a pre-existing mental health condition and 1715[85.8%]with no pre-existing mental health condition).Multivariable analysis demonstrated that death within one year was associated with the presence of pre-existing mental health conditions(odds ratio 8.97[3.48-23.15],P<0.001),even after controlling for the presence of a complex chronic ***:The present study demonstrates that the presence of pre-existing mental health conditions was associated with higher odds of death within 1 year after receiving critical ***,the confidence interval was wide and hence,the findings are *** studies with a larger sample size may be necessary to evaluate the true long-term impact of children with pre-existing mental health conditions who require critical care services.

关键词： Critical care Psychiatry Psychology Public health

Theory and classification of mass extinction causation

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National Science Review 2024年第1期11卷 16-36页

作者： thomas j.Algeo jun Shen State Key Laboratory of Biogeology and Environmental Geology China University of Geosciences—Wuhan State Key Laboratory of Geological Processes and Mineral Resources China University of Geosciences—Wuhan Department of Geosciences University of Cincinnati

Theory regarding the causation of mass extinctions is in need of systematization, which is the focus of this contribution. Every mass extinction has both an ultimate cause, i.e. the trigger that leads to various climato-environmental changes, and one or more proximate cause(s), i.e. the specific climato-environmental changes that result in elevated biotic mortality. With regard to ultimate causes, strong cases can be made that bolide(i.e. meteor) impacts, large igneous province(LIP) eruptions and bioevolutionary events have each triggered one or more of the Phanerozoic Big Five mass extinctions, and that tectono-oceanic changes have triggered some second-order extinction events. Apart from bolide impacts, other astronomical triggers(*** flares, gamma bursts and supernova explosions) remain entirely in the realm of speculation. With regard to proximate mechanisms, most extinctions are related to either carbon-release or carbon-burial processes, the former being associated with climatic warming, ocean acidification, reduced marine productivity and lower carbonate δ13C values, and the latter with climatic cooling, increased marine productivity and higher carbonate δ13C values. Environmental parameters such as marine redox conditions and terrestrial weathering intensity do not show consistent relationships with carbon-cycle *** this context, mass extinction causation can be usefully classified using a matrix of ultimate and proximate factors. Among the Big Five mass extinctions, the end-Cretaceous biocrisis is an example of a bolide-triggered carbon-release event, the end-Permian and end-Triassic biocrises are examples of LIP-triggered carbon-release events, and the Late Ordovician and Late Devonian biocrises are examples of bioevolution-triggered carbon-burial events. Whereas the bolide-impact and LIP-eruption mechanisms appear to invariably cause carbon release, bioevolutionary triggers can result in variable carbon-cycle changes, e.g. carbon burial durin

关键词： biocrisis ultimate cause proximate cause bolide large igneous province bioevolutionary event

EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell jun Okabe Ishant Khurana thomas Karagiannis julia j.Liang Lina Mariana thomas Loudovaris thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release *** type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-*** of these cells leads to a lifelong dependence on exogenous insulin administration for ***,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell *** and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation *** transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 *** the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell *** transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin *** EZH2 is fundamental toβ-cell regenerative *** pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex *** pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： jiang-Hui Wang Dominic j.Gessler Wei Zhan thomas L.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

Role of complex organic arsenicals in food in aggregate exposure to arsenic

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journal of Environmental Sciences 2016年第11期28卷 86-96页

作者： David j.thomas Karen Bradham Pharmacokinetics Branch Integrated Systems Toxicology Division National Health and Environmental Effects Research Laboratory Offilce of Research and Development U.S. Environmental Protection Agency Research Triangle Parle NC 27709 USA Public Health Chemistry Branch Exposure Methods and Measurements Division National Exposure Research Laboratory Offilce of Researchand Development U.S. Environmental Protection Agency Research Triangle Park NC 27709 USA

For much of the world＇s population, food is the major source of exposure to *** to this non-essential metalloid at relatively low levels may be linked to a wide range of adverse health effects. Thus, evaluating foods as sources of exposure to arsenic is important in assessing risk and developing strategies that protect public health. Although most emphasis has been placed on inorganic arsenic as human carcinogen and toxicant, an array of arsenic-containing species are found in plants and animals used as foods. Here,we 2evaluate the contribution of complex organic arsenicals（arsenosugars, arsenolipids,and trimethylarsonium compounds） that are found in foods and consider their origins,metabolism, and potential toxicity. Commonalities in the metabolism of arsenosugars and arsenolipids lead to the production of di-methylated arsenicals which are known to exert many toxic effects. Evaluating foods as sources of exposure to these complex organic arsenicals and understanding the formation of reactive metabolites may be critical in assessing their contribution to aggregate exposure to arsenic.

关键词： Arsenic Arsenobetaine Arsenolipids Arsenosugars

Examining the“revisability”benefit of hip resurfacing arthroplasty

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World journal of Orthopedics 2024年第6期15卷 554-559页

作者： jose George Adam j Taylor thomas P Schmalzried Department of Orthopedics Harbor UCLA Medical CenterTorranceCA 90509United States

BACKGROUND Hip resurfacing arthroplasty(HRA)is an alternative to total hip arthroplasty(THA)that is typically reserved for young active patients because it preserves ***,the benefits of HRA only hold true if conversion THA after failed HRA provides acceptable *** To compare patient reported outcomes for conversion THA after HRA failure to primary *** A retrospective review of 36 patients(37 hips)that underwent conversion THA for failed HRA between October 2006 and May 2019 by a single surgeon was *** reported outcomes[modified Harris Hip Score(mHHS),University of California Los Angeles(UCLA)activity score]were obtained via an email-based responder-anonymous *** were compared to normative data of a primary THA cohort with similar *** analysis was performed comparing outcomes of conversion THA for adverse local tissue reaction(ALTR)vs all other causes for *** The study group had a lower mHHS than the control group(81.7±13.8 vs 90.2±11.6,P<0.01);however,both groups had similar UCLA activity levels(7.5±2.3 vs 7.2±1.6,P=0.51).Patients that underwent conversion for non-ATLR causes had similar mHHS(85.2±11.5 vs 90.2±11.6,P=0.11)and higher UCLA activity levels(8.5±1.8 vs 7.2±1.6,P<0.01)compared to the control *** that underwent conversion for ATLR had worse mHHS(77.1±14.5 vs 90.2±11.6,P<0.01)and UCLA activity levels(6.1±2.3 vs 7.2±1.6,P=0.05)when compared to the control *** Patient outcomes equivalent to primary THA can be achieved following HRA conversion to ***,inferior outcomes were demonstrated for ALTR-related HRA *** selection and perhaps further studies examining alternative HRA bearing surfaces should be considered.

关键词： Total hip arthroplasty Hip resurfacing arthroplasty Conversion total hip arthroplasty Adverse local tissue reaction Patient reported outcome measures

Energy and blast performance of beryllium in a model thermobaric composition in comparison with aluminum and magnesium

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Defence Technology（防务技术） 2024年第6期36卷 13-19页

作者： thomas M.Klapotke Stanisław Cudziło Waldemar A.Trzcinski jozef Paszula Energetic Materials Research Department of ChemistryUniversity of Munich(LMU)Butenandtstrasse 5-13(D)81377MunichGermany Military University of Technology Faculty of Advanced Technologies and ChemistrySylwester Kaliski Str.200-908WarsawPoland

A direct comparison is made between the effectiveness of Al,Mg,and Be powders as additional fuels in model thermobaric compositions containing 20%fuel,20%ammonium perchlorate,and 60%RDX(1,3,5-Trinitro-1,3,5-triazacyclohexane)passivated with *** determined calorimetric measurements of the heat of detonation,along with the overpressure histories in an explosion chamber filled with nitrogen,were used to determine the quasi-static pressure(QSP)under anaerobic *** measurements were also performed in a semi-closed bunker,and all blast wave parameters generated after the detonation of 500 g charges of the tested explosives were *** calorimetry results,QSP values,and blast wave parameters(pressure amplitude,specific and total impulses)clearly indicate that Be is much more effective as an additional fuel than either Al or Mg in both anaerobic post-detonation reactions as well as the subsequent aerobic *** heat of detonation of the RDXwax/AP/Be explosive mixture is over 40%and 50%higher than that of the mixture containing aluminum and magnesium instead of beryllium,***,the TNT equivalent of the Be-containing composition due to the overpressure in the nitrogen-filled explosion chamber is 1.66,while the equivalent calculated using an air shock wave-specific impulse at a distance of 2.5 m is equal to *** high values of these parameters confirm the high reactivity of beryllium in both the anaerobic and aerobic stages of the thermobaric explosion.

关键词： Thermobaric explosives Beryllium Heat of detonation Quasi-static overpressure Blast wave parameters

Nearly Singular Integrals in 3D Stokes Flow

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Communications in Computational Physics 2013年第10期14卷 1207-1227页

作者： Svetlana Tlupova j.thomas Beale Department of Mathematics University of MichiganAnn ArborMI 48109-1043USA Department of Mathematics Duke UniversityDurhamNC 27708-0320USA

A straightforward method is presented for computing three-dimensional Stokes flow,due to forces on a surface,with high accuracy at points near the *** flowquantities arewritten as boundary integrals using the free-spaceGreen’s *** evaluate the integrals near the boundary,the singular kernels are regularized and a simple quadrature is applied in coordinate *** order accuracy is obtained by adding special corrections for the regularization and discretization errors,derived here using local asymptotic *** tests demonstrate the uniform convergence rates of the method.

关键词： Stokes equations boundary integral equation method nearly singular integrals