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The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

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World journal of Gastroenterology 2007年第1期13卷 104-124页

作者： Stephan Menne paul j Cote Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca New York United States Department of Microbiology and Immunology Georgetown University Medical Center Washington DC United States

This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and preventi

关键词： Woodchuck Woodchuck hepatitis virus Hepatitis B virus Neonatalacquired infection Adult-acquired infection Resolution Chronicity Humoral immune response Cellular immune response Antiviraltherapy Immunotherapy Combination therapy Hepatocellular carcinoma

Reconstituting mammalian spermatogenesis using stem ：ells

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Asian journal of Andrology 2011年第6期13卷 795-796页

作者： paul j Turek The Turek Clinic San Francisco CA 94133 USA

While stock markets and economies are smoldering all over the world, stem cell science is on fire. The promise of curing many untreatable forms of human male infertility is now one small step closer based on a recent paper in Cell. In this work, scientists from Kyoto University in japan created mature, fertile sperm from embryonic and induced pluripotent stem cells by grabbing the primitive germ cells called primordial germ cells just as they were being made from their pluripotent precursors in vitro and transplanting them back into genetically sterile mice.

关键词： stock markets economies stem cell science

Erratum to“The power of many brains:Catalyzing neuropsychiatric discovery through open neuroimaging data and large-scale collaboration”[Sci Bull 2024;69:1536-1555]

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Science Bulletin 2024年第17期69卷 2793-2793页

作者： Bin Lu Xiao Chen Francisco Xavier Castellanos paul MThompson Xi-Nian Zuo Yu-Feng Zang Chao-Gan Yan CAS Key Laboratory of Behavioral Science Institute of PsychologyBeijing 100101China Department of Psychology University of Chinese Academy of SciencesBeijing 100101China Department of Child and Adolescent Psychiatry NYU Grossman School of MedicineNew York 10016USA Nathan Kline Institute for Psychiatric Research Orangeburg 10962USA Imaging Genetics Center Mark&Mary Stevens Institute for Neuroimaging&InformaticsKeck School of MedicineUniversity of Southern CaliforniaLos Angeles 90033USA Developmental Population Neuroscience Research Center IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijing 100875China National Basic Science Data Center Beijing 100190China Centre for Cognition and Brain Disorders The Affiliated Hospital of Hangzhou Normal UniversityHangzhou 310004China Institute of Psychological Science Hangzhou Normal UniversityHangzhou 310030China Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairment Hangzhou 311121China International Big-Data Center for Depression Research Institute of PsychologyChinese Academy of SciencesBeijing 100101China Magnetic Resonance Imaging Research Center Institute of PsychologyChinese Academy of SciencesBeijing 100101China

The publisher regrets to note that reference citation errors have occurred in panels b,c,e-l in Fig 2 and the sentence“However,the literature reports both decreased and increased intra-network functional connections among patients with depression[115,116].”The publisher would like to apologise for any inconvenience *** neuroimaging findings in major depressive disorder.(a)Decreased intra-DMN FC is observed in recurrent MDD patients[35].(b)Eight-week antidepressant treatment reduce extensive large-scale functional networks[107].(c)Reduced global and local efficiency(Eglob/Eloc)are revealed in MDD patients[108].(d)Structural variations of the cortex and subcortical nuclei are found in ENIGMA-MDD studies[82].(e)Accelerated brain aging based on functional MRI is observed in MDD patients[114].(f)Accelerated brain aging based on structural MRI is observed in MDD patients[115].(g)Two subtypes of MDD can be identified through DMN FC[127].(h)A significant schizophrenia PRS by MDD interaction for rostral anterior cingulate cortex thickness is found in the UK Biobank dataset[215].(i)Stability of the four MDD subtypes based on FC[126].(j)The two subtypes of MDD exhibit distinct patterns of FC within and between SMS,DMN,and subcortical structures[130].(k)Performance of the functional connectivity-based classifiers across two multicenter datasets[135].(l)Salient brain regions that serve as important classification features for the graph convolutional network-based classifier[136].Brain-PAD:brain-predicted age difference;DAN:dorsal attention network;DMN:default mode network;FC:functional connectivity;FEDN:first-episode and drug-naïve;FPN:frontoparietal network;GCN:graph convolutional neural network;HC:healthy control;linear-SVM:linear support vector machine;MDD:major depressive disorder;mddrest:REST-meta-MDD dataset;NC:normal control;RACC:rostral anterior cingulate cortex;PRS:polygenic risk score;psymri:PsyMRI dataset;rbf-SVM:radial basis function support vector

关键词： cortex network scale

A facile strategy for tuning the density of surface-grafted biomolecules for melt extrusion-based additive manufacturing applications

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Bio-Design and Manufacturing 2024年第3期7卷 277-291页

作者： I.A.O.Beeren G.Dos Santos P.j.Dijkstra C.Mota j.Bauer H.Ferreira Rui L.Reis N.Neves S.Camarero-Espinosa M.B.Baker L.Moroni Department of Complex Tissue Regeneration MERLN Institute for Technology-Inspired Regenerative MedicineMaastricht University6229 ER MaastrichtThe Netherlands 3B’s Research Group I3Bs–Research Institute on BiomaterialsBiodegradables and BiomimeticsHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineUniversity of MinhoAveParkZona Industrial da Gandra4805-017 BarcoGuimarãesPortugal ICVS/3B’s-PT Government Associate Laboratory 4806-909 Braga/GuimarãesPortugal POLYMAT University of the Basque Country UPV/EHU20018 Donostia/San SebastiánSpain IKERBASQUE Basque Foundation for Science48009 BilbaoSpain

Melt extrusion-based additive manufacturing(ME-AM)is a promising technique to fabricate porous scaffolds for tissue engi-neering ***,most synthetic semicrystalline polymers do not possess the intrinsic biological activity required to control cell *** of biomolecules on polymeric surfaces of AM scaffolds enhances the bioactivity of a construct;however,there are limited strategies available to control the surface ***,we report a strategy to tune the surface density of bioactive groups by blending a low molecular weight poly(ε-caprolactone)5k(PCL5k)containing orthogonally reactive azide groups with an unfunctionalized high molecular weight PCL75k at different *** porous three-dimensional(3D)scaf-folds were then fabricated using a high weight percentage(75 wt.%)of the low molecular weight PCL *** a proof-of-concept test,we prepared films of three different mass ratios of low and high molecular weight polymers with a thermopress and reacted with an alkynated fluorescent model compound on the surface,yielding a density of 201-561 pmol/cm^(2).Subsequently,a bone morphogenetic protein 2(BMP-2)-derived peptide was grafted onto the films comprising different blend compositions,and the effect of peptide surface density on the osteogenic differentiation of human mesenchymal stromal cells(hMSCs)was *** two weeks of culturing in a basic medium,cells expressed higher levels of BMP receptor II(BMPRII)on films with the conjugated *** addition,we found that alkaline phosphatase activity was only significantly enhanced on films contain-ing the highest peptide density(i.e.,561 pmol/cm^(2)),indicating the importance of the surface *** together,these results emphasize that the density of surface peptides on cell differentiation must be considered at the cell-material ***,we have presented a viable strategy for ME-AM community that desires to tune the bulk and surface functionality via blending of(m

关键词： Additive manufacturing Blending Surface functionalization Surface density Click chemistry Human

Hyperbolic Divergence Cleaning in Lattice Boltzmann Magnetohydrodynamics

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Communications in Computational Physics 2023年第1期33卷 245-272页

作者： paul j.Dellar OCIAM Mathematical InstituteUniversity of OxfordRadcliffe Observatory QuarterOxford OX26GGUK

Magnetohydrodynamics couples the Navier-Stokes and Maxwell’s equations to describe the flow of electrically conducting fluids in magnetic ***’s equations require the divergence of the magnetic field to vanish,but this condition is typically not preserved exactly by numerical *** can develop artifacts because structural properties of the magnetohydrodynamic equations then fail to *** with hyperbolic divergence cleaning permits a nonzero divergence that evolves under a telegraph equation,designed to both damp the divergence,and propagate it away from any sources,such as poorly resolved regions with large spatial gradients,without significantly increasing the computational *** show that existing lattice Boltzmann algorithms for magnetohydrodynamics already incorporate hyperbolic divergence cleaning,though they typically use parameter values for which it reduces to parabolic divergence cleaning under a slowly-varying *** recover hyperbolic divergence cleaning by adjusting the relaxation rate for the trace of the tensor that represents the electric field,and absorb the contribution from the symmetric-traceless part of this tensor using a change of *** experiments confirm that the qualitative behaviour changes from parabolic to hyperbolic when the relaxation time for the trace of the electric field tensor is increased.

关键词： Magnetohydrodynamics divergence cleaning telegraph equations matrix collision operators linear viscoelasticity

Evolving landscape and novel treatments in, metastatic castrate-resistant prostate cancer

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Asian journal of Andrology 2013年第3期15卷 342-349页

作者： paul j Toren Martin E Gleave Department of Urologic Sciences Faculty of Medicine University of British Columbia Vancouver BC V5Z 1M9 Canada

Treatment options for castrate-resistant prostate cancer （CRPC） have advanced in recent years and significantly improved the Outlook for patients with this aggressive and lethal disease. Further understanding of the biology＇of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor （AR） directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

关键词： prostate cancer treatment resistance androgen receptor antagonists molecular targets

Adaptation in brain structure and respiratory and olfactory structures across environmental gradients in African and North American muroid rodents

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Integrative Zoology 2024年第1期19卷 165-181页

作者： Peter j.TAYLOR Aluwani NENGOVHELA Christiane DENYS Graham R.SCOTT Catherine M.IVY Department of Zoology School of Natural and Mathematical SciencesUniversity of VendaThohoyandouSouth Africa Afromontane Unit Department of Zoology and EntomologyUniversity of the Free StatePhuthaditjhabaSouth Africa Department of Mammalogy National MuseumBloemfonteinSouth Africa Institut de Systématique EvolutionBiodiversité(ISYEB)Muséum National d’Histoire NaturelleCNRSSorbonne UniversitéEPHEUniversitéDes AntillesParisFrance Department of Biology McMaster UniversityHamiltonOntarioCanada Guglielmo and Shoemaker Labs Advanced Facility for Avian ResearchUniversity of Western OntarioLondonOntarioCanada

Morphometric studies of 3D micro CT-scanned images can provide insights into the evolution of the brain and sensory structures but such data are still scarce for the most diverse mammalian order of *** reviewed and new data,we tested for convergence to extreme aridity and high elevation in the sensory and brain morphology of rodents,from morphometric data from micro-CT X-ray scans of 174 crania of 16 species of three distantly re-lated African murid(soft-furred mice,Praomyini,laminate-toothed rats,Otomyini,and gerbils,Gerbillinae)clades and one North American cricetid(deer mice and white-footed mice,Peromyscus)*** studies demon-strated convergent evolution acting on the oval window area of the cochlea(enlarged in extremely arid-adapted species of Otomyini and Gerbillinae)and on endocranial volume(reduced in high elevation taxa of Otomyini and Peromyscus).However,contrary to our predictions,we did notfind evidence of convergence in brain struc-ture to aridity,or in the olfactory/respiratory system(turbinate bones)to high *** structure differed,particularly in the petrosal lobules of the cerebellum and the olfactory bulbs,between Otomyini and Gerbillinae,with extreme arid-adapted species in each clade being highly divergent(not convergent)from other species in the same *** observed greater“packing”of the maxillary turbinate bones,which have important respiratory functions,in Peromyscus mice from high and low elevations compared to the high-elevation African Praomyini,but more complex patterns within Peromyscus,probably related to trade-offs in respiratory physiology and heat exchange in the nasal epithelium associated with high-elevation adaptation.

关键词： 3D morphometrics Africa brain size North America Rodentia sensory evolution

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

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General Psychiatry 2024年第1期37卷 103-111页

作者： Viktor H Ahlqvist Christina Dardani paul Madley-Dowd Harriet Forbes jessica Rast Caichen Zhong Renee M Gardner Christina Dalman Kristen Lyal cRAIG Newschaffer Torbjorn Tomson Michael Lundberg Daniel Berglind Neil M Davies Brian K Lee Cecilia Magnusson Dheeraj Rai Department of Global Public Health Karolinska InstitutetStockholmSweden Medical Research Council Integrative Epidemiology Unit Bristol Medical SchoolUniversity of BristolBristolUK Centre for Academic Mental Health Population Health SciencesBristol Medical SchoolUniversity of BristolBristolUK Faculty of Epidemiology and Population Health London School of Hygiene and Tropical MedicineLondonUK A.j.Drexel Autism Institute Drexel UniversityPhiladelphiaPAUSA Department of Epidemiology and Biostatistics School of Public HealthDrexel UniversityPhiladelphiaPAUSA College of Health and Human Development Pennsylvania State UniversityState CollegePAUSA Department of Clinical Neuroscience Karolinska InstitutetStockholmSweden Centre for Epidemiology and Community Medicine Region StockholmStockholmSweden K.G jebsen Center for Genetic Epidemiology Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway Division of Psychiatry University Collge LondonLondonUK Department of Statistical Sciences University Cllge LondonLondonK NIHR Biomedical Research Centre University of BristoBristolUK Avon and Wiltshire Partnership NHS Mental Health TrustBristolUK

Background Psychiatric comorbidities are common in patients with *** for the co-occurrence of psychiatric conditions and epilepsy remain poorly *** We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these *** Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with *** then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score ***,we assessed the potential bidirectional relationships using two-sample Mendelian *** In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric *** example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric *** Psychiatric comorbidities are common in patients with *** correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric *** findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psy

关键词： epilepsy Psychiat lifetime

Optimizing laser coupling,matter heating,and particle acceleration from solids using multiplexed ultraintense lasers

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Matter and Radiation at Extremes 2024年第4期9卷 16-28页

作者： Weipeng Yao Motoaki Nakatsutsumi Sébastien Buffechoux Patrizio Antici Marco Borghesi Andrea Ciardi Sophia N.Chen Emmanuel d’Humières Laurent Gremillet Robert Heathcote Vojtech Horny paul McKenna Mark N.Quinn Lorenzo Romagnani Ryan Royle Gianluca Sarri Yasuhiko Sentoku Hans-Peter Schlenvoigt Toma Toncian Olivier Tresca Laura Vassura Oswald Willi julien Fuchs LULI-CNRS CEASorbonne UniversitéEcole PolytechniqueInstitut Polytechnique de ParisF-91128 Palaiseau CedexFrance Sorbonne Université Observatoire de ParisUniversité PSLCNRSLERMAF-75005 ParisFrance INRS-EMT 1650 BoulLionel-BouletVarennesQuebec J3X 1S2Canada Center for Plasma Physics School of Mathematics and PhysicsQueen’s University BelfastBelfast BT71NNUnited Kingdom “Horia Hulubei”National Institute for Physics and Nuclear Engineering 30 Reactorului StreetRO-077125 Bucharest-MagureleRomania University of Bordeaux Centre Lasers Intenses et ApplicationsCNRSCEAUMR 5107F-33405 TalenceFrance CEA DAMDIFF-91297 ArpajonFrance Université Paris-Saclay CEALMCE91680 Bruyères-le-ChatelFrance Central Laser Facility STFC Rutherford Appleton LaboratoryDidcotUnited Kingdom SUPA Department of PhysicsUniversity of StrathclydeGlasgow G40NGUnited Kingdom Department of Physics University of NevadaRenoNevada 89557USA Institute of Laser Engineering Osaka University2-6 YamadaokaSuitaOsaka 565-0871Japan Institut fur Laser und Plasmaphysik Heinrich Heine Universitat DusseldorfDusseldorfGermany

Realizing the full potential of ultrahigh-intensity lasers for particle and radiation generation will require multi-beam arrangements due to technology ***,we investigate how to optimize their coupling with solid ***,we show that overlapping two intense lasers in a mirror-like configuration onto a solid with a large preplasma can greatly improve the generation of hot electrons at the target front and ion acceleration at the target *** underlying mechanisms are analyzed through multidimensional particle-in-cell simulations,revealing that the self-induced magnetic fields driven by the two laser beams at the target front are susceptible to reconnection,which is one possible mechanism to boost electron *** addition,the resistive magnetic field generated during the transport of the hot electrons in the target bulk tends to improve their *** simulations also indicate that such effects can be further enhanced by overlapping more than two laser beams.

关键词： laser acceleration particle