Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

Elizabeth Fisher and Victor collaboratively for many years on Tybulewicz have worked the Down syndrome mouse model project. Elizabeth Fisher＇s background is in molecular genetics and mouse models, with an interest in anueploidy. Victor Tybulewicz is an immunologist whose primary interest is in signal transduction from the antigen receptors of B and T cells.

Applications,of fluorescence lifetime imaging in clinical medicine

Fluorescence lifetime is not only associated with the molecular structure f fuorophores,but alsostrongly depends on the environment around them,which llows fuorescence lifetime imagingmicroscopy(FLIM)to be used as a tool for precise measurement of the cell or tisue microenvironment,This review introduces the basic principle of fuorescence lifetime imagingtechnology and its application in clinical medicine,including research and diagnosis of diseases inskin,brain,eyes,mouth,bone,blood vessels and cavity organs,and drug evaluation.As anoninvasive,nontoxic and nonionizing radiation technique,FLIM demonstrates excellent per-formance with high sensitivity and specificity,which allows to determine precise position of thelesion and,thus,has good potential for application in biomedical research and clinical diagnosis.

Quo vadis motor neuron disease?

Motor neuron disease(MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetiopathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena.

Ex vivo 100 μm isotropic diffusion MRI-based tractography of connectivity changes in the end-stage R6/2 mouse model of Huntington's disease

Background:Huntington's disease is a progressive neurodegenerative disorder.Brain atrophy,as measured by volumetric magnetic resonance imaging(MRI),is a downstream consequence of neurodegeneration,but microstructural changes within brain tissue are expected to precede this volumetric decline.The tissue microstructure can be assayed non-invasively using diffusion MRI,which also allows a tractographic analysis of brain connectivity.Methods:We here used ex vivo diffusion MRI(11.7 T)to measure microstructural changes in different brain regions of end-stage(14 weeks of age)wild type and R6/2 mice(male and female)modeling Huntington's disease.To probe the microstructure of different brain regions,reduce partial volume effects and measure connectivity between different regions,a 100μm isotropic voxel resolution was acquired.Results:Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice,mean,axial,and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice.Whole brain streamlines were only reduced in male R6/2 mice,but streamline density was increased.Region-to-region tractography indicated reductions in connectivity between the cortex,hippocampus,and thalamus with the striatum,as well as within the basal ganglia(striatum—globus pallidus—subthalamic nucleus—substantia nigra—thalamus).Conclusions:Biological sex and left/right hemisphere affected tractographic results,potentially reflecting different stages of disease progression.This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions.In a translation setting,these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models,as well as patients with Huntington's disease.

LRRK2的常见变异体与散发性帕金森病无关

Multiple mutations in the gene for the leucine-rich repeat kinase (LKRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson’s disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson’s disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson’s disease risk.

Factors influencing the effects of repetitive transcranial magnetic stimulation in Parkinson's disease

Barker first used transcranial magnetic stimulation in 1985 in human brain function research. Since then, it has gradually been developed into a secure and non-invasive treatment method for neurological diseases. In 1994, Pascual Leone first used it for the treatment of Parkinson's disease(PD) and observed an improvement in the motor symptoms of most of the patients. Recent studies have confirmed that both motor and non-motor symptoms of patients with PD could be improved through biochemical, electrophysiological, and functional magnetic resonance imaging analysis. Different therapeutic applications can be achieved by adjusting the stimulation parameters.Physical factors affecting the therapeutic effect include the shape and size of the coil, array orientation, materials and intensity, frequency of stimulus, etc.; the biological factors include stimulating targets, baseline, circadian rhythms, cerebral cortex thickness, and so on. This paper will review these factors and provide a reference for future research.

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Background:The molecular heterogeneity of Alzheimer’s amyloid-β(Aβ)deposits extends well beyond the clas-sic Aβ1-40/Aβ1-42 dichotomy,substantially expanded by multiple post-translational modifications that increase the proteome diversity.Numerous truncated fragments consistently populate the brain Aβpeptidome,and their homeo-static regulation and potential contribution to disease pathogenesis are largely unknown.Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease(AD).Methods:Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-char-acterized AD cases using custom-generated monoclonal antibody 18H6-specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42-in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteo-forms.Circular dichroism,thioflavin-T binding,and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues,whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics.Results:All types of amyloid deposits contained the probed Aβepitopes,albeit expressed in different proportions.Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques,strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues.In vivo clearance studies demonstrated a fast brain efflux of N-termi-nally truncated and full-length monomeric forms whereas their oligomeric counterparts-particularly of Aβ4-40 and Aβ4-42-consistently exhibited enhanced brain retention.Conclusions:The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation,self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.

No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors

Background:IgG-class autoantibodies to N-Methyl-D-Aspartate(NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis.Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results.We measured NMDA antibodies in a large,well phenotyped sample of Parkinson patients without and with cognitive impairment(n=296)and controls(n=295)free of neuropsychiatric disease.Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.Methods:NMDA antibodies were analysed in the serum of patients and controls using well established validated assays.We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.Results:The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients(13%)than in controls(22%)and higher than in previous studies in both groups.NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment,nor with quantitative indicators of disease severity and cognitive impairment.A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.Conclusion:It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g.to Parkinson disease with dementia,while NMDA IgG antibodies define a separate disease of its own.

Induced pluripotent stem cells(iPSCs):molecular mechanisms of induction and applications

The induced pluripotent stem cell(iPSC)technology has transformed in vitro research and holds great promise to advance regenerative medicine.iPSCs have the capacity for an almost unlimited expansion,are amenable to genetic engineering,and can be differentiated into most somatic cell types.iPSCs have been widely applied to model human development and diseases,perform drug screening,and develop cell therapies.In this review,we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications.We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs.We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency.Subsequently,we discuss various iPSC-based cellular models,from mono-cultures of a single cell type to complex three-dimensional organoids,and how these models can be applied to elucidate the mechanisms of human development and diseases.We use examples of neurological disorders,coronavirus disease 2019(COVID-19),and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells.We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies.Finally,we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.