Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons

Introduction:TAU isoforms as disease mediators:The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions.In Alzheimer’s disease(AD)and related tauopathies,TAU also mislocalizes("TAU missorting")to the soma and the dendrites,where it eventually forms aggregates,the so-called neurofibrillary tangles(for review see Zimmer-Bensch and Zempel,2021;Zempel,2023).

Fine mapping and characterization of a major QTL for grain length,QGl.cau-2D.1,that has pleiotropic effects in synthetic allohexaploid wheat

Grain size is one of the determinants of grain yield,and identifying the genetic loci that control grain size will be helpful for increasing grain yield.In our previous study,a quantitative trait locus(QTL)for grain length(GL),QGl.cau-2D.1,was identified from an F2 population developed from the cross between the natural(TAA10)and synthetic(XX329)allohexaploid wheat.In the present study,we mainly fine mapped and validated its genetic effects.To this end,multiple near-isogenic lines(NILs)were obtained through marker-assisted selection with TAA10 as the recurrent parent.The secondary populations derived from 25 heterozygous recombinants were used for fine mapping of QGl.cau-2D.1,and the allele from XX329 significantly increased GL,thousand-grain weight(TGW),total spikelet number per spike(TSN)and spike compactness(SC).Using NILs for XX329(2D+)and TAA10(2D−),we determined the genetic and pleiotropic effects of QGl.cau-2D.1.The target sequences were aligned with the wheat reference genome RefSeq v2.1 and spanned an~0.9 Mb genomic region.TraesCS2D03G0114900(ortholog of Os03g0594700)was predicted as the candidate gene based on whole-genome re-sequencing and expression analyses.In summary,the map-based cloning of QGl.cau-2D.1 will be useful for improving grain weight with enhanced GL and TSN.

Amyloid-β-induced disruption of axon-initial-segment mitochondria localization:consequences for TAU missorting in Alzheimer's disease pathology

TAU is a neuronal microtubule-associated protein preferentially located in axons.In a battery of neurodegenerative diseases termed"tauopathies,"including Alzheimer's disease (AD),TAU is missorted and abnormally phosphorylated,leading to filamentous accumulations of hyperphosphorylated TAU,a pathological hallmark and potential disease driver of AD and related tauopathies (Zempel,2024).

Developments in the study of Chinese herbal medicine's assessment index and action mechanism for diabetes mellitus

In traditional Chinese medicine(TCM),based on various pathogenic symptoms and the‘golden chamber’medical text,Huangdi Neijing,diabetes mellitus falls under the category‘collateral disease’.TCM,with its wealth of experience,has been treating diabetes for over two millennia.Different antidiabetic Chinese herbal medicines re-duce blood sugar,with their effective ingredients exerting unique advantages.As well as a glucose lowering effect,TCM also regulates bodily functions to prevent diabetes associated complications,with reduced side effects compared to western synthetic drugs.Chinese herbal medicine is usually composed of polysaccharides,saponins,al-kaloids,flavonoids,and terpenoids.These active ingredients reduce blood sugar via various mechanism of actions that include boosting endogenous insulin secretion,enhancing insulin sensitivity and adjusting key enzyme activity and scavenging free radicals.These actions regulate glycolipid metabolism in the body,eventually achiev-ing the goal of normalizing blood glucose.Using different animal models,a number of molecular markers are available for the detection of diabetes induction and the molecular pathology of the disease is becoming clearer.Nonetheless,there is a dearth of scientific data about the pharmacology,dose-effect relationship,and structure-activity relationship of TCM and its constituents.Further research into the efficacy,toxicity and mode of action of TCM,using different metabolic and molecular markers,is key to developing novel TCM antidiabetic formulations.

Small molecular decoys in Alzheimer's disease

Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.

Acylhydrazide and Isatin Schiff Bases as Alternate UV-Laser Desorption Ionization (LDI) Matrices for Low Molecular Weight (LMW) Peptides Analysis

Matrix-assisted laser desorption/ionization (MALDI) is a preferred and widely used mass spectrometric technique for the analysis of macromolecules. Limited UV-LDI matrices are available for the analysis of biomolecules due to the restricted structural features to serve in the laser desorption/ionization mechanism with a problem of background signals appearing in the low mass region. This paper describes the application of Schiff base derivatives of acylhydrazide and isatin as alternate UV-LDI matrices for the analysis of peptides with significantly low background signals. Thirty one compounds have been successfully employed as matrices for the analysis of low molecular weight (LMW) peptides (α-Cyano-4-hydroxycinnamic acid (HCCA), a preferred choice for peptide analysis.

Altered O-GlcNAcylation and mitochondrial dysfunction,a molecular link between brain glucose dysregulation and sporadic Alzheimer's disease

Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.

Combined cell-based therapy strategies for the treatment of Parkinson's disease:focus on mesenchymal stromal cells

Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.

SNP-based identification of QTLs for thousand-grain weight and related traits in wheat 8762/Keyi 5214 DH lines

As important yield-related traits,thousand-grain weight(TGW),grain number per spike(GNS)and grain weight per spike(GWS)are crucial components of wheat production.To dissect their underlying genetic basis,a double haploid(DH)population comprised of 198 lines derived from 8762/Keyi 5214 was constructed.We then used genechip to genotype the DH population and integrated the yield-related traits TGW,GNS and GWS for QTL mapping.Finally,we obtained a total of 18942 polymorphic SNP markers and identified 41 crucial QTLs for these traits.Three stable QTLs for TGW were identified on chromosomes 2D(QTgw-2D.3 and QTgw-2D.4)and 6A(QTgw-6A.1),with additive alleles all from the parent 8762,explaining 4.81–18.67%of the phenotypic variations.Five stable QTLs for GNS on chromosomes 3D,5B,5D and 6A were identified.QGns-5D.1 was from parent 8762,while the other four QTLs were from parent Keyi 5214,explaining 5.89–7.08%of the GNS phenotypic variations.In addition,a stable GWS genetic locus QGws-4A.3 was detected from the parent 8762,which explained 6.08–6.14%of the phenotypic variations.To utilize the identified QTLs,we developed STARP markers for four important QTLs,Tgw2D.3-2,Tgw2D.4-1,Tgw6A.1 and Gns3D.1.Our results provide important basic resources and references for the identification and cloning of genes related to TGW,GNS and GWS in wheat.

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood.Here,we used mouse genetics,mechanical loading,and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts.We created and compared the skeletal phenotypes of control Pkd1^(flox/)+;Wwtr1^(flox/)+,Pkd1^(Oc-cKO),Wwtr1^(Oc-cKO),and Pkd1/Wwtr1^(Oc-cKO)mice to investigate genetic interactions.Consistent with an interaction between polycystins and Wwtr1 in bone in vivo,Pkd1/Wwtr1^(Oc-cKO)mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKOor Pkd1^(Oc-cKO)mice.Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Pkd1/Wwtr1^(Oc-cKO)mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Moreover,we found that Pkd1/Wwtr1^(Oc-cKO)mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of loadinduced mechanosensing gene expression compared to control mice.Finally,control mice treated with a small molecule mechanomimetic,MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control.In contrast,Pkd1/Wwtr1^(Oc-cKO)mice were resistant to the anabolic effects of MS2.These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

MINIMIZING EXCITATION LIGHT LEAKAGE AND MAXIMIZING MEASUREMENT SENSITIVITY FOR MOLECULAR IMAGING WITH NEAR-INFRARED FLUORESCENCE

Near-infraredfluorescence(NIRF)imaging involves the separation of weakfluorescence signals from backscattered excitation light.The measurement sensitivity of current NIRF imaging systems is limited by the excitation light leakage through rejectionfilters.In this contribution,the authors demonstrate that the excitation light leakage can be suppressed upon using appropriatefilter combination and permutations.The excitation light leakage and measurement sensitivity were assessed and compared in this study by computing the transmission ratios of excitation to emission light collected and the signal-to-noise ratios in well-controlled phantom studies with differentfilter combinations and permutations.Using appropriatefilter combinations and permutations,we observe as much as two orders of magnitude reduction in the transmission ratio and higher signal-to-noise ratio.

Benchmark for establishment of organoids from gastrointestinal epithelium and cancer based on available consumables and reagents

Gastrointestinal cancers are a public health problem that threatens the lives of human being. A good experimental model is a powerful tool to promote the uncovering pathogenesis and establish novel treatment methods. High-quality biomedical research requires experimental models to recapitulate the physiological and pathological states of their parental tissues as much as possible. Organoids are such experimental models. Organoids refer to small organlike cellular clusters formed by the expansion and passaging of living tissues in 3D culture medium in vitro.Organoids are highly similar to the original tissues in terms of cellular composition, cell functions, and genomic profiling. Organoids have many advantages, such as short preparation cycles, long-term storage based on cryopreservation, and reusability. In recent years, researchers carried out the establishment of organoids from gastrointestinal mucosa and cancer tissues, and accumulated valuable experiences. In order to promote effective usage and further development of organoid-related technologies in the research of gastrointestinal diseases, this study proposes a benchmark based on utilization of available experimental consumables and reagents, which are involved in the key steps such as collection and pretreatment of biospecimen, organoid construction, organoid cryopreservation and recovery, growth status evaluation, and organoid quality control. We believe that the standard for the construction and preservation of organoids derived from human gastrointestinal epithelium and cancer tissues can provide an important reference for the majority of scientific researchers.

Microtubule affinity regulating kinase(MARK/Par1)isoforms differentially regulate Alzheimer-like TAU missorting and Aβ-mediated synapse pathology

Importance of TAU protein for dementia syndromes:Dementia currently affects about 55 million people worldwide,with Alzheimer's disease(AD)being the most prevalent form.The one crucial pathological hallmark of AD that correlates best with loss of synapses and cognitive decline are the so-called intracellular neurofibrillary tangles composed of mislocalized/missorted and hyperphosphorylated TAU protein(Naseri et al.,2019).Many other neurodegenerative diseases,both genetic and nongenetic,are characterized by neurofibrillary ta ngles or pathological accumulation of the protein TAU and are thus termed"tauopathies".

Breeding design in wheat by combining the QTL information in a GWAS panel with a general genetic map and computer simulation

A large amount of genome-wide association study(GWAS)panels together with quantitative-trait locus(QTL)information associated with breeding-targeted traits have been described in wheat(Triticum aestivum L.).However,the application of mapping results from a GWAS panel to conventional wheat breeding remains a challenge.In this study,we first report a general genetic map which was constructed from 44 published linkage maps.It permits the estimation of genetic distances between any two genetic loci with physical map positions,thereby unifying the linkage relationships between QTL,genes,and genomic markers from multiple genetic populations.Second,we describe QTL mapping in a wheat GWAS panel of 688 accessions,identifying 77 QTL associated with 12 yield and grain-quality traits.Because these QTL have known physical map positions,they could be mapped onto the general map.Finally,we present a design approach to wheat breeding by using known QTL information and computer simulation.Potential crosses between parents in the GWAS panel may be evaluated by the relative frequency of the target genotype,trait correlations in simulated progeny populations,and genetic gain of selected progenies.It is possible to simultaneously improve yield and grain quality by suitable parental selection,progeny population size,and progeny selection scheme.Applying the design approach will allow identifying the most promising crosses and selection schemes in advance of the field experiment,increasing predictability and efficiency in wheat breeding.

Improved Specificity for Breast Cancer Screening Using an Oncogenic(miRNA-21)and a Gene Suppressor(miRNA-195)miRNA in the Serum for a Point of Care(POC)Screening Solution

The overall incidence and burden caused by breast cancer is increasing,affecting the global socio-economic development and life expectancy[1].According to“WHO Global Breast Cancer Initiative(GBCI)reports”,if the mortality rate due to breast cancer can be reduced by 2.4%annually,we may prevent 2.5 million breast cancer deaths between2020-2040.

Exosomes in viral infection:Effects for pathogenesis and treatment strategies

Exosomes are small vesicles that carry molecules from one cell to another.They have many features that make them interesting for research,such as their stability,low immunogenicity,size of the nanoscale,toxicity,and selective delivery.Exosomes can also interact with viruses in diverse ways.Emerging research highlights the significant role of exosomes in viral infections,particularly in the context of diseases like COVID-19,HIV,HBV and HCV.Understanding the intricate interplay between exosomes and the human immune system holds great promise for the development of effective antiviral therapies.An important aspect is gaining clarity on how exosomes influence the immune system and enhance viral infectivity through their inherent characteristics.By leveraging the innate properties of exosomes,viruses exploit the machinery involved in exosome biogenesis to set replication,facilitate the spread of infection,and eliminate immune responses.They can either help or hinder viral infection by modulating the immune system.This review summarizes the recent findings on how exosomes mediate viral infection and how they can be used for diagnosis or therapy.This could lead to new clinical applications of exosomes in disease management.

Prevalence, risk factors, and BRAF mutation of colorectal sessile serrated lesions among Vietnamese patients

BACKGROUND Sessile serrated lesions(SSLs)are considered precancerous colorectal lesions that should be detected and removed to prevent colorectal cancer.Previous studies in Vietnam mainly investigated the adenoma pathway,with limited data on the serrated pathway.AIM To evaluate the prevalence,risk factors,and BRAF mutations of SSLs in the Vietnamese population.METHODS This is a cross-sectional study conducted on patients with lower gastrointestinal symptoms who underwent colonoscopy at a tertiary hospital in Vietnam.SSLs were diagnosed on histopathology according to the 2019 World Health Organi-zation classification.BRAF mutation analysis was performed using the Sanger DNA sequencing method.The multivariate logistic regression model was used to determine SSL-associated factors.RESULTS There were 2489 patients,with a mean age of 52.1±13.1 and a female-to-male ratio of 1:1.1.The prevalence of SSLs was 4.2%[95%confidence interval(CI):3.5-5.1].In the multivariate analysis,factors significantly associated with SSLs were age≥40[odds ratio(OR):3.303;95%CI:1.607-6.790],male sex(OR:2.032;95%CI:1.204-3.429),diabetes mellitus(OR:2.721;95%CI:1.551-4.772),and hypertension(OR:1.650,95%CI:1.045-2.605).The rate of BRAF mutations in SSLs was 35.5%.CONCLUSION The prevalence of SSLs was 4.2%.BRAF mutations were present in one-third of SSLs.Significant risk factors for SSLs included age≥40,male sex,diabetes mellitus,and hypertension.

Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Transcriptomic and epigenomic landscapes of muscle growth during the postnatal period of broilers

Background Broilers stand out as one of the fastest-growing livestock globally,making a substantial contribution to animal meat production.However,the molecular and epigenetic mechanisms underlying the rapid growth and development of broiler chickens are still unclear.This study aims to explore muscle development patterns and regulatory networks during the postnatal rapid growth phase of fast-growing broilers.We measured the growth performance of Cornish(CC)and White Plymouth Rock(RR)over a 42-d period.Pectoral muscle samples from both CC and RR were randomly collected at day 21 after hatching(D21)and D42 for RNA-seq and ATAC-seq library construction.Results The consistent increase in body weight and pectoral muscle weight across both breeds was observed as they matured,with CC outpacing RR in terms of weight at each stage of development.Differential expression analysis identified 398 and 1,129 genes in the two dimensions of breeds and ages,respectively.A total of 75,149 ATAC-seq peaks were annotated in promoter,exon,intron and intergenic regions,with a higher number of peaks in the promoter and intronic regions.The age-biased genes and breed-biased genes of RNA-seq were combined with the ATAC-seq data for subsequent analysis.The results spotlighted the upregulation of ACTC1 and FDPS at D21,which were primarily associated with muscle structure development by gene cluster enrichment.Additionally,a noteworthy upregulation of MUSTN1,FOS and TGFB3 was spotted in broiler chickens at D42,which were involved in cell differentiation and muscle regeneration after injury,suggesting a regulatory role of muscle growth and repair.Conclusions This work provided a regulatory network of postnatal broiler chickens and revealed ACTC1 and MUSTN1 as the key responsible for muscle development and regeneration.Our findings highlight that rapid growth in broiler chickens triggers ongoing muscle damage and subsequent regeneration.These findings provide a foundation for future research to investigate the functional aspects of muscle development.