Unveiling DNA methylation in Alzheimer’s disease:a review of array-based human brain studies

The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.

Harnessing the power of pericytes and hypoxia-inducible factor-1 to modulate stroke outcome

The human brain has exceedingly high metabolic demands.The cerebral vasculature has the critical task of providing sufficient blood supply to meet this demand.The sudden interruption of blood flow to the brain,as observed during ischemic stroke,results in acute neurological injury with devastating consequences-a high rate of adult disability and death.Ischemic stroke is thus a vascular disorder with a dramatic neurological impact.There is an urgent need for more effective disease management to combat stroke as current treatment paradigms,focusing on vascular recanalization and neuroprotection,have only limited clinical success.Since accumulating data suggests successful long-term neuroprotection is unlikely to be achievable without a functional microvascular network,strategies that reduce endothelial dysfunction could be indispensable.Encouragingly,very recent evidence highlighted herein suggests protecting the humble pericyte may be a new approach to reaching this goal.

Sustainable Intensification and Large-scale Operation of Cultivated Land Use at the Farmers’ Scale:A Case Study of Shandong Province,China

Sustainable intensification of cultivated land use(SICLU) and large-scale operations(LSO) are widely acknowledged strategies for enhancing agricultural performance.However,the existing literature has faced challenges in precisely defining SICLU and constructing comprehensive indicators,which has hindered the exploration of factors influencing LSO within the SICLU framework.To address this gap,we integrated self-efficacy theory into the design of an index framework for evaluating SICLU.We subsequently employed econometric models to analyze the significant factors that impact LSO.Our findings reveal that SICLU can be divided into four key dimensions:intensive management,efficient output,resource conservation,and ecological environment optimization.Furthermore,it is crucial to incorporate belief-based cognitive factors into the index system,as farmers’ understanding of fertilizer and pesticide application significantly influences their willingness to engage in LSO.Moreover,we identify grain market turnover as the most influential factor in promoting LSO,with single-factor contribution rates reaching 70.9% for cultivated land transfer willingness and 62.5% for the total planting areas.Interestingly,unlike irrigation and agricultural machinery inputs,increased labor inputs correspond to larger planting areas for farmers.This trend may be attributed to reduced labor availability because of rural labor migration,whereas the reduction in irrigation and agricultural input is contingent on innovations in production practices and the transfer of cultivated land management rights.Importantly,SICLU dynamically influences LSO,with each index related to SICLU having an optimal range that fosters LSO.These insights offer valuable guidance for policymakers,emphasizing farmers as their central focus,with the adjustment of input and output factors as a means to achieve LSO as the ultimate goal.In conclusion,we propose research avenues for further enriching the SICLU framework to ensure that it aligns with the specific characteristics of regional agricultural development.

Advances in non-invasive imaging of proteinopathies in animal models of neurodegenerative diseases

Neurodegenerative diseases,including Alzheimer's disease(AD),frontotemporal dementia,Parkinson's disease,and dementia with Lewy bodies,represent tremendous unmet clinical needs.A common feature of these diseases is the aberrant cerebral accumulation of pathological protein aggregates,affecting selectively vulnerable circuits in a disease-specific pattern.Earlier studies have established a relationship between abnormal aggregation and neuronal dysfunction or loss,suggesting multifactorial pathogenesis mechanisms in these neurodegenerative disorders.

Restoration of GABA_(B) receptor expression in cerebral ischemia:a promising novel neuroprotective strategy

Although stroke is a major global health problem, a pharmacological treatment to inhibit ongoing neuronal death in patients is still lacking. In cerebral ischemia, the prevailing form of stroke, severely reduced blood supply by obstruction of blood vessels deprives neurons from oxygen and glucose, eventually leading to metabolic derailment and death of neurons in the affected brain area.

Extracellular matrix remodelling in dental pulp tissue of carious human teeth through the prism of single-cell RNA sequencing

Carious lesions are bacteria-caused destructions of the mineralised dental tissues,marked by the simultaneous activation of immune responses and regenerative events within the soft dental pulp tissue.While major molecular players in tooth decay have been uncovered during the past years,a detailed map of the molecular and cellular landscape of the diseased pulp is still missing.In this study we used single-cell RNA sequencing analysis,supplemented with immunostaining,to generate a comprehensive single-cell atlas of the pulp of carious human teeth.Our data demonstrated modifications in the various cell clusters within the pulp of carious teeth,such as immune cells,mesenchymal stem cells(MSC)and fibroblasts,when compared to the pulp of healthy human teeth.Active immune response in the carious pulp tissue is accompanied by specific changes in the fibroblast and MSC clusters.These changes include the upregulation of genes encoding extracellular matrix(ECM)components,including COL1A1 and Fibronectin(FN1),and the enrichment of the fibroblast cluster with myofibroblasts.The incremental changes in the ECM composition of carious pulp tissues were further confirmed by immunostaining analyses.Assessment of the Fibronectin fibres under mechanical strain conditions showed a significant tension reduction in carious pulp tissues,compared to the healthy ones.The present data demonstrate molecular,cellular and biomechanical alterations in the pulp of human carious teeth,indicative of extensive ECM remodelling,reminiscent of fibrosis observed in other organs.This comprehensive atlas of carious human teeth can facilitate future studies of dental pathologies and enable comparative analyses across diseased organs.

Built‑In Electric Field‑Driven Ultrahigh‑Rate K‑Ion Storage via Heterostructure Engineering of Dual Tellurides Integrated with Ti_(3)C_(2)T_(x)MXene

Exploiting high-rate anode materials with fast K+diffusion is intriguing for the development of advanced potassium-ion batteries(KIBs)but remains unrealized.Here,heterostructure engineering is proposed to construct the dual transition metal tellurides(CoTe_(2)/ZnTe),which are anchored onto two-dimensional(2D)Ti_(3)C_(2)T_(x)MXene nanosheets.Various theoretical modeling and experimental findings reveal that heterostructure engineering can regulate the electronic structures of CoTe_(2)/ZnTe interfaces,improving K+diffusion and adsorption.In addition,the different work functions between CoTe_(2)/ZnTe induce a robust built-in electric field at the CoTe_(2)/ZnTe interface,providing a strong driving force to facilitate charge transport.Moreover,the conductive and elastic Ti_(3)C_(2)T_(x)can effectively promote electrode conductivity and alleviate the volume change of CoTe_(2)/ZnTe heterostructures upon cycling.Owing to these merits,the resulting CoTe_(2)/ZnTe/Ti_(3)C_(2)T_(x)(CZT)exhibit excellent rate capability(137.0 mAh g^(-1)at 10 A g^(-1))and cycling stability(175.3 mAh g^(-1)after 4000 cycles at 3.0 A g^(-1),with a high capacity retention of 89.4%).More impressively,the CZT-based full cells demonstrate high energy density(220.2 Wh kg^(-1))and power density(837.2 W kg^(-1)).This work provides a general and effective strategy by integrating heterostructure engineering and 2D material nanocompositing for designing advanced high-rate anode materials for next-generation KIBs.

Stationarity Preservation Properties of the Active Flux Scheme on Cartesian Grids

Hyperbolic systems of conservation laws in multiple spatial dimensions display features absent in the one-dimensional case,such as involutions and non-trivial stationary states.These features need to be captured by numerical methods without excessive grid refine-ment.The active flux method is an extension of the finite volume scheme with additional point values distributed along the cell boundary.For the equations of linear acoustics,an exact evolution operator can be used for the update of these point values.It incorporates all multi-dimensional information.The active flux method is stationarity preserving,i.e.,it discretizes all the stationary states of the PDE.This paper demonstrates the experimental evidence for the discrete stationary states of the active flux method and shows the evolution of setups towards a discrete stationary state.

Analysis of the SBP-SAT Stabilization for Finite Element Methods Part Ⅱ:Entropy Stability

In the hyperbolic research community,there exists the strong belief that a continuous Galerkin scheme is notoriously unstable and additional stabilization terms have to be added to guarantee stability.In the first part of the series[6],the application of simultaneous approximation terms for linear problems is investigated where the boundary conditions are imposed weakly.By applying this technique,the authors demonstrate that a pure continu-ous Galerkin scheme is indeed linearly stable if the boundary conditions are imposed in the correct way.In this work,we extend this investigation to the nonlinear case and focus on entropy conservation.By switching to entropy variables,we provide an estimation of the boundary operators also for nonlinear problems,that guarantee conservation.In numerical simulations,we verify our theoretical analysis.

Femoral Access with Ultrasound-Guided Puncture and Z-Stitch Hemostasis for Adults with Congenital Heart Diseases Undergoing Electrophysiological Procedures

Aims:Although the application of ultrasound-guided vascular puncture and Z-stitch hemostasis to manage femoral access has been widely utilized,there is limited data on this combined application in adult congenital heart disease(ACHD)patients undergoing electrophysiological(EP)procedures.We sought to evaluate the safety and efficacy of ultrasound-guided puncture and postprocedural Z-stitch hemostasis for ACHD patients under-going EP procedures.Methods and Results:The population of ACHD patients undergoing transfemoral EP pro-cedures at the University of Zurich Heart Center between January 2019 and December 2022 was observed and analyzed.During the study period,femoral access(left/right,arterial/venous)was performed under real-time ultrasound guidance.At the end of the procedure,a single Z-stitch was performed at the puncture site.We eval-uated the incidence of in-hospital complications associated with femoral access puncture in this population.Among 101 patients who had a total of 147 previous ipsilateral vascular punctures(mean 1.5 per person),100 patients underwent successful femoral vascular access for EP procedures.The median age of the patients was 47±15 years and 34(34%)were male.Z-stitches were performed after the procedure in 100 patients with 303 femoral vascular accesses(mean 3 punctures per person).No patient developed vascular puncture relevant inguinal hematoma,pseudo aneurysm,arteriovenousfistula,venous or arterial thrombosis.Conclusion:In ACHD patients undergoing EP procedures,optimal femoral access management can be achieved with ultra-sound-guided puncture and postprocedural Z-stitch hemostasis.

Review of current diagnostic methods and advances in Helicobacter pylori diagnostics in the era of next generation sequencing

Helicobacter pylori(H.pylori)infection is highly prevalent in the human population and may lead to severe gastrointestinal pathology including gastric and duodenal ulcers,mucosa associated tissue lymphoma and gastric adenocarcinoma.In recent years,an alarming increase in antimicrobial resistance and subsequently failing empiric H.pylori eradication therapies have been noted worldwide,also in many European countries.Therefore,rapid and accurate determination of H.pylori’s antibiotic susceptibility prior to the administration of eradication regimens becomes ever more important.Traditionally,detection of H.pylori and its antimicrobial resistance is done by culture and phenotypic drug susceptibility testing that are cumbersome with a long turn-around-time.Recent advances in diagnostics provide new tools,like real-time polymerase chain reaction(PCR)and line probe assays,to diagnose H.pylori infection and antimicrobial resistance to certain antibiotics,directly from clinical specimens.Moreover,high-throughput whole genome sequencing technologies allow the rapid analysis of the pathogen’s genome,thereby allowing identification of resistance mutations and associated antibiotic resistance.In the first part of this review,we will give an overview on currently available diagnostic methods for detection of H.pylori and its drug resistance and their implementation in H.pylori management.The second part of the review focusses on the use of next generation sequencing technology in H.pylori research.To this end,we conducted a literature search for original research articles in English using the terms“Helicobacter”,“transcriptomic”,“transcriptome”,“next generation sequencing”and“whole genome sequencing”.This review is aimed to bridge the gap between current diagnostic practice(histology,rapid urease test,H.pylori culture,PCR and line probe assays)and new sequencing technologies and their potential implementation in diagnostic laboratory settings in order to complement the currently recommended H.pylori management guidelines and subsequently improve public health.

Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury

Axonal regeneration and ifber regrowth is limited in the adult central nervous system, but re-search over the last decades has revealed a high intrinsic capacity of brain and spinal cord circuits to adapt and reorganize after smaller injuries or denervation. Short-distance ifber growth and synaptic rewiring was found in cortex, brain stem and spinal cord and could be associated with restoration of sensorimotor functions that were impaired by the injury. Such processes of struc-tural plasticity were initially observed in the corticospinal system following spinal cord injury or stroke, but recent studies showed an equally high potential for structural and functional reorganization in reticulospinal, rubrospinal or propriospinal projections. Here we review the lesion-induced plastic changes in the propriospinal pathways, and we argue that they represent a key mechanism triggering sensorimotor recovery upon incomplete spinal cord injury. The for-mation or strengthening of spinal detour pathways bypassing supraspinal commands around the lesion site to the denervated spinal cord were identiifed as prominent neural substrate inducing substantial motor recovery in different species from mice to primates. Indications for the exis-tence of propriospinal bypasses were also found in humans after cortical stroke. It is mandatory for current research to dissect the biological mechanisms underlying spinal circuit remodeling and to investigate how these processes can be stimulated in an optimal way by therapeutic inter-ventions （e.g., ifber-growth enhancing interventions, rehabilitation）. This knowledge will clear the way for the development of novel strategies targeting the remarkable plastic potential of pro-priospinal circuits to maximize functional recovery after spinal cord injury.

A fossil-calibrated relaxed clock for Ephedra indicates an Oligocene age for the divergence of Asian and New World clades and Miocene dispersal into South America

Ephedra comprises approximately 50 species, which are roughly equally distributed between the Old and New World deserts, but not in the intervening regions （amphitropical range）. Great heterogeneity in the substitution rates of Gnetales （Ephedra, Gnetum, and Welwitschia） has made it difficult to infer the ages of the major divergence events in Ephedra, such as the timing of the Beringian disjunction in the genus and the entry into South America. Here, we use data from as many Gnetales species and genes as available from GenBank and from a recent study to investigate the timing of the major divergence events. Because of the tradeoff between the amount of missing data and taxon/gene sampling, we reduced the initial matrix of 265 accessions and 12 loci to 95 accessions and 10 loci, and further to 42 species （and 7736 aligned nucleotides） to achieve stationary distributions in the Bayesian molecular clock runs. Results from a relaxed clock with an uncorrelated rates model and fossil-based calibration reveal that New World species are monophyletic and diverged from their mostly Asian sister clade some 30 mya, fitting with many other Beringian disjunctions. The split between the single North American and the single South American clade occurred approximately 25 mya, well before the closure of the Panamanian Isthmus. Overall, the biogeographic history of Ephedra appears dominated by long-distance dispersal, but finer-scale studies are needed to test this hypothesis.

Transforming growth factor-β1 induces intestinal myofibroblast differentiation and modulates their migration

AIM:To investigate the effects of transforming growth factorβ1(TGF-β1)on the differentiation of colonic lamina propria fibroblasts(CLPF)into myofibroblasts in vitro. METHODS:Primary CLPF cultures were incubated with TGF-β1 and analyzed for production ofα-smooth muscle actin(α-SMA),fibronectin(FN)and FN isoforms.Migration assays were performed in a modified 48-well Boyden chamber.Levels of total and phosphorylated focal adhesion kinase(FAK)in CLPF were analyzed after induction of migration.RESULTS:Incubation of CLPF with TGF-β1 for 2 d did not changeα-SMA levels,while TGF-β1 treatment for 6 d significantly increasedα-SMA production. Short term incubation(6 h)with TGF-β1 enhanced CLPF migration,while long term treatment(6 d)of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells.FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1(2 d)in contrast to long term incubation with TGF-β1 for 6 d.After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells. CONCLUSION:Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhancedα-SMA,reduced migratory potential and FAK phosphorylation,and increased FN production.In contrast,short term contact(6 h)of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction ofα-SMA production.

Root canal morphology and configuration of 123 maxillary second molars by means of micro-CT

The aim of this study was to investigate the root canal configuration, accessory canals and number of main foramina of 123 maxillary second molars by means of micro-computed tomography. The teeth were scanned and reproduced with 3D software imaging. The root canal configuration and number of main foramina were evaluated by means of a four-digit system. The morphological complexity of human maxillary second molars is depicted by the number of accessory and connecting canals. The most frequently observed root canal configurations in the mesiobuccal root were 2-2-2/2 （19.5%）, 2-2-1/1 （14.6%） and 2-1-1/1 （13.0%）. A 1-1-1/1 configuration was observed in 93.5% and in 96.7% in the distobuccal and palatal roots, respectively. The MB1 mot canal had one accessory canal （18.7%）, and 8.9% of the MB2 root canal had one or two accessory canals. The distobuccal （11.3%） and palatal （14.6%） root canals had at least one accessory canal, and connecting canals were observed in 16.3% of mesiobuccal roots. The MB1, MB2, distobuccal and palatal root canals had one main foramen in 99.2%, 43.1%, 98.4% and 99.2% of samples, respectively. In the mesiobuccal root, one accessory foramen was detected in 14.6%, two were detected in 7.3%, and three were detected in 5.7%. The distobuccal root showed one or two accessory foramina in 9.1% of samples. The root canal configuration of maxillary second molars is quite heterogeneous; the mesiobuccal root has predominantly two root canal entrances （58.4%, 1 in 41.1%） with one main foramen （54.4%）. Two main foramina were observed in 43.0%. Morphological variations, connecting and accessory canals were observed in all apical thirds.

Terrestrial behavior and use of forest strata in a group of black-and-white snub-nosed monkeys Rhinopithecus bieti at Xiaochangdu,Tibet

Food distribution and predation pressure are considered to be the main ecological factors that influence the use of forest strata(basically arboreality vs.terrestriality)in non-human primates.Here,we investigate ground use of wild,unprovisioned black-and-white snub-nosed monkeys Rhinopithecus bieti by means of the scan sampling method.The results show that the monkeys spent 15.0% of the day time on the ground;16.6%,12.7%,and 15.6% for adult males,adult females and juveniles,respectively.Adult males and juveniles of both sexes showed significantly higher rates of terrestrial time than adult females.Females without clinging infants spent significantly more time on the ground than expected,while females with clinging infants spent significantly less time on the ground than expected.These results suggest that the higher degree of terrestrial behavior for males and juveniles may be due to their higher agility in comparison with females.Our study showed that the monkeys fed more on lichens relative to other food items when in the trees,but more on buds/leaves,flowers,fruits/nuts,resin/bark,and herbs when on the ground.According to our investigation,the ecological significance of the species' terrestriality lies mainly in the utilization of terrestrial food

How signaling and search costs affect information asymmetry in P2P lending:the economics of big data

In the past decade,online Peer-to-Peer(P2P)lending platforms have transformed the lending industry,which has been historically dominated by commercial banks.Information technology breakthroughs such as big data-based financial technologies(Fintech)have been identified as important disruptive driving forces for this paradigm shift.In this paper,we take an information economics perspective to investigate how big data affects the transformation of the lending industry.By identifying how signaling and search costs are reduced by big data analytics for credit risk management of P2P lending,we discuss how information asymmetry is reduced in the big data era.Rooted in the lending business,we propose a theory on the economics of big data and outline a number of research opportunities and challenging issues.

The FinTech phenomenon:antecedents of financial innovation perceived by the popular press

The financial industry has been strongly influenced by digitalization in the past few years reflected by the emergence of“FinTech,”which represents the marriage of“finance”and“information technology.”FinTech provides opportunities for the creation of new services and business models and poses challenges to traditional financial service providers.Therefore,FinTech has become a subject of debate among practitioners,investors,and researchers and is highly visible in the popular media.In this study,we unveil the drivers motivating the FinTech phenomenon perceived by the English and German popular press including the subjects discussed in the context of FinTech.This study is the first one to reflect the media perspective on the FinTech phenomenon in the research.In doing so,we extend the growing knowledge on FinTech and contribute to a common understanding in the financial and digital innovation literature.These study contributes to research in the areas of information systems,finance and interdisciplinary social sciences.Moreover,it brings value to practitioners(entrepreneurs,investors,regulators,etc.),who explore the field of FinTech.

The role of ureteroscopy for treatment of staghorn calculi: A systematic review

Objective:To define the role of ureteroscopy for treatment of staghorn calculi.Methods:A systematic review was conducted using the Scopus and Medline databases.Original articles and systematic reviews were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines.Only studies relating to the role of ureteroscopy for treatment of staghorn calculi were included.Results:In five studies on ureteroscopic monotherapy,stone-free rate(SFR)ranged from 33%to 93%,with a maximum four ureteroscopy sessions per patient and no major complications.Endoscopic combined intrarenal surgery(ECIRS)was compared with percutaneous nephrolithotomy(PNL)in two studies and reached significantly higher SFR(88%e91%vs.59%e65%)and lower operative times(84e110 min vs.105e129 min).The role of salvage ureteroscopy for residual stones after primary PNL has been highlighted by two studies with a final SFR of 83%e89%.One study reported on the feasibility of ureteroscopy for ureteral stones and same-session PNL for contralateral staghorn calculi,with a SFR of 92%.Conclusion:Ureteroscopy plays a pivotal role in the setting of a combined approach to staghorn calculi.Ureteroscopy is also particularly suitable for clearance of residual stones.In specific cases,ureteroscopy may become the sole applicable therapeutic option to staghorn calculi.Technological advances and refinement of techniques suggest a major role of ureteroscopy for staghorn calculi treatment in close future.

SYSTEM FOR AUTOMATIC GENERALIZATION OF TOPOGRAPHIC MAPS

With the construction of spatial data infrastructure, automated topographic map generalization becomes an indispensable component in the community of cartography and geographic information science. This paper describes a topographic map generalization system recently developed by the authors. The system has the following cha- racteristics: 1) taking advantage of three levels of automation, i.e. fully automated generalization, batch generalization, and interactive generalization, to undertake two types of processes, i.e. intelligent inference process and repetitive operation process in generalization; 2) making use of two kinds of sources for generalizing rule library, i.e. written specifications and cartographers’ experiences, to define a six-element structure to describe the rules; 3) employing a hierarchical structure for map databases, logically and physically; 4) employing a grid indexing technique and undo/redo operation to improve database retrieval and object generalization efficiency. Two examples of topographic map generalization are given to demonstrate the system. It reveals that the system works well. In fact, this system has been used for a number of projects and it has been found that a great improvement in efficiency compared with traditional map generalization process can be achieved.