Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson...Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.展开更多
Laser powder bed fusion(LPBF)is highly suitable for forming 18Ni300 mold steel,thanks to its excellent capability in manufacturing complex shapes and outstanding capacity for regulating microstructures.It is widely us...Laser powder bed fusion(LPBF)is highly suitable for forming 18Ni300 mold steel,thanks to its excellent capability in manufacturing complex shapes and outstanding capacity for regulating microstructures.It is widely used in fields such as injection molding,die casting,and stamping dies.Adding reinforcing particles into steel is an effective means to improve its performance.Nb/18Ni300 composites were fabricated by LPBF using two kinds of Nb powders with different particle sizes,and their microstructures and properties were studied.The results show that the unmelted Nb particles are uniformly distributed in the 18Ni300 matrix and the grains are refined,which is particularly pronounced with fine Nb particles.In addition,element diffusion occurs between the particles and the matrix.The main phases of the base alloy are α-Fe and a small amount of γ-Fe.With the addition of Nb,part of the α-Fe is transformed into γ-Fe,and unmelted Nb phases appear.The addition of Nb also enhances the hardness and wear resistance of the composites but slightly reduces their tensile properties.After aging treatment,the molten pools and grain boundaries become blurred,grains are further refined,and the interfaces around the particles are thinned.The aging treatment also promotes the formation of reverted austenite.The hardness,ultimate tensile strength,and volumetric wear rate of the base alloy reach 51.9 HRC,1704 MPa,and 17.8×10^(-6) mm^(3)/(N·m),respectively.In contrast,the sample added with fine Nb particles has the highest hardness(56.1 HRC),ultimate tensile strength(1892 MPa)and yield strength(1842 MPa),and the volume wear rate of the sample added with coarse Nb particles is reduced by 90%to 1.7×10^(-6) mm^(3)/(N·m).展开更多
After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the tim...After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.展开更多
Background:The medicinal material known as Os Draconis(Longgu)originates from fossilized remains of ancient mammals and is widely used in treating emotional and mental conditions.However,fossil resources are nonrenewa...Background:The medicinal material known as Os Draconis(Longgu)originates from fossilized remains of ancient mammals and is widely used in treating emotional and mental conditions.However,fossil resources are nonrenewable,and clinical demand is increasingly difficult to meet,leading to a proliferation of counterfeit products.During prolonged geological burial,static pressure from the surrounding strata severely compromises the microstructural integrity of osteons in Os Draconis,but Os Draconis still largely retains the structural features of mammalian bone.Methods:Using verified authentic Os Draconis samples over 10,000 years old as a baseline,this study summarizes the ultrastructural characteristics of genuine Os Draconis.Employing electron probe microanalysis and optical polarized light microscopy,we examined 28 batches of authentic Os Draconis and 31 batches of counterfeits to identify their ultrastructural differences.Key points for ultrastructural identification of Os Draconis were compiled,and a new identification approach was proposed based on these differences.Results:Authentic Os Draconis exhibited distinct ultrastructural markers:irregularly shaped osteons with traversing fissures,deformed/displaced Haversian canals,and secondary mineral infill(predominantly calcium carbonate).Counterfeits showed regular osteon arrangements,absent traversal fissures,and homogeneous hydroxyapatite composition.Lab-simulated samples lacked structural degradation features.EPMA confirmed calcium carbonate infill in fossilized Haversian canals,while elemental profiles differentiated lacunae types(void vs.mineral-packed).Conclusion:The study established ultrastructural criteria for authentic Os Draconis identification:osteon deformation,geological fissures penetrating bone units,and heterogenous mineral deposition.These features,unattainable in counterfeits or modern processed bones,provide a cost-effective,accurate identification method.This approach bridges gaps in TCM material standardization and supports quality control for clinical applications.展开更多
Background:This study focused on developing and optimizing a self-microemulsifying drug delivery system(SMEDDS)to improve Lafutidine’s solubility and bioavailability,thereby enhancing its effectiveness in treating ga...Background:This study focused on developing and optimizing a self-microemulsifying drug delivery system(SMEDDS)to improve Lafutidine’s solubility and bioavailability,thereby enhancing its effectiveness in treating gastric ulcers.Traditional formulations are less effective due to their limited water solubility and bioavailability.Methods:The study used solubility tests,pseudo-ternary phase diagrams,and central composite design(CCD)to optimize.The formulation was optimized by varying the oil concentration(10–40%)and surfactant/cosurfactant ratio(0.33–3.00),and then tested for droplet size,drug content,emulsification,phase stability,and in vitro dissolution.Results:The study found that the optimized formulation contained 14%Capmul PG 8NF oil,62%Labrasol surfactant,and 24%Tween 80 cosurfactant.This combination generated an average droplet size of 111.02 nm and improved drug release properties.Furthermore,the formulation was stable without phase separation,with a drug content of 88.2–99.8%.Conclusion:SMEDDS significantly improves lafutidine delivery by increasing solubility and absorption,thereby overcoming oral administration challenges.The system quickly formed small droplets in water and released the drug in 15 min.Enhancing lafutidine’s bioavailability may improve its efficacy in treating gastric ulcers,resulting in better patient outcomes and potentially lower dosing frequency.展开更多
Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at...Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.展开更多
The thermal conductivity of nanofluids is an important property that influences the heat transfer capabilities of nanofluids.Researchers rely on experimental investigations to explore nanofluid properties,as it is a n...The thermal conductivity of nanofluids is an important property that influences the heat transfer capabilities of nanofluids.Researchers rely on experimental investigations to explore nanofluid properties,as it is a necessary step before their practical application.As these investigations are time and resource-consuming undertakings,an effective prediction model can significantly improve the efficiency of research operations.In this work,an Artificial Neural Network(ANN)model is developed to predict the thermal conductivity of metal oxide water-based nanofluid.For this,a comprehensive set of 691 data points was collected from the literature.This dataset is split into training(70%),validation(15%),and testing(15%)and used to train the ANN model.The developed model is a backpropagation artificial neural network with a 4–12–1 architecture.The performance of the developed model shows high accuracy with R values above 0.90 and rapid convergence.It shows that the developed ANN model accurately predicts the thermal conductivity of nanofluids.展开更多
Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-...Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.展开更多
This review is composed of three main parts each of which is written by well-known top specialists that have been,in a way or other,also the main participants of the majority of the developments reported.Thus,after a ...This review is composed of three main parts each of which is written by well-known top specialists that have been,in a way or other,also the main participants of the majority of the developments reported.Thus,after a general part covering the grand lines and more in-depth views of more recent tannin,lignin,carbohydrate and soy bioadhesives,somemix of the other bio raw materials with soy protein and soy flour and some other differently sourced bioadhesives for wood,this review presents a more in-depth part on starch-based wood adhesives and a more indepth part covering plant protein-based adhesives.It must be kept in mind that the review is focused on completely or almost completely biosourced adhesives,the fashionable adhesives derived from mixes of biosourced materials with synthetic resins having been intentionally excluded.This choice was made as the latter constitute only an intermediate interval,possibly temporary if even for a somewhat long times,towards a final full bioeconomy of scale in this field.This review also focuses on more recent results,mainly obtained in the last 10–20 years,thus on adhesive formulations really innovative and sometimes even non-traditional.In all these fields there is still a lot of possibility of innovation for relevant formulation as this field is still in rapid growth.展开更多
BACKGROUND Cardiac resynchronization therapy(CRT)has been a major therapeutic advancement for patients with heart failure and electrical dyssynchrony.While CRT improves symptoms,reduces hospitalizations,and enhances s...BACKGROUND Cardiac resynchronization therapy(CRT)has been a major therapeutic advancement for patients with heart failure and electrical dyssynchrony.While CRT improves symptoms,reduces hospitalizations,and enhances survival,the role of implantable cardioverter-defibrillators(ICDs)alongside CRT in patients with non-ischemic cardiomyopathy(NICM)remains controversial.To evaluate and compare the outcomes of CRT with ICD(CRT-D)versus CRT with pacemaker-only(CRT-P)in individuals diagnosed with NICM,with a specific focus on the elderly.METHODS A comprehensive search of PubMed,Embase,and the Cochrane Central Register of Controlled Trials was conducted in January 2024.Studies comparing CRT-D and CRT-P in patients with NICM were included,with subgroup analyses focusing on patients aged 75 years and older.RESULTS Twelve studies,including two randomized clinical trials,with a total of 62,145 patients and 16,754 pooled death events(9,171 in CRT-D and 7,583 in CRT-P),were analyzed.CRT-D was associated with a significantly lower risk of all-cause mortality compared to CRT-P(pooled OR=0.72;95%CI:0.61-0.85;P<0.01),with significant heterogeneity(I2=83%).RCT subgroup analysis,was not statistically significant(pooled OR=0.82;95%CI:0.64-1.06;P=0.41;I2=0%).In patients older than 75 years,no significant difference in mortality risk was observed(pooled OR 0.96;95%CI:0.81-1.15;I2=39%).CONCLUSION Our meta-analysis suggests that the addition of ICD therapy to CRT in patients with NICM significantly reduces all-cause mortality.However,this benefit does not extend to cardiovascular mortality,likely due to the primary role of ICDs in preventing sudden cardiac death rather than other causes such as progressive heart failure.The survival advantage of CRT-D is most pronounced in younger patients,with those over 75 years of age deriving less benefit.This highlights the importance of careful patient selection,considering age and comorbidities,when deciding on ICD implantation in NICM patients.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to th...BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.展开更多
There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 poly...There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.展开更多
The integration of digital tools and effective knowledge management practices is critical for enhancing administrative efficiency and institutional continuity in higher education. This study investigates the relations...The integration of digital tools and effective knowledge management practices is critical for enhancing administrative efficiency and institutional continuity in higher education. This study investigates the relationships between knowledge modeling, institutional memory, leadership styles, technology, and administrative efficiency at the University of Cape Coast (UCC). The study sought to identify the challenges and opportunities in integrating digital tools into administrative processes and to provide actionable recommendations for improvement. A mixed-methods research design was employed, combining quantitative analysis using Partial Least Squares Structural Equation Modeling (PLS-SEM) with qualitative thematic analysis of interviews. The findings revealed key challenges, including resistance to change, fragmented knowledge repositories, and inadequate funding, alongside opportunities such as centralized knowledge systems, cost-effective open-source tools, and capacity-building initiatives. The study highlights the importance of strategic leadership, robust policies, and investments in digital infrastructure to enhance administrative practices. Policy implications include the need for clear digital transformation guidelines and leadership training to foster innovation and collaboration. Recommendations include investing in scalable digital tools, implementing comprehensive capacity-building programs, and promoting stakeholder engagement to drive successful digital integration. These insights provide a roadmap for UCC and similar institutions seeking to optimize administrative efficiency through digital transformation.展开更多
Low-velocity impact tests are carried out to explore the energy absorption characteristics of bio-inspired lattices,mimicking the architecture of the marine sponge organism Euplectella aspergillum.These sea sponge-ins...Low-velocity impact tests are carried out to explore the energy absorption characteristics of bio-inspired lattices,mimicking the architecture of the marine sponge organism Euplectella aspergillum.These sea sponge-inspired lattice structures feature a square-grid 2D lattice with double diagonal bracings and are additively manufactured via digital light processing(DLP).The collapse strength and energy absorption capacity of sea sponge lattice structures are evaluated under various impact conditions and are compared to those of their constituent square-grid and double diagonal lattices.This study demonstrates that sea sponge lattices can achieve an 11-fold increase in energy absorption compared to the square-grid lattice,due to the stabilizing effect of the double diagonal bracings prompting the structure to collapse layer-bylayer under impact.By adjusting the thickness ratio in the sea sponge lattice,up to 76.7%increment in energy absorption is attained.It is also shown that sea-sponge lattices outperform well-established energy-absorbing materials of equal weight,such as hexagonal honeycombs,confirming their significant potential for impact mitigation.Additionally,this research highlights the enhancements in energy absorption achieved by adding a small amount(0.015 phr)of Multi-Walled Carbon Nanotubes(MWCNTs)to the photocurable resin,thus unlocking new possibilities for the design of innovative lightweight structures with multifunctional attributes.展开更多
Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief int...Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief introduction to the current state-of-the-art for neuroectoderm brain organoid development,emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models.However,despite their usefulness for developmental studies,a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin.As such,current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component.In this review,we will specifically focus on the development of immune-competent brain organoids.By summarizing the different approaches applied to incorporate microglia,it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation,but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brainlike environment.Therefore,our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids,with an outlook on how these findings could better understand neuronal network development or restoration,as well as the influence of physical stress on microglia-containing brain organoids.Finally,we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade,their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.展开更多
In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of...In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.展开更多
Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly devel...Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.展开更多
The H-K-ATPase (HKA), a potassium-dependent proton transporter in the outer medullary collecting duct (OMCD) plays an important role in acid-base homeostasis. The OMCD contains two HKA isoforms;gastric (HKAα1), domin...The H-K-ATPase (HKA), a potassium-dependent proton transporter in the outer medullary collecting duct (OMCD) plays an important role in acid-base homeostasis. The OMCD contains two HKA isoforms;gastric (HKAα1), dominant under normal dietary conditions (ND), and colonic (HKAα2), induced under a K-free diet (KD). The enzymatic activity (EA) of HKA in the OMCD is incompletely understood. The focus of the present study is elucidating the EA of the HKA in HKAα1 and HKAα2 knockout (KO) mice under ND and KD. KO mice were subjected to ND or KD for 10 days. Ten OMCD tubules were extracted, half placed in potassium-free media (Solution 2), half in potassium-containing media (Solution 3). Fluorescence measurements are based on the hydrolysis of ATP to ADP, coupled with the oxidation of NADH. ADP is determined by a decrease in NADH fluorescence. In K presence, NADH fluorescence of HKAα1 KO mice read 13.5 ± 0.7 ppm for ND and 10.3 ± 0.2 ppm for KD, indicating stimulation of the colonic isoform. HKAα2 KO mice averaged 6.8 ± 0.3 ppm for ND and 5.4 ± 0.3 ppm for KD in solution 2 (p p α2 isoform. A significant difference in ATP production in HKAα2 KO mice is likely due to enhanced EA of H-ATPase under potassium depletion.展开更多
Floods and storm surges pose significant threats to coastal regions worldwide,demanding timely and accurate early warning systems(EWS)for disaster preparedness.Traditional numerical and statistical methods often fall ...Floods and storm surges pose significant threats to coastal regions worldwide,demanding timely and accurate early warning systems(EWS)for disaster preparedness.Traditional numerical and statistical methods often fall short in capturing complex,nonlinear,and real-time environmental dynamics.In recent years,machine learning(ML)and deep learning(DL)techniques have emerged as promising alternatives for enhancing the accuracy,speed,and scalability of EWS.This review critically evaluates the evolution of ML models—such as Artificial Neural Networks(ANN),Convolutional Neural Networks(CNN),and Long Short-Term Memory(LSTM)—in coastal flood prediction,highlighting their architectures,data requirements,performance metrics,and implementation challenges.A unique contribution of this work is the synthesis of real-time deployment challenges including latency,edge-cloud tradeoffs,and policy-level integration,areas often overlooked in prior literature.Furthermore,the review presents a comparative framework of model performance across different geographic and hydrologic settings,offering actionable insights for researchers and practitioners.Limitations of current AI-driven models,such as interpretability,data scarcity,and generalization across regions,are discussed in detail.Finally,the paper outlines future research directions including hybrid modelling,transfer learning,explainable AI,and policy-aware alert systems.By bridging technical performance and operational feasibility,this review aims to guide the development of next-generation intelligent EWS for resilient and adaptive coastal management.展开更多
基金supported by the Spanish Ministry of Science and Innovation via a doctoral grant[FPU22/03656].supported by the Spanish Ministry of Science and Innovation(PID2022-137963OB-I00)Generalitat de Catalunya(2021-SGR-00635 AGAUR)+1 种基金CERCA Programme(Generalitat de Catalunya)by ICREA,ICREA-Academia 2020(to SV)。
文摘Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.
基金Key-Area Research and Development Program of Guangdong Province(2023B0909020004)Project of Innovation Research Team in Zhongshan(CXTD2023006)+1 种基金Natural Science Foundation of Guangdong Province(2023A1515011573)Zhongshan Social Welfare Science and Technology Research Project(2024B2022)。
文摘Laser powder bed fusion(LPBF)is highly suitable for forming 18Ni300 mold steel,thanks to its excellent capability in manufacturing complex shapes and outstanding capacity for regulating microstructures.It is widely used in fields such as injection molding,die casting,and stamping dies.Adding reinforcing particles into steel is an effective means to improve its performance.Nb/18Ni300 composites were fabricated by LPBF using two kinds of Nb powders with different particle sizes,and their microstructures and properties were studied.The results show that the unmelted Nb particles are uniformly distributed in the 18Ni300 matrix and the grains are refined,which is particularly pronounced with fine Nb particles.In addition,element diffusion occurs between the particles and the matrix.The main phases of the base alloy are α-Fe and a small amount of γ-Fe.With the addition of Nb,part of the α-Fe is transformed into γ-Fe,and unmelted Nb phases appear.The addition of Nb also enhances the hardness and wear resistance of the composites but slightly reduces their tensile properties.After aging treatment,the molten pools and grain boundaries become blurred,grains are further refined,and the interfaces around the particles are thinned.The aging treatment also promotes the formation of reverted austenite.The hardness,ultimate tensile strength,and volumetric wear rate of the base alloy reach 51.9 HRC,1704 MPa,and 17.8×10^(-6) mm^(3)/(N·m),respectively.In contrast,the sample added with fine Nb particles has the highest hardness(56.1 HRC),ultimate tensile strength(1892 MPa)and yield strength(1842 MPa),and the volume wear rate of the sample added with coarse Nb particles is reduced by 90%to 1.7×10^(-6) mm^(3)/(N·m).
基金supported by the National Key Research and Development Program of China,No.2023YFC3603705(to DX)the National Natural Science Foundation of China,No.82302866(to YZ).
文摘After spinal cord injury,impairment of the sensorimotor circuit can lead to dysfunction in the motor,sensory,proprioceptive,and autonomic nervous systems.Functional recovery is often hindered by constraints on the timing of interventions,combined with the limitations of current methods.To address these challenges,various techniques have been developed to aid in the repair and reconstruction of neural circuits at different stages of injury.Notably,neuromodulation has garnered considerable attention for its potential to enhance nerve regeneration,provide neuroprotection,restore neurons,and regulate the neural reorganization of circuits within the cerebral cortex and corticospinal tract.To improve the effectiveness of these interventions,the implementation of multitarget early interventional neuromodulation strategies,such as electrical and magnetic stimulation,is recommended to enhance functional recovery across different phases of nerve injury.This review concisely outlines the challenges encountered following spinal cord injury,synthesizes existing neurostimulation techniques while emphasizing neuroprotection,repair,and regeneration of impaired connections,and advocates for multi-targeted,task-oriented,and timely interventions.
基金supported by the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences(CI2021A04013)the National Natural Science Foundation of China(82204610)+1 种基金the Qihang Talent Program(L2022046)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ15-YQ-041 and L2021029).
文摘Background:The medicinal material known as Os Draconis(Longgu)originates from fossilized remains of ancient mammals and is widely used in treating emotional and mental conditions.However,fossil resources are nonrenewable,and clinical demand is increasingly difficult to meet,leading to a proliferation of counterfeit products.During prolonged geological burial,static pressure from the surrounding strata severely compromises the microstructural integrity of osteons in Os Draconis,but Os Draconis still largely retains the structural features of mammalian bone.Methods:Using verified authentic Os Draconis samples over 10,000 years old as a baseline,this study summarizes the ultrastructural characteristics of genuine Os Draconis.Employing electron probe microanalysis and optical polarized light microscopy,we examined 28 batches of authentic Os Draconis and 31 batches of counterfeits to identify their ultrastructural differences.Key points for ultrastructural identification of Os Draconis were compiled,and a new identification approach was proposed based on these differences.Results:Authentic Os Draconis exhibited distinct ultrastructural markers:irregularly shaped osteons with traversing fissures,deformed/displaced Haversian canals,and secondary mineral infill(predominantly calcium carbonate).Counterfeits showed regular osteon arrangements,absent traversal fissures,and homogeneous hydroxyapatite composition.Lab-simulated samples lacked structural degradation features.EPMA confirmed calcium carbonate infill in fossilized Haversian canals,while elemental profiles differentiated lacunae types(void vs.mineral-packed).Conclusion:The study established ultrastructural criteria for authentic Os Draconis identification:osteon deformation,geological fissures penetrating bone units,and heterogenous mineral deposition.These features,unattainable in counterfeits or modern processed bones,provide a cost-effective,accurate identification method.This approach bridges gaps in TCM material standardization and supports quality control for clinical applications.
文摘Background:This study focused on developing and optimizing a self-microemulsifying drug delivery system(SMEDDS)to improve Lafutidine’s solubility and bioavailability,thereby enhancing its effectiveness in treating gastric ulcers.Traditional formulations are less effective due to their limited water solubility and bioavailability.Methods:The study used solubility tests,pseudo-ternary phase diagrams,and central composite design(CCD)to optimize.The formulation was optimized by varying the oil concentration(10–40%)and surfactant/cosurfactant ratio(0.33–3.00),and then tested for droplet size,drug content,emulsification,phase stability,and in vitro dissolution.Results:The study found that the optimized formulation contained 14%Capmul PG 8NF oil,62%Labrasol surfactant,and 24%Tween 80 cosurfactant.This combination generated an average droplet size of 111.02 nm and improved drug release properties.Furthermore,the formulation was stable without phase separation,with a drug content of 88.2–99.8%.Conclusion:SMEDDS significantly improves lafutidine delivery by increasing solubility and absorption,thereby overcoming oral administration challenges.The system quickly formed small droplets in water and released the drug in 15 min.Enhancing lafutidine’s bioavailability may improve its efficacy in treating gastric ulcers,resulting in better patient outcomes and potentially lower dosing frequency.
基金supported by Postdoc Fellowship from the Foundation for Angelman Syndrome Therapeutics(FT2022-005 to JM,PD2023-001 to XY,and FT2024-001 to YAH)STTR R41 MH118747(to JM)。
文摘Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2021R1A6A1A10044950).
文摘The thermal conductivity of nanofluids is an important property that influences the heat transfer capabilities of nanofluids.Researchers rely on experimental investigations to explore nanofluid properties,as it is a necessary step before their practical application.As these investigations are time and resource-consuming undertakings,an effective prediction model can significantly improve the efficiency of research operations.In this work,an Artificial Neural Network(ANN)model is developed to predict the thermal conductivity of metal oxide water-based nanofluid.For this,a comprehensive set of 691 data points was collected from the literature.This dataset is split into training(70%),validation(15%),and testing(15%)and used to train the ANN model.The developed model is a backpropagation artificial neural network with a 4–12–1 architecture.The performance of the developed model shows high accuracy with R values above 0.90 and rapid convergence.It shows that the developed ANN model accurately predicts the thermal conductivity of nanofluids.
文摘Objective:Artemether is a semi-synthetic derivative of artemisinin and is widely used in the treatment of Plasmodium(P.)falciparum malaria.This study aimed to characterize the safety profile of artemether based on 15-year data retrived from FDA adverse event reporting system(FAERS).Methods:This is a retrospective analysis on 15-year data of artemether-related adverse effects(AEs)retrieved from the FAERS.AEs were classified according to System Organ Class(SOC)and Preferred Terms(PT).Signal detection was performed using Reporting Odds Ratios(ROR),Proportional Reporting Ratios(PRR),and Empirical Bayes Geometric Mean(EBGM).Stratified analyses examined the impact of demographic factors such as sex,age,and time-to-onset.Temporal patterns and associated risk factors were also investigated.Results:Haemolytic anaemia and haemolysis emerged as the most frequently reported AEs,exhibiting significantly elevated RORs(males:ROR 381.36,95%CI 247.06-588.60;females:ROR 455.11,95%CI 286.43-723.12).Sex-specific differences were evident,with females showing a higher incidence of reproductive-related AEs,including spontaneous abortion and premature labour.Temporal trend analysis revealed that the majority of AEs occurred within the first 30 days after the initiation of artemether administration,indicating a rapid onset.The most affected SOCs were blood and lymphatic system disorders and hepatobiliary disorders.Conclusions:Artemether is associated with a notable frequency of early-onset AEs,particularly hematological and hepatobiliary disorders.The observed sex-specific vulnerability to reproductive AEs highlights the need for sex-conscious clinical approaches.Enhanced post-treatment monitoring and further investigations into the drug’s pharmacokinetics and mechanistic pathways are recommended.
文摘This review is composed of three main parts each of which is written by well-known top specialists that have been,in a way or other,also the main participants of the majority of the developments reported.Thus,after a general part covering the grand lines and more in-depth views of more recent tannin,lignin,carbohydrate and soy bioadhesives,somemix of the other bio raw materials with soy protein and soy flour and some other differently sourced bioadhesives for wood,this review presents a more in-depth part on starch-based wood adhesives and a more indepth part covering plant protein-based adhesives.It must be kept in mind that the review is focused on completely or almost completely biosourced adhesives,the fashionable adhesives derived from mixes of biosourced materials with synthetic resins having been intentionally excluded.This choice was made as the latter constitute only an intermediate interval,possibly temporary if even for a somewhat long times,towards a final full bioeconomy of scale in this field.This review also focuses on more recent results,mainly obtained in the last 10–20 years,thus on adhesive formulations really innovative and sometimes even non-traditional.In all these fields there is still a lot of possibility of innovation for relevant formulation as this field is still in rapid growth.
文摘BACKGROUND Cardiac resynchronization therapy(CRT)has been a major therapeutic advancement for patients with heart failure and electrical dyssynchrony.While CRT improves symptoms,reduces hospitalizations,and enhances survival,the role of implantable cardioverter-defibrillators(ICDs)alongside CRT in patients with non-ischemic cardiomyopathy(NICM)remains controversial.To evaluate and compare the outcomes of CRT with ICD(CRT-D)versus CRT with pacemaker-only(CRT-P)in individuals diagnosed with NICM,with a specific focus on the elderly.METHODS A comprehensive search of PubMed,Embase,and the Cochrane Central Register of Controlled Trials was conducted in January 2024.Studies comparing CRT-D and CRT-P in patients with NICM were included,with subgroup analyses focusing on patients aged 75 years and older.RESULTS Twelve studies,including two randomized clinical trials,with a total of 62,145 patients and 16,754 pooled death events(9,171 in CRT-D and 7,583 in CRT-P),were analyzed.CRT-D was associated with a significantly lower risk of all-cause mortality compared to CRT-P(pooled OR=0.72;95%CI:0.61-0.85;P<0.01),with significant heterogeneity(I2=83%).RCT subgroup analysis,was not statistically significant(pooled OR=0.82;95%CI:0.64-1.06;P=0.41;I2=0%).In patients older than 75 years,no significant difference in mortality risk was observed(pooled OR 0.96;95%CI:0.81-1.15;I2=39%).CONCLUSION Our meta-analysis suggests that the addition of ICD therapy to CRT in patients with NICM significantly reduces all-cause mortality.However,this benefit does not extend to cardiovascular mortality,likely due to the primary role of ICDs in preventing sudden cardiac death rather than other causes such as progressive heart failure.The survival advantage of CRT-D is most pronounced in younger patients,with those over 75 years of age deriving less benefit.This highlights the importance of careful patient selection,considering age and comorbidities,when deciding on ICD implantation in NICM patients.
基金Supported by the Research Grants of the National Research,Development and Innovation Office,No.K125377,No.K134863 and No.K143549New National Excellence Program of the Ministry of Human Capacities,No.UNKP-20-5-SZTE-161,No.UNKP-22-3-SZTE-233,No.UNKP-23-5-SZTE-719,No.UNKP-22-4-SZTE-296 and No.UNKP-22-3-SZTE-278+1 种基金Janos Bolyai Research Grant,No.BO/00723/22the Géza Hetényi Research Grant by Albert Szent-Györgyi Medical School,University of Szeged.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.
基金supported by funding from Parkinson Canadafunded by a scholarship from Parkinson Canadaa scholarship from Fonds d’Enseignement et de Recherche (FER) (Faculty of Pharmacy, Université Laval)
文摘There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.
文摘The integration of digital tools and effective knowledge management practices is critical for enhancing administrative efficiency and institutional continuity in higher education. This study investigates the relationships between knowledge modeling, institutional memory, leadership styles, technology, and administrative efficiency at the University of Cape Coast (UCC). The study sought to identify the challenges and opportunities in integrating digital tools into administrative processes and to provide actionable recommendations for improvement. A mixed-methods research design was employed, combining quantitative analysis using Partial Least Squares Structural Equation Modeling (PLS-SEM) with qualitative thematic analysis of interviews. The findings revealed key challenges, including resistance to change, fragmented knowledge repositories, and inadequate funding, alongside opportunities such as centralized knowledge systems, cost-effective open-source tools, and capacity-building initiatives. The study highlights the importance of strategic leadership, robust policies, and investments in digital infrastructure to enhance administrative practices. Policy implications include the need for clear digital transformation guidelines and leadership training to foster innovation and collaboration. Recommendations include investing in scalable digital tools, implementing comprehensive capacity-building programs, and promoting stakeholder engagement to drive successful digital integration. These insights provide a roadmap for UCC and similar institutions seeking to optimize administrative efficiency through digital transformation.
基金supported by the Khalifa University of Science and Technology internal grants(Nos.2021-CIRA-109,2020-CIRA-007,and 2020-CIRA-024).
文摘Low-velocity impact tests are carried out to explore the energy absorption characteristics of bio-inspired lattices,mimicking the architecture of the marine sponge organism Euplectella aspergillum.These sea sponge-inspired lattice structures feature a square-grid 2D lattice with double diagonal bracings and are additively manufactured via digital light processing(DLP).The collapse strength and energy absorption capacity of sea sponge lattice structures are evaluated under various impact conditions and are compared to those of their constituent square-grid and double diagonal lattices.This study demonstrates that sea sponge lattices can achieve an 11-fold increase in energy absorption compared to the square-grid lattice,due to the stabilizing effect of the double diagonal bracings prompting the structure to collapse layer-bylayer under impact.By adjusting the thickness ratio in the sea sponge lattice,up to 76.7%increment in energy absorption is attained.It is also shown that sea-sponge lattices outperform well-established energy-absorbing materials of equal weight,such as hexagonal honeycombs,confirming their significant potential for impact mitigation.Additionally,this research highlights the enhancements in energy absorption achieved by adding a small amount(0.015 phr)of Multi-Walled Carbon Nanotubes(MWCNTs)to the photocurable resin,thus unlocking new possibilities for the design of innovative lightweight structures with multifunctional attributes.
基金funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skodowska-Curie grant agreement No.813263(PMSMat Train,granted to UF,PP,MV,and DP)provided by the Fund for Scientific Research Flanders(FWO-Vlaanderen)of the Flemish Government(FWO sabbatical bench fee K800224N granted to PP)and ERA-NET Re Park(granted to PP)。
文摘Brain organoids encompass a large collection of in vitro stem cell–derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function.First,this review provides a brief introduction to the current state-of-the-art for neuroectoderm brain organoid development,emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models.However,despite their usefulness for developmental studies,a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin.As such,current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component.In this review,we will specifically focus on the development of immune-competent brain organoids.By summarizing the different approaches applied to incorporate microglia,it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation,but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brainlike environment.Therefore,our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids,with an outlook on how these findings could better understand neuronal network development or restoration,as well as the influence of physical stress on microglia-containing brain organoids.Finally,we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade,their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.
基金supported by SIP-IPN,CONACYT (CB-168116)FIS/IMSS (FIS/IMSS/PROT/G11-2/1013)
文摘In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
文摘Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.
文摘The H-K-ATPase (HKA), a potassium-dependent proton transporter in the outer medullary collecting duct (OMCD) plays an important role in acid-base homeostasis. The OMCD contains two HKA isoforms;gastric (HKAα1), dominant under normal dietary conditions (ND), and colonic (HKAα2), induced under a K-free diet (KD). The enzymatic activity (EA) of HKA in the OMCD is incompletely understood. The focus of the present study is elucidating the EA of the HKA in HKAα1 and HKAα2 knockout (KO) mice under ND and KD. KO mice were subjected to ND or KD for 10 days. Ten OMCD tubules were extracted, half placed in potassium-free media (Solution 2), half in potassium-containing media (Solution 3). Fluorescence measurements are based on the hydrolysis of ATP to ADP, coupled with the oxidation of NADH. ADP is determined by a decrease in NADH fluorescence. In K presence, NADH fluorescence of HKAα1 KO mice read 13.5 ± 0.7 ppm for ND and 10.3 ± 0.2 ppm for KD, indicating stimulation of the colonic isoform. HKAα2 KO mice averaged 6.8 ± 0.3 ppm for ND and 5.4 ± 0.3 ppm for KD in solution 2 (p p α2 isoform. A significant difference in ATP production in HKAα2 KO mice is likely due to enhanced EA of H-ATPase under potassium depletion.
文摘Floods and storm surges pose significant threats to coastal regions worldwide,demanding timely and accurate early warning systems(EWS)for disaster preparedness.Traditional numerical and statistical methods often fall short in capturing complex,nonlinear,and real-time environmental dynamics.In recent years,machine learning(ML)and deep learning(DL)techniques have emerged as promising alternatives for enhancing the accuracy,speed,and scalability of EWS.This review critically evaluates the evolution of ML models—such as Artificial Neural Networks(ANN),Convolutional Neural Networks(CNN),and Long Short-Term Memory(LSTM)—in coastal flood prediction,highlighting their architectures,data requirements,performance metrics,and implementation challenges.A unique contribution of this work is the synthesis of real-time deployment challenges including latency,edge-cloud tradeoffs,and policy-level integration,areas often overlooked in prior literature.Furthermore,the review presents a comparative framework of model performance across different geographic and hydrologic settings,offering actionable insights for researchers and practitioners.Limitations of current AI-driven models,such as interpretability,data scarcity,and generalization across regions,are discussed in detail.Finally,the paper outlines future research directions including hybrid modelling,transfer learning,explainable AI,and policy-aware alert systems.By bridging technical performance and operational feasibility,this review aims to guide the development of next-generation intelligent EWS for resilient and adaptive coastal management.
