Progress in spinal cord organoid research:advancing understanding of neural development,disease modelling,and regenerative medicine

Stem cell-derived spinal cord organoids(SCOs)have revolutionised the study of spinal cord development and disease mechanisms,offering a three-dimensional model that recapitulates the complexity of native tissue.This review synthesises recent advancements in SCO technology,highlighting their role in modelling spinal cord morphogenesis and their application in neurodegenerative disease research.We discuss the methodological breakthroughs in inducing regional specification and cellular diversity within SCOs,which have enhanced their predictive ability for drug screening and their relevance in mimicking pathological conditions such as neurodegenerative diseases and neuromuscular disorders.Despite these strides,challenges in achieving vascularisation and mature neuronal integration persist.The future of SCOs lies in addressing these limitations,potentially leading to transformative impactions in regenerative medicine and therapeutic development.

Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Cellular interplay to 3D in vitro microphysiological disease model:cell patterning microbiota-gut-brain axis

The microbiota-gut-brain axis(MGBA)has emerged as a key prospect in the bidirectional communication between two major organ systems:the brain and the gut.Homeostasis between the two organ systems allows the body to function without disease,whereas dysbiosis has long-standing evidence of etiopathological conditions.The most common communication paths are the microbial release of metabolites,soluble neurotransmitters,and immune cells.However,each pathway is intertwined with a complex one.With the emergence of in vitro models and the popularity of three-dimensional(3D)cultures and Transwells,engineering has become easier for the scientific understanding of neurodegenerative diseases.This paper briefly retraces the possible communication pathways between the gut microbiome and the brain.It further elaborates on three major diseases:autism spectrum disorder,Parkinson’s disease,and Alzheimer’s disease,which are prevalent in children and the elderly.These diseases also decrease patients’quality of life.Hence,understanding them more deeply with respect to current advances in in vitro modeling is crucial for understanding the diseases.Remodeling of MGBA in the laboratory uses many molecular technologies and biomaterial advances.Spheroids and organoids provide a more realistic picture of the cell and tissue structure than monolayers.Combining them with the Transwell system offers the advantage of compartmentalizing the two systems(apical and basal)while allowing physical and chemical cues between them.Cutting-edge technologies,such as bioprinting and microfluidic chips,might be the future of in vitro modeling,as they provide dynamicity.

Rotating magnetic field inhibits Aβ protein aggregation and alleviates cognitive impairment in Alzheimer’s disease mice

Amyloid beta(Aβ)monomers aggregate to form fibrils and amyloid plaques,which are critical mechanisms in the pathogenesis of Alzheimer’s disease(AD).Given the important role of Aβ1-42 aggregation in plaque formation,leading to brain lesions and cognitive impairment,numerous studies have aimed to reduce Aβaggregation and slow AD progression.The diphenylalanine(FF)sequence is critical for amyloid aggregation,and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings.In this study,we examined the effects of a moderate-intensity rotating magnetic field(RMF)on Aβaggregation and AD pathogenesis.Results indicated that the RMF directly inhibited Aβamyloid fibril formation and reduced Aβ-induced cytotoxicity in neural cells in vitro.Using the AD mouse model APP/PS1,RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments,including exploration and spatial and non-spatial memory abilities.Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation,attenuated microglial activation,and reduced oxidative stress in the APP/PS1 mouse brain.These findings suggest that RMF holds considerable potential as a non-invasive,high-penetration physical approach for AD treatment.

Asymptotic Analysis of a Stochastic Model of Mosquito-Borne Disease with the Use of Insecticides and Bet Nets

Ross’ epidemic model describing the transmission of malaria uses two classes of infection, one for humans and one for mosquitoes. This paper presents a stochastic extension of a deterministic vector-borne epidemic model based only on the class of human infectious. The consistency of the model is established by proving that the stochastic delay differential equation describing the model has a unique positive global solution. The extinction of the disease is studied through the analysis of the stability of the disease-free equilibrium state and the persistence of the model. Finally, we introduce some numerical simulations to illustrate the obtained results.

Brain organoids are new tool for drug screening of neurological diseases

At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systematic reports on brain organoids,as a new three-dimensional in vitro model,in terms of model stability,key phenotypic fingerprint,and drug screening schemes,and particula rly rega rding the development of screening strategies for massive numbers of traditional Chinese medicine monomers.This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases.The paper also highlights the prospects from model stability,induction criteria of brain organoids,and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.

The generation and properties of human cortical organoids as a disease model for malformations of cortical development

As three-dimensional“organ-like”aggregates,human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of humanspecificity,fidelity and manipulation.Human cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular,cellular,structural,and functional levels,including the anatomy,functional neural network,and interaction among different brain regions,thus facilitating the discovery of brain development and evolution.In addition to studying the neuro-electrophysiological features of brain cortex development,human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease,especially in mimicking malformations of cortical development,thus revealing pathological mechanism and identifying effective drugs.In this review,we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype,underlying mechanisms and rescue strategies.

Immortalized hippocampal astrocytes from 3xTg-AD mice,a new model to study disease-related astrocytic dysfunction:a comparative review

Alzheimer's disease(AD)is characterized by complex etiology,long-lasting pathogenesis,and celltype-specific alterations.Currently,there is no cure for AD,emphasizing the urgent need for a comprehensive understanding of cell-specific pathology.Astrocytes,principal homeostatic cells of the central nervous system,are key players in the pathogenesis of neurodegenerative diseases,including AD.Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways.Tumor-derived and immortalized astrocytic cell lines,alongside the emerging technology of adult induced pluripotent stem cells,are widely used to study cellular dysfunction in AD.Surprisingly,no stable cell lines were available from genetic mouse AD models.Recently,we established immortalized hippocampal astroglial cell lines from amyloid-βprecursor protein/presenilin-1/Tau triple-transgenic(3xTg)-AD mice(denominated as wild type(WT)-and 3Tg-iAstro cells)using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection,thereby maintaining natural heterogeneity of primary cultures.Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling,mitochondrial dysfunctions,disproteostasis,altered homeostatic and signaling support to neurons,and blood-brain barrier models.Here we provide a comparative overview of the most used models to study astrocytes in vitro,such as primary culture,tumor-derived cell lines,immortalized astroglial cell lines,and induced pluripotent stem cell-derived astrocytes.We conclude that immortalized WT-and 3Tg-iAstro cells provide a noncompetitive but complementary,low-cost,easy-to-handle,and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.

Humanization for neurological disease modeling:A roadmap to increase the potential of Drosophila model systems

Neuroscience and neurology research is dominated by experimentation with rodents.Around 75%of neurology disease-associated genes have orthologs in Drosophila mel-anogaster,the fruit fly amenable to complex neurological and behavioral investiga-tions.However,non-vertebrate models including Drosophila have so far been unable to significantly replace mice and rats in this field of studies.One reason for this situ-ation is the predominance of gene overexpression(and gene loss-of-function)meth-odologies used when establishing a Drosophila model of a given neurological disease,a strategy that does not recapitulate accurately enough the genetic disease condi-tions.I argue here the need for a systematic humanization approach,whereby the Drosophila orthologs of human disease genes are replaced with the human sequences.This approach will identify the list of diseases and the underlying genes that can be adequately modeled in the fruit fly.I discuss the neurological disease genes to which this systematic humanization approach should be applied and provide an example of such an application,and consider its importance for subsequent disease modeling and drug discovery in Drosophila.I argue that this paradigm will not only advance our un-derstanding of the molecular etiology of a number of neurological disorders,but will also gradually enable researchers to reduce experimentation using rodent models of multiple neurological diseases and eventually replace these models.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure

Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

Stochastic Investigations for the Fractional Vector-Host Diseased Based Saturated Function of Treatment Model

The goal of this research is to introduce the simulation studies of the vector-host disease nonlinear system(VHDNS)along with the numerical treatment of artificial neural networks(ANNs)techniques supported by Levenberg-Marquardt backpropagation(LMQBP),known as ANNs-LMQBP.This mechanism is physically appropriate,where the number of infected people is increasing along with the limited health services.Furthermore,the biological effects have fadingmemories and exhibit transition behavior.Initially,the model is developed by considering the two and three categories for the humans and the vector species.The VHDNS is constructed with five classes,susceptible humans Sh(t),infected humans Ih(t),recovered humans Rh(t),infected vectors Iv(t),and susceptible vector Sv(t)based system of the fractional-order nonlinear ordinary differential equations.To solve the number of variations of the VHDNS,the numerical simulations are performed using the stochastic ANNs-LMQBP.The achieved numerical solutions for solving the VHDNS using the stochastic ANNs-LMQBP have been described for training,verifying,and testing data to decrease the mean square error(MSE).An extensive analysis is provided using the correlation studies,MSE,error histograms(EHs),state transitions(STs),and regression to observe the accuracy,efficiency,expertise,and aptitude of the computing ANNs-LMQBP.

Fundus photography,fluorescein angiography,optical coherence tomography and electroretinography of preclinical animal models of ocular diseases

The eye is an immune-privileged and sensory organ in humans and animals.Anatomical,physiological,and pathobiological features share significant similarities across divergent species(1).Each compartment of the eye has a unique structure and function.The anterior and posterior compartments of the eye contain endothelium(cornea),epithelium(cornea,ciliary body,iris),muscle(ciliary body),vitreous and neuronal(retina)tissues,which make the eye suitable to evaluate efficacy and safety of tissue specific drugs(2).

Bioengineered skin organoids:from development to applications

Signifcant advancements have been made in recent years in the development of highly sophisticated skin organoids.Serving as three-dimensional(3D)models that mimic human skin,these organoids have evolved into complex structures and are increasingly recognized as efective alternatives to traditional culture models and human skin due to their ability to overcome the limitations of two-dimensional(2D)systems and ethical concerns.The inherent plasticity of skin organoids allows for their construction into physiological and pathological models,enabling the study of skin development and dynamic changes.This review provides an overview of the pivotal work in the progression from 3D layered epidermis to cyst-like skin organoids with appendages.Furthermore,it highlights the latest advancements in organoid construction facilitated by state-of-the-art engineering techniques,such as 3D printing and microfuidic devices.The review also summarizes and discusses the diverse applications of skin organoids in developmental biology,disease modelling,regenerative medicine,and personalized medicine,while considering their prospects and limitations.

Human pluripotent stem cell-derived kidney organoids:Current progress and challenges

Human pluripotent stem cell(hPSC)-derived kidney organoids share similarities with the fetal kidney.However,the current hPSC-derived kidney organoids have some limitations,including the inability to perform nephrogenesis and lack of a corticomedullary definition,uniform vascular system,and coordinated exit path-way for urinary filtrate.Therefore,further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development,regeneration,disease modeling,and drug screening.In this review,we discussed recent advances in the generation of hPSC-derived kidney organoids,how these organoids contribute to the understanding of human kidney development and research in disease modeling.Additionally,the limitations,future research focus,and applications of hPSC-derived kidney organoids were highlighted.

Clinical value of precise rehabilitation nursing in management of cerebral infarction

BACKGROUND Cerebral infarction,previously referred to as cerebral infarction or ischemic stroke,refers to the localized brain tissue experiencing ischemic necrosis or softening due to disorders in brain blood supply,ischemia,and hypoxia.The precision rehabilitation nursing model for chronic disease management is a continuous,fixed,orderly,and efficient nursing model aimed at standardizing the clinical nursing process,reducing the wastage of medical resources,and improving the quality of medical services.AIM To analyze the value of a precise rehabilitation nursing model for chronic disease management in patients with cerebral infarction.METHODS Patients(n=124)admitted to our hospital with cerebral infarction between November 2019 and November 2021 were enrolled as the study subjects.The random number table method was used to divide them into a conventional nursing intervention group(n=61)and a model nursing intervention group(n=63).Changes in the nursing index for the two groups were compared after conventional nursing intervention and precise rehabilitation intervention nursing for chronic disease management.RESULTS Compared with the conventional intervention group,the model intervention group had a shorter time to clinical symptom relief(P<0.05),lower Hamilton Anxiety Scale and Hamilton Depression Scale scores,a lower incidence of total complications(P<0.05),a higher disease knowledge mastery rate,higher safety and quality,and a higher overall nursing satisfaction rate(P<0.05).CONCLUSION The precision rehabilitation nursing model for chronic disease management improves the clinical symptoms of patients with cerebral infarction,reducing the incidence of total complications and improving the clinical outcome of patients,and is worthy of application in clinical practice.

Animal models of eosinophilic esophagitis,review and perspectives

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis

The Chinese tree shrew(Tupaia belangeri chinensis)has emerged as a promising model for investigating adrenal steroid synthesis,but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans.Here,we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing,spatial transcriptome analysis,mass spectrometry,and immunohistochemistry.We compared the transcriptomes of various adrenal cell types across tree shrews,humans,macaques,and mice.Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans,including CYP11B2,CYP11B1,CYB5A,and CHGA.Biochemical analysis confirmed the production of aldosterone,cortisol,and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands.Furthermore,genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome,primary aldosteronism,hypertension,and related disorders in humans based on genome-wide association studies.Overall,this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland.Our comprehensive results(publicly available at http://gxmujyzmolab.cn:16245/scAGMap/)should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

Progress of organoid platform in cardiovascular research

Cardiovascular disease is a significant cause of death in humans. Various models are necessary for the study ofcardiovascular diseases, but once cellular and animal models have some defects, such as insufficient fidelity. As anew technology, organoid has certain advantages and has been used in many applications in the study of cardiovasculardiseases. This article aims to summarize the application of organoid platforms in cardiovasculardiseases, including organoid construction schemes, modeling, and application of cardiovascular organoids. Advancesin cardiovascular organoid research have provided many models for different cardiovascular diseases in avariety of areas, including myocardium, blood vessels, and valves. Physiological and pathological models ofdifferent diseases, drug research models, and methods for evaluating and promoting the maturation of differentkinds of organ tissues are provided for various cardiovascular diseases, including cardiomyopathy, myocardialinfarction, and atherosclerosis. This article provides a comprehensive overview of the latest research progress incardiovascular organ tissues, including construction protocols for cardiovascular organoid tissues and theirevaluation system, different types of disease models, and applications of cardiovascular organoid models invarious studies. The problems and possible solutions in organoid development are summarized.

Numerical Simulation and Parameter Estimation of Fractional-Order Dynamic Epidemic Model for COVID-19

The outbreak of COVID-19 in 2019 resulted in numerous infections and deaths. In order to better study the transmission of COVID-19, this article adopts an improved fractional-order SIR model. Firstly, the properties of the model are studied, including the feasible domain and bounded solutions of the system. Secondly, the stability of the system is discussed, among other things. Then, the GMMP method is introduced to obtain numerical solutions for the COVID-19 system and combined with the improved MH-NMSS-PSO parameter estimation method to fit the real data of Delhi, India from April 1, 2020 to June 30, 2020. The results show that the fitting effect is quite ideal. Finally, long-term predictions were made on the number of infections. We accurately estimate that the peak number of infections in Delhi, India, can reach around 2.1 million. This paper also compares the fitting performance of the integer-order COVID-19 model and the fractional-order COVID-19 model using the real data from Delhi. The results indicate that the fractional-order model with different orders, as we proposed, performs the best.

Establishment of a Fractional Order COVID-19 Model and Its Feasibility Analysis

This paper investigates an improved SIR model for COVID-19 based on the Caputo fractional derivative. Firstly, the properties of the model are studied, including the feasible domain and bounded solutions of the system. Secondly, the stability of the system is discussed, among other things. Then, the GMMP method is introduced to obtain numerical solutions for the COVID-19 system. Numerical simulations were conducted using MATLAB, and the results indicate that our model is valuable for studying virus transmission.