“Blind men and an elephant”:The need for animals in research,drug safety studies,and understanding civilizational diseases

Animal-based research and drug safety studies are essential to understanding the mysteries of nature and the long-term survival of humans.Due to the rapid increase in the global human population,conflict-and economically driven human migration,tourism-related activities,densely populated metropolitan areas,and local policies,humans will be affected by a multitude of novel disease-causing microorganisms and civilizational diseases.Despite disparities among countries,recent and planned changes in regulations concerning animal research and drug safety studies could have detrimental effects on both the animal research community and nations lacking sufficient social support systems.Based on existing scientific literature,I argue that we need animal research encompassing aspects such as animal development,behavior,drug safety studies,and for the understanding of future civilizational diseases.Depending on the nature of the research questions and local challenges,a suitable animal model organism should be made mandatory.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Genetically modified non-human primate models for research on neurodegenerative diseases

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

Aggravation of Cancer,Heart Diseases and Diabetes Subsequent to COVID-19 Lockdown via Mathematical Modeling

The global populationhas beenandwill continue to be severely impacted by theCOVID-19 epidemic.The primary objective of this research is to demonstrate the future impact of COVID-19 on those who suffer from other fatal conditions such as cancer,heart disease,and diabetes.Here,using ordinary differential equations(ODEs),two mathematical models are developed to explain the association between COVID-19 and cancer and between COVID-19 and diabetes and heart disease.After that,we highlight the stability assessments that can be applied to these models.Sensitivity analysis is used to examine how changes in certain factors impact different aspects of disease.The sensitivity analysis showed that many people are still nervous about seeing a doctor due to COVID-19,which could result in a dramatic increase in the diagnosis of various ailments in the years to come.The correlation between diabetes and cardiovascular illness is also illustrated graphically.The effects of smoking and obesity are also found to be significant in disease compartments.Model fitting is also provided for interpreting the relationship between real data and the results of thiswork.Diabetic people,in particular,need tomonitor their health conditions closely and practice heart health maintenance.People with heart diseases should undergo regular checks so that they can protect themselves from diabetes and take some precautions including suitable diets.The main purpose of this study is to emphasize the importance of regular checks,to warn people about the effects of COVID-19(including avoiding healthcare centers and doctors because of the spread of infectious diseases)and to indicate the importance of family history of cancer,heart diseases and diabetes.The provision of the recommendations requires an increase in public consciousness.

In vitro engineered models of neurodegenerative diseases

Neurodegeneration is a catastrophic process that develops progressive damage leading to functional andstructural loss of the cells of the nervous system and is among the biggest unavoidable problems of our age.Animalmodels do not reflect the pathophysiology observed in humans due to distinct differences between the neuralpathways,gene expression patterns,neuronal plasticity,and other disease-related mechanisms in animals andhumans.Classical in vitro cell culture models are also not sufficient for pre-clinical drug testing in reflecting thecomplex pathophysiology of neurodegenerative diseases.Today,modern,engineered techniques are applied to developmulticellular,intricate in vitro models and to create the closest microenvironment simulating biological,biochemical,and mechanical characteristics of the in vivo degenerating tissue.In THIS review,the capabilities and shortcomings ofscaffold-based and scaffold-free techniques,organoids,and microfluidic models that best reflect neurodegeneration invitro in the biomimetic framework are discussed.

Model Agnostic Meta-Learning(MAML)-Based Ensemble Model for Accurate Detection of Wheat Diseases Using Vision Transformer and Graph Neural Networks

Wheat is a critical crop,extensively consumed worldwide,and its production enhancement is essential to meet escalating demand.The presence of diseases like stem rust,leaf rust,yellow rust,and tan spot significantly diminishes wheat yield,making the early and precise identification of these diseases vital for effective disease management.With advancements in deep learning algorithms,researchers have proposed many methods for the automated detection of disease pathogens;however,accurately detectingmultiple disease pathogens simultaneously remains a challenge.This challenge arises due to the scarcity of RGB images for multiple diseases,class imbalance in existing public datasets,and the difficulty in extracting features that discriminate between multiple classes of disease pathogens.In this research,a novel method is proposed based on Transfer Generative Adversarial Networks for augmenting existing data,thereby overcoming the problems of class imbalance and data scarcity.This study proposes a customized architecture of Vision Transformers(ViT),where the feature vector is obtained by concatenating features extracted from the custom ViT and Graph Neural Networks.This paper also proposes a Model AgnosticMeta Learning(MAML)based ensemble classifier for accurate classification.The proposedmodel,validated on public datasets for wheat disease pathogen classification,achieved a test accuracy of 99.20%and an F1-score of 97.95%.Compared with existing state-of-the-art methods,this proposed model outperforms in terms of accuracy,F1-score,and the number of disease pathogens detection.In future,more diseases can be included for detection along with some other modalities like pests and weed.

Induced pluripotent stem cells: Mechanisms, achievements and perspectives in farm animals

Pluripotent stem cells are unspecialized cells withunlimited self-renewal, and they can be triggered to differentiate into desired specialized cell types. These features provide the basis for an unlimited cell source for innovative cell therapies. Pluripotent cells also allow to study developmental pathways, and to employ them or their differentiated cell derivatives in pharmaceutical testing and biotechnological applications. Via blastocyst complementation, pluripotent cells are a favoured tool for the generation of genetically modified mice. The recently established technology to generate an induced pluripotency status by ectopic co-expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc allows to extending these applications to farm animal species, for which the derivation of genuine embryonic stem cells was not successful so far. Most induced pluripotent stem(i PS) cells are generated by retroviral or lentiviral transduction of reprogramming factors. Multiple viral integrations into the genome may cause insertional mutagenesis and may increase the risk of tumour formation. Non-integration methods have been reported to overcome the safety concerns associated with retro and lentiviral-derived i PS cells, such as transient expression of the reprogramming factors using episomal plasmids, and direct delivery of reprogramming m RNAs or proteins. In this review, we focus on the mechanisms of cellular reprogramming and current methods used to induce pluripotency. We also highlight problems associated with the generation of i PS cells. An increased understanding of the fundamental mechanisms underlying pluripotency and refining the methodology of i PS cell generation will have a profound impact on future development and application in regenerative medicine and reproductive biotechnology of farm animals.

The Negative Effect of Heavy Metal Salts on the Body of Mammal Animals

The main purpose of this presented article was to explain the need to study the amount of heavy metal salts in the environment where animals live, in the water, in air, and in the food and fodder consumed. This article presents materials from the literature on the effects of heavy metal salts on the body of animals and the environment in which they live. The cited analytical data showed that the general information on the negative effects of heavy metal salts on the body is sufficient, but their effects on the digestive tract and morpho-functional properties of rabbits should be studied in depth. Therefore, we planned to focus our scientific work on this topic. The article mainly refers to salts of heavy metals cadmium, lead, and mercury (Cd, Pb, Hg). It is noted in the literature that heavy metal salts have a negative effect on the body of animals. We focused mainly on data on the effects of heavy metals on farm animals, including rabbits. But it is clear that the authors referred to were referring to experimental animals. These negative effects are manifested in the form of disorders of digestive functions, disorders of neurovegetative processes, increasing incidence of cardiovascular disease, rapid heart failure, deterioration of calcium metabolism, as well as impaired haemoglobin metabolism. Disorders of protein metabolism manifest themselves in the form of cases of hyperproteinaemia and dysproteinaemia. The results of the evaluation of the organism of healthy animals in chemically and radioactively contaminated areas showed the accumulation of significant levels of chemical elements in their organism. We mainly looked at the effects of heavy metal salts on farm animals. The cited analytical data showed that the general information on the negative effects of heavy metal salts on the body is sufficient, but the effects on the activity of organ systems in the body (respiration, blood and blood circulation, digestion, reproduction, productivity and immunological systems) have not been comprehensively studied.

Effect of hyperbaric oxygen on nerve impairment recovery of animals after organophosphorus:an experimental study

Objective To investigate the effect of hyperbarci oxygen(HBO) on recovery of nerves injury in rats suffered from acute organophosphorus poisoning. Method We established organophosphorus poisoning models and observed effect of HBO on recovery of injure nerves. Results Compared with control group, cerebrospinal fluid induced peak potential and incubation period in HBO group were significantly recovered(P<0.05).HBO could accelerated repair of injured nerves. Conclusion HBO could relieve injury of nerves during treatment of organophosphorus poisoning.

Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Neurophysiological, histological, and behavioral characterization of animal models of distraction spinal cord injury: a systematic review

Distraction spinal cord injury is caused by some degree of distraction or longitudinal tension on the spinal cord and commonly occurs in patients who undergo corrective operation for severe spinal deformity.With the increased degree and duration of distraction,spinal cord injuries become more serious in terms of their neurophysiology,histology,and behavior.Very few studies have been published on the specific characteristics of distraction spinal cord injury.In this study,we systematically review 22 related studies involving animal models of distraction spinal cord injury,focusing particularly on the neurophysiological,histological,and behavioral characteristics of this disease.In addition,we summarize the mechanisms underlying primary and secondary injuries caused by distraction spinal cord injury and clarify the effects of different degrees and durations of distraction on the primary injuries associated with spinal cord injury.We provide new concepts for the establishment of a model of distraction spinal cord injury and related basic research,and provide reference guidelines for the clinical diagnosis and treatment of this disease.

Genetically modified pigs:Emerging animal models for hereditary hearing loss

Hereditary hearing loss(HHL),a genetic disorder that impairs auditory function,significantly affects quality of life and incurs substantial economic losses for society.To investigate the underlying causes of HHL and evaluate therapeutic outcomes,appropriate animal models are necessary.Pigs have been extensively used as valuable large animal models in biomedical research.In this review,we highlight the advantages of pig models in terms of ear anatomy,inner ear morphology,and electrophysiological characteristics,as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss.Additionally,we discuss the prospects,challenges,and recommendations regarding the use pig models in HHL research.Overall,this review provides insights and perspectives for future studies on HHL using porcine models.

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.

Role of CD36 in central nervous system diseases

CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.

Big data technology in infectious diseases modeling,simulation,and prediction after the COVID-19 outbreak

After the outbreak of COVID-19,the interaction of infectious disease systems and social systems has challenged traditional infectious disease modeling methods.Starting from the research purpose and data,researchers im-proved the structure and data of the compartment model or used agents and artificial intelligence based models to solve epidemiological problems.In terms of modeling methods,the researchers use compartment subdivi-sion,dynamic parameters,agent-based model methods,and artificial intelligence related methods.In terms of factors studied,the researchers studied 6 categories:human mobility,nonpharmaceutical interventions(NPIs),ages,medical resources,human response,and vaccine.The researchers completed the study of factors through modeling methods to quantitatively analyze the impact of social systems and put forward their suggestions for the future transmission status of infectious diseases and prevention and control strategies.This review started with a research structure of research purpose,factor,data,model,and conclusion.Focusing on the post-COVID-19 infectious disease prediction simulation research,this study summarized various improvement methods and analyzes matching improvements for various specific research purposes.

Fusion of Region Extraction and Cross-Entropy SVM Models for Wheat Rust Diseases Classification

Wheat rust diseases are one of the major types of fungal diseases that cause substantial yield quality losses of 15%–20%every year.The wheat rust diseases are identified either through experienced evaluators or computerassisted techniques.The experienced evaluators take time to identify the disease which is highly laborious and too costly.If wheat rust diseases are predicted at the development stages,then fungicides are sprayed earlier which helps to increase wheat yield quality.To solve the experienced evaluator issues,a combined region extraction and cross-entropy support vector machine(CE-SVM)model is proposed for wheat rust disease identification.In the proposed system,a total of 2300 secondary source images were augmented through flipping,cropping,and rotation techniques.The augmented images are preprocessed by histogram equalization.As a result,preprocessed images have been applied to region extraction convolutional neural networks(RCNN);Fast-RCNN,Faster-RCNN,and Mask-RCNN models for wheat plant patch extraction.Different layers of region extraction models construct a feature vector that is later passed to the CE-SVM model.As a result,the Gaussian kernel function in CE-SVM achieves high F1-score(88.43%)and accuracy(93.60%)for wheat stripe rust disease classification.

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).

Study of tree shrew biology and models: A booming and prosperous field for biomedical research

The tree shrew(Tupaia belangeri)has long been proposed as a suitable alternative to non-human primates(NHPs)in biomedical and laboratory research due to its close evolutionary relationship with primates.In recent years,significant advances have facilitated tree shrew studies,including the determination of the tree shrew genome,genetic manipulation using spermatogonial stem cells,viral vector-mediated gene delivery,and mapping of the tree shrew brain atlas.However,the limited availability of tree shrews globally remains a substantial challenge in the field.Additionally,determining the key questions best answered using tree shrews constitutes another difficulty.Tree shrew models have historically been used to study hepatitis B virus(HBV)and hepatitis C virus(HCV)infection,myopia,and psychosocial stress-induced depression,with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases.Despite these efforts,the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research.This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model.We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies.The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models,meeting the increasing demands of life science and biomedical research.