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Background: Different countries, including Iran, have implemented various policies to address substance use disorder. This study aims to describe the policies related to substance use disorder treatment and identify challenges related to these policies in Iran since the beginning of the Iranian Revolution in 1979. Methods: This qualitative study utilized document analysis and interviews with policymakers and implementers. We reviewed a total of 22 documents related to substance use disorder treatment and harm reduction. The results from document analysis complemented and validated the interview data. The research population comprised policymakers and implementers, including individuals directly involved in formulating and implementing substance use disorder treatment policies. Purposive sampling was employed, with a snowball strategy utilized to maximize diversity. Data saturation was achieved after conducting 32 semi-structured interviews. Conventional content analysis was used for data analysis. Results: In general, the policy landscape for substance use disorder treatment in the Islamic Republic of Iran can be divided into two periods: the "Moral Model" era (1979–1993) and the "Disease Model" era (1993–present). Challenges within the content of substance use disorder treatment policies in Iran encompass the lack of law revisions, existence of contradictions in laws and nature of disease, the absence of evidence-based policymaking, and an inadequate comprehensive perspective on the phenomenon of substance use disorder. Conclusions: The presence of multiple authorities with different perspectives on substance use disorder and its treatment, coupled with the application of personal preferences in policymaking and the absence of evidence-based policymaking, have contributed to weaknesses in decision-making and policy formulation. The true philosophy of Disease Model appears not to have been fully grasped by health policymakers in Iran, as all Disease Model policies have been pursued with an emphasis on abstinence and quitting. Iran and other nations facing similar challenges should place more reliance on evidence-based approaches and shift away from the "Moral Model" paradigm to develop more effective substance use disorder treatment policies. [ABSTRACT FROM AUTHOR]

Pigs can be genetically engineered to resemble human monogenic diseases. Genetically tailored pig models may bridge the gap between proof-of-concept studies in cellular or rodent models and clinical trials. DMD pigs show the characteristic biochemical, clinical, and pathological features of DMD, with an accelerated development of the disease. DMD pigs provide new insights into the hierarchy of physiological abnormalities of dystrophic muscle. DMD pigs are a promising model for testing targeted therapies, such as exon skipping and gene editing, as well as for validating and optimizing novel diagnostic procedures such as MSOT. Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked DMD gene, resulting in the absence of dystrophin, progressive muscle degeneration, and heart failure. Genetically tailored pig models resembling human DMD mutations recapitulate the biochemical, clinical, and pathological hallmarks of DMD with an accelerated disease progression compared to human patients. DMD pigs have been used to evaluate therapeutic concepts such as gene editing to reframe a disrupted DMD reading frame or the delivery of artificial chromosome vectors carrying the complete DMD gene. Moreover, DMD pigs have been instrumental in validating new diagnostic modalities such as multispectral optoacoustic tomography (MSOT) for non-invasive monitoring of disease progression. DMD pigs may thus help to bridge the gap between proof-of-concept studies in cellular or rodent models and clinical studies in patients. [ABSTRACT FROM AUTHOR]

Organoids are miniature, highly accurate representations of organs that capture the structure and unique functions of specific organs. Although the field of organoids has experienced exponential growth, driven by advances in artificial intelligence, gene editing, and bioinstrumentation, a comprehensive and accurate overview of organoid applications remains necessary. This review offers a detailed exploration of the historical origins and characteristics of various organoid types, their applications—including disease modeling, drug toxicity and efficacy assessments, precision medicine, and regenerative medicine—as well as the current challenges and future directions of organoid research. Organoids have proven instrumental in elucidating genetic cell fate in hereditary diseases, infectious diseases, metabolic disorders, and malignancies, as well as in the study of processes such as embryonic development, molecular mechanisms, and host–microbe interactions. Furthermore, the integration of organoid technology with artificial intelligence and microfluidics has significantly advanced large‐scale, rapid, and cost‐effective drug toxicity and efficacy assessments, thereby propelling progress in precision medicine. Finally, with the advent of high‐performance materials, three‐dimensional printing technology, and gene editing, organoids are also gaining prominence in the field of regenerative medicine. Our insights and predictions aim to provide valuable guidance to current researchers and to support the continued advancement of this rapidly developing field. [ABSTRACT FROM AUTHOR]

BACKGROUND: Inherited heart disease has a high prevalence and mortality rate, but its pathogenesis has not yet been clarified. Although relevant animal models have been established to provide a foundation for the pathogenesis research of inherited heart disease, the value of these research results has been significantly reduced due to differences among species. Therefore, a new model is needed to explore its occurrence and development. OBJECTIVE: To review the current role of induced pluripotent stem cells in disease modeling and potential application prospects in various inherited heart diseases. METHODS: The first author searched the relevant articles published nearly 13 years in PubMed from January to March 2023. The search terms were “induced pluripotent stem cell, inherited heart disease, congenital heart disease”. Finally, 76 articles were included for analysis. RESULTS AND CONCLUSION: Since 2007, when induced pluripotent stem cells were induced from human somatic cells, many studies have been reported on disease-specific induced pluripotent stem cells. Due to the ability of disease-specific induced pluripotent stem cells to reproduce disease phenotypes, they are expected to become a new research tool for in vitro disease modeling, used to analyze pathogenesis and develop auxiliary drugs. In the research of cardiovascular genetic diseases, cardiomyocytes derived from patient-specific induced pluripotent stem cells contain gene mutations that are involved in cardiac dysplasia. Therefore, it can be used as a new tool to study the potential mechanisms of inherited heart disease. Up to now, induced pluripotent stem cells-derived cardiomyocytes have been widely used to study the molecular mechanisms of various genetic heart diseases, such as cardiac electrophysiological diseases, cardiomyopathy, and some syndromic inherited heart diseases. [ABSTRACT FROM AUTHOR]

In recent years, with rapid development of technology of regenerative medicine and tissue engineering, brain organoids, as an innovative in vitro model system, have become a hot spot in neuroscience research and drug development. Brain organoids simulate the complex structure and function of the human brain in terms of reproducing key processes of brain development in vitro, providing an unprecedented platform for understanding the mechanisms of neurological diseases and of evaluating drug efficacy and toxicity. This review summarizes the latest research progress in brain organoid technology, particularly its application in drug development and in exploring challenges and orientation of future development. [ABSTRACT FROM AUTHOR]

Traditional in vitro models have inevitable limitations and there are significant differences in assessing drug efficacy and side effects as compared to human trials. Organ-on-a-chip technology simulates human organs in a physiological environment and functional chip with a high fidelity physiological or pathophysiological level, offering great innovative prospects for drug development. This paper mainly introduces the research progress and application of organ chip from the perspective of various systems in vivo. At the same time, the limitations of the current development process of organ chip and the future development direction are proposed. [ABSTRACT FROM AUTHOR]

The discovery of human pluripotent stem cells (hiPSCs) and advances in DNA editing techniques have opened opportunities for personalized cell-based therapies for a wide spectrum of diseases. It has gained importance as a valuable tool to investigate genetic and functional variations in congenital heart defects (CHDs), enabling the customization of treatment strategies. The ability to understand the disease process specific to the individual patient of interest provides this technology with a significant advantage over generic animal models. However, its utility as a disease-in-a-dish model requires identifying effective and efficient differentiation protocols that accurately reproduce disease traits. Currently, iPSC-related research relies heavily on the quality of cells and the properties of the differentiation technique In this review, we discuss the utility of iPSCs in bench CHD research, the molecular pathways involved in the differentiation of cardiomyocytes, and their applications in CHD disease modeling, therapeutics, and drug application. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to improve our understanding of gastrointestinal tract cancer and the side effects of cancer treatment by using advanced in vitro systems. Traditional models like cell cultures and animal studies provide valuable insights but have limitations in replicating the complexity of human disease and raise ethical concerns. By focusing on bioreactor-based in vitro systems, which can mimic the physical and chemical environment of the gastrointestinal tract, this study aims to provide more accurate models for studying cancer and its treatment side effects. These advancements could lead to better insights into disease mechanisms, potentially improving treatment strategies and benefiting the broader research community. Human diseases are multifaceted, starting with alterations at the cellular level, damaging organs and their functions, and disturbing interactions and immune responses. In vitro systems offer clarity and standardisation, which are crucial for effectively modelling disease. These models aim not to replicate every disease aspect but to dissect specific ones with precision. Controlled environments allow researchers to isolate key variables, eliminate confounding factors and elucidate disease mechanisms more clearly. Technological progress has rapidly advanced model systems. Initially, 2D cell culture models explored fundamental cell interactions. The transition to 3D cell cultures and organoids enabled more life-like tissue architecture and enhanced intercellular interactions. Advanced bioreactor-based devices now recreate the physicochemical environments of specific organs, simulating features like perfusion and the gastrointestinal tract's mucus layer, enhancing physiological relevance. These systems have been simplified and adapted for high-throughput research, marking significant progress. This review focuses on in vitro systems for modelling gastrointestinal tract cancer and the side effects of cancer treatment. While cell cultures and in vivo models are invaluable, our main emphasis is on bioreactor-based in vitro modelling systems that include the gut microbiome. [ABSTRACT FROM AUTHOR]

In recent years, with rapid development of technology of regenerative medicine and tissue engineering, brain organoids, as an innovative in vitro model system, have become a hot spot in neuroscience research and drug development. Brain organoids simulate the complex structure and function of the human brain in terms of reproducing key processes of brain development in vitro, providing an unprecedented platform for understanding the mechanisms of neurological diseases and of evaluating drug efficacy and toxicity. This review summarizes the latest research progress in brain organoid technology, particularly its application in drug development and in exploring challenges and orientation of future development.

Traditional in vitro models have inevitable limitations and there are significant differences in assessing drug efficacy and side effects as compared to human trials. Organ-on-a-chip technology simulates human organs in a physiological environment and functional chip with a high fidelity physiological or pathophysiological level, offering great innovative prospects for drug development. This paper mainly introduces the research progress and application of organ chip from the perspective of various systems in vivo. At the same time, the limitations of the current development process of organ chip and the future development direction are proposed.

BACKGROUND: 3D organoids have characteristics that resemble physiological tissues and to some extent mimic organ function, making them excellent models for applications ranging from basic development/stem cell research to personalized medicine. OBJECTIVE: To review and discuss the types of diseases and application areas such as tumor modeling that organoids can be applied to, as well as their regulatory status and challenges. METHODS: With “organoid, stem cell, disease model, 3D printing technology, medical field” as Chinese and English search terms, we searched PubMed, Elsevier, WanFang, and CNKI databases to summarize and analyze organoid products at home and abroad, summarize the application of organoid technology in the medical field, and prospect the future development of organoid products in the medical field. RESULTS AND CONCLUSION: Organoids can break the limitations of traditional cell and animal models, avoid the ethical problems existing in clinical research, and have a high similarity to the source organ, a more similar performance to the physiology and pathology of human systems, and genetic stability, which has great advantages in current research. Organoids have been applied in the following fields: efficacy evaluation studies (preclinical models), including intestinal organoids, kidney organoids, liver organoids, gallbladder organoids, lung organoids, brain organoids, heart organoids, skin organoids, and reproductive system organoids; research on infectious diseases; cancer research and precision therapy; regenerative medicine; immune organoids. Although the United States, the European Union and China do not have perfect regulatory provisions, they are trying to promote the formulation of organoid regulatory laws and regulations. In China, although no organoid medical device products have been listed for the time being, its related regenerative medicine products have made breakthroughs. [ABSTRACT FROM AUTHOR]

The concomitant use of various types of models (in silico, in vitro, and in vivo) has been exemplified here within the context of biomedical researches performed in the Endocrinology and Metabolism Research Institute (EMRI) of Tehran University of Medical Sciences. Two main research aeras have been discussed: the search for new small molecules as therapeutics for diabetes and related metabolic conditions, and diseases related to protein aggregation. Due to their multidisciplinary nature, the majority of these studies have needed the collaboration of different specialties. In both cases, a brief overview of the subject is provided through literature examples, and sequential use of these methods is described. [ABSTRACT FROM AUTHOR]

A major shortcoming in the treatment of mesangial cell-associated diseases such as IgA nephropathy, diabetic nephropathy, or lupus nephritis, which frequently progress to end-stage renal disease, is poor drug availability in the glomerular mesangium. Drug delivery via active targeting of nanoparticles, using ligands attached to the particle surface for target cell recognition to increase the biodistribution to the mesangium, is a promising strategy to overcome this hurdle. However, although several glomerular tissue targeting approaches have been described, so far no study has demonstrated the particles' ability to deliver sufficient drug amounts combined with an appropriate nanoparticle target retention time to trigger relevant biological effects in the mesangium. In our study, we encapsulated erastin, a ferroptosis-inducing model compound, into adenovirus-mimetic, mesangial cell-targeting nanoparticles, enabling the direct visualisation of biological effects through ferroptosis-dependent histological changes. By intravital microscopy and analysis of histological sections, we were not only able to localise the injected particles over 10 days within the target cells but also to demonstrate biological activity in the renal glomeruli. In conclusion, we have characterised adenovirus-mimetic nanoparticles as a highly suitable drug delivery platform for the treatment of mesangial cell-associated diseases and additionally provided the basis for a potential renal disease model. [ABSTRACT FROM AUTHOR]

Now in its 25th year, the Mutant Mouse Resource and Research Center (MMRRC) consortium continues to serve the United States and international biomedical scientific community as a public repository and distribution archive of laboratory mouse models of human disease for research. Supported by the National Institutes of Health (NIH), the MMRRC consists of 4 regionally distributed and dedicated vivaria, offices, and specialized laboratory facilities and an Informatics Coordination and Service Center (ICSC). The overarching purpose of the MMRRC is to facilitate groundbreaking biomedical research by offering an extensive repertoire of mutant mice that are essential for advancing the understanding of human physiology and disease. The function of the MMRRC is to identify, acquire, evaluate, characterize, cryopreserve, and distribute mutant mouse strains to qualified biomedical investigators around the nation and the globe. Mouse strains accepted from the research community are held to the highest scientific standards to optimize reproducibility and enhance scientific rigor and transparency. All submitted strains are thoroughly reviewed, documented, and validated using extensive scientific quality control measures. In addition, the MMRRC conducts resource-related research on cryopreservation, mouse genetics, environmental conditions, and other topics that enhance operations of the MMRRC. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem (ES) cell lines, and murine hybridomas for nearly 65,000 alleles. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8441 institutions worldwide. The MMRRC also provides numerous services to assist researchers, including scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, cryorecovery, husbandry, breeding and colony management, infectious disease surveillance, and disease modeling. The ICSC coordinates MMRRC operations, interacts with researchers, and manages the website (mmrrc.org) and online catalogue. Researchers benefit from an expansive list of well-defined mouse models of disease that meet the highest scientific standards while submitting investigators benefit by having their mouse strains cryopreserved, protected, and distributed in compliance with NIH policies. [ABSTRACT FROM AUTHOR]

The ubiquitous presence of micro and nanoplastics (MNPs) in the environment has become a pressing global concern, particularly regarding the potential impacts on human health. This review underscores the urgent need for an integrative research framework that bridges the gap between epidemiological observations and toxicological insights. Human exposure to MNPs occurs predominantly through ingestion, inhalation and dermal contact pathways. Epidemiological findings have consistently demonstrated the presence of MNPs in diverse human tissues, signaling a broad exposure and emphasizing the imperative to explore potential health risks. Population surveys have shown that the concentration of MNPs in the feces of people using disposable plastic tableware reaches 24.65 items/g. These results are associated with changes in microbiota composition and metabolite levels relevant to central nervous system disorders, energy metabolism and inflammatory responses. The detectable abundance of MNPs in the nasal mucus of individuals wearing N95 masks was measured to be 10.6 ± 2.3 items/mg. Moreover, population- based studies have linked MNP exposure to adverse health outcomes, suggesting correlation relationships between exposure levels and specific diseases such as inflammatory bowel disease (IBD) and human pulmonary ground-glass nodules (GGN). These associations underscore the necessity for in-depth toxicological investigations to elucidate the toxicity mechanisms of MNPs. Meanwhile, laboratory-based toxicological studies have the potential to reveal causative relationships and various in vitro and in vivo models have been used to explore the mechanisms of the toxicity of MNPs in the gastrointestinal tract, lungs and cardiovascular system. However, early studies failed to reflect on the complexity of the real environment. To foster interdisciplinary collaborations, this paper aims to reconcile the disparities between exposure risks and human health impacts. By critically reviewing recent advancements in understanding the exposure risks of MNPs, epidemiological observations and organ-specific toxicity, this work furnishes a comprehensive perspective on the health implications of MNPs. [ABSTRACT FROM AUTHOR]

Tissue engineering (TE) is a field of science that combines biological, engineering, and medical sciences and allows the development of disease models, drug development and gene therapy studies, and even cellular or tissue-based treatments developed by engineering methods. The eye is an organ that is easily accessible and amenable to engineering applications, paving the way for TE in ophthalmology. TE studies are being conducted on a wide range of topics, including the tear film, eyelids, cornea, optic nerve, glaucoma, and retinal diseases. With the rapid scientific advances in the field, it seems that TE is radically modifying the management of ocular disorders.

Abstract Objective To assess the impact of self-medication on the transmission dynamics of COVID-19 across different age groups, examine the interplay of vaccination and self-medication in disease spread, and identify the age group most prone to self-medication. Methods We developed an age-structured compartmentalized epidemiological model to track the early dynamics of COVID-19. Age-structured data from the Government of Gauteng, encompassing the reported cumulative number of cases and daily confirmed cases, were used to calibrate the model through a Markov Chain Monte Carlo (MCMC) framework. Subsequently, uncertainty and sensitivity analyses were conducted on the model parameters. Results We found that self-medication is predominant among the age group 15-64 (74.52%), followed by the age group 0-14 (34.02%), and then the age group 65+ (11.41%). The mean values of the basic reproduction number, the size of the first epidemic peak (the highest magnitude of the disease), and the time of the first epidemic peak (when the first highest magnitude occurs) are 4.16499, 241,715 cases, and 190.376 days, respectively. Moreover, we observed that self-medication among individuals aged 15-64 results in the highest spreading rate of COVID-19 at the onset of the outbreak and has the greatest impact on the first epidemic peak and its timing. Conclusion Studies aiming to understand the dynamics of diseases in areas prone to self-medication should account for this practice. There is a need for a campaign against COVID-19-related self-medication, specifically targeting the active population (ages 15-64).

The 36th International Mammalian Genome Conference (IMGC) was held in a hybrid format at the Tsukuba International Congress Center in Tsukuba, Ibaraki, Japan, for 4 days from March 28 to 31, 2023. This international conference on functional genomics of mouse, human, and other mammalian species attracted 246 participants in total, of which 129 were from outside Japan, including Europe, the United States and Asia, and 117 participants were from Japan. The conference included three technical workshops, keynote lectures by domestic researchers, commemorative lectures for the conference awards, 57 oral presentations, and 97 poster presentations. The event was a great success. Topics included the establishment and analysis of disease models using genetically engineered or spontaneous mutant mice, systems genetic analysis using mouse strains such as wild‐derived mice and recombinant inbred mouse strains, infectious diseases, immunology, and epigenetics. In addition, as a joint program, a two‐day RIKEN Symposium was held, and active discussions continued over the four‐day period. Also, there was a trainee symposium, in which young researchers were encouraged to participate, and excellent papers were selected as oral presentations in the main session. [ABSTRACT FROM AUTHOR]

The CRISPR system, as an effective genome editing technology, has been extensively utilized for the construction of disease models in human pluripotent stem cells. Establishment of a gene mutant or knockout stem cell line typically relies on Cas nuclease-generated double-stranded DNA breaks and exogenous templates, which can produce uncontrollable editing byproducts and toxicity. The recently developed adenine base editors (ABE) have greatly facilitated related research by introducing A/T > G/C mutations in the coding regions or splitting sites (AG-GT) of genes, enabling mutant gene knock-in or knock-out without introducing DNA breaks. In this study, we edit the AG bases in exons anterior to achieve gene knockout via the ABE8e-SpRY, which recognizes most expanded protospacer adjacent motif to target the genome. Except for gene-knockout, ABE8e-SpRY can also efficiently establish disease-related A/T-to-G/C variation cell lines by targeting coding sequences. The method we generated is simple and time-saving, and it only takes two weeks to obtain the desired cell line. This protocol provides operating instructions step-by-step for constructing knockout and point mutation cell lines. [ABSTRACT FROM AUTHOR]

The liver is a major metabolic organ of the human body and has a high incidence of diseases. In recent years, the annual incidence of liver disease has increased, seriously endangering human life and health. The study of the occurrence and development mechanism of liver diseases, discovery of new therapeutic targets, and establishment of new methods of medical treatment are major issues related to the national economy and people's livelihood. The development of stable and effective research models is expected to provide new insights into the pathogenesis of liver diseases and the search for more effective treatment options. Organoid technology is a new in vitro culture system, and organoids constructed by human cells can simulate the morphological structure, gene expression, and glucose and lipid metabolism of organs in vivo, providing a new model for related research on liver diseases. This paper reviews the latest research progress on liver organoids from the establishment of cell sources and application of liver organoids and discusses their application potential in the field of liver disease research. [ABSTRACT FROM AUTHOR]

The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25–1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) affects the morphological structure and causes significant degradation in kidney function, leading to renal replacement treatment in affected individuals. Vascular rarefaction is thought to be an important factor in accelerating kidney damage in CKD patients, therefore, the assessment of renal morphology and vasculature is crucial in nephrology. The objective of this study was to evaluate the morphological and vascular changes caused by CKD in mice kidneys. In this study, dual photoacoustic microscopy (PAM) and optical coherence microscopy (OCM) oriented wide-field high-resolution imaging modalities were employed for diseased renal imaging. The unilateral ureteral obstruction (UUO) model was used to prepare renal samples with CKD, and the developed wide-field dual imaging system was used to image both control and CKD-affected kidneys for assessing vascular and morphological changes during CKD progression. The obtained results reveal a gradual alteration in vascular intensity and pelvis space with the progress of UUO disease. Furthermore, a quantitative micro-vessel analysis was performed based on the node, junction, and mesh of the vessel, which provides details on the increasing microvascular-related characteristics in the peripheral area as the disease progresses. Thus, by concurrently employing the advantages of each optical imaging technique, the proposed method of assessing the OCM-based morphological and PAM-based vascular properties of the renal sample using a wide-field multimodal imaging system can be an efficient technique for whole volume analysis without any exogenous contrast agents in kidney histopathology. [ABSTRACT FROM AUTHOR]

Most species can be coinfected by multiple pathogens that may interact through shared resources (i.e., resource competition) or the host immune system (i.e., apparent competition). Community theory developed for free‐living organisms suggests that coinfecting pathogens can persist if they satisfy the mutual invasion criterion of coexistence, establishing infections in hosts that are already infected. Furthermore, the likelihood of coexistence may depend on host nutrition which can affect shared resources and host immunity. Here, we apply the novel approach of combining a dynamical model and experimental mutual invasibility trials to explore the effects of host nutrient supply on the coexistence of two viral plant pathogens. We focus on among‐pathogen interactions mediated by shared resources. First, we used a model to generate hypotheses about how nitrogen (N) and phosphorus (P) supply rates affect the ability of two plant viruses to invade established infections of the other virus. Then, we experimentally manipulated the N and P supplied to oats (Avena sativa) in a growth chamber experiment and tested mutual invasion of two RNA viral pathogens, BYDV‐PAV and CYDV‐RPV. Nutrient supplies ranged from rates that barely kept hosts alive up to high, but sub‐toxic, rates. Model simulations suggested that the viruses were more likely to invade established infections either when they could replicate at lower N and P concentrations or when plant N and P concentrations increased due to a combination of nutrient supply rates and resident virus nutrient use. In the experiment, each virus successfully invaded hosts infected by the other and had consistent growth rates across N and P supply rates. Our results suggest that BYDV‐PAV and CYDV‐RPV can coexist across a wide range environmental nutrient supply, which is consistent with the high levels of co‐occurrence of these two viruses in field populations. [ABSTRACT FROM AUTHOR]

Opioid misuse continues to cause significant harm. To investigate current research, we conducted a scoping literature review of disease spread models of opioid misuse from January 2000 to December 2022. In total, 85 studies were identified and examined for the opioids modeled, model type, data sources used and model calibration and validation. Most of the studies (58%, 49) only modeled heroin; the next largest categories were prescription opioids and unspecified opioids which accounted for 9% (8) each. Most models were theoretical compartmental models (57) or applied compartmental models (21). Previously published research was the most used data source (38), and a majority of the model validation involved the researchers setting initial conditions to verify theoretical results (30). To represent typical opioid use more accurately, multiple opioids need to be incorporated into the disease spread models, and applying different modeling techniques may allow other insights into opioid misuse spread. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of self-medication on the transmission dynamics of COVID-19 across different age groups, examine the interplay of vaccination and self-medication in disease spread, and identify the age group most prone to self-medication. Methods: We developed an age-structured compartmentalized epidemiological model to track the early dynamics of COVID-19. Age-structured data from the Government of Gauteng, encompassing the reported cumulative number of cases and daily confirmed cases, were used to calibrate the model through a Markov Chain Monte Carlo (MCMC) framework. Subsequently, uncertainty and sensitivity analyses were conducted on the model parameters. Results: We found that self-medication is predominant among the age group 15-64 (74.52%), followed by the age group 0-14 (34.02%), and then the age group 65+ (11.41%). The mean values of the basic reproduction number, the size of the first epidemic peak (the highest magnitude of the disease), and the time of the first epidemic peak (when the first highest magnitude occurs) are 4.16499, 241,715 cases, and 190.376 days, respectively. Moreover, we observed that self-medication among individuals aged 15-64 results in the highest spreading rate of COVID-19 at the onset of the outbreak and has the greatest impact on the first epidemic peak and its timing. Conclusion: Studies aiming to understand the dynamics of diseases in areas prone to self-medication should account for this practice. There is a need for a campaign against COVID-19-related self-medication, specifically targeting the active population (ages 15-64). [ABSTRACT FROM AUTHOR]

Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research. [ABSTRACT FROM AUTHOR]

Tissue engineering (TE) is a field of science that combines biological, engineering, and medical sciences and allows the development of disease models, drug development and gene therapy studies, and even cellular or tissue-based treatments developed by engineering methods. The eye is an organ that is easily accessible and amenable to engineering applications, paving the way for TE in ophthalmology. TE studies are being conducted on a wide range of topics, including the tear film, eyelids, cornea, optic nerve, glaucoma, and retinal diseases. With the rapid scientific advances in the field, it seems that TE is radically modifying the management of ocular disorders. : [ABSTRACT FROM AUTHOR]

The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to (1) delineate dynamics of nuclear architecture at different timescales, from minutes to weeks as cells differentiate, in populations and in single cells, (2) characterize cis-determinants and trans-modulators of genome organization, (3) test functional consequences of changes in cis- and trans-regulators, and (4) develop predictive models of genome structure and function.

Abstract Organoids are miniature, highly accurate representations of organs that capture the structure and unique functions of specific organs. Although the field of organoids has experienced exponential growth, driven by advances in artificial intelligence, gene editing, and bioinstrumentation, a comprehensive and accurate overview of organoid applications remains necessary. This review offers a detailed exploration of the historical origins and characteristics of various organoid types, their applications—including disease modeling, drug toxicity and efficacy assessments, precision medicine, and regenerative medicine—as well as the current challenges and future directions of organoid research. Organoids have proven instrumental in elucidating genetic cell fate in hereditary diseases, infectious diseases, metabolic disorders, and malignancies, as well as in the study of processes such as embryonic development, molecular mechanisms, and host–microbe interactions. Furthermore, the integration of organoid technology with artificial intelligence and microfluidics has significantly advanced large‐scale, rapid, and cost‐effective drug toxicity and efficacy assessments, thereby propelling progress in precision medicine. Finally, with the advent of high‐performance materials, three‐dimensional printing technology, and gene editing, organoids are also gaining prominence in the field of regenerative medicine. Our insights and predictions aim to provide valuable guidance to current researchers and to support the continued advancement of this rapidly developing field.

Abstract Exposure to indoor air pollutants (IAP) has increased recently, with people spending more time indoors (i.e. homes, offices, schools and transportation). Increased exposures of IAP on a healthy population are poorly understood, and those with allergic respiratory conditions even less so. The objective of this study, therefore, was to implement a well-characterised in vitro model of the human alveolar epithelial barrier (A549 + PMA differentiated THP-1 incubated with and without IL-13, IL-5 and IL-4) to determine the effects of a standardised indoor particulate (NIST 2583) on both a healthy lung model and one modelling a type-II (stimulated with IL-13, IL-5 and IL-4) inflammatory response (such as asthma). Using concentrations from the literature, and an environmentally appropriate exposure we investigated 232, 464 and 608ng/cm2 of NIST 2583 respectively. Membrane integrity (blue dextran), viability (trypan blue), genotoxicity (micronucleus (Mn) assay) and (pro-)/(anti-)inflammatory effects (IL-6, IL-8, IL-33, IL-10) were then assessed 24 h post exposure to both models. Models were exposed using a physiologically relevant aerosolisation method (VitroCell Cloud 12 exposure system). No changes in Mn frequency or membrane integrity in either model were noted when exposed to any of the tested concentrations of NIST 2583. A significant decrease (p

Microcell-mediated chromosome transfer (MMCT) is anticipated as a unique strategy to manipulate numbers of chromosomes, including the generation of hyperaneuploidy syndrome models with human induced pluripotent stem cells (hiPSCs). Mouse A9/Chinese hamster ovary (CHO) cell libraries of human monochromosomal hybrids as chromosome donor cells frequently exhibit chromosomal rearrangement in the components. The generation of a new A9/CHO library is time-consuming and laborious. Here, we developed an MMCT method using hiPSCs as chromosome donor and recipient cells, through micronucleation using paclitaxel and reversine. Membrane fusion during the MMCT was mediated through interactions between the ecotropic viral envelope transiently expressed in chromosome donor cells and mCAT-1 in chromosome recipient cells. This approach involved tagging Chr21 and ChrY by CRISPR-Cas9 and transferring human/mouse artificial chromosomes, Chr21, ChrX, and ChrY, wherein there are no previous reports demonstrating a full-length introduction. Thus, a strategy that combing CRISPR-Cas9-mediated chromosome tagging and MMCT from hiPSCs as chromosome donor cells to hiPSCs as recipient cells systematically produced isogenic disease model hiPSCs with hyperaneuploidy. This approach allows the study of rare diseases and promises to provide new insights into early developmental mechanisms by introducing a comprehensive set of influential chromosomes/regions into hiPSCs.

With the rapid development of the field of life sciences, traditional 2D cell culture and animal models have long been unable to meet the urgent needs of modern biomedical research and new drug development. Establishing a new generation of experimental models and research models is of great significance for deeply understanding human health and disease processes, and developing effective treatment measures. As is well known, long research and development cycles, high risks, and high costs are the “three mountains” facing the development of new drugs today. Organoids and organ-on-chips technology can highly simulate and reproduce the human physiological environment and complex reactions in vitro, greatly improving the accuracy of drug clinical efficacy prediction, reducing drug development costs, and avoiding the defects of drug testing animal models. Therefore, organ-on-chips have enormous potential in medical diagnosis and treatment.

Exposure to indoor air pollutants (IAP) has increased recently, with people spending more time indoors (i.e. homes, offices, schools and transportation). Increased exposures of IAP on a healthy population are poorly understood, and those with allergic respiratory conditions even less so. The objective of this study, therefore, was to implement a well-characterised in vitro model of the human alveolar epithelial barrier (A549 + PMA differentiated THP-1 incubated with and without IL-13, IL-5 and IL-4) to determine the effects of a standardised indoor particulate (NIST 2583) on both a healthy lung model and one modelling a type-II (stimulated with IL-13, IL-5 and IL-4) inflammatory response (such as asthma). Using concentrations from the literature, and an environmentally appropriate exposure we investigated 232, 464 and 608ng/cm2 of NIST 2583 respectively. Membrane integrity (blue dextran), viability (trypan blue), genotoxicity (micronucleus (Mn) assay) and (pro-)/(anti-)inflammatory effects (IL-6, IL-8, IL-33, IL-10) were then assessed 24 h post exposure to both models. Models were exposed using a physiologically relevant aerosolisation method (VitroCell Cloud 12 exposure system). No changes in Mn frequency or membrane integrity in either model were noted when exposed to any of the tested concentrations of NIST 2583. A significant decrease (p < 0.05) in cell viability at the highest concentration was observed in the healthy model. Whilst cell viability in the "inflamed" model was decreased at the lower concentrations (significantly (p < 0.05) after 464ng/cm2). A significant reduction (p < 0.05) in IL-10 and a significant increase in IL-33 was seen after 24 h exposure to NIST 2583 (464, 608ng/cm2) in the "inflamed" model. Collectively, the results indicate the potential for IAP to cause the onset of a type II response as well as exacerbating pre-existing allergic conditions. Furthermore, the data imposes the importance of considering unhealthy individuals when investigating the potential health effects of IAP. It also highlights that even in a healthy population these particles have the potential to induce this type II response and initiate an immune response following exposure to IAP. [ABSTRACT FROM AUTHOR]

Background: Next-generation sequencing liquid biopsy (NGS-LB) for colorectal cancer (CRC) detection and surveillance remains an expensive technology as economies of scale have not yet been realized. Nevertheless, the cost of sequencing has decreased while sensitivity has increased, raising the question of whether cost-effectiveness (CE) has already been achieved from the perspective of European healthcare systems. Objectives: This health economic (HE) modeling study explores the CE of NGS-LB for CRC based on direct treatment costs compared to standard care without liquid biopsy in Spain, France, and Germany. Methods: A structured literature search was used to collect evidence from 2009 to 2020 on the stage-dependent quality of life (quality-adjusted life-years, QALY), efficacy, and total direct treatment costs (TDC) of NGS-LB. A decision-analytic Markov model was developed. Over the remaining lifetime, cumulative life expectancy (LE), TDC, and QALYs were calculated for 60-year-old men and women in CRC stage III with different assumed effects of NGS-LB of 1% or 3% on improved survival and reduced stage progression, respectively. Results: The use of NGS-LB increases LE by 0.19 years in Spanish men (France: 0.19 years, Germany: 0.13 years) and by 0.21 years in Spanish women (France: 0.21 years, Germany: 0.14 years), respectively. The 3% discounted cost per QALY gained was 35,571.95 € for Spanish men (France: 31,705.15 €, Germany: 37,537.68 €) and 35,435.71 € for Spanish women (France: 31,295.57 €, Germany: 38,137.08 €) in the scenario with 3% improved survival and reduced disease progression. Compared to the other two countries, Germany has by far the highest TDC, which can amount to >80k euros in the last treatment year. Conclusion: In this explorative HE modeling study, NGS-LB achieves generally accepted CE levels in CRC treatment from the health system perspective in three major European economies under assumptions of small improvements in cancer recurrence and survival. Confirmation of these findings through clinical trials is encouraged. Plain language summary: Is it worthwhile to use next generation liquid biopsy for cancer recurrence detection on patients with colorectal cancer? Colon cancer is common. Worldwide, almost one million people die from it every year. Next Generation Sequencing Liquid Biopsy is a very sensitive technology for detecting cancer cells and their genetic information in the blood. Therefore, it is a good way to detect cancer and to detect early recurrence of a previously treated tumor. This test procedure is not yet used very often. Therefore, it is still expensive. Furthermore, there are still no studies that have demonstrated that and how liquid biopsy can aid doctors and patients after initial treatment. The research team of this study has developed an analytical model to investigate what performance liquid biopsy should have to demonstrate an affordable patient benefit in terms of quality of life, survival and cost per additional quality-adjusted life year gained. To do this, they studied the existing medical literature and many cost studies on colorectal cancer for the countries of Spain, France and Germany to feed their model. Then, they made different assumptions about the performance of liquid biopsy and did calculations. In the process, they also particularly examined the significance of specific influencing factors such as costs or disease progression in so-called sensitivity analyses. As a result, the authors found that there are large differences in treatment costs for colorectal cancer between the three countries Spain, France and Germany. Furthermore, even small improvements in the progression of cancer and the survival of cancer patients lead to the economic efficiency of liquid biopsy for the health care system. However, these are still thought experiments, so the research team of this study says that there should be further clinical trials to assess the impact of liquid biopsy on cancer progression and patient survival by using this technology. By this, one could confirm or contradict the authors' educated assumptions and possibly pave a new way towards medical progress for people with colorectal cancer. [ABSTRACT FROM AUTHOR]

Overexpression of the CREM (cAMP response element-binding modulator) isoform CREM-IbΔC-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. To identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. Atrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. A total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and structural based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns reminiscent of those seen in humans with persistent AF. This study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF. [Display omitted] • Atrial proteomics of CREM-Tg mice revealed protein expression changes linked to persistent AF. • Proteins involved in actin filaments and ECM remodeling were enriched in persistent AF. • AF disease progression causes a switch in atrial proteome changes in CREM-Tg mice. • Proteome alterations seen in older CREM-Tg mice mirror those in patients with persistent AF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Many experts in the etiology, assessment, and treatment of substance use/addiction view stigma and stigmatization – negatively branding addiction and substance users – as obstacles to the solution of the substance misuse problem. Discussions on this topic impact research and policy, and result in oft-repeated calls to remove the stigma from substance use and users. The goal of the article is to analyze the stigmatization concept as applied to substance use/addiction. It is widely accepted in the literature that stigmatization negatively affects substance users because addiction stigma interferes in both seeking and receiving professional care. It is argued that the societal disapproval of substance use/addiction is inappropriate because it is a mental disorder, involving biological processes. Nonetheless, neither those processes nor negative attitudes towards substance use affirm the concept of stigmatization as currently applied. This concept conflates potential mistreatment and malpractice with the prosocial justified societal disapproval of a lethally dangerous behavior. Consequently, the stigmatization concept suffers from internal contradictions, is either misleading or redundant, and may do more harm than the supposed mistreatment of substance users that stigmatization connotes. On the contrary, the justified disapproval of harmful behavior may be a factor raising individual resistance to substance use. Instead of mitigating the effects of that disapproval, it may need to be capitalized on. If it is employed explicitly, conscientiously, and professionally, its internalization may be one of the resistance mechanisms needed to achieve any progress in the still elusive prevention of substance use and addiction. [ABSTRACT FROM AUTHOR]

Introduction: Veterinary biobanks store samples for future use and distribute samples to academic researchers and industry entities; however, informed consent provided by owners for pets contributing to biobanks can be complicated by limited understanding of goals, purpose, and logistics of biobanking. Methods: This survey-based study aimed to gather feedback from pet owners on how they viewed allowing their pet to contribute to a veterinary biobank, with the goal of identifying opportunities to improve education, awareness of veterinary biobanking initiatives, and the consent processes. An electronic survey was distributed to a listserv of 2,119 pet owners and responses were received from 118 respondents (5.6%). Results: Most respondents (67%) were not familiar with the concept of veterinary biobanking prior to having responded to the survey. Most (89%) were willing to allow their healthy pet to contribute samples to a veterinary biobanking program. Ninety-five percent would allow their sick pet to contribute. Most were neutral about financial incentives as a motivator to participate, although 40% indicated that if their pet's condition resulted in a decision to humanely euthanize, they would be more likely to contribute to the biobank if the veterinary biobanking program covered the cost of euthanasia. Common concerns included security/ confidentiality (36%), that results would not be shared with them (33%) or that samples would be used for other purposes beyond those advertised (22%). Discussion: These results suggest veterinary biobanking initiatives are well received by owners and most are willing to allow their pets to participate. Respondent concerns represent opportunities for veterinary biobanks to improve messaging and dissemination of results from work they support. [ABSTRACT FROM AUTHOR]

Abstract Most species can be coinfected by multiple pathogens that may interact through shared resources (i.e., resource competition) or the host immune system (i.e., apparent competition). Community theory developed for free‐living organisms suggests that coinfecting pathogens can persist if they satisfy the mutual invasion criterion of coexistence, establishing infections in hosts that are already infected. Furthermore, the likelihood of coexistence may depend on host nutrition which can affect shared resources and host immunity. Here, we apply the novel approach of combining a dynamical model and experimental mutual invasibility trials to explore the effects of host nutrient supply on the coexistence of two viral plant pathogens. We focus on among‐pathogen interactions mediated by shared resources. First, we used a model to generate hypotheses about how nitrogen (N) and phosphorus (P) supply rates affect the ability of two plant viruses to invade established infections of the other virus. Then, we experimentally manipulated the N and P supplied to oats (Avena sativa) in a growth chamber experiment and tested mutual invasion of two RNA viral pathogens, BYDV‐PAV and CYDV‐RPV. Nutrient supplies ranged from rates that barely kept hosts alive up to high, but sub‐toxic, rates. Model simulations suggested that the viruses were more likely to invade established infections either when they could replicate at lower N and P concentrations or when plant N and P concentrations increased due to a combination of nutrient supply rates and resident virus nutrient use. In the experiment, each virus successfully invaded hosts infected by the other and had consistent growth rates across N and P supply rates. Our results suggest that BYDV‐PAV and CYDV‐RPV can coexist across a wide range environmental nutrient supply, which is consistent with the high levels of co‐occurrence of these two viruses in field populations.

Mutations in the MAPT gene that encodes tau lead to frontotemporal dementia (FTD) with pathology evident in both cerebral neurons and glia. Human cerebral organoids (hCOs) from individuals harboring pathogenic tau mutations can reveal the earliest downstream effects on molecular pathways within a developmental context, generating interacting neurons and glia. We found that in hCOs carrying the V337M and R406W tau mutations, the cholesterol biosynthesis pathway in astrocytes was the top upregulated gene set compared with isogenic controls by single-cell RNA sequencing (scRNA-seq). The 15 upregulated genes included HMGCR, ACAT2, STARD4, LDLR, and SREBF2. This result was confirmed in a homozygous R406W mutant cell line by immunostaining and sterol measurements. Cholesterol abundance in the brain is tightly regulated by efflux and cholesterol biosynthetic enzyme levels in astrocytes, and dysregulation can cause aberrant phosphorylation of tau. Our findings suggest that cholesterol dyshomeostasis is an early event in the etiology of neurodegeneration caused by tau mutations.

SCN2A encodes NaV1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature of SCN2A variant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age. We established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrent SCN2A DEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Two male patient-derived iPSC isogenic pairs were differentiated using Neurogenin-2 overexpression yielding populations of cortical-like glutamatergic neurons. Functional properties were assessed using patch clamp and multielectrode array recordings and transcriptomic profiles obtained with total mRNA sequencing after 2-4 weeks in culture. At 3 weeks of differentiation, increased neuronal activity at cellular and network levels was observed for R1882Q iPSC-derived neurons. In contrast, R853Q neurons showed only subtle changes in excitability after 4 weeks and an overall reduced network activity after 7 weeks in vitro. Consistent with the reported efficacy in some GoF SCN2A patients, phe-nytoin (sodium channel blocker) reduced the excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways suggested potential shared mechanisms underlying SCN2A DEE. In summary, patient iPSC-derived neuronal models of SCN2A GoF and LoF pathogenic variants causing DEE show specific functional and transcriptomic in vitro phenotypes. [ABSTRACT FROM AUTHOR]

In this paper, we introduce a novel model for parental decision-making about vaccinations against a childhood disease that spreads through a contact network. This model considers a bilayer network comprising two overlapping networks, which are either Erdős-Rényi (random) networks or Barabási-Albert networks. The model also employs a Bayesian aggregation rule for observational social learning on a social network. This new model encompasses other decision models, such as voting and DeGroot models, as special cases. Using our model, we demonstrate how certain levels of social learning about vaccination preferences can converge opinions, influencing vaccine uptake and ultimately disease spread. In addition, we explore how two different cultures of social learning affect the establishment of social norms of vaccination and the uptake of vaccines. In every scenario, the interplay between the dynamics of observational social learning and disease spread is influenced by the network's topology, along with vaccine safety and availability. [ABSTRACT FROM AUTHOR]

Base editing technology originated from CRISPR/Cas system is the latest site-specific gene modification technology at present. According to the function characteristics of the base editor, the base editors can be divided into cytosine base editor (CBE), adenine base editor (ABE), glycosylase base editor (GBE), adenine translation base editor (AYBE), dual base editor (DBE) and prime editor (PE) . Since the emerging of base editing technology, it has been widely used in the research of animals and plants. And it has been proven to have great application value in animals and plants for genetic improvement or disease treatment. As an important agricultural economic animal and excellent disease model, genetic improvement to pig has become very important. Base editing technology has been rapidly applied in genetic improvement of animals and plants due to its convenient operation, high efficiency, fewer by-products, and high cost-effectiveness, and even it have a high prospect of providing important support for human gene therapy. In this paper, we focus on the development, optimization, application characteristics, existing issues and future prospects of base editing technology, and briefly summarize its application in pigs. It is expected to provide reference for relevant scientific workers to understand the base editing technology. [ABSTRACT FROM AUTHOR]

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Simple Summary: Despite remarkable progress in the treatment of acute lymphoblastic leukemia (ALL) in recent years, it remains a significant contributor to pediatric cancer-related deaths. This highlights the urgent need for innovative therapeutic strategies that target the genetic alterations driving ALL. We built a novel zebrafish disease model for ETV6::RUNX1-positive ALL, which harbors secondary lesions in the two commonly mutated genes, pax5, and cdkn2a/b. The introduction of secondary mutations significantly augmented the incidence of disease. This model provides a valuable tool for investigating the etiological role of secondary mutations and facilitating the evaluation of drug sensitivities in the future. Approximately 25% of children with B-cell precursor acute lymphoblastic leukemia (pB-ALL) harbor the t(12;21)(p13;q22) translocation, leading to the ETV6::RUNX1 (E::R) fusion gene. This translocation occurs in utero, but the disease is much less common than the prevalence of the fusion in newborns, suggesting that secondary mutations are required for overt leukemia. The role of these secondary mutations remains unclear and may contribute to treatment resistance and disease recurrence. We developed a zebrafish model for E::R leukemia using CRISPR/Cas9 to introduce the human RUNX1 gene into zebrafish etv6 intron 5, resulting in E::R fusion gene expression controlled by the endogenous etv6 promoter. As seen by GFP fluorescence at a single-cell level, the model correctly expressed the fusion protein in the right places in zebrafish embryos. The E::R fusion expression induced an expansion of the progenitor cell pool and led to a low 2% frequency of leukemia. The introduction of targeted pax5 and cdkn2a/b gene mutations, mimicking secondary mutations, in the E::R line significantly increased the incidence in leukemia. Transcriptomics revealed that the E::R;pax5mut leukemias exclusively represented B-lineage disease. This novel E::R zebrafish model faithfully recapitulates human disease and offers a valuable tool for a more detailed analysis of disease biology in this subtype. [ABSTRACT FROM AUTHOR]

Zebrafish (Danio rerio) is a well‐established model for studying the nervous system. Findings in zebrafish often inform studies on human diseases of the nervous system and provide crucial insight into disease mechanisms. The functions of the nervous system often rely on communication between neurons. Signal transduction is achieved via release of signaling molecules in the form of neuropeptides or neurotransmitters at synapses. Snapshots of membrane dynamics of these processes are imaged by electron microscopy. Electron microscopy can reveal ultrastructure and thus synaptic processes. This is crucial both for mapping synaptic connections and for investigating synaptic functions. In addition, via volumetric electron microscopy, the overall architecture of the nervous system becomes accessible, where structure can inform function. Electron microscopy is thus of particular value for studying the nervous system. However, today a plethora of electron microscopy techniques and protocols exist. Which technique is most suitable highly depends on the research question and scope as well as on the type of tissue that is examined. This review gives an overview of the electron microcopy techniques used on the zebrafish nervous system. It aims to give researchers a guide on which techniques are suitable for their specific questions and capabilities as well as an overview of the capabilities of electron microscopy in neurobiological research in the zebrafish model. [ABSTRACT FROM AUTHOR]

Biallelic mutations in AP4S1, the σ4 subunit of the adaptor protein complex 4 (AP‐4), lead to autosomal recessive spastic paraplegia 52 (SPG52). It is a subtype of AP‐4‐associated hereditary spastic paraplegia (AP‐4‐HSP), a complex childhood‐onset neurogenetic disease characterized by progressive spastic paraplegia of the lower limbs. This disease has so far lacked effective treatment, in part due to a lack of suitable animal models. Here, we used CRISPR/Cas9 technology to generate a truncation mutation in the ap4s1 gene in zebrafish. The ap4s1 truncation led to motor impairment, delayed neurodevelopment, and distal axonal degeneration. This animal model is useful for further research into AP‐4 and AP‐4‐HSP. [ABSTRACT FROM AUTHOR]

The fruit fly, Drosophila melanogaster, has been one of the finest systems for decoding myriad puzzles across different domains of biology. Beyond addressing the fundamental problems, it has been used as a fantastic model organism for human disease research. Being an insect, Drosophila has a robust and advanced olfactory system that has been used many times as a model neuronal circuit to study fundamental questions in neurobiology. The circuit is well-explored at anatomical, physiological, and functional levels. It provides several advantages for the study of neurobiological disorders, such as spatiotemporally regulated misexpression or knockdown of disease proteins, genetic tractability, well-studied neuroanatomy, simple behavioural training paradigms, and quantifiable assays. Hence, Drosophila olfaction has been a favourite choice for the study of several neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, fragile X syndrome, etc. This review aims to discuss earlier progress and future scope in using the Drosophila olfactory system for modelling human neurological pathophysiology for conducting fundamental and applied research. A major goal of research in biological science is to alleviate human disease burden. Diverse experimental systems are required to address different aspects of disease aetiology. Drosophila is one of the finest in vivo systems; its olfactory system is arguably the most well-characterized circuit for modelling human neurological disorders. A vast amount of research has been conducted to decipher cellular, molecular, and even cognitive aspects of human disorders using the Drosophila olfactory system. This review aims at summarizing such research progress to date and critically analysing the suitability of this system for modelling more complex neurological conditions. [ABSTRACT FROM AUTHOR]