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Purpose: To answer the following focus question: In preclinical in vivo experimental models, do oral implants placed in overdimensioned (OD) sites present greater biomechanical properties and histomorphometric parameters of osseointegration compared to implants placed in standard or undersized implant sockets? Materials and Methods: Online databases were searched for controlled animal studies reporting on OD sites up to February 2023. The relative implant-final drill discrepancy (IDD) was used to categorize the control and test groups according to surgical drilling protocol: (1) control: undersized (IDD > 0.5 mm) or standard (IDD = 0.2 to 0.5 mm); and (2) test OD: stress-free oversized (IDD = 0.0 to -0.1 mm); test GAP: friction-free oversized (IDD = -0.1 mm). Random-effects meta-analyses were performed for the outcomes of insertion and removal torque values (ITV and RTV, respectively), bone-to-implant contact (%BIC), and bone density (%BD) for short- (0 to 2 weeks), intermediate- (3 to 4 weeks), and long-term (= 5 weeks) healing periods. Results: Of the 527 records identified, 13 studies met the eligibility criteria. Histologically, the OD and GAP groups prevented ischemic necrosis and extensive bone resorption at the bone-implant interface in both the marginal cortical layer and the trabeculae. Faster and increased rates of bone formation, characterized by primary osteons and highly vascularized tissue, took place in OD sites between 1 and 5 weeks of healing. Meta-analyses indicated statistically significant benefits in favor of (1) control vs OD for short-term healing in extraoral sites, with pooled estimates (weighted mean difference) of ITV = 25.35 Ncm, %BIC = 2.10%, and %BD = 26.19%; (2) control vs OD for long-term healing in intraoral sites, with %BD = 11.69%; (3) control vs GAP for intermediate-term healing in extraoral sites, with %BD = 3.03%; and (4) control vs GAP for long-term healing in extraoral sites, with RTV = 5.57 Ncm. Conclusions: Oversized surgical preparation of the implant site does not seem to provide any additional benefit compared to standard or undersized sites regarding quantitative parameters of osseointegration. However, it does minimize marginal bone resorption and yields better-quality bone healing, despite the comparable results among different experimental animal models in the late postoperative period. [ABSTRACT FROM AUTHOR]

Anxiety disorders affect millions of people worldwide and present a challenge in neuroscience research because of their substantial heterogeneity in clinical presentation. While a great deal of progress has been made in understanding the neurobiology of fear and anxiety, these insights have not led to effective treatments. Understanding the relationship between phenotypic heterogeneity and the underlying biology is a critical first step in solving this problem. We show translation, reverse translation, and computational modeling can contribute to a refined, cross-species understanding of fear and anxiety as well as anxiety disorders. More specifically, we outline how animal models can be leveraged to develop testable hypotheses in humans by using targeted, cross-species approaches and ethologically informed behavioral paradigms. We discuss reverse translational approaches that can guide and prioritize animal research in nontraditional research species. Finally, we advocate for the use of computational models to harmonize cross-species and cross-methodology research into anxiety. Together, this translational neuroscience approach will help to bridge the widening gap between how we currently conceptualize and diagnose anxiety disorders, as well as aid in the discovery of better treatments for these conditions.

Orthopaedic trauma remains a leading cause of patient morbidity, mortality, and global health care burden. Although significant advances have been made in the diagnosis, treatment, and rehabilitation of these injuries, complications such as malunion, nonunion, infection, disuse muscle atrophy and osteopenia, and incomplete return to baseline function still occur. The significant inherent clinical variability in fracture care such as differing patient demographics, injury patterns, and treatment protocols make standardized and replicable study, especially of cellular and molecular based mechanisms, nearly impossible. Hence, the scientists dedicated to improving therapy and treatments for patients with orthopaedic trauma rely on preclinical models. Preclinical models have proven to be invaluable in understanding the timing between implant insertion and bacterial inoculation on the bioburden of infection. Posttraumatic arthritis (PTOA) can take years to develop clinically, but with a porcine pilon fracture model, posttraumatic arthritis can be reliably induced, so different surgical and therapeutic strategies can be tested in prevention. Conversely, the racehorse presents a well-accepted model of naturally occurring PTOA. With preclinical polytrauma models focusing on chest injury, abdominal injury, multiple fractures, and/or head injury, one can study how various injury patterns affect fracture healing can be systemically studied. Finally, these preclinical models serve as a translational bridge to for clinical application in human patients. With selection of the right preclinical model, studies can build a platform to decrease the risk of emerging technologies and provide foundational support for therapeutic clinical trials. In summary, orthopaedic trauma preclinical models allow scientists to simplify a complex clinical challenge, to understand the basic pathways starting with lower vertebrate models. Then, R&D efforts progress to higher vertebrate models to build in more complexity for translation of findings to the clinical practice.

Interstitial cystitis (IC) presents as a chronic pain condition with variable combinations of symptoms depending on the species and individual patient. It is diagnosed by the presence of lower urinary tract signs and symptoms in combination with a variety of comorbid health problems, a history of life adversities, and the absence of other conditions that could cause the lower urinary tract signs. IC occurs naturally in humans and cats as a dimensional condition, with patients presenting with mild, moderate, and severe symptoms. Most patients appear to recover without specific treatment. A number of rodent models of IC have been used to study its causes and treatments. Unfortunately, current therapies generally fail to ameliorate IC symptoms long-term. The recent classification of IC as a chronic primary pain disorder calls for a rethinking of current clinical and research approaches to it. Beginning when a patient encounters a clinician, precipitating, perpetuating, and palliating risk factors can be addressed until a cause or reliably effective therapy is identified, and identifying predisposing and preventive factors can inform epidemiological studies and health promotion interventions. Predisposing, precipitating, and perpetuating risk factors, including environmental, psychological, and biological, increase the activity of the central threat response system (CTRS), which plays a clinically important role in IC symptoms. Studies in cats and rodent models have revealed that environmental enrichment (EE), in the absence of bladder-directed therapies, leads to amelioration of IC symptoms, implying a central role for the CTRS in symptom precipitation and perpetuation. Conceptually moving the source of IC pain to the brain as a motivational state rather than one resulting from peripheral nociceptive input offers both clinicians and researchers novel opportunities to improve care for patients with IC and for researchers to use more ecologically valid rodent models. It may even be that IC results from an excess of risk to protective factors, making this imbalance a targetable cause rather than a consequence of IC.

BACKGROUND: Muscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X-linked dystrophin-deficient MD in cats is the first genetically characterized cat model for a human disease and a few novel forms have been identified. HYPOTHESIS/OBJECTIVES: Muscular dystrophy was suspected in a young male domestic shorthair cat. Clinical, molecular, and genetic techniques could provide a definitive diagnosis. ANIMALS: A 1-year-old male domestic shorthair cat presented for progressive difficulty walking, macroglossia and dysphagia beginning at 6 months of age. The tongue was thickened, protruded with constant ptyalism, and thickening and rigidity of the neck and shoulders were observed. METHODS: A complete neurological examination, baseline laboratory evaluation and biopsies of the trapezius muscle were performed with owner consent. Indirect immunofluorescence staining of muscle cryosections was performed using several monoclonal and polyclonal antibodies against dystrophy-associated proteins. DNA was isolated for genomic analyses by whole genome sequencing and comparison to DNA variants in the 99 Lives Cat Genome Sequencing dataset. RESULTS AND CLINICAL IMPORTANCE: Aspartate aminotransferase (687 IU/L) and creatine kinase (24 830 IU/L) activities were increased and mild hypokalemia (3.7 mmol/L) was present. Biopsy samples from the trapezius muscle confirmed a degenerative and regenerative myopathy and protein alterations identified by immunohistochemistry resulted in a diagnosis of a in dystrophin-deficient form of X-linked MD. A stop gain variant (c.4849C>T; p.Gln1617Ter) dystrophin was identified by genome sequencing. Precision/genomic medicine efforts for the domestic cat and in veterinary medicine support disease variant and animal model discovery and provide opportunities for targeted treatments for companion animals.

The prevalence of food allergies is on the rise, posing a significant challenge to public health. Rodents serve as the predominant animal model in food allergy research; yet, the application of rodent models proves to be a laborious and time-consuming endeavor. It is imperative to develop novel in vivo models. Ovalbumin (OVA) was administered as the allergen, following the recommended dosage used in other species. During the sensitization phase, a dosage of 0.25 mg per 10 tails per 1 L was administered twice daily, and during the challenge phase, the dosage was increased to 3 times the initial level. The study explored two dimensions of sensitization: the mode of exposure, which can be either continuous or intermittent, and the duration of exposure, which includes 3 days, 5 days, and 7 days. We examined midgut pathological changes, immunoglobulins contents, and mRNA expressions associated to T helper cells (Th) 2 cytokines following exposure. A significant 109.3 % increase in the number of eosinophils was observed in the midgut histopathology following intermittent 5-day OVA exposure, which emerged as the most effective model. OVA exposure increased concentrations of immunoglobulin M (IgM) (105.2 %), IgZ (312.1 %), and IgD (304.3 %) in this model. The mRNA expressions of Th2-related interleukin (IL)-4 and IL-13 were also elevated by 132.8 % and 421.0 %, respectively. The intermittent 5-day OVA exposure was suggested to be the best constructed zebrafish food allergy model, which may be a potential tool for research into food allergies. • Rodent food allergy models are laborious and tedious, novel models are needed. • The intermittent 5-day OVA exposure best simulates zebrafish food allergy model. • This work aims to enhance childhood health and promote sustainable aquaculture. [ABSTRACT FROM AUTHOR]

The mitochondrial translocator protein (TSPO) is an outer mitochondrial protein membrane with high affinity for cholesterol. It is expressed in most tissues but is more particularly enriched in steroidogenic tissues. TSPO is involved in various biological mechanisms and TSPO regulation has been related to several diseases. However, despite a considerable number of published studies interested in TSPO over the past forty years, the precise function of the protein remains obscure. Most of the functions attributed to TSPO have been identified using pharmacological ligands of this protein, leading to much debate about the accuracy of these findings. In addition, research on the physiological role of TSPO has been hampered by the lack of in vivo deletion models. Studies to perform genetic deletion of Tspo in animal models have long been unsuccessful, which led to the conclusions that the deletion was deleterious and the gene essential to life. During the last decades, thanks to the significant technical advances allowing genome modification, several models of animal genetically modified for TSPO have been developed. These models have modified our view regarding TSPO and profoundly improved our fundamental knowledge on this protein. However, to date, they did not allow to elucidate the precise molecular function of TSPO and numerous questions persist concerning the physiological role of TSPO and its future as a therapeutic target. This article chronologically reviews the development of deletion and induction models of TSPO. • TSPO is an outer mitochondrial membrane and a cholesterol high affinity protein. • TSPO is involved in various biological mechanisms but its exact function is unknown. • Tspo gene deletion in animal does not affect drastically their phenotype. • TSPO may be involved in pathological or cellular stress adaptation processes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors—the two most abundant muscarinic receptors in the striatum—reduced tic‐related behaviours in mouse models of TS. Experimental Approach: Studies were conducted using CIN‐d and D1CT‐7 mice, two TS models characterized by early‐life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic‐like and other TS‐related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c‐Fos. Key Results: Systemic and intrastriatal xanomeline reduced TS‐related behaviours in CIN‐d and D1CT‐7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline‐like ameliorative effects in both models. M4, but not M1, receptors were down‐regulated in the striatum of CIN‐d mice. Additionally, VU0467154 reduced striatal c‐Fos levels in these animals. Conclusion and Implications: Activation of striatal M4, but not M1, receptors reduced tic‐like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS. [ABSTRACT FROM AUTHOR]

Introduction: New onset refractory status epilepticus (NORSE) is a rare and devastating condition characterised by the sudden onset of refractory status epilepticus (RSE) without an identifiable acute or active structural, toxic, or metabolic cause in an individual without a pre-existing diagnosis of epilepsy. Febrile infection-related epilepsy syndrome (FIRES) is considered a subcategory of NORSE and presents following a febrile illness prior to seizure onset. NORSE/FIRES is associated with high morbidity and mortality in children and adults. Methods and results: In this review we first briefly summarise the reported clinical, paraclinical, treatment and outcome data in the literature. We then report on existing knowledge of the underlying pathophysiology in relation to in vitro and in vivo pre-clinical seizure and epilepsy models of potential relevance to NORSE/FIRES. Discussion: We highlight how pre-clinical models can enhance our understanding of FIRES/NORSE and propose future directions for research. [ABSTRACT FROM AUTHOR]

Background: The protective effects of metformin (Met) against doxorubicin (Dox)-induced cardiotoxicity via potential hypotheses of mechanisms of action with unknown reliability and credibility. Objectives: This study aimed to investigate the protective effects of Met against Dox-induced cardiotoxicity and the underlying mechanisms of action, as well as examine their reliability and credibility. Methods: A comprehensive search was conducted within the PubMed, Embase, Web of Science, Science Direct, Scopus, and CNKI databases from inception to 31 December 2023. Animal experiments evaluating the efficacy of Met against Dox-induced cardiotoxicity were included in this study. The primary efficacy outcomes were markers of myocardial injury. Effect size was measured using the standardized mean difference for continuous variables. Data were pooled using a random-effects model in the Stata 18 statistical software package. Results: Twenty-one studies involving 203-208 animals treated with Dox and 271-276 animals treated with Dox and Met were included in this analysis. Quality assessment revealed high-quality scores. Pooled results favored Met treatment based on the serum lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), and aspartate aminotransferase levels. Sensitivity analysis using the leave-one-out method demonstrated stable results. Funnel plots, Egger's test, and Begg's test confirmed potential publication bias. The oxidative stress hypothesis has been investigated extensively based on abundant evidence. Conclusion: Met is effective and safe for protecting against Dox-induced cardiotoxicity, thus making it an appropriate drug for clinical investigation. The oxidative stress hypothesis of mechanism of action is well established with highest reliability and credibility. [ABSTRACT FROM AUTHOR]

Novel work in adult zebrafish, Danio rerio, to recapitulate human neurodegenerative disease has proven useful in both pharmaceutical development and research on genetic disease. Due to high genetic homology to humans, affordable husbandry, relatively quick life cycle breeding times, and robust embryo production, zebrafish offer a promising model to test pharmaceutical performance in a high throughput, in vivo setting. Currently, most research in zebrafish models of Parkinson's disease induces the disease in larval or embryonic stage organisms due to ease of administration, with advancement through developmental stages taking only a matter of days. The use of early-stage organisms limits the usability of zebrafish as models for adult disease and specifically age-related neurodegenerative conditions. Recently, researchers have sought to extend the usability of zebrafish into models for Parkinson's disease. Specifically, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has emerged as a prodrug that upon injection well-encompasses the biochemical mechanisms and symptomology associated with Parkinson's disease. By utilizing MPTP in an adult zebrafish model, advancements in Parkinson's disease research may be achieved. This paper highlights the recent research on this model, comparing it to the human form of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Sustained community spread of influenza viruses relies on efficient person-to-person transmission. Current experimental transmission systems do not mimic environmental conditions (e.g., air exchange rates, flow patterns), host behaviors, or exposure durations relevant to real-world settings. Therefore, results from these traditional systems may not be representative of influenza virus transmission in humans. To address this pitfall, we developed a close-range transmission setup that implements a play-based scenario and used it to investigate the impact of ventilation rates on transmission. In this setup, four immunologically naive recipient ferrets were exposed to a donor ferret infected with a genetically barcoded 2009 H1N1 virus (H1N1pdm09) for 4 h. The ferrets interacted in a shared space that included toys, similar to a childcare setting. Transmission efficiency was assessed under low and high ventilation, with air exchange rates of ~1.3 h-1 and 23 h-1, respectively. Transmission efficiencies observed in three independent replicate studies were similar between ventilation conditions. The presence of infectious virus or viral RNA on surfaces and in air throughout the exposure area was also not impacted by the ventilation rate. While high viral genetic diversity in donor ferret nasal washes was maintained during infection, recipient ferret nasal washes displayed low diversity, revealing a narrow transmission bottleneck regardless of ventilation rate. Examining the frequency and duration of ferret physical touches revealed no link between these interactions and a successful transmission event. Our findings indicate that exposures characterized by frequent, close-range interactions and the presence of fomites can overcome the benefits of increased ventilation. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most devasting diseases affecting preterm neonates. However, despite a lot of research, NEC's pathogenesis remains unclear. It is known that the pathogenesis is a multifactorial process, including (1) a pathological microbiome with abnormal bacterial colonization, (2) an immature immune system, (3) enteral feeding, (3) an impairment of microcirculation, and (4) possibly ischemia-reperfusion damage to the intestine. Overall, the immaturity of the mucosal barrier and the increased expression of Toll-like receptor 4 (TLR4) within the intestinal epithelium result in an intestinal hyperinflammation reaction. Concurrently, a deficiency in counter-regulatory mediators can be seen. The sum of these processes can ultimately result in intestinal necrosis leading to very high mortality rates of the affected neonates. In the last decade no substantial advances in the treatment of NEC have been made. Thus, NEC animal models as well as in vitro models have been employed to better understand NEC's pathogenesis on a cellular and molecular level. This review will highlight the different models currently in use to study immunological aspects of NEC. [ABSTRACT FROM AUTHOR]

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alphasynuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases. [ABSTRACT FROM AUTHOR]

Traumatic brain injuries (TBIs) are a large societal and individual burden. In the first year of life, the vast majority of these injuries are the result of inflicted abusive events by a trusted caregiver. Abusive head trauma (AHT) in infants, formerly known as shaken baby syndrome, is the leading cause of inflicted mortality and morbidity in this population. In this review we address clinical diagnosis, symptoms, prognosis, and neuropathology of AHT, emphasizing the burden of repetitive AHT. Next, we consider existing animal models of AHT, and we evaluate key features of an ideal model, highlighting important developmental milestones in children most vulnerable to AHT. We draw on insights from other injury models, such as repetitive, mild TBIs (RmTBIs), post-traumatic epilepsy (PTE), hypoxic-ischemic injuries, and maternal neglect, to speculate on key knowledge gaps and underline important new opportunities in pre-clinical AHT research. Finally, potential treatment options to facilitate healthy development in children following an AHT are considered. Together, this review aims to drive the field toward optimized, well-characterized animal models of AHT, which will allow for greater insight into the underlying neuropathological and neurobehavioral consequences of AHT. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac disorder characterized by the gradual replacement of cardiomyocytes with fibrous and adipose tissue, leading to ventricular wall thinning, chamber dilation, arrhythmias, and sudden cardiac death. Despite advances in treatment, disease management remains challenging. Animal models, particularly mice and zebrafish, have become invaluable tools for understanding AC's pathophysiology and testing potential therapies. Mice models, although useful for scientific research, cannot fully replicate the complexity of the human AC. However, they have provided valuable insights into gene involvement, signalling pathways, and disease progression. Zebrafish offer a promising alternative to mammalian models, despite the phylogenetic distance, due to their economic and genetic advantages. By combining animal models with in vitro studies, researchers can comprehensively understand AC, paving the way for more effective treatments and interventions for patients and improving their quality of life and prognosis. [ABSTRACT FROM AUTHOR]

Nowadays, GSK3 is accepted as an enzyme strongly involved in the regulation of inflammation by balancing the pro- and anti-inflammatory responses of cells and organisms, thus influencing the initiation, progression, and resolution of inflammatory processes at multiple levels. Disturbances within its broad functional scope, either intrinsically or extrinsically induced, harbor the risk of profound disruptions to the regular course of the immune response, including the formation of severe inflammation-related diseases. Therefore, this review aims at summarizing and contextualizing the current knowledge derived from animal models to further shape our understanding of GSK3α and β and their roles in the inflammatory process and the occurrence of tissue/organ damage. Following a short recapitulation of structure, function, and regulation of GSK3, we will focus on the lessons learned from GSK3α/β knock-out and knock-in/overexpression models, both conventional and conditional, as well as a variety of (predominantly rodent) disease models reflecting defined pathologic conditions with a significant proportion of inflammation and inflammation-related tissue injury. In summary, the literature suggests that GSK3 acts as a crucial switch driving pro-inflammatory and destructive processes and thus contributes significantly to the pathogenesis of inflammation-associated diseases. [ABSTRACT FROM AUTHOR]

Advanced age is an independent risk factor for cardiovascular diseases in both sexes. This is thought to be due, in part, to age-dependent cellular, structural, and functional changes in the heart, a process known as cardiac aging. An emerging view is that cardiac aging leads to the accumulation of cellular and subcellular deficits that increase susceptibility to cardiovascular diseases. Still, people age at different rates, with those aging rapidly considered frail. Evidence suggests that frailty, rather than simply age, is a major risk factor for cardiovascular disease and predicts adverse outcomes in those affected. Recent studies in mouse models of frailty show that many adverse changes associated with cardiac aging are more prominent in mice with a high degree of frailty. This suggests that frailty sets the stage for late life cardiovascular diseases to flourish and raises the possibility that treating frailty may treat cardiovascular diseases. These studies show that ventricular dysfunction increases with frailty in males only, whereas atrial dysfunction increases with frailty in both sexes. These results may shed light on the reasons that men and women can be susceptible to different cardiovascular diseases as they age, and why frail individuals are especially vulnerable to these disorders. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1−/− mice are more susceptible to drug-induced liver injury, but PD-1−/− mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1−/− mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs. [ABSTRACT FROM AUTHOR]

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Eosinophilic esophagitis is a chronic inflammatory disorder of the esophagus. Over the past 25 yr, great strides have been made toward understanding its pathogenesis, in part due to studies in several types of animal models. The vast majority of these models have been characterized in mice. In this review, we summarize the histopathological features of eosinophilic esophagitis recapitulated by these animal models, as well as discuss their strengths and weaknesses. [ABSTRACT FROM AUTHOR]

Understanding the relations between mind, brain and behavior is an enduring challenge for science and philosophy. The present article focuses on the concept of internal states, of which emotions are the most studied subtype, in the recent neuroscientific literature. Internal states are conceived by neuroscientists as functional states implemented in neural circuits that drive behavior. To begin, we discuss current definitions of internal states, that emphasize both their intrinsic and relational properties. We stress the difference between preliminary characterizations of these states (that allow researchers to track them) and findings related to their intrinsic nature. We analyze three experimental studies interpreted within this framework, and outline the role of innovative methods in the process of discovery. We interpret the families of states under investigation as homeostatic property clusters, and suggest that the work of Anderson and Adolphs offers a solution to the problem of what constitutes a natural kind in neuroscience. Concerning the relationship between physical states of the brain and mental states, we make explicit the discrepancy between an eliminativist and a reductive project within the literature, and underline the importance of a choice between them. Finally, we suggest that studies of internal states have three interrelated objectives: a better grasp of brain-behavior relationships, a more principled attribution of mental states to nonhuman animals, and better animal models of our own internal states in clinical contexts. With this plurality of objectives comes a plurality of possible outcomes of ongoing research. [ABSTRACT FROM AUTHOR]

Background: Small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) have emerged as a promising therapy for treating type II diabetic cutaneous wounds. Currently, the evidence supporting the use of MSC-sEVs for treating diabetic skin wounds remains inconclusive and is limited to preclinical studies. To facilitate the clinical translation of cell-free therapy, conducting a comprehensive systematic review of preclinical studies assessing the efficacy of MSC-sEVs is imperative. Methods: A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library databases until June 14, 2023, to identify studies that met our pre-established inclusion criteria. The outcome indicators comprised wound closure rate (primary outcome), neovascular density, re-epithelialization rate, collagen deposition, and inflammatory factors (secondary Outcomes). A fixed-effects model was employed in instances of low heterogeneity (I2<50%), while a random-effects model was utilized for high heterogeneity (I2≥50%). The risk of bias in animal studies was assessed using the SYRCLE tool. Results: Twenty-one studies were included in this meta-analysis. Compared with the control group, MSC-sEVs were found to significantly facilitate the healing of cutaneous wounds in type II diabetic patients (standardized mean difference [SMD]=3.16, 95% confidence interval [CI]: 2.65 to 3.66, P<0.00001, I2 = 39%). Conclusions: According to the meta-analysis of preclinical studies, MSC-sEVs show promising applications in promoting type II diabetic wound healing. As a result, translating these findings into clinical applications appears warranted. [ABSTRACT FROM AUTHOR]

Several pivotal differences in sleep and sleep disorders are recognized between women and men. This is not only due to changes in hormonal balance during women's reproductive life, such as in pregnancy and menopause. Women are more likely to report insomnia and non-specific symptoms of apneas, such as fatigue or mood disturbance, compared to men. Thus, it is important for clinicians and researchers to take sex and gender differences into account when addressing sleep disorders in order to acknowledge the biology unique to women. We present a narrative review that delves into the primary sleep disorders, starting from basic science, to explore the impact of gender differences on sleep and the current status of research on women's sleep health. [ABSTRACT FROM AUTHOR]

The adult mammalian cardiomyocyte has a limited capacity for self-renewal, which leads to the irreversible heart dysfunction and poses a significant threat to myocardial infarction patients. In the past decades, research efforts have been predominantly concentrated on the cardiomyocyte proliferation and heart regeneration. However, the heart is a complex organ that comprises not only cardiomyocytes but also numerous noncardiomyocyte cells, all playing integral roles in maintaining cardiac function. In addition, cardiomyocytes are exposed to a dynamically changing physical environment that includes oxygen saturation and mechanical forces. Recently, a growing number of studies on myocardial microenvironment in cardiomyocyte proliferation and heart regeneration is ongoing. In this review, we provide an overview of recent advances in myocardial microenvironment, which plays an important role in cardiomyocyte proliferation and heart regeneration. [ABSTRACT FROM AUTHOR]

Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders. We then discuss strategies for novel methods of assessment using wearable sensors more broadly for neurodevelopmental disorders in general, including the importance of analytical validation. An increased understanding of the mechanistic contributions and potential biomarkers of disordered sleep may offer quantifiable targets for interventions that improve overall quality of life for affected individuals and their families. [ABSTRACT FROM AUTHOR]

Wound healing is a complex process that is still not fully understood despite extensive research. To address this, we aimed to design and characterize a standardized porcine model for the evaluation of wound healing, dressings, cell therapies, and pharmaceutical agents. Using a standardized approach, we examined the wound healing process in 1.2 mm-deep dermatome wounds at defined positions in 11 female pigs. Unlike previous studies that have only described/analyzed selected punch biopsies, we performed and described histological analyses along the complete wound length using quantitative morphometric methods. All animals remained fully healthy following surgery and showed no signs of infection. Our histopathological evaluation using a predetermined grading score and quantitative manual morphometry demonstrated the impact of different tissue sampling methods, sampling sites, and residual dermis thickness on wound healing. Our study presents a reproducible model for wound healing evaluation and demonstrates the usefulness of porcine models for assessing dermal and epidermal wound healing. The use of histological analyses over the complete wound length provides advantages over previous studies, leading to the possibility of a deeper understanding of the wound healing process. This model could potentially facilitate future research on novel wound dressings and local wound healing therapies. [ABSTRACT FROM AUTHOR]

Sham control groups are essential in experimental animal studies to reduce the influence of surgical intervention. The intraluminal filament procedure is one of the most common models of middle cerebral artery occlusion (MCAO) used in the study of brain ischemia. However, a sham group is usually not included in the experimental design of these studies. In this study, we aimed to evaluate the relevance of the sham group by analyzing and comparing the brain protein profiles of the sham and MCAO groups. In the sham group, 98 dysregulated proteins were detected, compared to 171 in the ischemic group. Moreover, a comparative study of protein profiles revealed the existence of a pool of 57 proteins that appeared to be dysregulated in both sham and ischemic animals. These results indicated that the surgical procedure required for the intraluminal occlusion of the middle cerebral artery (MCA) induces changes in brain protein expression that are not associated with ischemic lesions. This study highlights the importance of including sham control groups in the experimental design, to ensure that surgical intervention does not affect the therapeutic target under study. [ABSTRACT FROM AUTHOR]

ObjectivesMethodsResultsDiscussionTo synthesize evidence from animal models of neurodevelopmental disorders (NDD) using maternal choline supplementation, to characterize current knowledge on the mechanisms of choline’s protective effects against NDD, and to identify gaps in knowledge for future study.A literature review was conducted in PubMed to identify studies using prenatal choline supplementation interventions in rodent models of neurodevelopmental disorders. 24 studies were identified, and behavioral and biological findings were extracted from each. Studies examining both genetic and environmental risk factors were included.Maternal choline supplementation during gestation is protective against both genetic and environmental NDD risk factors. Maternal choline supplementation improves both cognitive and affective outcomes throughout the lifespan in NDD models. Prenatal choline improved these outcomes through its participation in processes like neurogenesis, epigenetic regulation, and anti-inflammatory signaling.Maternal choline supplementation improves behavioral and neurobiological outcomes in animal models of NDD, paralleling findings in humans. Animal models provide a unique opportunity to study the mechanisms by which gestational choline improves neurodevelopmental outcomes. This is especially important since nearly 90% of pregnant people in the United States are deficient in choline intake. However, much is still unknown about the mechanisms through which choline and its derivatives act. Further research into this topic, especially mechanistic studies in animal models, is critical to modernize maternal choline intake guidelines and to develop interventions to increase maternal choline intake in vulnerable populations. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) poses significant therapeutic challenges, particularly OA that affects the hand. Currently available treatment strategies are often limited in terms of their efficacy in managing pain, regulating invasiveness, and restoring joint function. The APRICOTⓇ implant system developed by Aurora Medical Ltd (Chichester, UK) introduces a minimally invasive, bone-conserving approach for treating hand OA (https://apricot-project.eu/). By utilizing polycarbonate urethane (PCU), this implant incorporates a caterpillar track-inspired design to promote the restoration of natural movement to the joint. Surface modifications of PCU have been proposed for the biological fixation of the implant. This study investigated the biocompatibility of PCU alone or in combination with two surface modifications, namely dopamine-carboxymethylcellulose (dCMC) and calcium-phosphate (CaP) coatings. In a rat soft tissue model, native and CaP-coated PCU foils did not increase cellular migration or cytotoxicity at the implant–soft tissue interface after 3 d, showing gene expression of proinflammatory cytokines similar to that in non-implanted sham sites. However, dCMC induced an amplified initial inflammatory response that was characterized by increased chemotaxis and cytotoxicity, as well as pronounced gene activation of proinflammatory macrophages and neoangiogenesis. By 21 d, inflammation subsided in all the groups, allowing for implant encapsulation. In a rat bone model, 6 d and 28 d after release of the periosteum, all implant types were adapted to the bone surface with a surrounding fibrous capsule and no protracted inflammatory response was observed. These findings demonstrated the biocompatibility of native and CaP-coated PCU foils as components of APRICOTⓇ implants. Hand osteoarthritis treatments require materials that minimize irritation of the delicate finger joints. Differing from existing treatments, the APRICOTⓇ implant leverages polycarbonate urethane (PCU) for minimally invasive joint replacement. This interdisciplinary, preclinical study investigated the biocompatibility of thin polycarbonate urethane (PCU) foils and their surface modifications with calcium-phosphate (CaP) or dopamine-carboxymethylcellulose (dCMC). Cellular and morphological analyses revealed that both native and Ca-P coated PCU elicit transient inflammation, similar to sham sites, and a thin fibrous encapsulation in soft tissues and on bone surfaces. However, dCMC surface modification amplified initial chemotaxis and cytotoxicity, with pronounced activation of proinflammatory and neoangiogenesis genes. Therefore, native and CaP-coated PCU possess sought-for biocompatible properties, crucial for patient safety and performance of APRICOTⓇ implant. [Display omitted] [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection causes chronic gastritis, ulcers, and gastric cancer, making it a threat to human health. Despite the use of antibiotic therapy, the global prevalence of H. pylori infection remains high, necessitating early eradication measures. Immunotherapy, especially vaccine development, is a promising solution in this direction, albeit the selection of an appropriate animal model is critical in efficient vaccine production. Accordingly, we conducted a literature, search and summarized the commonly used H. pylori strains, H. pylori infection‐related animal models, and models for evaluating H. pylori vaccines. Based on factors such as the ability to replicate human diseases, strain compatibility, vaccine types, and eliciting of immune responses, we systematically compared the advantages and disadvantages of different animal models, to obtain the informed recommendations. In addition, we have proposed novel perspectives on H. pylori–related animal models to advance research and vaccine evaluation for the prevention and treatment of diseases such as gastric cancer. [ABSTRACT FROM AUTHOR]

Context: The purpose of this study is to review the effectiveness of medicinal plants on memory and learning in both human and animal models. Material and Methods: Various electronic databases, including PubMed, Embase, Scopus, and Cochrane Library, were searched for randomized controlled trials published between 2010 and 2023. Results: The studies focused on thirty different herbs, including Bacopa monnieri , Polygonum odoratum , Morus alba , Ginkgo biloba , Salvia officinalis L., Rosmarinus officinalis L., Melissa officinalis , Panax ginseng , Saraca asoca , Polygala tenuifolia , Boswellia papyrifera , Boswellia serrata , and Aegle marmelos. Conclusions: The inclusion criteria were adults, participants with cognitive impairment, and healthy participants, without age or gender restrictions. The studies were assessed for risk of bias using the Cochrane tool for randomized trials, and the findings were synthesized narratively. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder affecting approximately 25.2% of the global population, posing risks of liver fibrosis, cancer, and metabolic disturbances. Despite its increasing prevalence, many facets of NAFLD's pathogenesis remain elusive, and there are currently no approved therapeutic drugs, underscoring the critical need for a comprehensive understanding of its pathophysiology to enable early diagnosis and intervention. Experimental animal studies play a pivotal role in elucidating the mechanisms underlying NAFLD and in the exploration of novel pharmacotherapies. Despite the widespread integration of deep learning techniques in human histopathology, their application to scrutinize histological features in animal models warrants exploration. This study presents a pioneering NAFLD assessment system leveraging IFNet and ResNet34 architectures. This automated system adeptly identifies inflammatory cell foci and hepatic steatosis in histopathology sections of rat livers. Remarkably, our approach achieved an impressive 95.6% accuracy in the assessment of hepatic steatosis and 77.7% in the evaluation of inflammation cell foci. By introducing a novel histopathology scoring system, our methodology mitigated subjective variations inherent in traditional pathologist evaluations, concurrently streamlining time and labor costs. This system ensured a standardized and precise assessment of rat liver histology in NAFLD and represented a significant stride toward enhancing the efficiency and objectivity of experimental outcomes. [ABSTRACT FROM AUTHOR]

Background: Infections are complications in the wound healing process, and their treatment can lead to antibiotic overuse and bacterial resistance. Antimicrobial photodynamic therapy (aPDT) is used to treat infectious diseases caused by fungi, viruses, or bacteria. Methylene blue (MB) and its derivatives are commonly used dyes in antimicrobial photodynamic therapy (aPDT–MB). Methods: This study is a PRISMA systematic review of animal models used to discuss the usefulness and therapeutic parameters of aPDT–MB or its derivatives for treating infected skin wounds. Results: After an extensive literature review, 13 controlled trials totaling 261 animals were selected to evaluate skin infection by leishmaniasis and cutaneous bacterial and fungal infections. All studies found results favoring the use of aPDT–MB. Great variability in parameters was found for radiant exposure from 12 to 360 J/cm2, MB diluted in saline solution or distilled water, irradiation time from 40 to 3600 s, irradiance most commonly at a maximum of 100 mW/cm2, and wavelength used mainly in the 630–670 nm range. Conclusion: MB is a safe and promising agent used as a photosensitizer in aPDT for skin‐infected lesions. There is great variability in the parameters found. Comparisons concerning concentration, irradiation time, and light intensity need to be performed. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the most prevalent human viruses worldwide. They are known to cause a variety of diseases including genital herpes, meningitis, encephalitis, cold sores and herpes stromal keratitis. The seropositive rate for HSV-1 is around 90%, whereas for HSV-2 it remains around 20–25% for the general adult population. The infections caused by these viruses remain difficult to study because a large proportion of infected individuals are asymptomatic. Furthermore, given the neurotropic characteristics of the virus, studies aimed at understanding the complex pathogenesis in humans is difficult. As a result, animal models have been developed to understand several characteristics of HSV biology, pathogenesis, disease and host responses to infection. These models are also commonly used as the first evaluation of new drugs and vaccines. There are several well-established animal models to study infection with HSV, including mice, guinea pigs and rabbits. Variables within the animal models depend on the species of animal, route of infection, viral strain, dosage, etc. This review aims at summarizing the most commonly used animal models to study HSV pathogenesis and therapies. [ABSTRACT FROM AUTHOR]

Substance use disorders (SUDs) are seen as a continuum ranging from goal‐directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real‐life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug‐related behaviours and (iii) to provide non‐invasive mechanism‐based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug‐taking state to an addiction or resilience‐like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non‐invasive interventions (e.g., Just‐In‐Time‐Adaptive‐Interventions (JITAIs), various non‐invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy. [ABSTRACT FROM AUTHOR]

Translational research applies laboratory‐generated scientific discoveries to real‐world practice with the goal of potentiating more rapid solutions to health challenges. In 2023, the authors of this editorial (Hildebrandt and Goldschmidt) aimed to develop a special issue for the International Journal of Eating Disorders (IJED) focusing on translational eating disorder research. The goal for this issue was to begin closing the gap between basic and applied research by soliciting articles that improve our understanding of mechanisms that cause or maintain eating disorders, which could result in more robust research advances and dissemination of information to the public. Further goals for the issue included exposing IJED's readership to a wide range of translational research and inspiring new collaborative efforts. While strong submissions were received, challenges were encountered in soliciting enough articles, potentially reflecting long‐standing communication barriers between basic and clinical scientists within the eating disorders field. In this editorial, we highlight work included in the special section, identify potential barriers in translational eating disorder research, and offer a multipronged approach to support more rapid progress across the translational spectrum. By improving how our field approaches translational research, we can promote better outcomes for those with or at risk for eating disorders. [ABSTRACT FROM AUTHOR]

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models. [ABSTRACT FROM AUTHOR]

While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients. [ABSTRACT FROM AUTHOR]

This study assessed the biocompatibility of two types of nanogold composites: fibronectin-gold (FN-Au) and collagen-gold (Col-Au). It consisted of three main parts: surface characterization, in vitro biocompatibility assessments, and animal models. To determine the structural and functional differences between the materials used in this study, atomic force microscopy, Fourier-transform infrared spectroscopy, and ultraviolet-visible spectrophotometry were used to investigate their surface topography and functional groups. The F-actin staining, proliferation, migration, reactive oxygen species generation, platelet activation, and monocyte activation of mesenchymal stem cells (MSCs) cultured on the FN-Au and Col-Au nanocomposites were investigated to determine their biological and cellular behaviors. Additionally, animal biocompatibility experiments measured capsule formation and collagen deposition in female Sprague–Dawley rats. The results showed that MSCs responded better on the FN-Au and Col-AU nanocomposites than on the control (tissue culture polystyrene) or pure substances, attributed to their incorporation of an optimal Au concentration (12.2 ppm), which induced significant surface morphological changes, nano topography cues, and better biocompatibility. Moreover, neuronal, endothelial, bone, and adipose tissues demonstrated better differentiation ability on the FN-Au and Col-Au nanocomposites. Nanocomposites have a crucial role in tissue engineering and even vascular grafts. Finally, MSCs were demonstrated to effectively enhance the stability of the endothelial structure, indicating that they can be applied as promising alternatives to clinics in the future. [ABSTRACT FROM AUTHOR]

Kidney anion exchanger 1 (kAE1) is an isoform of the AE1 protein encoded by the SLC4A1 gene. It is a basolateral membrane protein expressed by α-intercalated cells in the connecting tubules and collecting duct of the kidney. Its main function is to exchange bicarbonate and chloride ions between the blood and urine to maintain blood pH at physiological threshold. The kAE1 protein undergoes multiple post-translational modifications such as phosphorylation and ubiquitination and interacts with many different proteins such as claudin-4 and carbonic anhydrase II. Mutations in the gene may lead to the development of distal renal tubular acidosis, characterized by the failure to acidify the urine, which may result in nephrocalcinosis and in more severe cases, renal failure. In this review, we discuss the structure and function of kAE1, its post-translational modifications, and protein–protein interactions. Finally, we discuss insights gained from the study of kAE1 mutations in humans and in mice. [ABSTRACT FROM AUTHOR]

Body weight is an economically important trait in poultry that shows sexual dimorphism (SD). In the present study, variation in SD in Mazandaran native chickens was investigated in terms of the (Co) variance components and genetic parameters of body weight between males and females. Studied traits were body weights at hatch (BW1), 8 weeks (BW8) and 12 weeks of age (BW12). Also, for weight at sexual maturity (WSM) covariance components were only estimated in females. Cross‐sex direct and maternal correlations were also estimated for studied traits except for WSM. For this purpose, a deep 21‐generation pedigree and body weight data (57,576 BW1, 72,925 BW8, 62,727 BW12 and, 42,496 WSM) were used. Evaluation of SD of body weight was performed using six bivariate animal models with and without considering the genetic and permanent maternal environmental effects under the restricted maximum likelihood method in WOMBAT software. Model with direct additive genetic effects and maternal genetic effects without covariance between them was identified as the best model for BW1 and BW8. The Model including direct additive genetic effects and permanent maternal environmental effects was the best model for BW12 and WSM. Direct heritability (h2) estimates for BW1, BW8 and, BW12 were, respectively, 0.05 ± 0.013, 0.17 ± 0.02 and, 0.25 ± 0.03 in males and, 0.05 ± 0.012, 0.15 ± 0.01 and 0.21 ± 0.01 in females. Also, the direct heritability of WSM based on univariate analysis in females was estimated to be 0.40 ± 0.01. Maternal heritability (hm2) varied from 0.39 ± 0.01 (BW1) to 0.04 ± 0.009 (BW8) in males, and 0.36 ± 0.10 (BW1) to 0.04 ± 0.006 (BW8) in females. The correlation between direct genetic effects between males and females for BW1 was not significantly different from one. The direct genetic correlation between the two sexes for BW8 and BW12 was significantly different from 1 concluding that these traits are dimorphic in terms of direct genetic effects and therefore independent selection in both sexes is possible. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Genome‐wide association studies have identified over 70 genetic loci associated with late‐onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD‐sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss‐of‐function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. Highlights: A novel approach to validate genetic risk factors for late‐onset AD (LOAD) is presented.LOAD risk variants were knocked in to conserved mouse loci.Variant effects were assayed by transcriptional analysis.Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease.This approach should generate more translationally relevant animal models. [ABSTRACT FROM AUTHOR]

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment. [ABSTRACT FROM AUTHOR]

In recent years, dyslipidemia, a major risk factor for cardiovascular diseases is on the rise globally due to sedentary lifestyles and unhealthy diets. Though abundant data pertaining to the factors influencing dyslipidemia, the mechanism of action of various drugs and the pathogenesis of the disease are available in the literature, the disease is poorly understood. Animal models play a crucial role in investigating the pathophysiology and aid in developing effective formulations. Despite extensive research being carried out in the arena of dyslipidemia, there is no adequate knowledge about the most suitable in vivo model. A systematic literature search was carried out to review the animal models such as rats, mice, rabbits and zebrafish models with chemical-induced, diet-induced and drug-induced methods that have been used to study dyslipidemia. This review focuses on the mechanism involved in the dyslipidemia induction techniques explored by researchers along with their applications and limitations. The induction methods reported are expected to provide better insight in selecting an appropriate model to draw precise conclusions. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis is a chronic inflammatory skin disease with variable clinical presentation, multifactorial etiology and an immunogenetic basis. Several studies demonstrate that it results from a dysregulated interaction between skin keratinocytes, immune cells, and the environment that leads to a persistent inflammatory process modulated by cytokines and T cells. The development of new treatment options requires increased understanding of pathogenesis. However, the successful implementation of effective drugs requires well-characterized and highly available preclinical models that allow researchers to quickly and reproducibly determine their safety and efficacy. Methods: A systematic search on PubMed and Scopus databases was performed and assessed to find appropriate articles about psoriasis models applying the key words previously defined. The PRISMA guidelines were employed. Results: A total of 45 original articles were selected that met the selection criteria. Among these, there are articles on in vivo, in vitro, and ex vivo models, with the in vitro model being the majority due to its ease of use. Within animal models, the most widely used in recent years are chemically induced models using a compound known as imiquimod. However, the rest of the animal models used throughout the disease's research were also discussed. On the other hand, in vitro models were divided into two and three dimensions. The latter were the most used due to their similarity to human skin. Lastly, the ex vivo models were discussed, although they were the least used due to their difficulty in obtaining them. Conclusions: Therefore, this review summarizes the current preclinical models (in vivo, in vitro, and ex vivo), discussing how to develop them, their advantages, limitations, and applications. There are many challenges to improve the development of the different models. However, research in these in vitro model studies could reduce the use of animals. This is favored with the use of future technologies such as 3D bioprinting or organ-on-a-chip technologies. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), a mosquito-borne flavivirus, is prominently associated with microcephaly in babies born to infected mothers as well as Guillain-Barré Syndrome in adults. Each cell type infected by ZIKV—neuronal cells (radial glial cells, neuronal progenitor cells, astrocytes, microglia cells, and glioblastoma stem cells) and non-neuronal cells (primary fibroblasts, epidermal keratinocytes, dendritic cells, monocytes, macrophages, and Sertoli cells)—displays its own characteristic changes to their cell physiology and has various impacts on disease. Here, we provide an in-depth review of the ZIKV life cycle and its cellular targets, and discuss the current knowledge of how infections cause neuropathologies, as well as what approaches researchers are currently taking to further advance such knowledge. A key aspect of ZIKV neuropathogenesis is virus-induced neuronal apoptosis via numerous mechanisms including cell cycle dysregulation, mitochondrial fragmentation, ER stress, and the unfolded protein response. These, in turn, result in the activation of p53-mediated intrinsic cell death pathways. A full spectrum of infection models including stem cells and co-cultures, transwells to simulate blood–tissue barriers, brain-region-specific organoids, and animal models have been developed for ZIKV research. [ABSTRACT FROM AUTHOR]

Animal models are crucial to preclinical oncological research and drug development. Animal experiments must be performed in accordance with the 3R principles of replacement and reduction, if possible, and refinement where these procedures remain crucial. In addition, European Union legislations demand a continuous refinement approach, as well as pro- and retrospective severity assessment. In this study, an objective databased severity assessment was performed in murine models for pancreatic cancer induced by orthotopic, subcutaneous, or intravenous injection of Panc02 cells. Parameters such as body weight change, distress score, perianal temperature, mouse grimace scale, burrowing, nesting behavior, and the concentration of corticosterone in plasma and its metabolites in feces were monitored during tumor progression. The most important parameters were combined into a score and mapped against a reference data set by the Relative Severity Assessment procedure (RELSA) to obtain the maximum achieved severity for each animal (RELSAmax). This scoring revealed a significantly higher RELSAmax for the orthotopic model than for the subcutaneous and intravenous models. However, compared to animal models such as pancreatitis and bile duct ligation, the pancreatic cancer models are shown to be less severe. Data-based animal welfare assessment proved to be a valuable tool for comparing the severity of differently induced cancer models. [ABSTRACT FROM AUTHOR]

Swine are increasingly studied as animal models of human disease. The anatomy, size, longevity, physiology, immune system, and metabolism of swine are more like humans than traditional rodent models. In addition, the size of swine is preferred for surgical placement and testing of medical devices destined for humans. These features make swine useful for biomedical, pharmacological, and toxicological research. With recent advances in gene-editing technologies, genetic modifications can readily and efficiently be made in swine to study genetic disorders. In addition, gene-edited swine tissues are necessary for studies testing and validating xenotransplantation into humans to meet the critical shortfall of viable organs versus need. Underlying all of these biomedical applications, the knowledge of husbandry, background diseases and lesions, and biosecurity needs are important for productive, efficient, and reproducible research when using swine as a human disease model for basic research, preclinical testing, and translational studies. [ABSTRACT FROM AUTHOR]

Curcumin, a polyphenol derived from the herb turmeric, has emerged as a prospective potential therapy in the treatment of Alzheimer's disease (AD). However, the efficacy of curcumin treatment in improving cognitive decline caused controversy recently. We aimed to systematically review the effect of curcumin on cognitive impairment in an animal model of AD. We conducted an exhaustive database search of related studies. Two investigators identified studies and independently extracted data. Stratified meta-analyses and meta-regression analyses were carried out to explore the sources of heterogeneity. Publication bias was assessed using funnel plots and Egger's test. Our systematic review included 33 articles. A meta-analysis of 29 publications showed that curcumin exerts significant positive effects on cognitive performance. For acquisition, the global estimated effect of curcumin was − 2.027 (95% CI − 2.435 to − 1.619, p < 0.001); for retention, the global estimated effect of curcumin was 1.606 (95% CI 1.101 to 2.111, p < 0.001). The stratified meta-analysis demonstrated that an increased effect size depended on diverse study characteristics. Additionally, publication bias was detected. We conclude that curcumin may reduce cognitive deficits in experimental AD. Furthermore, we emphasize that additional well-designed and well-reported animal studies are needed to inform further clinical studies. [ABSTRACT FROM AUTHOR]