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The nasal potential difference test (nPD) is an electrophysiological measurement which is altered in patients and animal models with cystic fibrosis (CF). Because protocols and outcomes vary substantially between laboratories, there are concerns over its validity and precision. We performed a systematic literature review (SR) of the nPD to answer the following review questions: A. Is the nasal potential difference similarly affected in CF patients and animal models?", and B. "Is the nPD in human patients and animal models of CF similarly affected by various changes in the experimental set-up?". The review protocol was preregistered on PROSPERO (CRD42021236047). We searched PubMed and Embase with comprehensive search strings. Two independent reviewers screened all references for inclusion and extracted all data. Included were studies about CF which described in vivo nPD measurements in separate CF and control groups. Risk of bias was assessed, and three meta-analyses were performed. We included 130 references describing nPD values for CF and control subjects, which confirmed substantial variation in the experimental design and nPD outcome between groups. The meta-analyses showed a clear difference in baseline nPD values between CF and control subjects, both in animals and in humans. However, baseline nPD values were, on average, lower in animal than in human studies. Reporting of experimental details was poor for both animal and human studies, and urgently needs to improve to ensure reproducibility of experiments within and between species. [ABSTRACT FROM AUTHOR]

Despite extensive preclinical research over the years, a significant gap remains in our understanding of the specific effects of methamphetamine (METH) and amphetamine (AMPH) withdrawal. Understanding these differences could be pivotal to unveiling the unique pathophysiology underlying each stimulant. This may facilitate the development of targeted and effective treatment strategies tailored to the specific characteristics of each substance. Following PRISMA guidelines, this systematic review was conducted to examine alterations in spontaneous locomotor activity, specifically horizontal activity, in animals experiencing withdrawal from extended and repeated administration of AMPH or METH. Original articles were retrieved from four electronic databases, supplemented by a review of the references cited in the published papers. A total of thirty-one full-length articles (n = 31) were incorporated in the analysis. The results indicated that six studies documented a significant increase in horizontal activity among animals, seven studies reported decreased locomotion, and eighteen studies (8 AMPH; 10 METH) reported no significant alterations in the animals' locomotor activity. Studies reporting heightened locomotion mainly employed mice undergoing withdrawal from METH, studies reporting diminished locomotion predominantly involved rats undergoing withdrawal from AMPH, and studies reporting no significant changes in horizontal activity employed both rats and mice (12 rats; 6 mice). Drug characteristics, routes of administration, animal models, dosage regimens, duration, and assessment timing seem to influence the observed outcomes. Despite more than 50% of papers enlisted in this review indicate no significant changes in the locomotion during the stimulant withdrawal, the unique reactions of animals to withdrawal from METH and AMPH reported by some underscore the need for a more nuanced understanding of stimulant withdrawal. [ABSTRACT FROM AUTHOR]

Simple Summary: Zebrafish have emerged as invaluable model organisms in biological research, offering a cost-effective alternative to rodents. However, the absence of standardized feeding protocols and nutritional requirements poses a significant challenge, potentially compromising the validity of experimental outcomes, particularly in preclinical studies. Our systematic review analyzes a plethora of studies focused on zebrafish feed intake, feeding regimes, and diet compositions. We uncover substantial variability in dietary parameters, notably in crude protein and lipid content. Despite this diversity, energy levels remain quite consistent across zebrafish diets. By using these insights, we propose a novel feeding protocol for zebrafish of different developmental stages, based on a formulated feed optimized for protein and energy content. This protocol might represent the first step towards standardizing zebrafish feeding practices, thereby enhancing experimental reproducibility and data reliability. Zebrafish are one of the most used animal models in biological research and a cost-effective alternative to rodents. Despite this, nutritional requirements and standardized feeding protocols have not yet been established for this species. This is important to avoid nutritional effects on experimental outcomes, and especially when zebrafish models are used in preclinical studies, as many diseases have nutritional confounding factors. A key aspect of zebrafish nutrition is related to feed intake, the amount of feed ingested by each fish daily. With the goal of standardizing feeding protocols among the zebrafish community, this paper systematically reviews the available data from 73 studies on zebrafish feed intake, feeding regimes (levels), and diet composition. Great variability was observed regarding diet composition, especially regarding crude protein (mean 44.98 ± 9.87%) and lipid content (9.91 ± 5.40%). Interestingly, the gross energy levels of the zebrafish diets were similar across the reviewed studies (20.39 ± 2.10 kilojoules/g of feed). In most of the reviewed papers, fish received a predetermined quantity of feed (feed supplied). The authors fed the fish according to the voluntary intake and then calculated feed intake (FI) in only 17 papers. From a quantitative point of view, FI was higher than when a fixed quantity (pre-defined) of feed was supplied. Also, the literature showed that many biotic and abiotic factors may affect zebrafish FI. Finally, based on the FI data gathered from the literature, a new feeding protocol is proposed. In summary, a daily feeding rate of 9–10% of body weight is proposed for larvae, whereas these values are equal to 6–8% for juveniles and 5% for adults when a dry feed with a proper protein and energy content is used. [ABSTRACT FROM AUTHOR]

Simple Summary: Some basic and preclinical biomedical research models require the use of animals. It is not always clear which model is best suited to a project—animals or models based on, e.g., in vitro or in silico methods? This choice is influenced not only by personal beliefs and experience, but also by societal debates. Moreover, people often process information unconsciously. In this study, 13 people involved in relevant areas of research were interviewed. The responses were qualitatively assessed and subjected to an ethical analysis. This paper presents 66 reasons why researchers use animals (27 reasons) or alternative methods (39). Many reasons are tied to the work environment (29) and to scientific standards (22). Such reasons are often pragmatic and can only be influenced by individuals to a limited extent. Other reasons were assigned to personal attitudes (11) and animal welfare (4). Even if few reasons can be rejected outright from an ethical point of view, there are good reasons to give some more weight than others, as an exemplary discussion shows. The study raises awareness of the ethical decision-making process and the underlying reasons that we are often unaware of. This can help to reflect on and justify decisions. Background: Research model selection decisions in basic and preclinical biomedical research have not yet been the subject of an ethical investigation. Therefore, this paper aims, (1) to identify a spectrum of reasons for choosing between animal and alternative research models (e.g., based on in vitro or in silico models) and (2) provides an ethical analysis of the selected reasons. Methods: In total, 13 researchers were interviewed; the interviews were analyzed qualitatively. The ethical analysis was based on the principlism approach and a value judgement model. Results: This paper presents 66 reasons underlying the choice of researchers using animal (27 reasons) or alternative models (39). Most of the reasons were assigned to the work environment (29) and scientific standards (22). Other reasons were assigned to personal attitudes (11) and animal welfare (4). Qualitative relevant normative differences are presented in the ethical analysis. Even if few reasons can be rejected outright from an ethical point of view, there are good reasons to give some more weight than others. Conclusions: The spectrum of reasons and their ethical assessment provide a framework for reflection for researchers who may have to choose between animal models and (investing in) alternatives. This can help to reflect on and ethically justify decisions. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma." The authors identified minor errors in the image-typesetting in Figure 3 of the original article. The image for the NCI-N87 cell line in Figure 3C was mistakenly included, and the corresponding statistical analysis for NCI-N87 in Figure 3D needs to be corrected. The corrected figure has been provided, and the correction does not affect the results or conclusions of the paper. The correction notice is authored by Mei Feng, Hao Xu, Wenyuan Zhou, and Yisheng Pan. [Extracted from the article]

Simple Summary: Pediatric high-grade gliomas are aggressive and deadly brain tumors that arise in children and are notoriously difficult to cure. Researchers require accurate methods, or "model systems," to better understand these tumors. Model systems include culturing cancer cells in a dish, observing how cancer cells grow in an animal brain, and growing cells in self-organizing 3D cultures called organoids, which more accurately resemble the brain. In this paper, we describe the molecular changes that these cancers acquire that cause them to be so aggressive, the development of past and present model systems, highlight the newest model systems being developed, and offer suggestions regarding how these model systems can be used in the future to develop better therapies for patients. Further, we outline the benefits and limitations of each model system to better guide researchers in the design of their experiments. Developing a variety of model systems that adequately and faithfully represent how tumors exist, progress, recur, and respond to treatment in a patient is absolutely essential to the eventual development of effective therapeutics. Therefore, investing in the continued development of these model systems is paramount to improving patient outcomes. Pediatric high-grade gliomas (pHGG) are malignant and usually fatal central nervous system (CNS) WHO Grade 4 tumors. The majority of pHGG consist of diffuse midline gliomas (DMG), H3.3 or H3.1 K27 altered, or diffuse hemispheric gliomas (DHG) (H3.3 G34-mutant). Due to diffuse tumor infiltration of eloquent brain areas, especially for DMG, surgery has often been limited and chemotherapy has not been effective, leaving fractionated radiation to the involved field as the current standard of care. pHGG has only been classified as molecularly distinct from adult HGG since 2012 through Next-Generation sequencing approaches, which have shown pHGG to be epigenetically regulated and specific tumor sub-types to be representative of dysregulated differentiating cells. To translate discovery research into novel therapies, improved pre-clinical models that more adequately represent the tumor biology of pHGG are required. This review will summarize the molecular characteristics of different pHGG sub-types, with a specific focus on histone K27M mutations and the dysregulated gene expression profiles arising from these mutations. Current and emerging pre-clinical models for pHGG will be discussed, including commonly used patient-derived cell lines and in vivo modeling techniques, encompassing patient-derived xenograft murine models and genetically engineered mouse models (GEMMs). Lastly, emerging techniques to model CNS tumors within a human brain environment using brain organoids through co-culture will be explored. As models that more reliably represent pHGG continue to be developed, targetable biological and genetic vulnerabilities in the disease will be more rapidly identified, leading to better treatments and improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Wildlife research in both terrestrial and aquatic ecosystems now deploys drone technology for tasks such as monitoring, census counts and habitat analysis. Unlike camera traps, drones offer real-time flexibility for adaptable flight paths and camera views, thus making them ideal for capturing multi-view data on wildlife like zebras or lions. With recent advancements in animals' 3D shape & pose estimation, there is an increasing interest in bringing 3D analysis from ground to sky by means of drones. The paper reports some activities of the EU-funded WildDrone project and performs, for the first time, 3D analyses of animals exploiting oblique drone imagery. Using parametric model fitting, we estimate 3D shape and pose of animals from frames of a monocular RGB video. With the goal of appending metric information to parametric animal models using photogrammetric evidence, we propose a pipeline where we perform a point cloud reconstruction of the scene to scale and localize the animal within the 3D scene. Challenges, planned next steps and future directions are also reported. [ABSTRACT FROM AUTHOR]

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7–10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow. NEW & NOTEWORTHY: When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma. [ABSTRACT FROM AUTHOR]

The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov, and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed. [ABSTRACT FROM AUTHOR]

Impaired healing wounds do not proceed through the normal healing processes in a timely and orderly manner, and while they do eventually heal, their healing is not optimal. Chronic wounds, on the other hand, remain unhealed for weeks or months. In the US alone, chronic wounds impact ~8.5 million people and cost ~USD 28–90 billion per year, not accounting for the psychological and physical pain and emotional suffering that patients endure. These numbers are only expected to rise in the future as the elderly populations and the incidence of comorbidities such as diabetes, hypertension, and obesity increase. Over the last few decades, scientists have used a variety of approaches to treat chronic wounds, but unfortunately, to date, there is no effective treatment. Indeed, while there are thousands of drugs to combat cancer, there is only one single drug approved for the treatment of chronic wounds. This is in part because wound healing is a very complex process involving many phases that must occur sequentially and in a timely manner. Furthermore, models that fully mimic human chronic wounds have not been developed. In this review, we assess various models currently being used to study the biology of impaired healing and chronic non-healing wounds. Among them, this paper also highlights one model which shows significant promise; this model uses aged and obese db/db−/− mice and the chronic wounds that develop show characteristics of human chronic wounds that include increased oxidative stress, chronic inflammation, damaged microvasculature, abnormal collagen matrix deposition, a lack of re-epithelialization, and the spontaneous development of multi-bacterial biofilm. We also discuss how important it is that we continue to develop chronic wound models that more closely mimic those of humans and that can be used to test potential treatments to heal chronic wounds. [ABSTRACT FROM AUTHOR]

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstemresponses. These positive resultsmotivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyosarcoma (RMS) is the most common pediatric softtissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical in vivo models are essential for advancing our understanding of RMS oncobiology and developing novel treatment strategies. However, the diversity of scholarly data on preclinical RMS studies may challenge scientists and clinicians. Hence, we performed a systematic literature survey of contemporary RMS mouse models to characterize their phenotypes and assess their translational relevance. Methods: We identified papers published between 01/07/2018 and 01/07/2023 by searching PubMed and Web of Science databases. Results: Out of 713 records screened, 118 studies (26.9%) were included in the qualitative synthesis. Cell line-derived xenografts (CDX) were the most commonly utilized (n = 75, 63.6%), followed by patient-derived xenografts (PDX) and syngeneic models, each accounting for 11.9% (n = 14), and genetically engineered mouse models (GEMM) (n = 7, 5.9%). Combinations of different model categories were reported in 5.9% (n = 7) of studies. One study employed a virus-induced RMS model. Overall, 40.0% (n = 30) of the studies utilizing CDX models established alveolar RMS (aRMS), while 38.7% (n = 29) were embryonal phenotypes (eRMS). There were 20.0% (n = 15) of studies that involved a combination of both aRMS and eRMS subtypes. In one study (1.3%), the RMS phenotype was spindle cell/sclerosing. Subcutaneous xenografts (n = 66, 55.9%) were more frequently used compared to orthotopic models (n = 29, 24.6%). Notably, none of the employed cell lines were derived from primary untreated tumors. Only a minority of studies investigated disseminated RMS phenotypes (n = 16, 13.6%). The utilization areas of RMS models included testing drugs (n = 64, 54.2%), studying tumorigenesis (n = 56, 47.5%), tumor modeling (n = 19, 16.1%), imaging (n = 9, 7.6%), radiotherapy (n = 6, 5.1%), long-term effects related to radiotherapy (n = 3, 2.5%), and investigating biomarkers (n = 1, 0.8%). Notably, no preclinical studies focused on surgery. Conclusions: This up-to-date review highlights the need for mouse models with dissemination phenotypes and cell lines from primary untreated tumors. Furthermore, efforts should be directed towards underexplored areas such as surgery, radiotherapy, and biomarkers. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a multifactorial metabolic disease, of which type 2 diabetes (T2D) is one of the most common. The complications of diabetes are far more harmful than diabetes itself. Type 2 diabetes complications include diabetic nephropathy (DN), diabetic heart disease, diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) et al. Many animal models have been developed to study the pathogenesis of T2D and discover an effective strategy to treat its consequences. In this sense, it is crucial to choose the right animal model for the corresponding diabetic complication. This paper summarizes and classifies the animal modeling approaches to T2D complications and provides a comprehensive review of their advantages and disadvantages. It is hopeful that this paper will provide theoretical support for animal trials of diabetic complications. [ABSTRACT FROM AUTHOR]

In the present study we have discussed around sixteen different animal models used worldwide for the scientific research and new drug discovery. The main aim of the using experimental animal models in drug discovery is to establish and provide evidence for non-clinical 'proof-of-concept' for the safety, efficacy, and target of interest for specific drug molecules. Experimental preparations developed in one species for the purpose of studying phenomena occurring in another species. The use of experimental animal models serves to better understand the origins, pathology, and the overall nature of comparable diseases of humans being. Similarly, animal models perform duties for in the development of safe and effective treatments and cures of such diseases and/or associated symptoms. Experimental animal models for drug discovery and development have played a major role in the characterization of the pathophysiology of diseases and associated mechanisms of injury, drug target identification, and evaluation of novel therapeutic agents for toxicity, pharmacokinetics and pharmacodynamics activity. Through animal model researchers can perform experiments that would be impractical or ethically prohibited with humans. There are various animal models used for screening of uncountable therapeutic activities, in this review our main focus is animal models used for peptic ulcer. Peptic ulcer is one of the worldwide diseases where 10% of adults are affected by peptic ulcer once in their lifetime. The antiulcer models for drug development against gastric and duodenal ulcer studies are limited in number that has hindered the progress of targeted therapy in this field. Therefore, it is necessary to review the literature on experimental animal models that are used to screen agents with potential antigastric ulcer activity and describe their biochemical basis in order to facilitate their use in the development of new preventive and curative antiulcer drugs. There are many models used to induce ulcer such as pylorus ligation or it can be chemically induced by ethanol, NSAIDs (e.g. indomethacin) or many more. In this review paper, current in-vivo animal models of ulcers and the pathophysiological mechanisms underlying their induction, their drawbacks, as well as the challenges associated with their use have been discussed. [ABSTRACT FROM AUTHOR]

The past several decades have borne witness to several breakthroughs and paradigm shifts within the field of cardiovascular medicine, but one component that has remained constant throughout this time is the need for accurate animal models for the refinement and elaboration of the hypotheses and therapies crucial to our capacity to combat human disease. Numerous sophisticated and high-throughput molecular strategies have emerged, including rational drug design and the multi-omics approaches that allow extensive characterization of the host response to disease states and their prospective resolutions, but these technologies all require grounding within a faithful representation of their clinical context. Over this period, our lab has exhaustively tested, progressively refined, and extensively contributed to cardiovascular discovery on the basis of one such faithful representation. It is the purpose of this paper to review our porcine model of chronic myocardial ischemia using ameroid constriction and the subsequent myriad of physiological and molecular–biological insights it has allowed our lab to attain and describe. We hope that, by depicting our methods and the insight they have yielded clearly and completely—drawing for this purpose on comprehensive videographic illustration—other research teams will be empowered to carry our work forward, drawing on our experience to refine their own investigations into the pathogenesis and eradication of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Botulinum toxin (BoNT) is an effective and safe therapy for the symptomatic treatment of several neurological disturbances. An important line of research has provided numerous pieces of evidence about the mechanisms of action of BoNT in the central nervous system, especially in the context of dystonia and spasticity. However, only a few studies focused on the possible central effects of BoNT in Parkinson's disease (PD). We performed a systematic review to describe and discuss the evidence from studies focused on possible central effects of BoNT in PD animal models and PD patients. To this aim, a literature search in PubMed and SCOPUS was performed in May 2023. The records were screened according to title and abstract by two independent reviewers and relevant articles were selected for full-text review. Most of the papers highlighted by our review report that the intrastriatal administration of BoNT, through local anticholinergic action and the remodulation of striatal compensatory mechanisms secondary to dopaminergic denervation, induces an improvement in motor and non-motor symptoms in the absence of neuronal loss in animal models of PD. In human subjects, the data are scarce: a single neurophysiological study in tremulous PD patients found that the change in tremor severity after peripheral BoNT administration was associated with improved sensory–motor integration and intracortical inhibition measures. Further clinical, neurophysiological, and neuroimaging studies are necessary to clarify the possible central effects of BoNT in PD. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion It is well‐known that oral surgical procedures pose a high risk for medication‐related osteonecrosis of the jaw in patients taking bisphosphonates. Although some position papers and guidelines have been published with regard to its treatment, few studies have investigated prevention methods. This study investigates the effectiveness of methenolone enanthate, an anabolic steroid, for the prevention of medication‐related osteonecrosis of the jaw.Thirty‐six Wistar rats were divided into three groups. Two experimental groups, Z and ZM, took zoledronic acid for 6 weeks prior to extraction of the left maxillary first molar. The Group ZM also was given methenolone enanthate continuously for 1 week before and 4 weeks after the extraction. The control group was not given any medication. The rats were euthanized 5 weeks after extraction. The extraction socket was evaluated clinically for bone exposure and histologically for inflammation, hyperemia, collagen fibers, epithelialization, number of osteoclasts, and empty lacunae.Six rats died during the experimental research. The bone exposure rate, mean numbers of attached osteoclasts (in 40× magnification), and empty lacunae (in 100× magnification) were 0%, 4%, and 0.8% in Group C; 75%, 1%, and 8% in Group Z; and 10%, 2.1%, and 3% in Group ZM, respectively. Significant differences exist between all groups regarding the number of empty lacunae. There were significant differences between Group C/ZM and Group Z in terms of bone exposure rate, inflammation, hyperemia, collagen fiber organization, and epithelialization.In our tested preclinical model, methenolone enanthate has shown potential for preventing medication‐related osteonecrosis of the jaw. [ABSTRACT FROM AUTHOR]

Phenolic compounds show promise in treating obesity and enhancing intestinal health. This systematic review addressed the following question: “What are the effects of polyphenols on intestinal health in preclinical studies with diet-induced obesity?”. The review followed PRISMA guidelines and was registered in PROSPERO(CRD42021262445). Studies published until April 2024 were selected from Medline(PubMed), Web of Science, Scopus, Embase, and ScienceDirect using terms related to polyphenols, obesity, and microbiota in rats and mice. Thirty papers meeting PICOS criteria were included. Bias risk was assessed with the SYRCLE tool, yielding scores between 4.5 and 7.0 out of 10. Findings indicated that 22 phenolic compounds improved gut microbiota diversity, reduced the Firmicutes/Bacteroides ratio, and modulated microbiota at various taxonomic levels. They also increased short-chain fatty acids, tight-junction expression, enhanced intestinal morphology, and reduced endotoxemia and inflammatory cytokines. These results suggest phenolic compounds may help treat obesity by modifying the microbiota and improving intestinal health. However, further research is needed to standardize data and facilitate meta-analyses. [ABSTRACT FROM AUTHOR]

Background and Objectives: Children undergoing airway management during general anesthesia may experience airway complications resulting in a rare but life‐threatening situation known as "Can't Intubate, Can't Oxygenate". This situation requires immediate recognition, advanced airway management, and ultimately emergency front‐of‐neck access. The absence of standardized procedures, lack of readily available equipment, inadequate knowledge, and training often lead to failed emergency front‐of‐neck access, resulting in catastrophic outcomes. In this narrative review, we examined the latest evidence on emergency front‐of‐neck access in children. Methods: A comprehensive literature was performed the use of emergency front‐of‐neck access (eFONA) in infants and children. Results: Eighty‐six papers were deemed relevant by abstract. Finally, eight studies regarding the eFONA technique and simulations in animal models were included. For all articles, their primary and secondary outcomes, their specific animal model, the experimental design, the target participants, and the equipment were reported. Conclusion: Based on the available evidence, we propose a general approach to the eFONA technique and a guide for implementing local protocols and training. Additionally, we introduce the application of innovative tools such as 3D models, ultrasound, and artificial intelligence, which can improve the precision, safety, and training of this rare but critical procedure. [ABSTRACT FROM AUTHOR]

Advancements in molecular imaging and drug targeting have created a renaissance in the development of radiopharmaceuticals for therapy and theranostics. While some radiopharmaceuticals, such as Na[131I]I, have been used clinically for decades, new agents are being approved using small‐molecules, peptides, and antibodies for targeting. As these agents are being developed, the need to understand dosimetry and biologic effects of the systemically delivered radiotherapy becomes more important, particularly as highly potent radiopharmaceuticals using targeted alpha therapy become clinically utilized. As the processes being targeted become more complex, and the radiobiology of different particulate radiation becomes more diverse, models that better recapitulate human cancer and geometry are necessary. Companion animals develop many of the same types of cancer, carrying many of the same genetic drivers as those seen in people, and the scale and geometry of tumours in dogs more closely mimics those in humans than murine tumour models. Key translational challenges in oncology, such as alterations in tumour microenvironment, hypoxia, heterogeneity, and geometry are addressed by companion animal models. This review paper will provide background on radiopharmaceutical targeting techniques, review the use of radiopharmaceuticals in companion animal oncology, and explore the translational value of treating these patients in terms of dosimetry, treatment outcomes, and normal tissue complication rates. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic central nervous system (CNS) disorder characterized by demyelination, neuronal damage, and oligodendrocyte depletion. Reliable biomarkers are essential for early diagnosis and disease management. Emerging research highlights the role of mitochondrial dysfunction and oxidative stress in CNS disorders, including MS, in which mitochondria are central to the degenerative process. Adenosine monophosphate‐activated protein kinase (AMPK) regulates the mitochondrial energy balance and initiates responses in neurodegenerative conditions. This systematic review, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, aimed to comprehensively assess the literature on AMPK pathways, mitochondrial dysfunction, and in vivo studies using MS animal models. The search strategy involved the use of AMPK syntaxes, MS syntaxes, and animal model syntaxes. The PubMed, Scopus, Web of Science, and Google Scholar databases were systematically searched on August 26, 2023 without publication year restrictions. The review identified and analyzed relevant papers to provide a comprehensive overview of the current state of related research. Eight studies utilizing various interventions and methodological approaches were included. Risk of bias assessment revealed some areas of low risk but lacked explicit reporting in others. These studies collectively revealed a complex relationship between AMPK, mitochondrial dysfunction, and MS pathogenesis, with both cuprizone and experimental autoimmune encephalomyelitis models demonstrating associations between AMPK and mitochondrial disorders, including oxidative stress and impaired expression of mitochondrial genes. These studies illuminate the multifaceted role of AMPK in MS animal models, involving energy metabolism, inflammatory processes, oxidative stress, and gene regulation leading to mitochondrial dysfunction. However, unanswered questions about its mechanisms and clinical applications underscore the need for further research to fully harness its potential in addressing MS‐related mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Preclinical research is an essential aspect of biomedical science that aids in clarifying the pathophysiology of underlying illness and devising new treatments. This special issues brings together original research and review papers that pertain to the development of novel models and behavioral assays of symptoms of neuropsychiatric disorders, which may help to refine preclinical studies and to improve their translatability to the human condition. [ABSTRACT FROM AUTHOR]

Polyglutamine disorders are a complex group of incurable neurodegenerative disorders caused by an abnormal expansion in the trinucleotide cytosine-adenine-guanine tract of the affected gene. To better understand these disorders, our dependence on animal models persists, primarily relying on transgenic models. In an effort to complement and deepen our knowledge, researchers have also developed animal models of polyglutamine disorders employing viral vectors. Viral vectors have been extensively used to deliver genes to the brain, not only for therapeutic purposes but also for the development of animal models, given their remarkable flexibility. In a time- and cost-effective manner, it is possible to use different transgenes, at varying doses, in diverse targeted tissues, at different ages, and in different species, to recreate polyglutamine pathology. This paper aims to showcase the utility of viral vectors in disease modelling, share essential considerations for developing animal models with viral vectors, and provide a comprehensive review of existing viral-based animal models for polyglutamine disorders. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the effect of pomegranate juice consumption on bone histomorphometric parameters using an animal model. The animals (rats) were divided into 7 experimental groups. The groups differed in the concentration of pomegranate juice administered. The control group received only water, the other groups were supplied with commercial or freshly squeezed pomegranate juice at concentrations of 10%, 25% and 50%. To study the structure of the proximal end of the tibia, a Skyscan 1174 X-ray microtomography device, equipped with a 1.3Mp FW VDS camera, was used. The proximal end (metaphysis) of the left tibia was examined. The following bone tissue parameters were analysed: bone mineral density (BMD) (mm3), the number of trabeculae (Tb.N) (mm-1), trabecular separation (Tb.Sp) (mm) and trabecular thickness (Tb. Th) (mm), BS/BV(mm-1). It was found that 25% pomegranate juice, both freshly squeezed and commercial, significantly increased bone density (BMD), increased trabecular thickness (Tb.TH), and reduced the distance between trabeculae (Tb.SP) compared to the control group and groups receiving juice at other concentrations. The highest BMD, the thickest trabeculae and the smallest distance between trabeculae were observed after the application of fresh 25% pomegranate juice. Thus, it can be concluded that pomegranate juice, especially freshly squeezed, improves bone density. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "High resolution optical mapping of cardiac electrophysiology in pre-clinical models" published in Scientific Data. The correction addresses an incorrect DOI URL for the main data citation in the original version of the article. The correct link has been updated in the PDF and HTML versions of the paper. The authors of the article are Christopher O'Shea, James Winter, S. Nashitha Kabir, Molly O'Reilly, Simon P. Wells, Olivia Baines, Laura C. Sommerfeld, Joao Correia, Ming Lei, Paulus Kirchhof, Andrew P. Holmes, Larissa Fabritz, Kashif Rajpoot, and Davor Pavlovic. [Extracted from the article]

The aim of the study was to analyze the effect of cranberry juice on bone microstructure. The research was carried out on an animal model (experimental animals, Windstar rats). The structure of the proximal tibial metaphysis was analyzed using micro CT, and X-ray microtomography equipment with a VDS 1.3Mp FW camera. It was found that cranberry juice increased bone mineral density (BMD). It also increased the thickness of the bone trabeculae (Tb.Th). The highest BMD value was observed in group drinking a 10% concentration of cranberry juice. In rats drinking 25% concentration, an increase in Tb.Th was observed compared to the two other groups, including the control group. [ABSTRACT FROM AUTHOR]

The objective of this study was to estimate the breeding value and heritability for calving score using an animal model for population from Aberdeen Angus breed. Data consisted of records of 1297 calves of Aberdeen Angus breed from Aberdeen Angus Association Romania. The mean for calving score was 1.007±0.002. The breeding values for calving score for calves were between -0.013 and 0.075. The heritability for calving score was low 0.08 in Aberdeen Angus breed. The animal model was adequate due it is simpler than threshold model for calculate the genetic parameters for calving score. [ABSTRACT FROM AUTHOR]

Social gradients in health and aging have been reported in studies across many human populations, and - as the papers included in this special collection highlight – also occur across species. This paper serves as a general introduction to the special collection of Neuroscience and Biobehavioral Reviews entitled "Social dimensions of health and aging: population studies, preclinical research, and comparative research using animal models". Authors of the fourteen reviews are primarily members of a National Institute of Aging-supported High Priority Research Network on "Animal Models for the Social Dimensions of Health and Aging". The collection is introduced by a foreword, commentaries, and opinion pieces by leading experts in related fields. The fourteen reviews are divided into four sections: Section 1: Biodemography and life course studies; Section 2: Social behavior and healthy aging in nonhuman primates; Section 3: Social factors, stress, and hallmarks of aging; Section 4: Neuroscience and social behavior. [ABSTRACT FROM AUTHOR]

Animal experimentation has long been an integral part of biomedical and cosmetics research, with historical roots dating back to ancient Greece. During that period, physicians constrained by cultural taboos that forbade the use of human cadavers, turned to the dissection of animals for their anatomical studies. The use of specific animal models in research has often been justified by the remarkable biological similarities between animals and humans. However, there are instances where animal models, such as fish and frogs, are used, despite significant disparities in their anatomy and physiology compared to humans. In herbal medicine research, animal experimentation has found various applications. Numerous plant species from diverse global regions, including the United Kingdom, United States, China, India, and Africa, have been studied to identify their pharmacological properties and therapeutic indications. Nevertheless, the use of animals in these studies, while offering undeniable advantages, remains a subject of intense debate and contention, mainly arising from the ethical challenges it presents, as well as the substantial financial burden it imposes, and its inability to reliably predict human responses. This paper, therefore, proposes a comprehensive list of research methodologies that are ethical, practical, cost-effective, and consistent with the real ethos of herbal medicine. These alternative methods, which include in vitro studies, human cell cultures, computational modelling, culturally sensitive clinical trials, and ethnobotanical surveys, have the potential to provide cost-effective healthcare solutions, without subjecting animals to unnecessary suffering. [ABSTRACT FROM AUTHOR]

Moderate-to-severe systemic lupus erythematosus (SLE) is characterized by extensive autoantibody deposition and persistent autoinflammation. As the existing animal models are limited in accurately reproducing the pathological characteristics of human SLE, we introduced a novel animal model simulating multi-organ autoinflammation through intra-organ injections. The model closely mimicked key features of SLE, including IgG deposition, inflammation, and tissue damage. The model could be used to assess the roles of IgG, immune cells, cytokines, and Fc gamma receptor (FcγR) in the pathogenesis of autoinflammation. The results obtained from this model could be confirmed by lupus MRL/ lpr mice. The review suggested that the diagnostic criteria should be reconsidered to incorporate IgG deposition in tissues and highlighted the limitations of current T-cell and B-cell-focused treatments. To summarize, the IgG deposition model can be used to investigate the pathogenesis and treatment of multi-organ tissue damage associated with SLE. • Introduction of a novel animal model: a new animal model mimicing the pathogenesis of lupus autoantibodies IgG-induced organ-tissue damage. • Comprehensive Exploration and Validation of New Model: The roles of lupus autoantibody IgG, immune cells, cytokines and FcγR in organ tissue inflammation were investigated by using this new model. Confirmation of the results from the new model using lupus-prone MRL/lpr mice. • Implications for SLE Research and Treatment: Importance and convenience of the IgG deposition model in investigating the pathogenesis of SLE and its potential for developing targeted therapies. • This paper significantly contributes to the understanding of SLE pathogenesis by introducing a novel animal model that accurately replicates key aspects of the disease, providing a platform for more effective therapeutic exploration and diagnostic considerations. [ABSTRACT FROM AUTHOR]

Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7. Researchers identified 7 biological group of diffuse large B-cell lymphoma, one with poor prognosis. They developed a gene expression classifier to detect these groups, potentially improving prognosis and future treatments for the high-risk patients. [ABSTRACT FROM AUTHOR]

Objective. 225Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however, 225Ac (t 1/2 = 9.9 d) lacks direct gamma emissions for in vivo imaging. 226Ac (t 1/2 = 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation of 225Ac radiopharmaceuticals. 226Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study for in vivo quantitative 226Ac SPECT imaging and validation of activity estimation. Approach. 226Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [226Ac]Ac3+ was radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours. Mice with AR42J tumour xenografts were injected with either 2 MBq of [226Ac]Ac-crown-TATE or 4 MBq of free [226Ac]Ac3+ activity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-based 226Ac activity measurements were assessed from volumes of interest within tumours and organs of interest. Imaging data was compared with ex vivo biodistribution measured via gamma counter. Main results. We present, to the best of our knowledge, the first ever in vivo quantitative SPECT images of 226Ac activity distributions. Time-activity curves derived from SPECT images quantify the in vivo biodistribution of [226Ac]Ac-crown-TATE and free [226Ac]Ac3+ activity. Image-based activity measurements in the tumours and organs of interest corresponded well with ex vivo biodistribution measurements. Significance. Here in, we established the feasibility of in vivo 226Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitative in vivo pharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC) is a multifactorial and complex syndrome experienced by up to 80% of patients with cancer and implicated in ∼40% of cancer-related deaths. Given its significant impact on patients' quality of life and prognosis, there has been a growing emphasis on elucidating the underlying mechanisms of CC using preclinical models. However, the mechanisms of cachexia appear to differ across several variables including tumor type and model and biologic variables such as sex. These differences may be exacerbated by variance in experimental approaches and data reporting. This review examines literature spanning from 2011 to March 2024, focusing on common preclinical models of CC, including Lewis Lung Carcinoma, pancreatic KPC, and colorectal colon-26 and Apcmin/+ models. Our analysis reveals considerable heterogeneity in phenotypic outcomes, and investigated mechanisms within each model, with particular attention to sex differences that may be exacerbated through methodological differences. Although searching for unified mechanisms is critical, we posit that effective treatment approaches are likely to leverage the heterogeneity presented by the tumor and pertinent biological variables to direct specific interventions. In exploring this heterogeneity, it becomes critical to consider methodological and data reporting approaches to best inform further research. [ABSTRACT FROM AUTHOR]

Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by the rapid emergence of viral variants with immunoevasive properties. The development of an off-the-shelf, effective, and safe therapy against respiratory viral infections is thus desirable. Here, we develop NanoSTING, a nanoparticle formulation of the endogenous STING agonist, 2′−3′ cGAMP, to function as an immune activator and demonstrate its safety in mice and rats. A single intranasal dose of NanoSTING protects against pathogenic strains of SARS-CoV-2 (alpha and delta VOC) in hamsters. In transmission experiments, NanoSTING reduces the transmission of SARS-CoV-2 Omicron VOC to naïve hamsters. NanoSTING also protects against oseltamivir-sensitive and oseltamivir-resistant strains of influenza in mice. Mechanistically, NanoSTING upregulates locoregional interferon-dependent and interferon-independent pathways in mice, hamsters, as well as non-human primates. Our results thus implicate NanoSTING as a broad-spectrum immune activator for controlling respiratory virus infection. Respiratory viral infection causes fast onset of pathology, and is often compounded by vaccination-resistant variants. Here, the authors show that a STING agonist nanoparticle, termed NanoSTING, helps protect against SARS-CoV-2 in hamsters and influenza in mice, thereby implicating NanoSTING as a broad-spectrum treatment for respiratory viral infections. [ABSTRACT FROM AUTHOR]

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer’s disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches. [ABSTRACT FROM AUTHOR]

Humanized mice with human-like immune systems are commonly used to study immune responses to human-specific pathogens. However, one limitation of using humanized mice is their native murine gut microbiota, which significantly differs from that in humans. Given the importance of the gut microbiome to human health, these differences may profoundly impact the ability to translate results from humanized mouse studies to humans. Further, there is a critical need for improved pre-clinical models to study the complex in vivo relationships of the gut microbiome, immune system, and human disease. We previously created double humanized mice with a functional human immune system and a stable, human-like gut microbiome. Here, we characterized the engrafted human gut bacterial microbiome in our double humanized mouse model generated by transplanting fecal material from healthy human donors into the gut of humanized mice. Analysis of bacterial microbiomes in fecal samples from double humanized mice revealed they had unique 16S rRNA gene profiles consistent with those of the individual human donor samples. Importantly, transplanted human-like gut microbiomes were stable in mice for the duration of the study, extending up to 14.5 weeks post-transplant. Microbiomes of double humanized mice also harbored predicted functional capacities that more closely resembled those of the human donors than humanized mice. In conclusion, our study highlights the successful engraftment of human fecal microbiota in BLT humanized mice and underscores the stability of this model, offering a valuable platform for investigating the intricate interplay among the human gut microbiome, immune system, and various diseases in vivo. [ABSTRACT FROM AUTHOR]

The well-established anti-inflammatory and antioxidant properties of red fruits leave room for a biological pathway of improved muscle health promoted by berries in the diet. Our objective was to systematically review the number of trials conducted on human and animal species around the relationship between a berry diet and muscle health outcomes. Two independent examiners conducted a search for studies that utilized keywords associated with muscle health outcomes and a berry-based diet in both human and animal trials, in accordance with the PRISMA statement guidelines. The literature was searched through six electronic databases until December 2023. Screening of 152 retrieved articles resulted in a final selection of 16 reports investigating the effect of exposure to a berry-based diet and skeletal muscle health outcomes. The study protocol was registered on PROSPERO (CRD42023479682). Among the selected studies, nine involved humans and seven animal models (rats and mice). Overall, most of the studies reported positive effects on performance or muscle health. Specifically, five studies investigated the possible effects of blackcurrant on active human subjects or athletes; three studies focused on blueberry and presented results on running performance (human sample) and muscle health (rat models). The rest of the studies involved raspberries (two studies, rat models), aronia (one study, rat models), elderberry (one study, rat models), and a mixed compound (one study, rat models). In conclusion, there is some early evidence that a berry-rich diet may increase performance or muscle health, but more research is needed to fully understand the underlying biological trajectories, and thus, no firm conclusions can yet be drawn. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. GC is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies. [ABSTRACT FROM AUTHOR]

Virus-like nanoparticles (VNP) are regarded as efficient vaccination platforms and have proven to be useful for the non-anaphylactogenic delivery of allergen-specific immunotherapy in preclinical models previously. Herein, we sought to determine the mode of VNP uptake by antigen presenting cells (APC). Accordingly, we screened a collection of substances known to inhibit different uptake pathways by APC. The human leukemia monocytic cell line THP-1 and the murine dendritic cell line DC 2.4 were examined for the uptake of fluorescently labelled VNP in the presence or absence of inhibitors. The inhibitory effect of candidate substances that blocked VNP uptake in APC lines was subsequently evaluated in studies with primary APC present in splenocyte and lung cell homogenates in vitro and upon intratracheal application of VNP in vivo. The uptake of allergen-specific VNP in vitro and in vivo was mainly observed by macrophages and CD103+ dendritic cells and was sensitive to inhibitors that block macropinocytosis, such as hyperosmolarity induced by sucrose or the polyphenol compound Rottlerin at low micromolar concentrations but not by other inhibitors. Also, T-cell proliferation induced by allergen-specific VNP was significantly reduced by both substances. In contrast, substances that stimulate macropinocytosis, such as Heparin and phorbol myristate acetate (PMA), increased VNP-uptake and may, thus, help modulate allergen-specific T-cell responses. We have identified macropinocytosis as the principal uptake mechanism of APC for allergen-specific VNP in vitro and in vivo, paving the way for further improvement of VNP-based therapies, especially those that can be used for tolerance induction in allergy, in the future. [ABSTRACT FROM AUTHOR]

Necroptosis, a recently discovered form of cell-programmed death that is distinct from apoptosis, has been confirmed to play a significant role in the pathogenesis of bacterial infections in various animal models. Necroptosis is advantageous to the host, but in some cases, it can be detrimental. To understand the impact of necroptosis on the pathogenesis of bacterial infections, we described the roles and molecular mechanisms of necroptosis caused by different bacterial infections in this review. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the feasibility of using [68Ga]-fibroblast-activating protein inhibitor (FAPI) positron emission tomography (PET) imaging for diagnosing pulmonary fibrosis in a mouse model. We also examined its value in monitoring treatment response and compared it with traditional [18F]-fluorodeoxyglucose (FDG) PET and computed tomography (CT) imaging. Methods: A model of idiopathic pulmonary fibrosis was established using intratracheal injection of bleomycin (BLM, 2 mg/kg) into C57BL/6 male mice. For the treatment of IPF, a daily oral dose of 400 mg/kg/day of pirfenidone was administered from 9 to 28 days after the establishment of the model. Disease progression and treatment efficacy were assessed at different stages of the disease every week for four weeks using CT, [18F]FDG PET, and [68Ga]FAPI PET (baseline imaging performed at week 0). Mice were sacrificed and lung tissues were harvested for hematoxylin-eosin staining, picrosirius red staining, and immunohistochemical staining for glucose transporter 1 (GLUT1) and FAP. Expression levels of GLUT1 and FAP in pathological sections were quantified. Correlations between imaging parameters and pathological quantitative values were analyzed. Results: CT, [18F]FDG PET and [68Ga]FAPI PET revealed anatomical and functional changes in the lung that reflected progression of pulmonary fibrosis. In untreated mice with pulmonary fibrosis, lung uptake of [18F]FDG peaked on day 14, while [68Ga]FAPI uptake and mean lung density peaked on day 21. In mice treated with pirfenidone, mean lung density and lung uptake of both PET tracers decreased. Mean lung density, [18F]FDG uptake, and [68Ga]FAPI uptake correlated well with quantitative values of picrosirius red staining, GLUT1 expression, and FAP expression, respectively. Conclusions: Although traditional CT and [18F]FDG PET reflect anatomical and metabolic status in fibrotic lung, [68Ga]FAPI PET provides a means of evaluating fibrosis progression and monitoring treatment response. [ABSTRACT FROM AUTHOR]

Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A® and Alhydrogel® as adjuvants to further stimulate the immune response. MPL-A® induces a Th1-mediated immune response and Alhydrogel® (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of −19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4+ helper and CD8+ cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally. [ABSTRACT FROM AUTHOR]

Recent years have seen a surge in research focused on NAD+ decline and potential interventions, and despite significant progress, new discoveries continue to highlight the complexity of NAD+ biology. Nicotinamide mononucleotide (NMN), a well-established NAD+ precursor, has garnered considerable interest due to its capacity to elevate NAD+ levels and induce promising health benefits in preclinical models. Clinical trials investigating NMN supplementation have yielded variable outcomes while shedding light on the intricacies of NMN metabolism and revealing the critical roles played by gut microbiota and specific cellular uptake pathways. Individual variability in factors such as lifestyle, health conditions, genetics, and gut microbiome composition likely contributes to the observed discrepancies in clinical trial results. Preliminary evidence suggests that NMN's effects may be context-dependent, varying based on a person's physiological state. Understanding these nuances is critical for definitively assessing the impact of manipulating NAD+ levels through NMN supplementation. Here, we review NMN metabolism, focusing on current knowledge, pinpointing key areas where further research is needed, and outlining future directions to advance our understanding of its potential clinical significance. [ABSTRACT FROM AUTHOR]

Movement models are frequently fit to animal location data to understand how individuals respond to and interact with local environmental features. Several open‐source software packages are available for analysing animal movements and can facilitate parameter estimation, yet there are relatively few methods available for evaluating model goodness of fit.We describe how a simple graphical technique, the lineup protocol, can be used to evaluate goodness of fit of integrated step‐selection analyses and hidden Markov models, but the method can be applied much more broadly. We leverage the ability to simulate data from fitted models and demonstrate the approach using both an integrated step‐selection analysis and a hidden Markov model applied to fisher (Pekania pennanti) data.A variety of responses and movement metrics can be used to evaluate models, and the lineup protocol can be tailored to focus on specific model assumptions or movement features that are of primary interest. Although it is possible to evaluate statistical significance using a formal hypothesis test, the method can also be used in a more exploratory fashion (e.g. to explore variability in model behaviour across stochastic simulations or to identify areas where the model could be improved).We provide coded examples and vignettes to demonstrate the flexibility of the approach. We encourage movement ecologists to consider how their models will be applied when choosing appropriate graphical responses for evaluating goodness of fit. [ABSTRACT FROM AUTHOR]

In the field of the cosmetic industry, significant efforts are made to develop methods that are not only cost effective and time effective but are also environmentally friendly and cruelty free. Cosmetic tests using in vivo animal models are currently banned in the European Union. To fulfil regulatory requirements, new approach methodologies (NAMs) are implemented, and thereupon, in silico techniques have constantly acquired significance. This review aimed to show the general picture of the available computational methods and approaches, give some examples of their applications, present capabilities and limitations, and propose the way forward. The general information about in silico modelling and examples of its usage in the context of cosmetics and its legal regulation are presented. The review is divided with a focus on three endpoints of interest: (1) safety assessment, (2) exposure assessment, and (3) formulation characterization. With this comprehensive analysis, we try to answer the question as to whether we are using the opportunity. [ABSTRACT FROM AUTHOR]

In this study, a mixed porcine–human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research. [ABSTRACT FROM AUTHOR]

Glucocorticoids may be given prior to major orthopedic surgery to decrease postoperative nausea, vomiting, and pain. Additionally, many orthopedic patients may be on chronic glucocorticoid therapy. The aim of our study was to investigate whether glucocorticoid administration influences Orthopedic-Device-Related Infection (ODRI) in a rat model. Screws colonized with Staphylococcus epidermidis were implanted in the tibia of skeletally mature female Wistar rats. The treated groups received either a single shot of dexamethasone in a short-term risk study, or a daily dose of dexamethasone in a longer-term interference study. In both phases, bone changes in the vicinity of the implant were monitored with microCT. There were no statistically significant differences in bacteriological outcome with or without dexamethasone. In the interference study, new bone formation was statistically higher in the dexamethasone-treated group (p = 0.0005) as revealed by CT and histopathological analysis, although with relatively low direct osseointegration of the implant. In conclusion, dexamethasone does not increase the risk of developing periprosthetic osteolysis or infection in a pre-clinical model of ODRI. Long-term administration of dexamethasone seemed to offer a benefit in terms of new bone formation around the implant, but with low osseointegration. [ABSTRACT FROM AUTHOR]

Animal models are frequently used as surrogates to understand human disease. In the fungal pathogen Cryptococcus species complex, several variations of a mouse model of disease were developed that recapitulate different aspects of human disease. These mouse models have been implemented using various inbred and outbred mouse backgrounds, many of which have genetic differences that can influence host response and disease outcome. In this review, we will discuss the most commonly used inbred mouse backgrounds in C. neoformans infection models. [ABSTRACT FROM AUTHOR]

Canine oral melanoma is the most prevalent malignant tumor in dogs and has a poor prognosis due to its high aggressiveness and high metastasis and recurrence rates. More research is needed into its treatment and to understand its pathogenic factors. In this study, we isolated a canine oral mucosal melanoma (COMM) cell line designated as COMM6605, which has now been stably passaged for more than 100 generations, with a successful monoclonal assay and a cell multiplication time of 22.2 h. G-banded karyotype analysis of the COMM6605 cell line revealed an abnormal chromosome count ranging from 45 to 74, with the identification of a double-armed chromosome as the characteristic marker chromosome of this cell line. The oral intralingual and dorsal subcutaneous implantation models of BALB/c-nu mice were successfully established; Melan-A (MLANA), S100 beta protein (S100β), PNL2, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) were stably expressed positively in the canine oral tumor sections, tumor cell lines, and tumor sections of tumor-bearing mice. Sublines COMM6605-Luc-EGFP and COMM6605-Cherry were established through lentiviral transfection, with COMM6605-Luc-EGFP co-expressing firefly luciferase (Luc) and enhanced green fluorescent protein (EGFP) and COMM6605-Cherry expressing the Cherry fluorescent protein gene. The COMM6605-Luc-EGFP fluorescent cell subline was injected via the tail vein and caused lung and lymph node metastasis, as detected by mouse live imaging, which can be used as an animal model to simulate the latter steps of hematogenous spread during tumor metastasis. The canine oral melanoma cell line COMM6605 and two sublines isolated and characterized in this study can offer a valuable model for studying mucosal melanoma. [ABSTRACT FROM AUTHOR]