An efficient numerical simulation and mathematical modeling for the prevention of tuberculosis

The main purpose of this research is to use a fractional-mathematical model including Atangana–Baleanu derivatives to explore the clinical associations and dynamical behavior of the tuberculosis. Herein, we used a lately introduced fractional operator having Mittag-Leffler kernel. The existence and inimitability problems to the relevant model were examined through the fixed-point theory. To verify the significance of the arbitrary fractional-order derivative, numerical outcomes were explored from the biological and mathematical viewpoints using the values of model parameters. The graphical simulations show the comparison of the predictor–corrector method (PCM) and Caputo method (CM) for different fractional orders and the results indicated the significant preference of PCM over CM.

Oxidative DNA Damage in Tamoxifen Injected THPfl/+ ROSACre/+ Mice

Background and Hypothesis: Tamm-Horsfall protein (THP) is an important regulator of urinary and systemic homeostasis expressed exclusively in the kidney. Complete knockout of THP has been shown to lead to systemic oxidative damage in a mouse model. To develop a more clinically relevant model, we generated a tamoxifen inducible knockout/heterozygote mouse using the Cre/Lox system. We hypothesize that inducing a heterozygous state would increase levels of oxidative damage in mice. Methods: Experimental mice were generated by breeding THPfl/fl mice with ROSACreERT2/CreERT2 mice to develop the inducible heterozygote THPfl/+RosaCreERT2. These mice, along with controls (THPfl/fl) were treated with daily intraperitoneal injections of 75 mg/kg tamoxifen for 5 days. Serum samples were obtained from mice at baseline and 1, 2 and 3 weeks from the first injection, while kidneys were harvested at 1 or 3 weeks. PCR of kidney genomic DNA demonstrated excision of the floxed allele in mice expressing Cre-ERT2. Western Blot analysis of kidney lysates was used to measure kidney THP, while circulating THP was measured by ELISA. Oxidative DNA damage was measured in the kidney and circulation by ELISA. Results: Though kidney THP levels decreased in mice expressing Cre-ERT2, circulating levels of THP remained stable, with evidence of transient increases at 1 or 2 weeks for most animals. Mice expressing Cre-ERT2 had significantly increased oxidative DNA damage within the kidney and there was a trend toward increased oxidative DNA damage in the serum, though larger sample sizes are required to verify this finding. Conclusion: Despite decreased THP in the kidney, mice maintained normal levels of circulating THP. However, higher levels of oxidative damage were found in both the kidney and circulation. Together, these results suggest that THP levels in the serum are tightly controlled and that an acute loss of THP leads to rapid increases in oxidative damage.

Challenges in Establishing a Relevant Model of Polycystic Ovary Syndrome in Rats – A Mini Review

Polycystic ovary syndrome (PCOS) is one of the most com-mon female endocrinopathy and one of the leading causes of in-fertility. However, the exact etiopathogenetic mechanisms are not discovered yet, while therapeutic strategies in PCOS commonly rely on symptomatic rather than curative. Regarding reasonable ethical limitations in human population, animal experimental studies can provide better insights into mechanisms underlying etiopathogenesis of PCOS, as well as investigations of different therapeutic strategies. Rodent models for PCOS are very useful for experimental studies due to their great genetic similarities with human genome, short reproductive and life span, feasible gener-ating of genetically adapted animals, and convenient and acces-sible use. To our knowledge, androgens (dehydroepiandroste-rone, testosterone propionate, 5a-dihydrotestosterone), as well as estradiol valerate, represent the most frequently used hormones for PCOS modeling. Furthermore, the administration of antipro-gesterone or letrozole has been reported as effective for PCOS induction. In our review, the presented PCOS models were ac-complished by the administration of different hormones or drugs and alterations of environment. The main focus of this review was to summarize the alterations in ovarian morphology, hypotha-lamic-pituitary-ovarian axis, and hormone levels across above-mentioned protocols for postnatal PCOS modeling in rats.

The dynamics of decision-making and action during active sampling

Embodied Cognition Theories (ECTs) of decision-making propose that the decision process pervades the execution of choice actions and manifests itself in these actions. Decision-making scenarios where actions not only express the choice but also help sample information can provide a valuable, ecologically relevant model for this framework. We present a study to address this paradigmatic situation in humans. Subjects categorized (2AFC task) a central object image, blurred to different extents, by moving a cursor toward the left or right of the display. Upward cursor movements reduced the image blur and could be used to sample information. Thus, actions for decision and actions for sampling were orthogonal to each other. We analyzed response trajectories to test whether information-sampling movements co-occurred with the ongoing decision process. Trajectories were bimodally distributed, with one kind being direct towards one response option (non-sampling), and the other kind containing an initial upward component before veering off towards an option (sampling). This implies that there was an initial decision at the early stage of a trial, whether to sample information or not. Importantly, in sampling trials trajectories were not purely upward, but rather had a significant horizontal deviation early on. This result suggests that movements to sample information exhibit an online interaction with the decision process, therefore supporting the prediction of the ECTs under ecologically relevant constrains.

The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model

Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.

Pathology and Immunity After SARS-CoV-2 Infection in Male Ferrets Is Affected by Age and Inoculation Route

Improving COVID-19 intervention strategies partly relies on animal models to study SARS-CoV-2 disease and immunity. In our pursuit to establish a model for severe COVID-19, we inoculated young and adult male ferrets intranasally or intratracheally with SARS-CoV-2. Intranasal inoculation established an infection in all ferrets, with viral dissemination into the brain and gut. Upon intratracheal inoculation only adult ferrets became infected. However, neither inoculation route induced observable COVID-19 symptoms. Despite this, a persistent inflammation in the nasal turbinates was prominent in especially young ferrets and follicular hyperplasia in the bronchi developed 21 days post infection. These effects -if sustained- might resemble long-COVID. Respiratory and systemic cellular responses and antibody responses were induced only in animals with an established infection. We conclude that intranasally-infected ferrets resemble asymptomatic COVID-19 and possibly aspects of long-COVID. Combined with the increasing portfolio to measure adaptive immunity, ferrets are a relevant model for SARS-CoV-2 vaccine research.

Organoids in image-based phenotypic chemical screens

Image-based phenotypic screening relies on the extraction of multivariate information from cells cultured under a large variety of conditions. Technical advances in high-throughput microscopy enable screening in increasingly complex and biologically relevant model systems. To this end, organoids hold great potential for high-content screening because they recapitulate many aspects of parent tissues and can be derived from patient material. However, screening is substantially more difficult in organoids than in classical cell lines from both technical and analytical standpoints. In this review, we present an overview of studies employing organoids for screening applications. We discuss the promises and challenges of small-molecule treatments in organoids and give practical advice on designing, running, and analyzing high-content organoid-based phenotypic screens.

Neuronal Deposition of Amyloid-β Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs

Background: Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer’s disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently. Objective: The aim of the present study was to investigate the presence of p-Tau and amyloid-β oligomer (Aβo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau. Methods: Immunohistochemical and immunofluorescence analysis of the cortical and hippocampal regions of five CCD-affected and two nondemented aged dogs using 4G8 anti-Aβp, anti-Aβ 1 - 42 nanobody (PrioAD13) and AT8 anti-p-Tau (Ser202, Thr205) antibody were used to demonstrate the presence of Aβ plaques (Aβp) and Aβ 1 - 42 oligomers and p-Tau deposits, respectively. Results: The extracellular Aβ senile plaques were of the diffuse type which lack the dense core normally seen in human AD. While p-Tau deposits displayed a widespread pattern and closely resembled the typical human neuropathology, they did not co-localize with the Aβp. Of considerable interest, however, widespread intraneuronal deposition of Aβ 1 - 42 oligomers were exhibited in the frontal cortex and hippocampal region that co-localized with p-Tau. Conclusion: Taken together, these findings reveal further shared neuropathologic features of AD and CCD, supporting the case that aged dogs afflicted with CCD offer a relevant model for investigating human AD.