Mouse Body Research Articles

Combining Vascular Targeting Agents with Radiation: An Effective Anti-Tumor Treatment but Associated with Radiation-Induced Systemic Toxicity

This study investigated the effect of combining radiation with an angiogenesis inhibitor and vascular disrupting agent on tumor response and systemic toxicity. CDF1 mice with 200 mm3 foot implanted C3H mammary carcinomas were treated with TNP-470 (100 mg/kg every second day for 2 weeks; s.c.) and combretastatin A-4 phosphate (CA4P; 1 × 250 mg/kg, i.p.). Radiation (230-kV X-rays) was locally administered to tumors of restrained non-anesthetized mice. Response was tumor growth delay and change in mouse body weight. Radiation induced changes in serum levels of 10 cytokines up to 72-h after irradiation were measured using a Luminex assay. The results showed that TNP-470 (100 mg/kg × 7) or CA4P (250 mg/kg × 1) significantly (Student’s t-test; p < 0.05) inhibited tumor growth; the greatest effect when these two drugs were combined. TNP-470 and CA4P, alone or together, also significantly enhanced tumor response to radiation. No systemic toxicity occurred with drugs administered alone or in combination, but toxicity was observed when TNP-470 was combined with radiation. Serum cytokine levels only showed a significant transient increase in IL-6 1-h after irradiating. In conclusion, combining different acting vascular targeting agents with radiation increased anti-tumor activity. However, this benefit may sometimes be associated with a radiation-induced inflammatory response increasing systemic toxicity.

Tap Water Shorts the Lifespan of Mice with Prolonged Exposure to Fractionated γ-Radiation

Assessing the role of social factors in the formation of radioresistance in chronic exposure and finding ways to increase it are important for understanding the mechanisms of the damaging effects of radiation and developing practical methods for reducing radiation risk in professionals exposed to ionizing radiation and patients undergoing radiation therapy. In this work, we investigated the ability to influence the lifespan of animals exposed to γ-radiation fractionally for a long time by replacing drinking water from tap water to distilled water. Female ICR mice (CD-1) were exposed to total 60Co γ radiation weekly in fractions for 33 weeks starting at 9 weeks of age. The dose of a single irradiation was 50 mGy, the average dose rate was 2 mGy/sec. The total radiation dose was 1.65 Gy. Control non-irradiated mice and irradiated animals were divided into 2 groups. The first received tap water, and the second received distilled water throughout the experiment. Non-irradiated animals kept on tap water showed a statistically insignificant (log-rank test, p = 0.483) reduction in average life expectancy compared to mice kept on distilled water. In animals after exposure to 60Co γ-radiation, a statistically significant (p = 0.0013) decrease in life expectancy was noted when kept on tap water and statistically insignificant (p = 0.1511) when kept on distilled water. Tap water and irradiation showed a clear synergy with a combined effect on the body of mice, expressed in a more than threefold decrease in the period of post-radiation shortening of life expectancy. Distilled water reduced the rate of death of irradiated animals and modified the rate of death of non-irradiated animals. Our data demonstrate that the reduction in life expectancy of mice kept on tap water caused by long-term fractionated irradiation can be reduced when animals are kept on distilled water.

Multiplane Spectroscopic Whole‐Body Photoacoustic Computed Tomography of Small Animals In Vivo

AbstractTo understand complex biological process and disease progression, it is essential to comprehensively track biodynamics across entire organisms. The invaluable tracking tool, photoacoustic computed tomography (PACT), provides insights into structural, functional, and molecular aspects of living tissues. However, current small‐animal PACT systems suffer from low temporal/spatial resolution and a restricted field of view, and they are limited in the biological information they can provide, hindering research on whole‐body biodynamics. Here, it is demonstrated a continuous rotary‐scanning PACT system for rapid monitoring of various parameters within the relatively large torso of a small animal. In this PACT system, a hemispherical transducer array is continuously rotated at high speed, enabling a 3D scan of an entire mouse body in just 54 s, with a spatial resolution of 172–212 µm. The rapid rotary scanning allows us to not only image whole‐body structures but also to monitor pharmacokinetics and changes in hemoglobin oxygen saturation in living animals. This approach holds great promise for advancing the understanding of in vivo biological dynamics, opening up a new avenue of preclinical research in areas such as metabolic diseases and drug delivery.

Dietary lipid is largely deposited in skin and rapidly affects insulating properties.

Skin has been shown to be a regulatory hub for energy expenditure and metabolism: mutations of skin lipid metabolism enzymes can change the rate of thermogenesis and susceptibility to diet-induced obesity. However, little is known about the physiological basis for this function. Here we show that the thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We found that skin was the largest target in a mouse body for dietary fat delivery, and that dietary triglyceride was assimilated both by epidermis and by dermal white adipose tissue. Skin from mice calorie-restricted for 3 weeks did not take up circulating lipids and showed a highly depleted stratum corneum. Dietary triglyceride acyl groups persist in skin for weeks after feeding. Using multi-modal lipid profiling, we have implicated both keratinocytes and sebocytes in the altered lipids which correlate with thermal function. In response to high fat feeding, wax diesters and ceramides accumulate, and triglycerides become more saturated. In contrast, in response to the dramatic loss of adipose tissue that accompanies restriction of the branched chain amino acid isoleucine, skin becomes more heat-permeable, resisting changes induced by Western diet feeding, with a signature of depleted signaling lipids. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

Long-term arsenic exposure decreases mice body weight and liver lipid droplets

Arsenic (As) is a widespread global pollutant, and there is significant controversy surrounding its complex relationship with obesity, primarily focused on short-term exposure. Recognizing the prolonged nature of dietary arsenic exposure, this study involved feeding mice with arsenic-contained food for 14 months. The results showed that mice exposed to arsenic developed a non-alcoholic fatty liver condition, characterized by a light-yellow hue on the liver surface and various pathological alterations in the liver cells, including enlarged nuclei, cellular necrosis, inflammatory infiltration, dysfunctional mitochondria, and endoplasmic reticulum disorganization. There were also disruptions in biochemistry indices, with a significant increase in total cholesterol (TC) level and a decrease in high-density lipoprotein (HDL) level. However, some contradictory observations occurred, such as a significant decrease in body weight, triglyceride (TG) level, and the numbers of lipid droplets. Several genes related to lipid metabolism were tested, and a model was used to explain these discrepancies. Besides, examinations of the colon revealed compromised intestinal barrier function and signs of inflammation. Fecal 16S rRNA sequencing and pseudo-targeted metabolomics revealed disruptions in internal homeostasis, such as modules, nodes, connections, and lipid-related KEGG pathways. Fecal targeted metabolomics analyses of short-chain fatty acids (SCFAs) and bile acids (BAs) demonstrated a significant upregulation in three primary bile acids (CA, CDCA, TCDCA), four secondary bile acids (TUDCA, DCA, LCA, GUDCA), and total SCFAs level. Oxidative stress and inflammation were also evident. Additionally, based on correlation analysis and mediation analysis, it was assumed that changes in the microbiota (e.g., Dubosiella) can impact the liver metabolites (e.g., TGs) through alterations in fecal metabolites (e.g., LPCs). These findings provide a theoretical reference for the long-term effect of arsenic exposure on liver lipid metabolism.

Impact of Microplastic Exposure on Blood Glucose Levels and Gut Microbiota: Differential Effects under Normal or High-Fat Diet Conditions.

Microplastics are emerging pollutants that have garnered significant attention, with evidence suggesting their association with the pathogenesis of type 2 diabetes mellitus. In order to assess the impact of polystyrene microplastic exposure on alterations in the gut microbiota and the subsequent implications for glucose dysregulation under different dietary conditions in mice, we investigated the effects and disparities in the blood glucose levels induced by polystyrene microplastic exposure in mice fed a high-fat diet versus those fed a normal diet. Using 16S rRNA sequencing and bioinformatics analyses, we explored the dynamic changes and discrepancies in the gut microbiota stability induced by polystyrene microplastic exposure under varied dietary conditions, and we screened for gut genera associated with the potential of polystyrene microplastics to disrupt glucose homeostasis. Our findings indicate that a high-fat diet resulted in abnormal mouse body weight, energy intake, blood glucose levels and related metabolic parameters. Additionally, polystyrene microplastic exposure exacerbated the glucose metabolism disorders induced by a high-fat diet. Furthermore, the composition and diversity of the mouse gut microbiota were significantly altered following microplastic exposure, with 11 gut genera exhibiting a differential presence between mice fed a high-fat diet combined with microplastic exposure compared to those fed a normal diet with microplastic exposure. Moreover, Ucg-009 played an intermediary role in the association between a high-fat diet and the fasting blood glucose. Hence, our study demonstrates that polystyrene microplastic exposure exacerbates high-fat diet-induced glucose metabolism disorders, whereas its impact on the blood glucose under normal dietary conditions is not significant, highlighting the differential influence attributable to distinct alterations in characteristic gut genera.

Beta-caryophyllene attenuates experimental hepatocellular carcinoma through downregulation of oxidative stress and inflammation.

Hepatocellular carcinoma (HCC) is caused by various factors including toxic substances and xenobiotics. Numerous treatment strategies are used to address toxicity to the liver and HCC, yet their adverse effects are drawbacks. This study aimed to assess the effect of DEN/CCl4 on morphological changes in the liver, body weight, tumor incidence, and hematological tumor incidence, hematological parameters, hepatic markers, and histopathological analysis in mice following a preventive measure by using β-caryophyllene (BCP). Adult Balb/c mice were administered a single dose of DEN 1-mg/kg body weight and 0.2-mL CCl4/kg body weight intraperitoneal twice a week (i.p.) for 22 weeks. BCP was treated in one group of mice at 30-mg/kg body weight, intraperitoneal, for 7 weeks. BCP alone was treated in one group of mice at 300-mg/kg body weight intraperitoneal for 22 weeks. DEN/CCl4 caused a reduction in mice's body weight, which was significantly attenuated by BCP administration. BCP supplementation attenuated the tumor incidence DEN/CCl4 (100%) to about 25%. DEN/CCl4 caused alterations in the hematological parameters, serum total protein albumin globulin, A/G ratio, liver function markers (AST, ALT, ALP, GGT, ACP, and bilirubin), and lipid profile markers that were significantly reinstated by BCP administration. Oxidative stress markers (MDA, SOD, CAT, NO, LDH, and GST) were reduced by DEN/CCl4, which were significantly increased in BCP-treated groups. The liver histopathology alterations caused by DEN/CCl4 were amended considerably by BCP treatment. Immunohistochemical studies suggest that AFP, caspase-3, and COX-2 were chronically overexpressed in DEN/CCl4-exposed mice, notably attenuated by BCP administration. BCP suppressed tumor incidence by downregulating inflammation and inducing caspase-3-mediated apoptosis. Conclusively, BCP appears to be a potent natural supplement capable of repressing liver inflammation and carcinoma through the mitigation of oxidative stress and inflammation pathways.

Repurposing Niclosamide to Modulate Renal RNA-Binding Protein HuR for the Treatment of Diabetic Nephropathy in db/db Mice.

Hu antigen R (HuR) plays a key role in regulating genes critical to the pathogenesis of diabetic nephropathy (DN). This study investigates the therapeutic potential of niclosamide (NCS) as an HuR inhibitor in DN. Uninephrectomized mice were assigned to four groups: normal control; untreated db/db mice terminated at 14 and 22 weeks, respectively; and db/db mice treated with NCS (20 mg/kg daily via i.p.) from weeks 18 to 22. Increased HuR expression was observed in diabetic kidneys from db/db mice, which was mitigated by NCS treatment. Untreated db/db mice exhibited obesity, progressive hyperglycemia, albuminuria, kidney hypertrophy and glomerular mesangial matrix expansion, increased renal production of fibronectin and a-smooth muscle actin, and decreased glomerular WT-1+-podocytes and nephrin expression. NCS treatment did not affect mouse body weight, but reduced blood glucose and HbA1c levels and halted the DN progression observed in untreated db/db mice. Renal production of inflammatory and oxidative stress markers (NF-κBp65, TNF-a, MCP-1) and urine MDA levels increased during disease progression in db/db mice but were halted by NCS treatment. Additionally, the Wnt1-signaling-pathway downstream factor, Wisp1, was identified as a key downstream mediator of HuR-dependent action and found to be markedly increased in db/db mouse kidneys, which was normalized by NCS treatment. These findings suggest that inhibition of HuR with NCS is therapeutic for DN by improving hyperglycemia, renal inflammation, and oxidative stress. The reduction in renal Wisp1 expression also contributes to its renoprotective effects. This study supports the potential of repurposing HuR inhibitors as a novel therapy for DN.

Integrated Ultrasound Characterization of the Diet-Induced Obesity (DIO) Model in Young Adult c57bl/6j Mice: Assessment of Cardiovascular, Renal and Hepatic Changes.

Consuming an unbalanced diet and being overweight represent a global health problem in young people and adults of both sexes, and may lead to metabolic syndrome. The diet-induced obesity (DIO) model in the C57BL/6J mouse substrain that mimics the gradual weight gain in humans consuming a "Western-type" (WD) diet is of great interest. This study aims to characterize this animal model, using high-frequency ultrasound imaging (HFUS) as a complementary tool to longitudinally monitor changes in the liver, heart and kidney. Long-term WD feeding increased mice body weight (BW), liver/BW ratio and body condition score (BCS), transaminases, glucose and insulin, and caused dyslipidemia and insulin resistance. Echocardiography revealed subtle cardiac remodeling in WD-fed mice, highlighting a significant age-diet interaction for some left ventricular morphofunctional parameters. Qualitative and parametric HFUS analyses of the liver in WD-fed mice showed a progressive increase in echogenicity and echotexture heterogeneity, and equal or higher brightness of the renal cortex. Furthermore, renal circulation was impaired in WD-fed female mice. The ultrasound and histopathological findings were concordant. Overall, HFUS can improve the translational value of preclinical DIO models through an integrated approach with conventional methods, enabling a comprehensive identification of early stages of diseases in vivo and non-invasively, according to the 3Rs.

Luteolin as potential treatment for Huntington's disease: Insights from a transgenic mouse model.

The study aimed to evaluate the potential benefits of luteolin treatment in Huntington's disease (HD), an inherited progressive neurodegenerative disorder. HD N171-82Q transgenic and WT mice received luteolin or vehicle for treatment at 6 weeks of age. The mice's body weight changes and survival rates were monitored throughout the study, and a series of motor functional tests were conducted. Serum level of the marker NfL was also determined. Immunohistochemical staining and western blotting were utilized to assess the expression of huntingtin aggregates. Luteolin treatment enhanced survival and prevented weight loss in HD mice compared to the vehicle-treated HD group. Furthermore, the luteolin-treated HD mice exhibited enhanced motor coordination and balance and significantly reduced motor dysfunction. Also, luteolin decreased serum NfL levels in HD mice. Notably, the accumulation of huntingtin aggregates was significantly reduced in the brain's cortex, hippocampus, and striatum of luteolin-treated HD mice compared to the vehicle-treated HD group. Luteolin holds promise as a therapeutic agent for improving survival outcomes, managing motor dysfunction, and reducing huntingtin aggregates in HD. The findings are of significance as currently, there are no approved therapeutic interventions that reverse HD pathology or slow down its progression.

Влияние содержания действующего вещества в родентицидном средстве на эффективность дератизационных обработок

House mice, gray rats and other mouse-like rodents pose a threat to human health and cause significant damage to its activities. Despite significant advances in deratization practice, rodent control currently remains a significant problem, since these biological species have a unique genetic ability to rapidly recover and increase their numbers. The rodent control program should be based on data on the ecology, behavior and preferences of rodents, their sensitivity to active substances, the specific situation of a certain object and territory. Each species has its own characteristics. It is necessary to take into account species preferences when developing the composition and form of application of rodenticidal baits. It is important to ensure the achievement of target values in the consumption of the product by rodents, its effectiveness, safety in relation to non-target species and safety during its placement and use. It is necessary to take into account what concentration of the active substance (DV) for rodents will be fatal, how much rodenticidal bait will be required for their death and for how long this amount of bait will be eaten by them. The effectiveness of the conducted deratization treatments is directly influenced by the content of the active substance in the applied rodenticidal agent. The analysis of the effectiveness of rodenticidal baits with different contents of the active substance bromadiolone in relation to house mice and gray rats showed that with a decrease in the concentration of DV in the bait, the period from the beginning of its eating to the onset of irreversible changes in the body of rodents leading to their death occurs. The placement of baits during deratization treatments should take place taking into account the species characteristics of rodents. In terms of body weight, the amount of absorbed DV by the body of a house mouse in comparison with a gray rat when eating rodenticidal bait is significantly higher, which is observed in the average daily and total intake. But in quantitative terms, gray rats consume significantly more bait. For the death of a house mouse, an average of about 8 g of bait is required with a bromadiolone content of 0.005?%, and the minimum amount was 3.2 g. For a gray rat, the average amount of bait was 32.4 g, and the minimum ~ 10 g. Taking into account these data, the amount of bait placed at the facility will vary from the number of rodents and the feedability of baits. A lower content of DV in baits contributes to an increase in their consumption during deratization treatments. With a high number of rodents, the amount of bait placed must be multiplied. Keywords: synanthropic rodents, gray rat, house mouse, deratization measures, anticoagulants, bromadiolone.

In-vivo Toxicity Evaluation of 3-(2-(3,4 dimethoxyphenyl)-2 oxoethylidene) Indolin-2-one (RAJI) in Zebrafish and Mice Model.

Breast cancer is a global health concern, with millions of cases reported annually worldwide, making it the most common cancer among women. In India, the incidence of breast cancer has been steadily rising, reflecting a growing public health challenge and hence in the development of new drug moieties. Toxicity analysis of such novel drug candidates play a critical role in drug development, ensuring the safety and efficacy of potential therapeutics. Animal models, especially mice and zebrafish in the recent days, have been extensively used for toxicity evaluation owing to their physiological and genetic similarities to humans. This study was hence conducted with an aim to assess the toxicity using animal models, particularly mice and zebrafish. In this study, 3-(2-(3,4-dimethoxyphenyl)-2-oxoethylidene)indolin-2-one (RAJI) - a chemically synthesised novel drug, was assessed for its toxicological potential in both zebrafish and mice models highlighting its survival, hatching, locomotor, neuromotor, behavioural abnormalities in zebrafish model and haematological and biochemical abnormalities in mice model. The results obtained emphasise that no significant damages were seen in both zebrafish (survival, hatching, locomotor, neuromotor, behavioural abnormalities) and mice (body weight, haematological and biochemical abnormalities) models when administered in low doses. All results obtained signifies that RAJI poses no harmful effects in the model organisms until administered in higher concentrations, thereby emphasising the fact that RAJI is a safe drug.

The Shadow Bodies of Mice: Invisible Work in Translational Medicine

The clinician-scientist is often viewed as the crucial nexus in the translational processes that turn scientific research into medical technologies, including but not limited to pharmaceuticals. To create a point of contrast, and to consider the theme of invisible labor, this paper foregrounds an alternative actant who has also been deemed a vital nexus in translational medicine within Science and Technology Studies: the laboratory animal as model organism. Based on observational research conducted in an animal facility that was caring for laboratory mice as well as the immunological laboratory that was conducting research regarding ageing and vaccine uptake using those mice, this paper explores how mouse bodies and animal technicians’ knowledge of those mouse bodies are rendered invisible through the everyday flows of translation. I draw on Balka and Star's concept of “shadow bodies” to consider variations in how mouse bodies are understood across the translational process and probe the consequences this has for what knowledge is legitimately produced and by whom. By making the invisible work of mice and of technicians visible, I argue that the organizational filters of translational medicine may inadvertently make the work of animal technicians all the harder, in a manner that reproduces social inequalities.

Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model

PurposeOver 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function.MethodsWe created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent.ResultsContrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways.ConclusionOur murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.

LX1 Targets Androgen Receptor Variants and AKR1C3 to overcome Therapy Resistance in Advanced Prostate Cancer.

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.

Expression of MAF bZIP transcription factor B protects against ulcerative colitis through the inhibition of the NF-κB pathway.

The aim of this study was to explore whether MAF bZIP transcription factor B (MAFB) might alleviate ulcerative colitis (UC) in dextran sulfate sodium (DSS)-induced mice and LPS-induced IEC-6 cells. UC in vivo and in vitro model was established by using DSS and LPS, respectively. The mice body weight and disease activity index (DAI) score were recorded daily, and colon length was measured. Moreover, the permeability was evaluated utilizing a fluorescein isothiocyanate dextran (FITC-Dextran) probe. Histopathological changes of DSS-induced colitis mice was assessed utilizing H&E staining. Next, qRT-PCR was performed to detect IL-1β, IL-6, TNF-α, and IL-10 level in in vivo and in vitro. Furthermore, the level of MDA, SOD, CAT, and GSH were evaluated in colon tissues. Besides, the expressions of tight junction proteins and NF-κB pathway relative proteins were examined in colitis mice and IEC-6 cells using western blot, immunohistochemistry and immunofluorescence. MAFB level was downregulated in DSS-induced colitis mice. Moreover, the upregulation of MAFB protected mice from DSS-induced colitis by suppressing DSS-induced inflammation, oxidative stress, and intestinal barrier impairment. We also demonstrated that the upregulation of MAFB inactivated NF-κB pathway in DSS-caused colitis mice. Subsequently, we observed that MAFB upregulation could inhibit LPS-caused epithelial barrier impairment and inflammation in IEC-6 cells. Additionally, MAFB overexpression could suppress the activation of NF-κB pathway in IEC-6 cells. The upregulation of MAFB could protect against UC via the suppression of inflammation and the intestinal barrier impairment through inhibiting the NF-κB pathway.

Sensory feedback and central neuronal interactions in mouse locomotion.

Locomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyse a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behaviour to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.

Investigating the Effect of Enterally Administered Capromorelin on Body Weight in Mice (Mus musculus).

Significant weight loss in mice (Mus musculus) is a welfare concern and can alter physiology and behavior in ways that may confound research aims. In this study, factorial design was used to investigate the effect of enterally administered capromorelin on changes in mouse body weight overall and with various research-related interventions, such as administration of analgesics, anesthesia, or surgery. BALB/c mice (n = 61 [27 males/34 females] for analysis) were randomized into 8 intervention-treatment groups with 2 treatment allocations: capromorelin (10 mg/kg) or control, and 4 intervention allocations: no intervention; buprenorphine extended-release (XR) alone; buprenorphine XR, meloxicam, and anesthesia; or surgery under anesthesia with buprenorphine XR, meloxicam, and bupivacaine administered. Mice were habituated to handling, weighing, and voluntary consumption of condensed milk, which was used as the control solution and later a vehicle for capromorelin delivery, for 5 d (days 0 to 4). Then, mice received their interventions followed by 3 days of daily treatment or control administration (days 7 to 9). Body weights were measured daily (days 8 to 11 and day 14) to compare with baseline weights (days 0 to 4 and day 7) and evaluate for treatment and intervention effects on body weight. The interventions resulted in a decrease in group body weights 3 and 4 d after the interventions were conducted. Overall, body weights increased more in mice given capromorelin compared with control, and mice treated with capromorelin returned to, or exceeded, baseline weights faster. The weight loss was mitigated by capromorelin administration in all interventions except for the buprenorphine XR-only group. It is recommended to clinically consider enterally administered capromorelin to mitigate research-induced weight loss in mice.

A bright Ce-based downshifting luminescence nanoprobe for NIR-IIb vessel imaging

Nanomaterials with unique emission in the second near-infrared window (NIR-II, 1000–1700 nm) are regarded as the promising probes for visualization of tumor vessels and cerebrovascular architecture, because of their superior features such as deep tissue penetration and large imaging resolution. Herein, the new Ce-based fluoride nanoparticles (NPs) with high-efficiency NIR-IIb emission were explored for high-resolution vascular imaging and tumor associated vessel detection. Under the same synthesis conditions, the Ce-based fluoride present the preferential formation CeF3 host and low upconversion (UC) emission, but possess more strong (1.45 times) NIR-IIb downconversion (DC) emission centered at 1525 nm under the irradiation of a 980 nm laser, which is significantly different from the traditional NaYF4:Yb/Er host. Through the efficient cross relaxation between Ce3+ and Er3+, intense NIR-IIb luminescence from Er3+ with high quantum yields were achieved, which make sure the entire mouse body and brain blood vessel imaging with supernal resolution (47.6 μm) were demonstrated. Moreover, the optical imaging in NIR-IIb region guided tumorous vascular visualization was successfully achieved. Therefore, the explored CeF3 NPs with boosting NIR-IIb emission can be employed as new diagnostic bio-probes used in high spatial resolution tumorous vessel detection.

High-intensity interval training stimulates remyelination via the Wnt/β-catenin pathway in cuprizone-induced demyelination mouse model

ABSTRACT Objectives This study aims to investigate the role of high-intensity interval training (HIIT) in promoting myelin sheath recovery during the remyelination phase in cuprizone (CPZ)-induced demyelination mice and elucidate the mechanisms involving the Wnt/β-catenin pathway. Methods After 5 weeks of a 0.2% CPZ diet to induce demyelination, a 4-week recovery phase with a normal diet was followed by HIIT intervention. Mice body weight was monitored. Morris water maze (MWM) gauged spatial cognition and memory, while the open field test (OFT) assessed anxiety levels. Luxol fast blue (LFB) staining measured demyelination, and immunofluorescence examined myelin basic protein (MBP) and platelet-derived growth factor receptor-alpha (PDGFR-α). Western blotting analyzed protein expression, including MBP, PDGFR-α, glycogen synthase kinase-3β (GSK3β), β-catenin, and p-β-catenin. Real-time PCR detected mRNA expression levels of CGT and CST. Results HIIT promoted remyelination in demyelinating mice, enhancing spatial cognition, memory, and reducing anxiety. LFB staining indicated decreased demyelination in HIIT-treated mice. Immunofluorescence demonstrated increased MBP fluorescence intensity and PDGFR-α+ cell numbers with HIIT. Western blotting revealed HIIT reduced β-catenin levels while increasing p-β-catenin and GSK3β levels. Real-time PCR demonstrated that HIIT promoted the generation of new myelin sheaths. Additionally, the Wnt/β-catenin pathway agonist, SKL2001, decreased MBP expression but increased PDGFR-α expression. Discussion HIIT promotes remyelination by inhibiting the Wnt/β-catenin pathway and is a promising rehabilitation training for demyelinating diseases. It provides a new theoretical basis for clinical rehabilitation and care programs.