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Mice respond to a cage change (CC) with altered activity, disrupted sleep and increased anxiety. A bi-weekly cage change is, therefore, preferred over a shorter CC interval and is currently the prevailing routine for Individually ventilated cages (IVCs). However, the build-up of ammonia (NH3) during this period is a potential threat to the animal health and the literature holds conflicting reports leaving this issue unresolved. We have therefor examined longitudinally in-cage activity, animal health and the build-up of ammonia across the cage floor with female and male C57BL/6 mice housed four per IVC changed every other week. We used a multicentre design with a standardised husbandry enabling us to tease-out features that replicated across sites from those that were site-specific. CC induce a marked increase in activity, especially during daytime (~50%) when the animals rest. A reduction in density from four to two mice did not alter this response. This burst was followed by a gradual decrease till the next cage change. Female but not male mice preferred to have the latrine in the front of the cage. Male mice allocate more of the activity to the latrine free part of the cage floor already the day after a CC. A behaviour that progressed through the CC cycle but was not impacted by the type of bedding used. Reducing housing density to two mice abolished this behaviour. Female mice used the entire cage floor the first week while during the second week activity in the latrine area decreased. Measurement of NH3 ppm across the cage floor revealed x3 higher values for the latrine area compared with the opposite area. NH3 ppm increases from 0–1 ppm to reach ≤25 ppm in the latrine free area and 50–100 ppm in the latrine area at the end of a cycle. As expected in-cage bacterial load covaried with in-cage NH3 ppm. Histopathological analysis revealed no changes to the upper airways covarying with recorded NH3 ppm or bacterial load. We conclude that housing of four (or equivalent biomass) C57BL/6J mice for 10 weeks under the described conditions does not cause any overt discomfort to the animals. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorders (AUD) associate with structural and functional brain differences, including impairments in neuropsychological function; however, reviews (mostly cross-sectional) are inconsistent with regards to recovery of such functions following abstinence. Recovery is important, as these impairments associate with treatment outcomes and quality of life., Objective(s): To assess neuropsychological function recovery following abstinence in individuals with a clinical AUD diagnosis. The secondary objective was to assess predictors of neuropsychological recovery in AUD., Methods: Following the preregistered protocol (PROSPERO: CRD42022308686), APA PsycInfo, EBSCO MEDLINE, CINAHL, and Web of Science Core Collection were searched between 1999-2022. Study reporting follows the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis, study quality was assessed using the JBI Checklist for Cohort Studies. Eligible studies were those with a longitudinal design that assessed neuropsychological recovery following abstinence from alcohol in adults with a clinical diagnosis of AUD. Studies were excluded if participant group was defined by another or co-morbid condition/injury, or by relapse. Recovery was defined as function reaching 'normal' performance., Results: Sixteen studies (AUD n = 783, controls n = 390) were selected for narrative synthesis. Most functions demonstrated recovery within 6-12 months, including sub-domains within attention, executive function, perception, and memory, though basic processing speed and working memory updating/tracking recovered earlier. Additionally, verbal fluency was not impaired at baseline (while verbal function was not assessed compared to normal levels), and concept formation and reasoning recovery was inconsistent., Conclusions: These results provide evidence that recovery of most functions is possible. While overall robustness of results was good, methodological limitations included lack of control groups, additional methods to self-report to confirm abstinence, description/control for attrition, statistical control of confounds, and of long enough study durations to capture change., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Powell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Deficiency in thymidine kinase 2 (TK2) causes mitochondrial DNA depletion. Liver mitochondria are severely affected in Tk2 complete knockout models and have been suggested to play a role in the pathogenesis of the Tk2 knockout phenotype, characterized by loss of hypodermal fat tissue, growth retardation and reduced life span. Here we report a liver specific Tk2 knockout (KO) model to further study mechanisms contributing to the phenotypic changes associated with Tk2 deficiency. Interestingly, the liver specific Tk2 KO mice had a normal life span despite a much lower mtDNA level in liver tissue. Mitochondrial DNA encoded peptide COXI did not differ between the Tk2 KO and control mice. However, the relative liver weight was significantly increased in the male Tk2 KO mouse model. Histology analysis indicated an increased lipid accumulation. We conclude that other enzyme activities can partly compensate Tk2 deficiency to maintain mtDNA at a low but stable level throughout the life span of the liver specific Tk2 KO mice. The lower level of mtDNA was sufficient for survival but led to an abnormal lipid accumulation in liver tissue., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Alcohol use disorders (AUD) associate with structural and functional brain differences, including impairments in neuropsychological functions; however, review level research (largely cross-sectional) is inconsistent with regards to recovery of such functions following abstinence. Such recovery is important, as these impairments associate with treatment outcomes and quality of life., Objective(s): To assess neuropsychological function recovery following abstinence in individuals with a clinical AUD diagnosis. The secondary objective is to assess predictors of neuropsychological recovery in AUD., Methods: Four electronic databases (APA PsycInfo, EBSCO MEDLINE, CINAHL, Web of Science Core Collection) will be searched between 1999-2022, with search strategies adapted for each source. Study reporting will follow the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis, study quality will be assessed using the JBI Checklist for Cohort Studies. Eligible studies are those with a longitudinal design that assessed neuropsychological recovery following abstinence from alcohol in adults with a clinical diagnosis of AUD. Studies will be excluded if participant group is defined by another or co-morbid condition/injury, or by relapse., Results: This is an ongoing review. As of July 2022, the review protocol is registered on PROSPERO (CRD42022308686), searches have been conducted, and screening is in progress. Results are predicted to be complete by October 2022., Conclusions: Comparing data on neuropsychological recovery from AUD will improve understanding of the impact of alcohol on the brain, and the relationship between AUD recovery and quality of life/treatment outcomes. It may provide information that could one day inform aspects of treatment and aftercare (e.g., options for cognitive training of functions that do not improve on their own)., Competing Interests: The authors have declared that no competing interests exist.

Thymidine kinase 2 (TK2) deficiency in humans leads to a myopathic form of mitochondrial DNA (mtDNA) deficiency. Here we present a skeletal and cardiac muscle specific TK2 knockout mouse (mTk2 KO). The mice showed dilated hearts and markedly reduced adipose tissue during week 12 to 16. A severe decrease of mtDNA was found only in skeletal muscle and heart tissue in mTk2 KO mice. Expression analysis of key metabolic genes of 16 weeks knockout mice showed significant changes of genes involved in lipid metabolism, with different patterns in heart and skeletal muscle. Our study further suggests that lipoprotein lipase (LPL) from liver supports the metabolism when heart and skeletal muscle were impaired due to mitochondrial dysfunction. The angiotensin-converting enzyme 2 (ACE2), which is involved in glucose homeostasis, was also affected by mtDNA deficiency in our study. Interestingly, both the gene and protein expression of ACE2 were increased in cardiac tissue of mTk2 KO mice. Since ACE2 is a receptor for the SARS-CoV-2 virus, its regulation in relation to mitochondrial function may have important clinical implications., Competing Interests: The authors have declared that no competing interests exist.

In a large scale screen for skin, hair, and nail abnormalities in null mice generated by The Jackson Laboratory's KOMP center, homozygous mutant Far2tm2b(KOMP)Wtsi/2J (hereafter referrred to as Far2-/-) mice were found to develop focal areas of alopecia as they aged. As sebocytes matured in wildtype C57BL/NJ mice they became pale with fine, uniformly sized clear lipid containing vacuoles that were released when sebocytes disintegrated in the duct. By contrast, the Far2-/- null mice had sebocytes that were similar within the gland but become brightly eosinophilic when the cells entered the sebaceous gland duct. As sebocytes disintegrated, their contents did not readily dissipate. Scattered throughout the dermis, and often at the dermal hypodermal fat junction, were dystrophic hair follicles or ruptured follicles with a foreign body granulomatous reaction surrounding free hair shafts (trichogranuloma). The Meibomian and clitoral glands (modified sebaceous glands) of Far2-/- mice showed ducts dilated to various degrees that were associated with mild changes in the sebocytes as seen in the truncal skin. Skin surface lipidomic analysis revealed a lower level of wax esters, cholesterol esters, ceramides, and diacylglycerols compared to wildtype control mice. Similar changes were described in a number of other mouse mutations that affected the sebaceous glands resulting in primary cicatricial alopecia., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JPS, KAS, and VEK have or had research contracts with Biocon, Takeda, Theravance, and Curadim and JPS is a consultant for Bioniz all of which have no relevance to this project. This does not alter our adherence to PLOS ONE policies on sharing data and materials. TS, NEG, LAD, LSB, OF, RK, SAM, RHR, and CHP state no conflicts of interest.

Tumorigenesis is often associated with loss of tumor suppressor genes (such as TP53), genomic instability and telomere lengthening. Previously, we generated and characterized a rat p53 knockout model in which the homozygous rats predominantly develop hemangiosarcomas whereas the heterozygous rats mainly develop osteosarcomas. Using genome-wide analyses, we find that the tumors that arise in the heterozygous and homozygous Tp53C273X mutant animals are also different in their genomic instability profiles. While p53 was fully inactivated in both heterozygous and homozygous knockout rats, tumors from homozygous animals show very limited aneuploidy and low degrees of somatic copy number variation as compared to the tumors from heterozygous animals. In addition, complex structural rearrangements such as chromothripsis and breakage-fusion-bridge cycles were never found in tumors from homozygous animals, while these were readily detectable in tumors from heterozygous animals. Finally, we measured telomere length and telomere lengthening pathway activity and found that tumors of homozygous animals have longer telomeres but do not show clear telomerase or alternative lengthening of telomeres (ALT) activity differences as compared to the tumors from heterozygous animals. Taken together, our results demonstrate that host p53 status in this rat p53 knockout model has a large effect on both tumor type and genomic instability characteristics, where full loss of functional p53 is not the main driver of large-scale structural variations. Our results also suggest that chromothripsis primarily occurs under p53 heterozygous rather than p53 null conditions.

Programmed cell death ligand-1 (PD-L1/CD274) is an immunomodulatory molecule involved in cancer and complications of bone marrow transplantation, such as graft rejection and graft-versus-host disease. The present study was designed to assess the dynamic expression of this molecule after hematopoietic stem cell transplantation in relation to acute graft-versus-host disease. Female BALB/c mice were conditioned with busulfan and cyclophosphamide and transplanted with either syngeneic or allogeneic (male C57BL/6 mice) bone marrow and splenic cells. The expression of PD-L1 was evaluated at different time points employing qPCR, western blot and immunohistochemistry. Allogeneic- but not syngeneic-transplanted animals exhibited a marked up-regulation of PD-L1 expression in the muscle and kidney, but not the liver, at days 5 and 7 post transplantation. In mice transplanted with allogeneic bone marrow cells, the enhanced expression of PD-L1 was associated with high serum levels of IFNγ and TNFα at corresponding intervals. Our findings demonstrate that PD-L1 is differently induced and expressed after allogeneic transplantation than it is after syngeneic transplantation, and that it is in favor of target rather than non-target organs at the early stages of acute graft-versus-host disease. This is the first study to correlate the dynamics of PD-L1 at the gene-, protein- and activity levels with the early development of acute graft-versus-host disease. Our results suggest that the higher expression of PD-L1 in the muscle and kidney (non-target tissues) plays a protective role in skeletal muscle during acute graft-versus-host disease.