Mouse Populations Research Articles

Abstract 12437: Network-Based Identification of Tissue-Specific Regulators and Drug Repurposing Candidates for Coronary Artery Disease

Coronary artery disease (CAD) is the leading cause of mortality worldwide. Recent genomic studies in human populations and mouse models have revealed numerous novel genetic loci that may affect pathways and gene networks in CAD relevant tissues. In this study, we aim to use network-based systems biology approaches to identify regulators and drug repurposing candidates based on CAD gene networks. Through integration of multiomics datasets encompassing genetic association studies, transcriptomic profiles, and tissue-specific gene regulation from human and mouse populations, we previously modeled gene networks in vascular and liver tissues that are affected by CAD genetic loci in both species. Based on the shared CAD gene networks between human and mouse, we predicted candidate key regulatory genes and further examined multiple single-cell RNA sequencing datasets of vascular and liver tissues to pinpoint the specific cell types and molecular pathways in each tissue through which the top predicted regulators function. We further used network-based drug repositioning approaches to predict drugs targeting the CAD networks in each tissue, revealing both currently used medications and potential novel therapeutic agents. The cross-species networks, predicted key regulatory genes, their cellular and tissue context, and the network-based drug repositioning analyses offer tissue and cell-type specific targets and potential existing drugs that can be repurposed for CAD treatment.

A mouse zoonotic virus (LCMV): A possible candidate in the causation of SIDS

Lymphocytic choriomeningitis virus (LCMV) is a ubiquitous virus carried by rodents. It causes human disease through contact with infectious mouse faeces, urine or secretions. The virus initially infects the human respiratory tract and lungs and produces typical viral symptoms and signs. The infection is usually self-limiting and recovery is the norm. A small proportion of individuals may develop aseptic meningitis. It is hypothesised that in infancy the virus may cause respiratory tract infection through contact with mouse excreta. The infection could activate production of staphylococcal enterotoxin in babies who are colonised by Staphylococcus aureus. Indeed, a mouse animal model has shown that the combination of LCMV infection and introduction of enterotoxin B produces fatal haematogenous shock. Neither agent alone is lethal.Pathological (and physiological) evidence indicates shock could be the underlying terminal event in SIDS (the observed tissue damage seen in the heart and diaphragmatic muscles, and apoptosis observed in the brain and brainstem of SIDS cases). These features are consistent with a haematogenous shock event. The epidemiology of SIDS is entirely consistent with a mouse-related viral zoonosis. Moreover, rural cases of SIDS tend to feature more often than urban cases and their occurrence would be consistent with the dynamics of mouse populations. Low socioeconomic living conditions (a major risk factor for SIDS) is consistent with prevalence of mouse populations and poor hygienic conditions, with overcrowding. Prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. and poor hygienic conditions, with overcrowding, and prone sleeping would facilitate aspiration or ingestion of infectious material from contaminated surfaces. The epidemiology and pathology of SIDS and the dynamics and ubiquity of mouse populations together with human serological data would support the hypothesis that LCMV is a potential candidate as a key factor in the causation of SIDS.

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model.

Sex differences in gene expression are widespread in the liver, where many autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57BL/6J and CAST/EiJ, representing two subspecies separated by 0.5-1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24, Tox, and Zfp809, lose their sex-biased expression in CAST/EiJ mouse liver. To elucidate the observed strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of the sex differences in expression between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-dependent gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs apparently lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.

Hantavirus outbreaks in the American Southwest: Propagation and retraction of rodent and virus diffusion waves from sky-island refugia

Hantavirus outbreaks in the American Southwest are hypothesized to be driven by episodic seasonal events of high precipitation, promoting rapid increases in virus-reservoir rodent species that then move across the landscape from high quality montane forested habitats (refugia), eventually over-running human residences and increasing disease risk. In this study, the velocities of rodents and virus diffusion wave propagation and retraction were documented and quantified in the sky-islands of northern New Mexico and related to rodent-virus relationships in refugia versus nonrefugia habitats. Deer mouse (Peromyscus maniculatus) refugia populations exhibited higher Sin Nombre Virus (SNV) infection prevalence than nonrefugia populations. The velocity of propagating diffusion waves of Peromyscus from montane to lower grassland habitats was measured at [Formula: see text] m/day (SE), with wave retraction velocities of [Formula: see text] m/day. SNV infection diffusion wave propagation velocity within a deer mouse population averaged [Formula: see text] m/day, with a faster retraction wave velocity of [Formula: see text] m/day. A spatio-temporal analysis of human Hantavirus Pulmonary Syndrome (HPS) cases during the initial 1993 epidemic revealed a positive linear relationship between the time during the epidemic and the distance of human cases from the nearest deer mouse refugium, with a landscape diffusion wave velocity of [Formula: see text] m/day ([Formula: see text]). These consistent diffusion propagation wave velocity results support the traveling wave component of the HPS outbreak theory and can provide information on space–time constraints for future outbreak forecasts.

Effects of physical impairments on fitness correlates of the white-footed mouse, Peromyscus leucopus.

Physical impairments are widely assumed to reduce the viability of individual animals, but their impacts on individuals within natural populations of vertebrates are rarely quantified. By monitoring wild populations of white-footed mice over 26 years, we assessed whether missing or deformed limbs, tail or eyes influenced the survival, body mass, movement and ectoparasite burden of their bearers. Of the 27 244 individuals monitored, 543 (2%) had visible physical impairments. Persistence times (survival) were similar between mice with and without impairments. Mice with eye and tail impairments had 5% and 6% greater mass, respectively, than unimpaired mice. Mice with tail impairments had larger home ranges than did unimpaired mice. Burdens of black-legged ticks (Ixodes scapularis) were higher among mice with tail and limb impairments while burdens of bot fly larvae (Cuterebra) were higher among mice with cataracts compared to mice without impairments. Our findings do not support the presupposition that physical impairments reduce viability in their bearers and are inconsistent with the devaluation of impaired individuals that pervaded early thinking in evolutionary biology.

Rat and Mice Species (Sub Family : Murinae) Diversity from East Lombok Indonesia

Field study on the murine biodiversity in Lombok Island in early 2020 has spent 581 traps-night efforts in five localities of East Lombok. They were Kembang Kuning, Aikmel, Wanasaba, and Kelayu Jorong. Fifty one individuals have been collected used live trap with dry-salty fish baits. Of those 51 individuals were collected, we successed to indentify five species of murines.They were Rattus argentiventer, R. rattus diardii, R. exulans, R. tanezumi, and Mus musculus castaneus, respectively. R. argentiventer and R Tanezumi were highly abundance and wide-spread species in East Lombok. Surprisingly, R. rattus diardii was only two individuals collected out 100 trap.nights efforts. Those two individuals of restricted to Kembang Kuning. Mus musculus castaneus was the only member of genus Mus collected in this study. This study would be drive our knowledge on the diversity of rat and mice in Lombok Island and their ecology. Furthermore, the prelimary results of this study will allow us for better understand on managing rat and mice population and their interaction with human being.

Increased Reliance on Carbohydrates for Aerobic Exercise in Highland Andean Leaf-Eared Mice, but Not in Highland Lima Leaf-Eared Mice

Exercise is an important performance trait in mammals and variation in aerobic capacity and/or substrate allocation during submaximal exercise may be important for survival at high altitude. Comparisons between lowland and highland populations is a fruitful approach to understanding the mechanisms for altitude differences in exercise performance. However, it has only been applied in very few highland species. The leaf-eared mice (LEM, genus Phyllotis) of South America are a promising taxon to uncover the pervasiveness of hypoxia tolerance mechanisms. Here we use lowland and highland populations of Andean and Lima LEM (P. andium and P. limatus), acclimated to common laboratory conditions, to determine exercise-induced maximal oxygen consumption (O2max), and submaximal exercise metabolism. Lowland and highland populations of both species showed no difference in O2max running in either normoxia or hypoxia. When run at 75% of O2max, highland Andean LEM had a greater reliance on carbohydrate oxidation to power exercise. In contrast, highland Lima LEM showed no difference in exercise fuel use compared to their lowland counterparts. The higher carbohydrate oxidation seen in highland Andean LEM was not explained by maximal activities of glycolytic enzymes in the gastrocnemius muscle, which were equivalent to lowlanders. This result is consistent with data on highland deer mouse populations and suggests changes in metabolic regulation may explain altitude differences in exercise performance.

Zoonotic Cryptosporidium spp. in Wild Rodents and Shrews

There has been a significant increase in the number of reported human cryptosporidiosis cases in recent years. The aim of this study is to estimate the prevalence of Cryptosporidium spp. in wild rodents and shrews, and investigate the species and genotype distribution to assess zoonotic risk. Partial 18S rRNA gene nested-PCR reveals that 36.8, 53.9 and 41.9% of mice, voles and shrews are infected with Cryptosporidium species. The highest prevalence occurred in the Microtus agrestis (field vole) and Myodes glareolus (bank vole). Interestingly, bank voles caught in fields were significantly more often Cryptosporidium-positive compared to those caught in forests. The proportion of infected animals increases from over-wintered (spring and summer) to juveniles (autumn) suggesting acquired immunity in older animals. Based on Sanger sequencing and phylogenetic analyses, Apodemus flavicollis (yellow-necked mouse) is commonly infected with zoonotic C. ditrichi. Voles carry multiple different Cryptosporidium sp. and genotypes, some of which are novel. C. andersoni, another zoonotic species, is identified in the Craseomys rufocanus (grey-sided vole). Shrews carry novel shrew genotypes. In conclusion, this study indicates that Cryptosporidium protozoan are present in mouse, vole and shrew populations around Finland and the highest zoonotic risk is associated with C. ditrichi in Apodemus flavicollis and C. andersoni in Craseomys rufocanus. C. parvum, the most common zoonotic species in human infections, was not detected.

Genetic variability affects the skeletal response to immobilization in founder strains of the diversity outbred mouse population

Mechanical unloading decreases bone volume and strength. In humans and mice, bone mineral density is highly heritable, and in mice the response to changes in loading varies with genetic background. Thus, genetic variability may affect the response of bone to unloading. As a first step to identify genes involved in bones' response to unloading, we evaluated the effects of unloading in eight inbred mouse strains: C57BL/6J, PWK/PhJ, WSB/EiJ, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, and CAST/EiJ. C57BL/6J and NOD/ShiLtJ mice had the greatest unloading-induced loss of diaphyseal cortical bone volume and strength. NZO/HlLtJ mice had the greatest metaphyseal trabecular bone loss, and C57BL/6J, WSB/EiJ, NOD/ShiLtJ, and CAST/EiJ mice had the greatest epiphyseal trabecular bone loss. Bone loss in the epiphyses displayed the highest heritability. With immobilization, mineral:matrix was reduced, and carbonate:phosphate and crystallinity were increased. A/J mice displayed the greatest unloading-induced loss of mineral:matrix. Changes in gene expression in response to unloading were greatest in NOD/ShiLtJ and CAST/EiJ mice. The most upregulated genes in response to unloading were associated with increased collagen synthesis and extracellular matrix formation. Our results demonstrate a strong differential response to unloading as a function of strain. Diversity outbred (DO) mice are a high-resolution mapping population derived from these eight inbred founder strains. These results suggest DO mice will be highly suited for examining the genetic basis of the skeletal response to unloading.

Tick infestation effects on haemoglobin levels of deer mice (Peromyscus maniculatus).

Deer mice (Peromyscus maniculatus) are hosts to ixodid ticks as well as the associated tick-borne pathogens they can spread. As the ranges of black-legged ticks (Ixodes scapularis) and American dog ticks (Dermacentor variabilis) expand northwards, naïve host populations of deer mice are likely to become infested by ticks and experience the physiological effects that ticks can have on them via blood-feeding. The prevalence of these haematophagous ticks can affect the haemoglobin levels of the mice they infest. Haemoglobin levels were compared and analysed in deer mice populations at three different sites with varying tick exposure. These results suggested that without confounding effects, the abundance of black-legged and American dog ticks on individual mice had a significant negative effect on the hosts' haemoglobin levels, but only in an area with high tick infestation. This was seen across the average haemoglobin levels between populations, where there was a significant difference between the source population with the longest established tick populations and the source population where neither black-legged nor American dog ticks were prevalent. As the ticks' ranges expand and they become more abundant, it is important to understand how their prevalence and intensity can alter host physiology, potentially affecting their own range expansion and the spread of the diseases they may carry.

New Perspective on the Geographic Distribution and Evolution of Lymphocytic Choriomeningitis Virus, Central Europe.

Lymphocytic choriomeningitis virus (LCMV) is an Old World mammarenavirus found worldwide because of its association with the house mouse. When LCMV spills over to immunocompetent humans, the virus can cause aseptic meningitis; in immunocompromised persons, systemic infection and death can occur. Central Europe is a strategic location for the study of LCMV evolutionary history and host specificity because of the presence of a hybrid zone (genetic barrier) between 2 house mouse subspecies, Mus musculus musculus and M. musculus domesticus. We report LCMV prevalence in natural mouse populations from a Czech Republic–Germany transect and genomic characterization of 2 new LCMV variants from the Czech Republic. We demonstrate that the main division in the LCMV phylogenetic tree corresponds to mouse host subspecies and, when the virus is found in human hosts, the mouse subspecies found at the spillover location. Therefore, LCMV strains infecting humans can be predicted by the genetic structure of house mice.

Genomic variation in captive deer mouse (Peromyscus maniculatus) populations

BackgroundDeer mice (genus Peromyscus) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P. maniculatus that are maintained at the Peromyscus Genetic Stock Center (PGSC) for polymorphisms across their 2.5 × 109 bp genome.ResultsHigh density of variation was identified, corresponding to one SNP every 55 bp for the high altitude stock (SM2) or 207 bp for the low altitude stock (BW) using snpEff (v4.3). Indels were detected every 1157 bp for BW or 311 bp for SM2. The average Watterson estimator for the BW and SM2 populations is 248813.70388 and 869071.7671 respectively. Some differences in the distribution of missense, nonsense and silent mutations were identified between the stocks, as well as polymorphisms in genes associated with inflammation (NFATC2), hypoxia (HIF1a) and cholesterol metabolism (INSIG1) and may possess value in modeling pathology.ConclusionsThis genomic resource, in combination with the availability of P. maniculatus from the PGSC, is expected to promote genetic and genomic studies with this animal model.

Imaging the dynamics of individual processes of microglia in the living retina in vivo.

Microglia are an essential population of resident immune cells in the central nervous system (CNS) and retina. These microscopic cells possess sub-cellular processes that make them challenging to image due to limited resolution and contrast. The baseline behavior of microglial processes in the living retina has been poorly characterized, and yet are essential to understanding how these cells respond under conditions of health, development, stress and disease. Here we use in vivo adaptive optics scanning light ophthalmoscopy combined with time-lapse imaging and quantification of process motility, to reveal the detailed behavior of microglial cells in a population of healthy mice. We find microglial processes to be dynamic at all branch-levels, from primary to end-protrusions. Cell-processes remodel at average speeds of 0.6 ± 0.4 µm/min with growth and deletion bursts of 0-7.6 µm/min. Longitudinal imaging in the same mice showed cell-somas to remain stable over seconds to minutes, but show migration over days to months. In addition to characterizing in vivo process motility and Sholl analysis using a microglial reporter mouse, we also demonstrate that microglia can be imaged without fluorescent labels at all. Phase-contrast imaging using safe levels of near-infrared light successfully imaged microglia soma and process remodeling with micron-level detail noninvasively, confirmed by simultaneous imaging of fluorescent microglial cells in transgenic mice. This label-free approach provides a new opportunity to investigate CNS immune system noninvasively without requiring transgenic or antibody labeling which could have off-target effects of changing normal microglial behavior. Additionally, CNS microglia study can now be conducted without the need for cranial window surgery which have the potential to change their behavior due to local or systemic inflammation.

Regulation of protein abundance in genetically diverse mouse populations

SUMMARYGenetically diverse mouse populations are powerful tools for characterizing the regulation of the proteome and its relationship to whole-organism phenotypes. We used mass spectrometry to profile and quantify the abundance of 6,798 proteins in liver tissue from mice of both sexes across 58 Collaborative Cross (CC) inbred strains. We previously collected liver proteomics data from the related Diversity Outbred (DO) mice and their founder strains. We show concordance across the proteomics datasets despite being generated from separate experiments, allowing comparative analysis. We map protein abundance quantitative trait loci (pQTLs), identifying 1,087 local and 285 distal in the CC mice and 1,706 local and 414 distal in the DO mice. We find that regulatory effects on individual proteins are conserved across the mouse populations, in particular for local genetic variation and sex differences. In comparison, proteins that form complexes are often co-regulated, displaying varying genetic architectures, and overall show lower heritability and map fewer pQTLs. We have made this resource publicly available to enable quantitative analyses of the regulation of the proteome.

Abstract MP252: Genetic Architecture Of Heart Mitochondrial Proteome Influencing Cardiac Hypertrophy

Our lab studies how natural genetic variations affect common diseases using a mouse population called hybrid mouse diversity panel (HMDP). In this study, we have explored the genetic regulation of mitochondrial pathways and their contribution to heart function using an integrative proteomics approach. We first performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and surveyed mitochondrial localization using MitoCarta2.0. We retrieved 840 of these proteins (quantified in ≥50 strains) and performed high-resolution association mapping on their respective abundance levels to the HMDP genotypes. Our analyses identified three genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively. All three are associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. Next, to identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA) and identified five modules. Eigengenes, representing the first principal component of two of these modules (Brown and Green), mapped to the same regions as the chr13 and chr17 loci, respectively. DAVID enrichment analyses revealed that the Brown module (72 proteins, 96% overlap with chr13) was highly enriched for complex-I proteins (35 proteins, P = 8.8E-74) and the Green module (44 proteins, 73% overlap with chr17) for mitochondrial ribosomal proteins (25 proteins, P = 1.3E-53). The proteins in the chr7 locus were found primarily in the Turquoise module (393 proteins, 81% overlap) but this module was not enriched for any single mitochondrial protein complex. In summary, we now report the identification of three genetic loci that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Our results provide strong support for a role of the mitochondrial proteome in heart pathophysiology.

Analysis of different factors contributing the rodent infestations in urban areas in Faisalabad, Pakistan

In the last decade there is a huge increase in the human population that has witnessed the important changes in the ecology, climate and human behaviour which ultimately favours the survival and increase in the population of urban pests. More alarmingly, a dramatic expansion in the rodent’s populations is a growing threat to the humans living in different urban settings. It is supposed that several socio-economic issues, environmental factors and type of housing facilities are contributing towards this higher increase in the rodent’s population in these areas. However, urban rat control programs are still ineffective as very little is known about their ecology. This study sought to investigate the type of housing and environment factors that provide food, water, shelter and harborage to rats and mice and risk factors of rodent infestations in three of the housing systems i.e. in squatter’s settlements, departmental colonies and posh residences including bungalows in Faisalabad. A total of 720 structures (240 each) were selected from these three housing systems. Snap and live trapping of commensal rats and mice (Rattus rattus, Rattus norvegicus,Mus musculus) was carried out fortnightly from November, 2017 to October, 2018 suspecting the rats and mice population as variable as different structured housing systems. The removal data were used to estimate the size of the population of rats and mice per system. For rat and mice population estimation, Change-in-ratio (CIR) and Regression of daily capture on cumulative captures (RR) were employed. The higher number of rats/mice (814 specimens) were collected in squatter’ settlements. Among these 560, 184 and 70 specimens were of Mus musculus, Rattus rattus and Suncus murinus, respectively. The number of rodents captured from departmental colonies and posh residences/bungalows was 210 specimens (129 of M. musculus, 71 of R. rattus and 10 specimens of S. murinus) and 30 specimens of M. musculus, respectively. The major socio-economic factors contributing to these higher rodent infestations were low-grade residences with inadequate or no building maintenance measures and higher housing densities along with heterogenous breeding sites. These higher densities of rats and mice may pose a serious disease threats to human populations as they are carriers of a number of pathogens. The findings of the present study provide the specific features of rats and mice population in concern to human residences and may help to formulate controlling strategies against these culprits.

Efficacy of brodifacoum 50ppm-based rodenticidal baits on the control of the mice Mus musculus in Cotonou

In Benin, cities with a high population rate such as Cotonou are colonized by several species of rats such as Rattus rattus, Mastomys sp, Mus musculus and Crocidura olivieri which are agents of destruction of stored products especially in the area of the big Dantokpa market. Indeed, anticoagulants are the most frequently used rodenticides worldwide in the fight against these rodents. However, very few studies have evaluated the biological efficacy of high dose rodenticides on the resistant strain of the mouse population (Mus musculus) in Cotonou. The present work compared the efficacy of three original brodifacoum-based baits: vertox pellets, vertox block and vertox past on the wild domestic mouse strain (Mus musculus) in Cotonou. The results showed that in the no-choice feeding tests in the laboratory, 100% of the animals died in all experimental groups and zero in the control groups. Time to death did not differ significantly between vertox pellet and vertox block bait in either test/feeding regime. However, with vertox past, a relatively longer time to death was observed. The three baits were therefore tested under field conditions on mouse populations and showed the following efficacy in terms of mouse mortality after three weeks: 83.33% with vertox pellets; 72% with vertox block and 95.33% with vertox past. The results obtained highlighted the good efficacy of the three brodifacoum-based baits in heterogeneous (resistant or not) mouse populations. However, an additional study is needed with the same anticoagulants only on resistant rodent populations.

Renaissance of mouse favus : Retrospective analysis of Trichophyton quinckeanum infections at Jena University Hospital in the period 2015-2020

The number of Trichophytonquinckeanum infections has increased significantly in recent years. In 2020 in particular, the number of cases increased fivefold compared to 2015. Infections multiplied, especially in the second half of the year, which correlated with the upsurge in field mouse populations. Typical vectors are mice and rats as well as dogs and cats, which hunt the rodents. The animals are usually asymptomatic. In humans, on the other hand, the course is usually more inflammatory corresponding to other zoophilic mycoses. Typical clinical manifestations of the infections are tinea corporis and tinea capitis. Treatment of T.quinckeanum infections is similar to other dermatophyte infections, depending on the severity, location and age of the patient as well as the immune status, previous illnesses and medication. The duration of local therapy should be at least 4weeks and continued for up to 14days after the normalization of the skin presentation. Systemic treatment should take place with terbinafine 250 mg once aday orally (in adults). Alternatives are itraconazole, fluconazole and griseofulvin. Only the preparation griseofulvin, which is no longer available in Germany, is approved for children. Alternatively, terbinafine, itraconazole or fluconazole can also be used in children as an "off-label" treatment in an individual healing attempt.

Patterns and mechanisms of sex ratio distortion in the Collaborative Cross mouse mapping population.

In species with single-locus, chromosome-based mechanisms of sex determination, the laws of segregation predict an equal ratio of females to males at birth. Here, we show that departures from this Mendelian expectation are commonplace in the 8-way recombinant inbred Collaborative Cross (CC) mouse population. More than one-third of CC strains exhibit significant sex ratio distortion (SRD) at wean, with twice as many male-biased than female-biased strains. We show that these pervasive sex biases persist across multiple breeding environments, are stable over time, and are not mediated by random maternal effects. SRD exhibits a heritable component, but QTL mapping analyses fail to nominate any large effect loci. These findings, combined with the reported absence of sex ratio biases in the CC founder strains, suggest that SRD manifests from multilocus combinations of alleles only uncovered in recombined CC genomes. We explore several potential complex genetic mechanisms for SRD, including allelic interactions leading to sex-biased lethality, genetic sex reversal, chromosome drive mediated by sex-linked selfish elements, and incompatibilities between specific maternal and paternal genotypes. We show that no one mechanism offers a singular explanation for this population-wide SRD. Instead, our data present preliminary evidence for the action of distinct mechanisms of SRD at play in different strains. Taken together, our work exposes the pervasiveness of SRD in the CC population and nominates the CC as a powerful resource for investigating diverse genetic causes of biased sex chromosome transmission.

Analysis of the dynamic changes in the proportion of immune cells and the proportion of cells with stem cell characteristics in the corresponding immune cell population of C57 mice during the natural aging process.

The aging of the immune system is not only an inevitable result but also an important cause of physical aging. The aging of the immune system is rooted in the aging of hematopoietic cells (HSCs), which manifests as decreasing functionality of the adaptive immune system and the innate immune system. C57BL/6 mice of different ages were collected in this study to better understand the changes in the structures of the innate and adaptive immune systems in individuals of different ages and the distribution and changes in immune cells with stem cell properties. The immune cells of the innate and adaptive immune systems, including DCs, monocytes, macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes, were assessed, and the proportions of cells with stem cell properties among these immune cell populations were also tested. Overall, immune cells in the peripheral blood, spleen, and bone marrow of mice exhibit certain regular properties with increasing age. The trend of changes in immune cells in different immune organs differs with age. The changes in lymphocytes in the peripheral blood are more sensitive. Their proportions increase slowly with age and then decrease rapidly to a very low level (less than 5%) after a certain point (9 or 13months old). Nine to 13months of age is the most critical time point for assessing changes in the immune system of mice and the most critical time point for detecting changes in the proportion of stem cells. After 13months of age, the balance and stability of stem cells in mice are disrupted, and animals begin to age rapidly. The ratio of Ly6A to E+CD117+ cells in the peripheral blood, particularly lymphocytes involved in adaptive immunity, represents a specific marker for predicting immune senescence and body senescence.