scholarly journals Premature ovarian insufficiency in the XO female mouse on the C57BL/6J genetic background

2020 ◽  
Vol 26 (9) ◽  
pp. 678-688
Author(s):  
B Vaz ◽  
F El Mansouri ◽  
X Liu ◽  
T Taketo
Keyword(s):  
Female Mouse ◽  
Genetic Background ◽  
Congenital Abnormalities ◽  
Ovarian Insufficiency ◽  
Female Progeny ◽  
X Chromosomes ◽  
Monosomy X ◽  
Physical Defects ◽  
Female Germline ◽  
The Impact

Abstract In humans, all but 1% of monosomy 45.X embryos die in utero and those who reach term suffer from congenital abnormalities and infertility termed Turner’s syndrome (TS). By contrast, XO female mice on various genetic backgrounds show much milder physical defects and normal fertility, diminishing their value as an animal model for studying the infertility of TS patients. In this article, we report that XO mice on the C57BL/6J (B6) genetic background showed early oocyte loss, infertility or subfertility and high embryonic lethality, suggesting that the effect of monosomy X in the female germline may be shared between mice and humans. First, we generated XO mice on either a mixed N2(C3H.B6) or B6 genetic background and compared the number of oocytes in neonatal ovaries; N2.XO females retained 45% of the number of oocytes in N2.XX females, whereas B6.XO females retained only 15% of that in B6.XX females. Second, while N2.XO females were as fertile as N2.XX females, both the frequency of delivery and the total number of pups delivered by B6.XO females were significantly lower than those by B6.XX females. Third, after mating with B6 males, both N2.XO and B6.XO females rarely produced XO pups carrying paternal X chromosomes, although a larger percentage of embryos was found to be XO before implantation. Furthermore, B6.XO females delivered 20% XO pups among female progeny after mating with C3H males. We conclude that the impact of monosomy X on female mouse fertility depends on the genetic background.

A form of Autoimmune Diabetes in Adults Named LADA – An Update on Essential Features and Controversies

2019 ◽  
Vol 15 (3) ◽  
pp. 172-173 ◽  
Author(s):  
Valdemar Grill ◽  
Bjørn O. Åsvold
Keyword(s):  
Genetic Background ◽  
Clinical Utility ◽  
Autoimmune Diabetes ◽  
Classical Type ◽  
Phenotypic Characteristics ◽  
Latent Autoimmune Diabetes ◽  
The Impact

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than “classical” type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive to LADA, this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.

scholarly journals Impact of premature ovarian insufficiency on cardiovascular health

2018 ◽  
Vol 7 (9) ◽  
pp. 3837
Author(s):  
Kavitha Abraham ◽  
Vaibhav Londhe ◽  
Tunny Sebastian ◽  
Thomas Paul ◽  
Aruna Kekre
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cardiovascular Health ◽  
Menopausal Symptoms ◽  
Premature Ovarian Insufficiency ◽  
P Value ◽  
Ovarian Insufficiency ◽  
Hs Crp ◽  
Artery Disease ◽  
The Impact

Background: The objectives of the study were to identify the causes of premature ovarian insufficiency (POI) and to assess the severity of menopausal symptoms as well as the impact on cardiovascular health in these patients.Methods: Authors did a cross sectional case control study with 100 cases and 100 age matched controls. Women <40years of age with amenorrhoea >4months and FSH >25mIU/ml were identified with POI. Women <40years with normal cycles were the controls. Causes were identified from medical records and menopausal symptoms were categorized using menopause rating score questionnaire. Hypercholesterolemia (≥200mg/dl), hypoalbuminemia (<3.5g/dl) and high sensitive C reactive protein (HS-CRP ≥3mg/dl) were assessed as the early markers of coronary artery disease. Statistical methods included Chi square test and logistic regression analysis. P value <0.05 was considered significant.Results: 64% of the patients were between 31-40 years. 66% of them were into menopause for <5 years. The cause was idiopathic in 62%. 91% had no or minimal menopausal symptoms. Hypoalbuminemia (6 versus 1, 95% CI 1.8-2.4, OR 2.1, p=0.01) and hypercholesterolemia (75 versus 51, 95%CI 2.5-3.1, OR 2.8, p= 0.001) were significantly high in cases. HS-CRP was not found to be different between the groups (59 versus 49, OR 1.5, 95%CI 0.8-2.6, p=0.2).Conclusions: In majority with POI the cause is idiopathic and menopausal symptoms are minimal. Hypoalbuminemia and hypercholesterolemia, markers of coronary artery disease, were significantly elevated in POI. Early screening for these variables within 5 years of menopause would reduce the cardiovascular mortality in these patients.

scholarly journals The impact of genetic background and sex on the phenotype of IL-23 induced murine arthritis

2021 ◽  
Author(s):  
Emma Haley ◽  
Mederbek Matmusaev ◽  
Imtiyaz N. Hossain ◽  
Sean Davin ◽  
Tammy M. Martin ◽  
...  
Keyword(s):  
Weight Loss ◽  
Genetic Background ◽  
Skin Inflammation ◽  
Control Mechanisms ◽  
Adult Mice ◽  
Severe Arthritis ◽  
Cytokine Levels ◽  
Clinical Arthritis ◽  
Organ Specific ◽  
The Impact

AbstractBackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsSystemic IL-23 overexpression results in spondyloarthritis-like disease in B10.RIII mice. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests organ-specific genetic control mechanisms of IL-23 driven inflammation. Discrepancies regarding the phenotype of IL-23 induced disease in different labs and the sexual dimorphism observed in this study warrant further exploration.

scholarly journals Age and genetic background modify hybrid male sterility in house mice

2020 ◽  
Author(s):  
Samuel J. Widmayer ◽  
Mary Ann Handel ◽  
David L. Aylor
Keyword(s):  
Male Sterility ◽  
House Mouse ◽  
Genetic Background ◽  
Genetic Architecture ◽  
Hybrid Male ◽  
Hybrid Male Sterility ◽  
X Chromosomes ◽  
Age Related ◽  
Age Dependent ◽  
In The Wild

AbstractHybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse (Mus musculus) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of the M. m. musculus subspecies to males from a classical inbred strain representative of M. m. domesticus: 129S1/SvImJ, A/J, C57BL/6J, or DBA/2J. We detected three distinct trajectories of fertility among the hybrids using breeding experiments. The PWK129S1 males were always infertile. PWKDBA2 males were fertile, despite their genotypes at the major HMS loci. We also observed age-dependent changes in fertility parameters across multiple genetic backgrounds. The PWKB6 and PWKAJ males were always infertile before 15 weeks and after 35 weeks, yet some PWKB6 and PWKAJ males were fertile between fifteen and 35 weeks. This observation could resolve previous contradictory reports about the fertility of PWKB6. Taken together, these results point to multiple segregating HMS modifier alleles, some of which have age-related modes of action. The ultimate identification of these alleles and their age-related mechanisms will advance understanding both of the genetic architecture of HMS and of how reproductive barriers are maintained between house mouse subspecies.

scholarly journals Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia

2019 ◽  
Author(s):  
Tatiana V. Tkatchenko ◽  
Rupal L. Shah ◽  
Takayuki Nagasaki ◽  
Andrei V. Tkatchenko ◽  
◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Refractive Error ◽  
Genetic Background ◽  
Eye Development ◽  
Continuous Distribution ◽  
Genetic Networks ◽  
Visual Environment ◽  
Eye Growth ◽  
Refractive Development ◽  
The Impact

AbstractPopulation studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from −21.2 diopters (D) in 129S1/svlmj mice to +22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from −5.6 D in NZO/HILtJ mice to −20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with refractive error development in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different species. These results provide attractive targets for the development of anti-myopia drugs.Author SummarySeveral lines of evidence suggest that variations in genetic background have a strong impact on a default (baseline) trajectory of eye growth and refractive development. Many studies also highlighted differences in susceptibility of different individuals to environmentally induced changes in refractive eye development, suggesting that genetic background plays an important role in visual regulation of eye growth. However, genes and signaling pathways that control the baseline trajectory of refractive eye development and those that regulate the impact of visual environment on refractive eye development are still poorly understood. Our data suggest that both processes are regulated by elaborate retinal genetic networks. Surprisingly, we found that although genes that control baseline refractive eye development and genes regulating the impact of visual environment on refractive development overlap, there is a large number of genes and pathways which exclusively control either the baseline trajectory of refractive eye development or the impact of visual environment on refractive development. Moreover, we found that many of the genes and pathways, which we found to be associated with either baseline refractive development or susceptibility to environmentally induced myopia in mice, are also associated with refractive error development in the human population and are highly conserved across different species. Identification of genes and pathways that underlie visual regulation of eye growth versus genes and pathways that control default trajectory of refractive eye development sheds light on the basic mechanisms of eye emmetropization and provides previously unexplored possibilities for the development of new treatment options for myopia.

P–514 RAN-Translation in Fragile X associated Premature Ovarian Insufficiency (FXPOI): FMRpolyG as a predictive tool

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
X P Nguyen ◽  
B Messmer ◽  
J E Dietrich ◽  
K Hinderhofer ◽  
T Strowitzki ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Fragile X ◽  
Human Lymphocytes ◽  
Predictive Tool ◽  
Ovarian Insufficiency ◽  
Glass Coverslip ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
The Impact ◽  
Ran Translation

Abstract Study question Does repeat-associated non-AUG (RAN) translation lead to accumulation of polyglycine- containing protein (FMRpolyG) in human lymphocytes and mural granulosa cells of FMR1 premutation carriers? Summary answer Lymphocytes and granulosa cells from FMR1 premutation carriers contain intracellular inclusions that stain positive for both FMRpolyG and ubiquitin. What is known already: Fragile-X-associated-Primary-Ovarian-Insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism associated with the expansion of CGG-repeats in the 5’UTR of FMR1, called premutation (PM) (n: 55–200). Approximately 20% of women carrying a FMR1-premutation (PM) allele develop FXPOI. RAN-translation dependent on variable CGG-repeat length is hypothesized to cause FXPOI due to the production of a polyglycine-containing FMR1-protein, FMRpolyG. Recently, FMRpolyG inclusions were found in neuronal brain cells of FXTAS patients and stromal cells of the ovary of an FXPOI patient. Study design, size, duration: Lymphocytes and granulosa cells (GCs) from women with PM (6) and women without PM (10) (controls) were analyzed by immunofluorescence (IF) staining for the presence of inclusions positive for ubiquitin and FMRpolyG. Cell lysis and protein extraction samples were subjected to Fluorescent Western Blot (WB) analysis to detect FMRP and FMRpolyG Participants/materials, setting, methods Human GCs were obtained from follicular fluid after oocyte retrieval and lymphocytes were isolated from peripheral blood using Ficoll-Paque. Cells suspended in PBS were adhered to a glass-coverslip placed at the bottom of the 6-well culture plate, via gravity sedimentation. Adhered cells were fixed, IF staining for FMRpolyG and ubiquitin was performed and analyzed by fluorescence microscopy. Fluorescent WB was used to demonstrate the expression of FMRP, FMRpolyG in extracted protein from lymphocytes and GCs. Main results and the role of chance FMRP was successfully detected by fluorescence WB in both lymphocytes and GCs. FMRP is mainly present in cytoplasm and was expressed in greater amount in GCs than in leukocytes. Moreover, FMRP expression was significantly decreased in GCs from FMR1-PM compared with controls. Lymphocytes from PM-carriers and controls were immunostained for FMRpolyG and ubiquitin. In PM-carriers, FMRpolyG was present as aggregates, whereas in controls only a weak signal without inclusions was detectable. The expression pattern of FMRpolyG in GCs was similar to that in lymphocytes with a significant increase in PM-carriers. There, the FMRpolyG-aggregates additionally demonstrated as ubiquitin-positive inclusions. These may resemble the toxic potential of these protein fractions involved the ovarian damage in developing FXPOI. Limitations, reasons for caution More patients are needed to support the present findings. Further investigation into the possible consequences of these FMRpolyG-positive inclusions in PM-carriers is also advisable. Wider implications of the findings: We found for the first time FMRpolyG-accumulation in lymphocytes and GCs from FMR1-PM-carriers in ubiquitin-positive inclusions. Future experiments evaluating consistency in more patients and elucidating the impact on fertility and prospective value for individual ovarian reserve are therefore in preparation. Trial registration number Not applicable

Role of strain differences on host resistance and the transcriptional response of macrophages to infection withYersinia enterocolitica

2006 ◽  
Vol 25 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Katrin van Erp ◽  
Kristina Dach ◽  
Isabel Koch ◽  
Jürgen Heesemann ◽  
Reinhard Hoffmann
Keyword(s):  
Transcription Factors ◽  
Host Resistance ◽  
Genetic Background ◽  
Antibacterial Properties ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Yersinia Infection ◽  
Ifn Γ ◽  
The Impact

The outcome of a host-pathogen encounter is determined by virulence factors of the pathogen and defense factors of the host. We characterized the impact of host factors [resistant (C57BL/6) or susceptible (BALB/c) genetic background and exposure to interferon (IFN)-γ] on transcriptional responses of bone marrow-derived macrophages (BMDM) to infection with Yersinia enterocolitica. IFN-γ treatment more profoundly altered the transcriptome of BMDM than did bacterial infection or genetic background. In BALB/c BMDM, 1,161 genes were differentially expressed in response to Yersinia infection with or without IFN-γ prestimulation. Fourteen genes (1.2%) could only be induced by BALB/c BMDM in response to Yersinia infection after IFN-γ pretreatment. These genes inhibit apoptosis, activate NF-κB and Erk signaling, are chemotactic to neutrophils, and are involved in cytoskeletal reorganization, hence possibly in phagocytosis. Ten of these genes possess a common module of binding sites for Hox, Pou, and Creb transcription factors in 2 kb of upstream genomic sequence, suggesting a possible novel role of these transcription factors in regulation of immune responses. Fifty-two of one thousand fifty differentially expressed genes (4.9%) were induced more strongly by C57BL/6 BMDM in response to Yersinia infection than BALB/c BMDM. These genes activate NK cells, have antibacterial properties, or are involved in sensing chemokines and lipopolysaccharide (LPS). These data show that host resistance factors modulate a surprisingly small, but identifiable and functionally significant, portion of the macrophage transcriptome in response to Yersinia infection.

scholarly journals The impact of genetic background and cell lineage on the level and pattern of gene expression in position effect variegation

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sidney H. Wang ◽  
Sarah C. R. Elgin
Keyword(s):  
Genetic Variants ◽  
Genetic Background ◽  
Position Effect ◽  
Cell Lineage ◽  
Inbred Lines ◽  
Position Effect Variegation ◽  
Fourth Chromosome ◽  
Heterochromatin Formation ◽  
Effect Variegation ◽  
The Impact

Abstract Background Chromatin-based transcriptional silencing is often described as a stochastic process, largely because of the mosaic expression observed in position effect variegation (PEV), where a euchromatic reporter gene is silenced in some cells as a consequence of juxtaposition with heterochromatin. High levels of variation in PEV phenotypes are commonly observed in reporter stocks. To ascertain whether background mutations are the major contributors to this variation, we asked how much of the variation is determined by genetic variants segregating in the population, examining both the level and pattern of expression using the fruit fly, Drosophila melanogaster, as the model. Results Using selective breeding of a fourth chromosome PEV reporter line, 39C-12, we isolated two inbred lines exhibiting contrasting degrees of variegation (A1: low expression, D1: high expression). Within each inbred population, remarkable similarity is observed in the degree of variegation: 90% of the variation between the two inbred lines in the degree of silencing can be explained by genotype. Further analyses suggest that this result reflects the combined effect of multiple independent trans-acting loci. While the initial observations are based on a PEV phenotype scored in the fly eye (hsp70-white reporter), similar degrees of silencing were observed using a beta-gal reporter scored across the whole fly. Further, the pattern of variegation becomes almost identical within each inbred line; significant pigment enrichment in the same quadrant of the eye was found for both A1 and D1 lines despite different degrees of expression. Conclusions The results indicate that background genetic variants play the major role in determining the variable degrees of PEV commonly observed in laboratory stocks. Interestingly, not only does the degree of variegation become consistent in inbred lines, the patterns of variegation also appear similar. Combining these observations with the spreading model for local heterochromatin formation, we propose an augmented stochastic model to describe PEV in which the genetic background drives the overall level of silencing, working with the cell lineage-specific regulatory environment to determine the on/off probability at the reporter locus in each cell. This model acknowledges cell type-specific events in the context of broader genetic impacts on heterochromatin formation.

Influence of globulin subunit composition of soybean proteins on silken tofu quality. 2. Absence of 11SA4 improves the effect of protein content on tofu hardness

2014 ◽  
Vol 65 (3) ◽  
pp. 268 ◽  
Author(s):  
Andrew T. James ◽  
Aijun Yang
Keyword(s):  
Protein Content ◽  
Genetic Background ◽  
Seed Protein ◽  
Subunit Composition ◽  
Seed Protein Content ◽  
Soybean Variety ◽  
Soybean Proteins ◽  
Tofu Quality ◽  
The Impact

Soybean variety Bunya was developed in Australia to provide a better quality bean for tofu manufacturers. It is null for globulin subunit 11SA4. We investigated the effect of both the Bunya genetic background and the11SA4 subunit on tofu properties using genotypes containing 11SA4, with and without Bunya parentage, or lacking 11SA4 with Bunya parentage. Both Bunya parentage and 11SA4 significantly influenced globulin subunit composition and tofu texture. The group lacking 11SA4 had lower seed protein content, the largest seeds and the highest 7S and the lowest 11S content and produced the hardest tofu. Examination of the impact of 11SA4 null on tofu texture at four protein contents (380–440 g kg–1) over four coagulant (2.0–3.5 g kg–1) levels revealed that the absence of 11SA4 produced firmer tofu across the protein and coagulation levels tested, and this difference was larger than that from higher protein or coagulation levels. These results demonstrated that the absence of the 11SA4 subunit could increase tofu hardness to a level that otherwise could only be achieved with much higher seed protein content.

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