CARS microscopy of lipid stores in yeast: the impact of nutritional state and genetic background

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.

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

10.1101/2021.02.03.429523 ◽

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.

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

10.1101/530766 ◽

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.

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

Physiological Genomics ◽

10.1152/physiolgenomics.00188.2005 ◽

2006 ◽

Vol 25 (1) ◽

pp. 75-84 ◽

Cited By ~ 20

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.

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

Epigenetics & Chromatin ◽

10.1186/s13072-019-0314-5 ◽

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.

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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

Crop and Pasture Science ◽

10.1071/cp13399 ◽

2014 ◽

Vol 65 (3) ◽

pp. 268 ◽

Cited By ~ 9

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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Genetic background influences the impact of KLOTHO deficiency

Physiological Genomics ◽

10.1152/physiolgenomics.00094.2020 ◽

2020 ◽

Vol 52 (10) ◽

pp. 512-516

Author(s):

Jawad S. Salloum ◽

Diane E. Garsetti ◽

Melissa B. Rogers

Keyword(s):

Genetic Background ◽

Genetic Architecture ◽

Disease Susceptibility ◽

Inbred Mouse ◽

Mouse Strains ◽

Disease Models ◽

Inbred Mouse Strains ◽

Metabolic Interactions ◽

Klotho Protein ◽

The Impact

Genetic background is a key but sometimes overlooked factor that profoundly impacts disease susceptibility and presentation in both humans and disease models. Here we show that deficiency of KLOTHO protein, an important renal regulator of mineral homeostasis and a cofactor for FGF23, causes different phenotypes in 129S1/SvlmJ (129) and C57BL/6J (B6) mouse strains. The 129 strain is more severely affected, with decreased longevity, decreased body weight, and increased amounts of kidney calcification compared with B6 mice. Reciprocal F1 crosses of the strains also indicate a parentage effect on the Klotho phenotype with F1 KLOTHO-deficient progeny of B6 mothers and 129 fathers having more kidney calcification than progeny of 129 mothers and B6 fathers. Comparing and contrasting the genetic architecture leading to different phenotypes associated with specific inbred mouse strains may reveal previously unrecognized and important metabolic interactions affecting chronic kidney disease.

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Transgenic Mouse Modeling of Therapeutic Responses in Myeloma

Blood ◽

10.1182/blood.v112.11.2747.2747 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2747-2747

Author(s):

Brian G. Van Ness ◽

Christine Ramos ◽

Mary Gosse

Keyword(s):

Transgenic Mouse ◽

Plasma Cell ◽

Genetic Background ◽

Tumor Heterogeneity ◽

Chromosomal Abnormalities ◽

Expression Profiles ◽

Major Influence ◽

Therapeutic Approaches ◽

Mouse Population ◽

The Impact

Abstract While myeloma is still considered a fatal disease, new therapeutic approaches, including combination of drugs that target different intracellular pathways, have shown marked improvements in response and survival. Yet there are wide variations in responses seen in the patient population. One major source is the variation in chromosomal abnormalities and the genes deregulated among the plasma cell (PC) tumors. Another may be in inherited variations (SNPs) that can have a major influence on drug distribution, transport and metabolism. Our laboratory has developed a transgenic mouse model targeting overexpression of c-myc and bcl-xL in late B cells, that results in early expansion of non-malignant PCs, followed by development of clonal plasma cell malignancies in 100% of the mice. We have reported on cell surface, chromosomal abnormalities, and gene expression profiles of the mouse plasma cell tumors, that demonstrate a very similar profile and heterogeneity to human myelomas. The mouse PC tumors can be adoptively transferred to syngenic recipient mice, as well as grown in culture. The advantage of this model is that the impact of tumor heterogeneity can be assessed in a common germline genetic background in the mice; and an intact immune system is maintained, unlike many common xenograft models. We find that disease progression is variable among tumors and have extended this observed heterogeneity of progression to analysis of drug sensitivity; for example, identifying tumors that are highly sensitive to dexamethasone, and others extremely resistant, and others that show protection in the presence of IL-6. Although bcl-xL expression is important in the initiation of the transgenic malignancy, it was not clear if Bcl-xL was required to maintain the transformed phenotype. To test this, we blocked Bcl-xL with the inhibitor BH3I-2′(Calbiochem). We find that inhibition of Bcl-xL is effective in killing the PC tumors in vitro, and dose is directly related to levels of bcl-xL expression. We also examined various dose combinations of dexamethasone and BH3I-2′ and found an antagonistic relationship of the two drugs. We are in the process of expanding the tumor mouse population to target other therapeutic approaches in the transgenic mouse that models tumor heterogeneity in a common genetic background.

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