When gene regulatory networks diverge between species, their dysfunctional expression in inter-species hybrid individuals can create genetic incompatibilities that generate the developmental defects ...responsible for intrinsic post-zygotic reproductive isolation. Both cis- and trans-acting regulatory divergence can be hastened by directional selection through adaptation, sexual selection, and inter-sexual conflict, in addition to cryptic evolution under stabilizing selection. Dysfunctional sex-biased gene expression, in particular, may provide an important source of sexually-dimorphic genetic incompatibilities. Here, we characterize and compare male and female/hermaphrodite transcriptome profiles for sibling nematode species Caenorhabditis briggsae and C. nigoni, along with allele-specific expression in their F1 hybrids, to deconvolve features of expression divergence and regulatory dysfunction. Despite evidence of widespread stabilizing selection on gene expression, misexpression of sex-biased genes pervades F1 hybrids of both sexes. This finding implicates greater fragility of male genetic networks to produce dysfunctional organismal phenotypes. Spermatogenesis genes are especially prone to high divergence in both expression and coding sequences, consistent with a "faster male" model for Haldane's rule and elevated sterility of hybrid males. Moreover, underdominant expression pervades male-biased genes compared to female-biased and sex-neutral genes and an excess of cis-trans compensatory regulatory divergence for X-linked genes underscores a "large-X effect" for hybrid male expression dysfunction. Extensive regulatory divergence in sex determination pathway genes likely contributes to demasculinization of XX hybrids. The evolution of genetic incompatibilities due to regulatory versus coding sequence divergence, however, are expected to arise in an uncorrelated fashion. This study identifies important differences between the sexes in how regulatory networks diverge to contribute to sex-biases in how genetic incompatibilities manifest during the speciation process.
Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and ...physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.
Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic ...stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection.
We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS.
Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort.
Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of –0.32 (95% confidence interval CI –0.35 to –0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050–0.32); we called these patterns histologic signatures.
Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64–0.83; accuracy P < .001).
In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.
Display omitted
We report molecular evidence of Tula virus infection in an immunocompetent patient from Germany who had typical signs of hantavirus disease. Accumulating evidence indicates that Tula virus infection, ...although often considered nonpathogenic, represents a threat to human health.
Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and ...transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release—a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.
Display omitted
•Agxt is hypermethylated and downregulated in mouse and human steatotic hepatocytes•Detoxification of mitochondrial glyoxylate is insufficient in the fatty liver•Challenge with dietary hydroxyproline leads to higher oxalate in the fatty liver•Rescuing Agxt expression in the fatty liver reduces hepatic oxalate production
Gianmoena et al. identify an altered glyoxylate pathway in both mouse and human NAFLD. Functional analysis reveals reduced capacity of the fatty liver to detoxify glyoxylate derived from hydroxyproline breakdown, causing overproduction of the harmful waste product oxalate. This study provides a potential mechanism underlying kidney complications in NAFLD patients.
Outside Asia, Seoul virus (SEOV) is an underestimated pathogen. In Germany, autochthonous SEOV-associated hantavirus disease has not been unequivocally diagnosed. We found clinical and molecular ...evidence for SEOV infection in a young woman; her pet rat was the source of infection.
The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease. ...Various hypertensive stimuli cause T-cell activation and infiltration into target organs such as the vessel and the kidney, which promotes vascular dysfunction and blood pressure elevation. Classically, T-cell activation requires T-cell receptor ligation and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen-presenting cells with the T-cell coreceptor CD28. This study was therefore performed to examine the role of this pathway in hypertension.
Angiotensin II-induced hypertension increased the presence of activated (CD86(+)) dendritic cells in secondary lymphatic tissues. Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Activation of circulating T cells, T-cell cytokine production, and vascular T-cell accumulation caused by these hypertensive stimuli were abrogated by CTLA4-Ig. Furthermore, in mice lacking B7 ligands, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplantation with wild-type bone marrow.
T-cell costimulation via B7 ligands is essential for development of experimental hypertension, and inhibition of this process could have therapeutic benefit in the treatment of this disease.
Building on an exercise that identified potential harms from simulated investigational releases of a population suppression gene drive for malaria vector control, a series of online workshops ...identified nine recommendations to advance future environmental risk assessment of gene drive applications.
PDF
