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1. Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning

   https://doi.org/10.1007/s12192-020-01132-x  

   Zhang, Y. ; Chatzistamou, I. ; Kiaris, H. ( June 2020 , Cell Stress and Chaperones)

   The unfolded protein response (UPR) is an adaptive response that is implicated in multiple metabolic pathologies, including hepatic steatosis. In the present study we analyzed publicly available RNAseq data to explore how the execution of the UPR is orchestrated in specimens that exhibit hepatocyte ballooning, a landmark feature of steatosis. By focusing on a panel of well-established UPR genes we assessed how the UPR is coordinated with the whole transcriptome in specimens with or without hepatocyte ballooning. Our analyses showed that neither average levels nor correlation in expression between major UPR genes such as HSPA5 (BiP/GRP78), HSP90b1 (GRP94) or DDIT3more »(CHOP), is altered in different groups. However, a panel of transcripts that depending on the stringency of the analysis ranged from 16 to 372, lost its coordination with HSPA5, the major UPR chaperone, when hepatocyte ballooning occurred. In 13 genes the majority of which is associated with metabolic processes, the coordination with the HSPA5 was reversed from positive to negative in livers with ballooning hepatocytes. In order to examine if during ballooning, UPR genes abolish established and acquire novel functionalities we performed gene ontology analyses. These studies showed that among the various UPR genes interrogated, DDIT3 was the only that during ballooning was not associated with conventional functions linked to endoplasmic reticulum stress while HSPA90b1 exhibited the highest function retention between the specimens with or without ballooning. Our results challenge conventional notions on the impact of specific genes in disease and suggest that besides abundance, the mode of coordination of UPR may be more important for disease development.« less
2. Integrative-omics for discovery of network-level disease biomarkers: a case study in Alzheimer’s disease

   https://doi.org/10.1093/bib/bbab121  

   Xie, Linhui ; He, Bing ; Varathan, Pradeep ; Nho, Kwangsik ; Risacher, Shannon L ; Saykin, Andrew J ; Salama, Paul ; Yan, Jingwen ( November 2021 , Briefings in Bioinformatics)

   Abstract A large number of genetic variations have been identified to be associated with Alzheimer’s disease (AD) and related quantitative traits. However, majority of existing studies focused on single types of omics data, lacking the power of generating a community including multi-omic markers and their functional connections. Because of this, the immense value of multi-omics data on AD has attracted much attention. Leveraging genomic, transcriptomic and proteomic data, and their backbone network through functional relations, we proposed a modularity-constrained logistic regression model to mine the association between disease status and a group of functionally connected multi-omic features, i.e. single-nucleotide polymorphismsmore »(SNPs), genes and proteins. This new model was applied to the real data collected from the frontal cortex tissue in the Religious Orders Study and Memory and Aging Project cohort. Compared with other state-of-art methods, it provided overall the best prediction performance during cross-validation. This new method helped identify a group of densely connected SNPs, genes and proteins predictive of AD status. These SNPs are mostly expression quantitative trait loci in the frontal region. Brain-wide gene expression profile of these genes and proteins were highly correlated with the brain activation map of ‘vision’, a brain function partly controlled by frontal cortex. These genes and proteins were also found to be associated with the amyloid deposition, cortical volume and average thickness of frontal regions. Taken together, these results suggested a potential pathway underlying the development of AD from SNPs to gene expression, protein expression and ultimately brain functional and structural changes.« less
3. Diet alters age-related remodeling of aortic collagen in mice susceptible to atherosclerosis

   https://doi.org/10.1152/ajpheart.00420.2020  

   Watson, Shana R. ; Cooper, Kara M. ; Liu, Piaomu ; Gharraee, Nazli ; Du, Liya ; Han, Savannah M. ; Peña, Edsel A. ; Sutton, Michael A. ; Eberth, John F. ; Lessner, Susan M. ( January 2021 , American Journal of Physiology-Heart and Circulatory Physiology)

   Vascular cells restructure extracellular matrix in response to aging or changes in mechanical loading. Here, we characterized collagen architecture during age-related aortic remodeling in atherosclerosis-prone mice. We hypothesized that changes in collagen fiber orientation reflect an altered balance between passive and active forces acting on the arterial wall. We examined two factors that can alter this balance, endothelial dysfunction and reduced smooth muscle cell (SMC) contractility. Collagen fiber organization was visualized by second-harmonic generation microscopy in aortic adventitia of apolipoprotein E (apoE) knockout (KO) mice at 6 wk and 6 mo of age on a chow diet and at 7.5 mo of agemore »on a Western diet (WD), using image analysis to yield mean fiber orientation. Adventitial collagen fibers became significantly more longitudinally oriented with aging in apoE knockout mice on chow diet. Conversely, fibers became more circumferentially oriented with aging in mice on WD. Total collagen content increased significantly with age in mice fed WD. We compared expression of endothelial nitric oxide synthase and acetylcholine-mediated nitric oxide release but found no evidence of endothelial dysfunction in older mice. Time-averaged volumetric blood flow in all groups showed no significant changes. Wire myography of aortic rings revealed decreases in active stress generation with age that were significantly exacerbated in WD mice. We conclude that the aorta displays a distinct remodeling response to atherogenic stimuli, indicated by altered collagen organization. Collagen reorganization can occur in the absence of altered hemodynamics and may represent an adaptive response to reduced active stress generation by vascular SMCs. NEW & NOTEWORTHY The following major observations were made in this study: 1) aortic adventitial collagen fibers become more longitudinally oriented with aging in apolipoprotein E knockout mice fed a chow diet; 2) conversely, adventitial collagen fibers become more circumferentially oriented with aging in apoE knockout mice fed a high-fat diet; 3) adventitial collagen content increases significantly with age in mice on a high-fat diet; 4) these alterations in collagen organization occur largely in the absence of hemodynamic changes; and 5) circumferential reorientation of collagen is associated with decreased active force generation (contractility) in aged mice on a high-fat diet.« less
4. Metabolic alterations caused by the mutation and overexpression of the Tmem135 gene

   https://doi.org/10.1177/1535370220932856  

   Lee, Wei-Hua ; Bhute, Vijesh J ; Higuchi, Hitoshi ; Ikeda, Sakae ; Palecek, Sean P ; Ikeda, Akihiro ( November 2020 , Experimental Biology and Medicine)

   Mitochondria are dynamic organelles that undergo fission and fusion. While they are essential for cellular metabolism, the effect of dysregulated mitochondrial dynamics on cellular metabolism is not fully understood. We previously found that transmembrane protein 135 ( Tmem135) plays a role in the regulation of mitochondrial dynamics in mice. Mice homozygous for a Tmem135 mutation ( Tmem135 FUN025/FUN025 ) display accelerated aging and age-related disease pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene ( Tmem135 TG). In several tissues and cells that we studied such asmore »the retina, heart, and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while overexpression of Tmem135 results in fragmented mitochondria. To investigate how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells, we identified metabolic changes in primary RPE cell cultures as well as heart, cerebellum, and hippocampus isolated from Tmem135 FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance spectroscopy. Metabolomics analysis revealed a tissue-dependent response to Tmem135 alterations, whereby significant metabolic changes were observed in the heart of both Tmem135 mutant and TG mice as compared to wild-type, while negligible effects were observed in the cerebellum and hippocampus. We also observed changes in Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis and glucose and phospholipid metabolism. We observed depletion of NAD + in both Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD + level. Metabolic changes identified in this study might be associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities. Impact statement Mitochondria are dynamic organelles undergoing fission and fusion. Proper regulation of this process is important for healthy aging process, as aberrant mitochondrial dynamics are associated with several age-related diseases/pathologies. However, it is not well understood how imbalanced mitochondrial dynamics may lead to those diseases and pathologies. Here, we aimed to determine metabolic alterations in tissues and cells from mouse models with over-fused (fusion > fission) and over-fragmented (fusion < fission) mitochondria that display age-related disease pathologies. Our results indicated tissue-dependent sensitivity to these mitochondrial changes, and metabolic pathways likely affected by aberrant mitochondrial dynamics. This study provides new insights into how dysregulated mitochondrial dynamics could lead to functional abnormalities of tissues and cells.« less
5. The genetics of venom ontogeny in the eastern diamondback rattlesnake ( Crotalus adamanteus )

   https://doi.org/10.7717/peerj.3249  

   Rokyta, Darin R. ; Margres, Mark J. ; Ward, Micaiah J. ; Sanchez, Elda E. ( April 2017 , PeerJ)

   The same selective forces that give rise to rapid inter- and intraspecific divergence in snake venoms can also favor differences in venoms across life-history stages. Ontogenetic changes in venom composition are well known and widespread in snakes but have not been investigated to the level of unambiguously identifying the specific loci involved. The eastern diamondback rattlesnake was previously shown to undergo an ontogenetic shift in venom composition at sexual maturity, and this shift accounted for more venom variation than geography. To characterize the genetics underlying the ontogenetic venom compositional change inC. adamanteus, we sequenced adult/juvenile pairs of venom-gland transcriptomes frommore »five populations previously shown to have different adult venom compositions. We identified a total of 59 putative toxin transcripts for C. adamanteus, and 12 of these were involved in the ontogenetic change. Three toxins were downregulated, and nine were upregulated in adults relative to juveniles. Adults and juveniles expressed similar total levels of snake-venom metalloproteinases but differed substantially in their featured paralogs, and adults expressed higher levels of Bradykinin-potentiating and C-type natriuretic peptides, nerve growth factor, and specific paralogs of phospholipases A₂and snake venom serine proteinases. Juvenile venom was more toxic to mice, indicating that the expression differences resulted in a phenotypically, and therefore potentially ecologically, significant difference in venom function. We also showed that adult and juvenile venom-gland transcriptomes for a species with known ontogenetic venom variation were equally effective at individually providing a full characterization of the venom genes of a species but that any particular individual was likely to lack several toxins in their transcriptome. A full characterization of a species’ venom-gene complement therefore requires sequencing more than one individual, although the ages of the individuals are unimportant.

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