Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

Dissimilarity in the Folding of Human Cytosolic Creatine Kinase Isoenzymes

Creatine kinase (CK, EC 2.7.3.2) plays a key role in the energy homeostasis of excitable cells. The cytosolic human CK isoenzymes exist as homodimers (HMCK and HBCK) or a heterodimer (MBCK) formed by the muscle CK subunit (M) and/or brain CK subunit (B) with highly conserved three-dimensional structures composed of a small N-terminal domain (NTD) and a large C-terminal domain (CTD). The isoforms of CK provide a novel system to investigate the sequence/structural determinants of multimeric/multidomain protein folding. In this research, the role of NTD and CTD as well as the domain interactions in CK folding was investigated by comparing the equilibrium and kinetic folding parameters of HMCK, HBCK, MBCK and two domain-swapped chimeric forms (BnMc and MnBc). Spectroscopic results indicated that the five proteins had distinct structural features depending on the domain organizations. MBCK BnMc had the smallest CD signals and the lowest stability against guanidine chloride-induced denaturation. During the biphasic kinetic refolding, three proteins (HMCK, BnMc and MnBc), which contained either the NTD or CTD of the M subunit and similar microenvironments of the Trp fluorophores, refolded about 10-fold faster than HBCK for both the fast and slow phase. The fast folding of these three proteins led to an accumulation of the aggregation-prone intermediate and slowed down the reactivation rate thereby during the kinetic refolding. Our results suggested that the intra- and inter-subunit domain interactions modified the behavior of kinetic refolding. The alternation of domain interactions based on isoenzymes also provides a valuable strategy to improve the properties of multidomain enzymes in biotechnology

General preparation for Pt-based alloy nanoporous nanoparticles as potential nanocatalysts

Although Raney nickel made by dealloying has been used as a heterogeneous catalyst in a variety of organic syntheses for more than 80 years, only recently scientists have begun to realize that dealloying can generate nanoporous alloys with extraordinary structural characteristics. Herein, we achieved successful synthesis of a variety of monodisperse alloy nanoporous nanoparticles via a facile chemical dealloying process using nanocrystalline alloys as precursors. The as-prepared alloy nanoporous nanoparticles with large surface area and small pores show superior catalytic properties compared with alloyed nanoparticles. It is believed that these novel alloy nanoporous nanoparticles would open up new opportunities for catalytic applications

Chitosan–Starch–Keratin composites: Improving thermo-mechanical and degradation properties through chemical modification

The lysozyme test shows an improved in the degradability rate, the weight loss of the films at 21 days is reduced from 73 % for chitosan-starch matrix up to 16 % for the composites with 5wt% of quill; but all films show a biodegradable character depending on keratin type and chemical modification. The outstanding properties related to the addition of treated keratin materials show that these natural composites are a remarkable alternative to potentiat-ing chitosan–starch films with sustainable featuresChitosan–starch polymers are reinforced with different keratin materials obtained from chicken feather. Keratin materials are treated with sodium hydroxide; the modified surfaces are rougher in comparison with untreated surfaces, observed by Scanning Electron Microscopy. The results obtained by Differential Scanning Calorimetry show an increase in the endothermic peak related to water evaporation of the films from 92 °C (matrix) up to 102–114 °C (reinforced composites). Glass transition temperature increases from 126 °C in the polymer matrix up to 170–200 °C for the composites. Additionally, the storage modulus in the composites is enhanced up to 1614 % for the composites with modified ground quill, 2522 % for composites with modified long fiber and 3206 % for the composites with modified short fiber. The lysozyme test shows an improved in the degradability rate, the weight loss of the films at 21 days is reduced from 73 % for chitosan-starch matrix up to 16 % for the composites with 5wt% of quill; but all films show a biodegradable character depending on keratin type and chemical modification. The outstanding properties related to the addition of treated keratin materials show that these natural composites are a remarkable alternative to potentiat-ing chitosan–starch films with sustainable featuresUniversidad Autónoma del Estado de México Tecnológico Nacional de México, Instituto Tecnológico de Querétaro Universidad Nacional Autónoma de México Tecnológico Nacional de México, Instituto Tecnológico de Celaya Universidad Autónoma de Cd. Juáre

Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4–6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca2+ channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling