Correlation between Very Short and Short-Term Blood Pressure Variability in Diabetic-Hypertensive and Healthy Subjects

Background: Blood pressure (BP) variability can be evaluated by 24-hour ambulatory BP monitoring (24h-ABPM), but its concordance with results from finger BP measurement FBPM) has not been established yet. Objective: The aim of this study was to compare parameters of short-term (24h-ABPM) with very short-term BP variability (FBPM) in healthy (C) and diabetic-hypertensive (DH) subjects. Methods: Cross-sectional study with 51 DH subjects and 12 C subjects who underwent 24h-ABPM [extracting time-rate, standard deviation (SD), coefficient of variation (CV)] and short-term beat-to-beat recording at rest and after standing-up maneuvers [FBPM, extracting BP and heart rate (HR) variability parameters in the frequency domain, autoregressive spectral analysis]. Spearman correlation coefficient was used to correlate BP and HR variability parameters obtained from both FBPM and 24h-ABPM (divided into daytime, nighttime, and total). Statistical significance was set at p < 0.05. Results: There was a circadian variation of BP levels in C and DH groups; systolic BP and time-rate were higher in DH subjects in all periods evaluated. In C subjects, high positive correlations were shown between time-rate index (24h-ABPM) and LF component of short-term variability (FBPM, total, R = 0.591, p = 0.043); standard deviation (24h-ABPM) with LF component BPV (FBPM, total, R = 0.608, p = 0.036), coefficient of variation (24h-ABPM) with total BPV (FBPM, daytime, -0.585, p = 0.046) and alpha index (FBPM, daytime, -0.592, p = 0.043), time rate (24h-ABPM) and delta LF/HF (FBPM, total, R = 0.636, p = 0.026; daytime R = 0,857, p < 0.001). Records obtained from DH showed weak positive correlations. Conclusions: Indices obtained from 24h-ABPM (total, daytime) reflect BP and HR variability evaluated by FBPM in healthy individuals. This does not apply for DH subjects

Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors

Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship (QSAR) of known TPH1 inhibitors. A multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of TPH1 kinase based on three crystal structures of TPH1-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 32 structurally diverse substituted phenylalanine derivatives. The QSAR analyses have been performed on these TPH1 inhibitors based on the MCBP guided alignment. These results may provide important information for further design and virtual screening of novel TPH1 inhibitors

Trna-derived fragments (Trfs): Emerging new roles for an ancient RNA in the regulation of gene expression

© 2015 by the authors; licensee MDPI, Basel, Switzerland. This review will summarise the recent discoveries and current state of research on short noncoding RNAs derived from tRNAs—known as tRNA-derived fragments (tRFs). It will describe the features of the known subtypes of these RNAs; including sequence characteristics, protein interactors, expression characteristics, biogenesis, and similarity to canonical miRNA pathways. Also their role in regulating gene expression; including mediating translational suppression, will be discussed. We also highlight their potential use as biomarkers, functions in gene regulation and links to disease. Finally, this review will speculate as to the origin and rationale for the conservation of this novel class of noncoding RNAs amongst both prokaryotes and eukaryotes

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Background and ObjectivesKCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.ResultsWe identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability

GridShield—Optimizing the Use of Grid Capacity during Increased EV Adoption

With the increasing adoption rate of electric vehicles, power peaks caused by many cars simultaneously charging on the same low-voltage grid can cause local overloading and power outages. Smart charging solutions should spread this load, but there is a residual risk of incidental peaks. A decentralized and autonomous technology called GridShield is being developed to reduce the likelihood of a transformer’s fuse blowing when other congestion solutions have failed. It serves as a measure of last resort to protect the grid against local power failures from unpredicted congestion by temporarily limiting the virtual capacity of charging stations. This paper describes the technical development and demonstrates how GridShield can keep a transformer load below a critical limit using simulations and real-world tests. It optimizes grid capacity while ensuring grid reliability.</p

Within-tree distribution and survival of the eucalyptus longhorned borer Phoracantha semipunctata (Coleoptera: Cerambycidae) in a Mediterranean-type ecosystem

The attack patterns, infestation success and larval development of woodborers within living trees are complex and are largely shaped by host tree characteristics. Following a severe drought in a native eucalypt forest where outbreak densities of a native Australian beetle, the eucalyptus longhorned borer (Phoracantha semipunctata), occurred, a tree dissection study was conducted in Australia. This involved felling 40 trees each of jarrah (Eucalyptus marginata) and marri (Corymbia calophylla) that were cut into 1-m sections and neonate larval galleries, larvae in pupal cells and adult borer emergence were measured and added to give total numbers per tree to determine the within-tree distribution and survival of P. semipunctata. There was a significant impact on larval survival in both species, in contrast, pupal survival remained high. Within-tree distribution of P. semipunctata was directional with borer emergence and incidence of larval galleries both negatively associated with tree section height above the ground and positively associated with section diameter and bark thickness, reaching a maximum towards the base of trees. High incidence and survival in lower thicker tree sections indicate a more conducive environment for larval development, in contrast to poor larval survival in smaller thinner sections at the top of trees. The dependence of larval survival on tree characteristics controlling the within-tree distribution of borer emergence is emphasized, and needs to be considered when estimating the spread of borer populations during outbreaks

Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50–60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex

Ergosta-7,9(11),22-trien-3β-ol alleviates intracerebral hemorrhage-induced brain injury and BV-2 microglial activation

Intracerebral hemorrhage (ICH) is a devastating neurological disorder characterized byan exacerbation of neuroinflammation and neuronal injury, for which few effective therapies areavailable at present. Inhibition of excessive neuroglial activation has been reported to alleviateICH-related brain injuries. In the present study, the anti-ICH activity and microglial mechanismof ergosta-7,9(11),22-trien-3β-ol (EK100), a bioactive ingredient from Asian medicinal herb Antrodia camphorate, were evaluated. Post-treatment of EK100 significantly attenuated neurobehavioraldeficit and MRI-related brain lesion in the mice model of collagenase-induced ICH. Additionally,EK100 alleviated the inducible expression of cyclooxygenase (COX)-2 and the activity of matrixmetalloproteinase (MMP)-9 in the ipsilateral brain regions. Consistently, it was shown that EK100concentration-dependently inhibited the expression of COX-2 protein in Toll-like receptor (TLR)-4activator lipopolysaccharide (LPS)-activated microglial BV-2 and primary microglial cells. Furthermore, the production of microglial prostaglandin E2 and reactive oxygen species were attenuatedby EK100. EK100 also attenuated the induction of astrocytic MMP-9 activation. Among severalsignaling pathways, EK100 significantly and concentration-dependently inhibited activation of c-JunN-terminal kinase (JNK) MAPK in LPS-activated microglial BV-2 cells. Consistently, ipsilateral JNKactivation was markedly inhibited by post-ICH-treated EK100 in vivo. In conclusion, EK100 exertedthe inhibitory actions on microglial JNK activation, and attenuated brain COX-2 expression, MMP-9activation, and brain injuries in the mice ICH model. Thus, EK100 may be proposed and employedas a potential therapeutic agent for ICH

Diels-Alder Adducts of Morphinan-6,8-Dienes and Their Transformations.

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels-Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors