X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

Genome structure and evolutionary history of frankincense producing Boswellia sacra.

Boswellia sacra Flueck (family Burseraceae) tree is wounded to produce frankincense. We report its de novo assembled genome (667.8 Mb) comprising 18,564 high-confidence protein-encoding genes. Comparing conserved single-copy genes across eudicots suggest >97% gene space assembly of B. sacra genome. Evolutionary history shows B. sacra gene-duplications derived from recent paralogous events and retained from ancient hexaploidy shared with other eudicots. The genome indicated a major expansion of Gypsy retroelements in last 2 million years. The B. sacra genetic diversity showed four clades intermixed with a primary genotype-dominating most resin-productive trees. Further, the stem transcriptome revealed that wounding concurrently activates phytohormones signaling, cell wall fortification, and resin terpenoid biosynthesis pathways leading to the synthesis of boswellic acid-a key chemotaxonomic marker of Boswellia. The sequence datasets reported here will serve as a foundation to investigate the genetic determinants of frankincense and other resin-producing species in Burseraceae.

Investigating optimal region for thermal and electrical properties of epoxy nanocomposites under high frequencies and temperatures.

This research investigates the optimal region to achieve balanced thermal and electrical insulation properties of epoxy (EP) under high frequency (HF) and high temperature (HT) via integration of surface-modified hexagonal boron nitride (h-BN) nanoparticles. The effects of nanoparticle content and high temperature on various electrical (DC, AC, and high frequency) and thermal properties of EP are investigated. It is found that the nano h-BN addition enhances thermal performance and weakens electrical insulation properties. On the other side, under HF and HT stress, the presence of h-BN nanoparticles significantly improves the electrical performance of BN/EP nanocomposites. The EP has superior insulation properties at low temperature and low frequency, whereas the BN/EP nanocomposites exhibit better insulation performance than EP under HF and HT. The factors such as homogeneous nanoparticle dispersion in EP, enhanced thermal conductivity, nanoparticle surface modification, weight percent of nanoparticles, the mismatch between the relative permittivity of EP and nano h-BN, and the presence of voids in nanocomposites play the crucial role. The optimal nanoparticle content and homogenous dispersion can produce suitable EP composites for the high frequency and high temperature environment, particularly solid-state transformer applications.

Regular Aerobic Exercise Attenuates Pain and Anxiety in Mice by Restoring Serotonin-Modulated Synaptic Plasticity in the Anterior Cingulate Cortex.

PURPOSE: Clinical studies found that regular aerobic exercise has analgesic and antianxiety effects; however, the underlying neural mechanisms remain unclear. Multiple studies have suggested that regular aerobic exercise may exert brain-protective effects by promoting the release of serotonin, which may be a pain modulator. Anterior cingulate cortex (ACC) is a key brain area for pain information processing, receiving dense serotonergic innervation. As a result, we hypothesized that exercise may increase the release of serotonin in the ACC, thus improving pain and anxiety behaviors. METHODS: Integrative methods were used, including behavioral, electrophysiological, pharmacological, biochemical, and genetic approaches, to explore the effects of regular aerobic exercise and the underlying neural mechanisms. RESULTS: Regular aerobic exercise in the form of voluntary wheel running for 30 min daily for 15 d showed significant effectiveness in relieving pain and concomitant anxiety in complete Freund's adjuvant-induced chronic inflammation pain models. c-Fos staining and multielectrode array recordings revealed alterations in neuronal activities and synaptic plasticity in the ACC. Moreover, systemic pharmacological treatment with 4-chloro-dl-phenylalanine (PCPA) to deplete endogenous serotonin and local delivery of serotonin to the ACC revealed that exercise-related serotonin release in the ACC bidirectionally modulates pain sensitization and anxiety behaviors by modulating synaptic plasticity in the ACC. Furthermore, we found that 5-HT1A and 5-HT7 receptors mediated the serotonin modulation effects under conditions of regular aerobic exercise through local infusion of a selective antagonist and shRNA in the ACC. CONCLUSIONS: Our results reveal that regular aerobic exercise can increase serotonin release and modulate synaptic plasticity in the ACC, ultimately improving pain and concomitant anxiety behaviors through the functions of the 5-HT1A and 5-HT7 receptors.

Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells.

γδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16-5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-ß1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16-5p/SMAD5-regulatory axis potentiates TGF-ß1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.

Nanobubbles Water Curcumin Extract Reduces Injury Risks on Drop Jumps in Women: A Pilot Study.

PURPOSE: To verify the beneficial effects of Nanobubbles water curcumin extract (NCE) supplementation on health promotion and to demonstrate the application of NCE in reducing the risk of musculoskeletal injury. METHODS: In the current study, 12 females were randomly assigned to NCE (15g/day) and maltodextrin groups. Performance and related body composition were evaluated at 2 time points-presupplementation (pre-) and after 4 weeks of postsupplementation (post-). The posttest consists of a set of biochemical parameters for antifatigue activity and injury status evaluation. RESULTS: NCE group exhibited significantly lower levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglycerides (TG), and higher high-density lipoprotein (HDL) after a 4-week supplementation, compared with the placebo group. After a 15-minute session on the spinning bike, serum lactate and ammonia levels were decreased and glucose was economized in the NEC group. 4-week-NCE supplementation was also able to reduce the peak vertical ground reaction force (PVGRF) during drop jump. Therefore, the risk of musculoskeletal system in lower extremity could be reduced. CONCLUSION: We demonstrate that 4-week-NCE supplementation can also be used in explosiveness exercise for better physiological adaptation. Thus, NCE has potential for use with nutrient supplements toward a variety of benefits for athletics.

Two Likely Auto-Tetraploidization Events Shaped Kiwifruit Genome and Contributed to Establishment of the Actinidiaceae Family.

The genome of kiwifruit (Actinidia chinensis) was sequenced previously, the first in the Actinidiaceae family. It was shown to have been affected by polyploidization events, the nature of which has been elusive. Here, we performed a reanalysis of the genome and found clear evidence of 2 tetraploidization events, with one occurring ∼50-57 million years ago (Mya) and the other ∼18-20 Mya. Two subgenomes produced by each event have been under balanced fractionation. Moreover, genes were revealed to express in a balanced way between duplicated copies of chromosomes. Besides, lowered evolutionary rates of kiwifruit genes were observed. These findings could be explained by the likely auto-tetraploidization nature of the polyploidization events. Besides, we found that polyploidy contributed to the expansion of key functional genes, e.g., vitamin C biosynthesis genes. The present work also provided an important comparative genomics resource in the Actinidiaceae and related families.

Thrombolysis for acute intermediate-risk pulmonary embolism: A meta-analysis.

BACKGROUND: The use of thrombolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. To compare with anticoagulation alone, no analysis before has determined whether thrombolytic therapy is associated with improved survival or lower incidence of adverse clinical outcomes for intermediate-risk pulmonary embolism. OBJECTIVE: This meta-analysis was performed to assess mortality benefits, bleeding and recurrent pulmonary embolism risks associated with thrombolytic therapy compared with anticoagulation in patients with intermediate-risk pulmonary embolism. METHODS: The Web of Science, PubMed, Embase, EBSCO, and the Cochrane Library databases were searched for randomized clinical trials comparing thrombolytic therapy with anticoagulation in intermediate-risk pulmonary embolism patients (in which the mortality data were reported) from inception to August 5, 2014. Primary outcomes were all-cause mortality and major bleeding. Secondary outcomes were recurrent pulmonary embolism and minor bleeding. The pooled relative risk (RR), Mantel-Haenszel corresponding method and fixed-effect model were used to estimate the efficacy and safety of thrombolytic therapy with 95% confidence intervals. RESULTS: Eight clinical randomized controlled trials involving 1755 patients with intermediate-risk pulmonary embolism were included. Patients treated with thrombolytics presented lower mortality than patients in the anticoagulation cohort (RR, 0.52; 95% CI, 0.28-0.97; 1.39% [12/866] vs. 2.92% [26/889]). Compared with anticoagulation, thrombolytic therapy was associated with a higher risk of major (RR, 3.35; 95% CI, 2.03-5.54; 7.80% [64/820] vs. 2.28% [19/834]) and minor (RR, 3.66; 95% CI, 2.77-4.84; 32.78% [197/601] vs. 8.94% [53/593]) bleeding. Furthermore, thrombolytic therapy was associated with a lower incidence of recurrent pulmonary embolism (RR, 0.33; 95% CI, 0.15-0.73; 0.73% [6/826] vs. 2.72% [23/846]). CONCLUSION: Compared with anticoagulation, thrombolytic therapy in patients with intermediate-risk pulmonary embolism is associated with lower all-cause mortality and recurrent pulmonary embolism risk despite increased major and minor bleeding risks.

A randomized, double blind, placebo-controlled, multicenter phase II trial of Allisartan Isoproxil in essential hypertensive population at low-medium risk.

BACKGROUND: Angiotensin II receptor blockers (ARBs) is a well-tolerated class of antihypertensive agents, exhibiting effective antihypertensive and cardiovascular protective function. The objective of the study was to examine the efficacy and safety of Allisartan Isoproxil, a newly developed, selective, nonpeptide blocker of the angiotensin II type 1 receptor (AT1R), in essential hypertensive patients at low-medium risk. METHODS AND FINDINGS: A Phase II prospective, randomized, double-blind, placebo-controlled, multicenter trial comparing Allisartan Isoproxil 240mg versus placebo was conducted in essential hypertensive patients at low-medium risk at 8 sites in China. After a 2-week placebo baseline period, 275 patients received once-daily treatment with Allisartan Isoproxil 240mg or placebo randomly for 8 weeks. Systolic/diastolic blood pressure (SBP/DBP) was measured at week 2, 4 and 8. By the end of treatment, mean reductions from baseline of SBP and DBP in Allisartan Isoproxil and placebo groups were 14.5/10.4 and 8.3/7.7 mmHg, respectively (P<0.01). The rate of effective blood pressure control in Allisartan Isoproxil group was significantly higher than in placebo group at week 4 (61.3% vs 50.0%, P<0.05) and week 8 (67.2% vs 48.6%, P<0.01). In terms of safety and tolerability, there were no report of death and serious adverse event (SAE) in all subjects. There was no difference of frequency between two groups in adverse event (AE) and adverse drug reaction (ADR) (P>0.05). No one withdraw because of an ADR in two groups. 124 patients received additional 56 weeks treatment with Allisartan Isoproxil and 84 of them completed the study. The rate of effective BP control kept up to 80% since week 24. No significant clinical change was observed and ADRs were generally mild or moderate during the long-term study. CONCLUSIONS/SIGNIFICANCE: Allisartan Isoproxil 240mg was effective and safe for essential hypertension patients at low-medium risk. TRIAL REGISTRATION: http://www.chictr.org/cn/ ChiCTR-TRC-10000886.

Microarray analysis of differential gene expression profile in peripheral blood cells of patients with human essential hypertension.

The polygenic nature of essential hypertension and its dependence on environmental factors pose a challenge for biomedical research. We hypothesized that the analysis of gene expression profiles from peripheral blood cells would distinguish patients with hypertension from normotensives. In order to test this, total RNA from peripheral blood cells was isolated. RNA was reversed-transcribed and labeled and gene expression analyzed using significance Analysis Microarrays (Stanford University, CA, USA). Briefly, Significance Analysis Microarrays (SAM) thresholding identified 31 up-regulated and 18 down-regulated genes with fold changes of ≥2 or ≤0.5 and q-value≤5% in expression. Statistically significantly gene ontology (GO) function and biological process differentially expressed in essential hypertension were MHC class II receptor activity and immune response respectively. Biological pathway analysis identified several related pathways which are associated with immune/inflammatory responses. Quantitative Real-Time RT-PCR results were consistent with the microarray results. The levels of C-reactive protein were higher in hypertensive patients than normotensives and inflammation-related genes were increased as well. In conclusion, genes enriched for "immune/inflammatory responses" may be associated with essential hypertension. In addition, there is a correlation between systemic inflammation and hypertension. It is anticipated that these findings may provide accurate and efficient strategies for prevention, diagnosis and control of this disorder.

[Fluorescence fluctuation spectroscopy with strong background fluorescence--a Monte Carlo approach].

Fluorescence fluctuation spectroscopy is a method in which fluorescence fluctuations arising from a very small sample volume are analysed to obtain brightness, diffusion coefficient and concentration of particles. Using Monte Carlo simulation, the influences of background autofluorescence and noises on fluorescence fluctuation spectroscopy are studied. Results show that a two-component photon counting histogram can effectively remove the effects due to background autofluorescence from low brightness and high concentration components and uniform noise. The result will help to bring applications of fluorescence fluctuation spectroscopy to intracellular environment.