Human beta3-adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides

Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.     

Aurora-A Identifies Early Recurrence and Poor Prognosis and Promises a Potential Therapeutic Target in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (P<0.001). In TNBC patients with Aur-A high expression, the risk of distant recurrence peaked at the first 3 years and declined rapidly thereafter, whereas patients with Aur-A low expression showed a relatively constant risk of recurrence during the entire follow-up period. Univariate and multivariate analysis showed that overexpression of Aur-A predicted poor overall survival (P = 0.002) and progression-free survival (P = 0.012) in TNBC. Furthermore, overexpression of Aur-A, associated with high Ki-67, predicted an inferior prognosis compared with low expression of both Aur-A and Ki-67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy.     

MicroRNA-188-5p promotes apoptosis and inhibits cell proliferation of breast cancer cells via the MAPK signaling pathway by targeting Rap2c

Breast cancer is a common malignancy that is highly lethal with poor survival rates and immature therapeutics that urgently needs more effective and efficient therapies. MicroRNAs are intrinsically involved in different cancer remedies, but their mechanism in breast cancer has not been elucidated for prospective treatment. The function and mechanism of microRNA-188-5p (miR-188) have not been thoroughly investigated in breast cancer. In our study, we found that the expression of miR-188 in breast cancer tissues was obviously reduced. Our findings also revealed the abnormal overexpression of miR-188 in 4T1 and MCF-7 cells significantly suppressed cell proliferation and migration and also enhanced apoptosis. miR-188 induced cell cycle arrest in the G1 phase. To illuminate the molecular mechanism of miR-188, Rap2c was screened as a single target gene by bioinformatics database analysis and was further confirmed by dual-luciferase assay. Moreover, Rap2c was found to be a vital molecular switch for the mitogen-activated protein kinase signaling pathway in tumor progression by decreasing apoptosis and promoting proliferation and migration. In conclusion, our results revealed that miR-188 is a cancer progression suppressor and a promising future target for breast cancer therapy.     

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner. MOV10 that was further shown to be induced specifically by SFTSV and related bunyaviruses in turn inhibits the bunyaviral replication in infected cells in series of loss/gain-of-function assays. Moreover, animal infection experiments with MOV10 knockdown corroborated the role of MOV10 in restricting SFTSV infection and pathogenicity in vivo. Minigenome assays and additional functional and mechanistic investigations demonstrate that the anti-bunyavirus activity of MOV10 is likely achieved by direct impact on viral RNP machinery but independent of its helicase activity and the cellular interferon pathway. Indeed, by its N-terminus, MOV10 binds to a protruding N-arm domain of N consisting of only 34 amino acids but proving important for N function and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study not only advances the understanding of bunyaviral replication and host restriction mechanisms but also presents novel paradigms for both direct antiviral action of MOV10 and host targeting of viral RNP machinery.     

Critical assessment of coalescent simulators in modeling recombination hotspots in genomic sequences

Background

Coalescent simulation is pivotal for understanding population evolutionary models and demographic histories, as well as for developing novel analytical methods for genetic association studies for DNA sequence data. A plethora of coalescent simulators are developed, but selecting the most appropriate program remains challenging.

Results

We extensively compared performances of five widely used coalescent simulators – Hudson’s ms, msHOT, MaCS, Simcoal2, and fastsimcoal, to provide a practical guide considering three crucial factors, 1) speed, 2) scalability and 3) recombination hotspot position and intensity accuracy. Although ms represents a popular standard coalescent simulator, it lacks the ability to simulate sequences with recombination hotspots. An extended program msHOT has compensated for the deficiency of ms by incorporating recombination hotspots and gene conversion events at arbitrarily chosen locations and intensities, but remains limited in simulating long stretches of DNA sequences. Simcoal2, based on a discrete generation-by-generation approach, could simulate more complex demographic scenarios, but runs comparatively slow. MaCS and fastsimcoal, both built on fast, modified sequential Markov coalescent algorithms to approximate standard coalescent, are much more efficient whilst keeping salient features of msHOT and Simcoal2, respectively. Our simulations demonstrate that they are more advantageous over other programs for a spectrum of evolutionary models. To validate recombination hotspots, LDhat 2.2 rhomap package, sequenceLDhot and Haploview were compared for hotspot detection, and sequenceLDhot exhibited the best performance based on both real and simulated data.

Conclusions

While ms remains an excellent choice for general coalescent simulations of DNA sequences, MaCS and fastsimcoal are much more scalable and flexible in simulating a variety of demographic events under different recombination hotspot models. Furthermore, sequenceLDhot appears to give the most optimal performance in detecting and validating cross-over hotspots.     

Forest pattern dynamics and landscape connectivity changes in the Manwan Basin after dam construction in the Lancang River,China

Regional habitat quality and landscape connectivity can be greatly impaired by dam construction and subsequent land-use changes. This study examined landscape pattern and connectivity changes in the Manwan Basin from 1974 to 2006 to quantify the effects of dam construction. Landscape pattern indices and kernel density estimation (KDE) were used to analyze forest pattern dynamics, while the probability of connectivity (PC) index was applied to evaluate landscape connectivity changes. The results showed that forest area decreased by nearly 20 %, while the number of forest patches increased more than sixfold from 1974 to 2006 in the Manwan Basin. During the study period, forest fragmentation mainly occurred in the western and northern parts of the Manwan Basin. Due to the changes in the forest landscape pattern, landscape connectivity decreased by an average of 54.74 %. In addition, we detected changes to key stepping-stone patches by calculating the percentage importance of each resource patch. The results showed that 300.38 km² of high-importance forest patches transformed to medium- and low-importance patches from 1974 to 2006.     

Metabolomic profiling of three brain regions from a postnatal infected Borna disease virus Hu-H1 rat model

Neonatal rat infection with Borna disease virus (BDV), termed neonatal Borna disease, is an established model for investigating the BDV-associated pathogenesis of neurodevelopmental abnormalities. BDV produces a persistent noncytolytic infection in all culture cell systems assayed to date, while persistent infection in neonatal rats results in a progressive loss of hippocampal granule cells, cerebellar Purkinje cells, and cortical GABA-ergic neurons. Persistent infection also results in behavioral deficits including hyperactivity, cognitive impairment, and abnormal social behavior. However, the molecular mechanisms underlying the neuronal degeneration and behavioral abnormalities remain unclear. Using a metabolomic approach based on gas chromatography coupled with mass spectrometry in conjunction with statistical pattern recognition, the metabolic changes in response to BDV Hu-H1 infection were characterized in the rat hippocampus, cerebellum, and cortex. Metabonomic profiling revealed significant perturbations in nucleotide (e.g., adenosine, uracil, inosine, adenosine-5′-monophosphate, uridine-5′-monophosphate, d-ribose 5-phosphate, and sedoheptulose 7-phosphate), amino acid (e.g., lysine, glycine, phenylalanine, tyrosine, proline, serine, cysteine, aspartic acid, pyroglutamic acid, and γ-aminobutyric acid), lipid (e.g., cholesterol, myristic acid, stearic acid, palmitic acid, 1-monopalmitoylglycerol, and arachidonic acid), and energy (e.g., glucose, lactose, 3-phosphoglyceric acid, and pyruvic acid) metabolites. These metabolites participate in pathways crucial to viral proliferation and neurotransmitter homeostasis. This metabolomic profiling study provides insight into the pathogenic mechanisms of BDV and new directions with which to investigate the in vivo effects of persistent BDV infection.     

SMAD蛋白家族:一类新的细胞内信号传导蛋白

SMADs是新近发观的一族细胞内信号传导蛋白,包括8个成员,即SMAD1～8。SMAD1、2、3、5和8是一类,它们被TGF-β受体或BMP受体激活而磷酸化,称为受体调节SMAD,传导TGF-β或BMP的信号。SMAD6和7是另一类,它们抑制受体调节SMAD传导信号。SMAD4是第2类,它是受体调节SMAD传导信号的伴侣。受体调节SMAD传导信号必须先与SMAD4结合形成异源复合物,才能进到核中,调节转录活动。本文简要介绍了各成员的特性及作用。