Opening the unlicensed bands provides additional spectrum resources for the next generation wireless network, while severe unfairness and performance degradation occur when one coexists with the ...incumbent users of these bands. Therefore, plenty of efforts have been made towards fair coexistence, mainly focusing on parameter tuning of listen-before-talk (LBT) and duty-cycle (DC) mechanisms. For better utilization of the unlicensed bands, it is of paramount importance to establish an access mechanism that guarantees the fairness objective among feasible mechanisms. Such access mechanism and the corresponding benchmark, nevertheless, remain largely unknown. To address this issue, this paper considers the coexistence between WiFi and the other unlicensed nodes, and aims to maximize the α-fairness between them. A benchmark is first given by solving the optimization problem. Then we propose a deep reinforcement learning (DRL) mechanism to help the unlicensed nodes make access decisions, such that they coexist with WiFi harmoniously. Extensive simulations have been carried out, and the results show that the DRL mechanism can approach the benchmark.
Drug resistance in Gram-negative bacteria, such as
Acinetobacter baumannii, is emerging as a significant healthcare problem. New antibiotics with a novel mechanism of action are urgently needed to ...overcome the drug resistance. Methionine aminopeptidase (MetAP) carries out an essential cotranslational methionine excision in many bacteria and is a potential target to develop such novel antibiotics. Two putative MetAP genes were identified in
A. baumannii genome, but whether they actually function as MetAP enzymes was not known. Therefore, we established an efficient
E. coli expression system for their production as soluble and metal-free proteins for biochemical characterization. We demonstrated that both could carry out the metal-dependent catalysis and could be activated by divalent metal ions with the order Fe(II) ≈ Ni(II) > Co(II) > Mn(II) for both. By using a set of metalloform-selective inhibitors discovered on other MetAP enzymes, potency and metalloform selectivity on the
A. baumannii MetAP proteins were observed. The similarity of their catalysis and inhibition to other MetAP enzymes confirmed that both may function as competent MetAP enzymes in
A. baumannii and either or both may serve as the potential drug target.
Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) ...and copy number (CN) changes in tumors. In the current study we focus on biallelic loss and its relation to expression of mRNA and miRNA in ESCC using results from 500 K SNP, mRNA, and miRNA arrays in 30 cases from a high-risk region of China.
(i) Biallelic loss was uncommon but when it occurred it exhibited a consistent pattern: only 77 genes (<0.5%) showed biallelic loss in at least 10% of ESCC samples, but nearly all of these genes were concentrated on just four chromosomal arms (i.e., 42 genes on 3p, 14 genes on 9p, 10 genes on 5q, and seven genes on 4p). (ii) Biallelic loss was associated with lower mRNA expression: 52 of the 77 genes also had RNA expression data, and 41 (79%) showed lower expression levels in cases with biallelic loss compared to those without. (iii) The relation of biallelic loss to miRNA expression was less clear but appeared to favor higher miRNA levels: of 60 miRNA-target gene pairs, 34 pairs (57%) had higher miRNA expression with biallelic loss than without, while 26 pairs (43%) had lower miRNA expression. (iv) Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex. Biallelic loss was most commonly associated with a pattern of elevated miRNA and reduced mRNA (43%), but a pattern of both reduced miRNA and mRNA was also common (35%).
Our results indicate that biallelic loss in ESCC is uncommon, but when it occurs it is localized to a few specific chromosome regions and is associated with reduced mRNA expression of affected genes. The effect of biallelic loss on miRNA expression and on the relation between miRNA and mRNA expressions was complex.
Analog over-the-air computing enables a swarm of end-user devices to efficiently conduct distributed learning, where the intermediate parameters of users, such as gradients, are modulated and ...transmitted via a group of orthogonal waveforms, and can be mixed directly at a server without individually detecting the feedback parameters of each user. Nonetheless, the scarcity of orthogonal waveforms, as well as communication resources of the end-user devices, are throttling this paradigm in adopting complex deep learning models. To balance the tradeoff between communication efficiency and accuracy performance, we study model pruning for analog over-the-air distributed learning in this paper. First, a model pruning scheme is proposed to improve the communication efficiency of analog over-the-air training. An importance measure for model parameter pruning is also designed based on the analog over-the-air aggregated gradient, which can characterize the contribution of each parameter without removing channel fading and electromagnetic interference. Second, an analytical expression of the training error upper bound is derived, which shows the proposed scheme is able to converge even when the aggregated gradient is corrupted by heavy-tailed electromagnetic interference with an infinite variance. Finally, several experimental results are provided to show the performance gains achieved by our proposed scheme, and also verify the correctness of analytical results.
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One of the hurdles in the discovery of antibiotics is the difficulty of linking antibacterial compounds to their cellular targets. Our laboratory has employed a genome-wide approach ...of over-expressing essential genes in order to identify cellular targets of antibacterial inhibitors. Our objective in this project was to develop and validate a more sensitive disk diffusion based platform of target identification (Target Identification Platform for Antibacterials version 2; TIPA II) using a collection of cell clones in an Escherichia coli mutant (AS19) host with increased outer membrane permeability. Five known antibiotics/inhibitors and 28 boron heterocycles were tested by TIPA II assay, in conjunction with the original assay TIPA. The TIPA II was more sensitive than TIPA because eight boron heterocycles previously found to be inactive to AG1 cells in TIPA assays exhibited activity to AS19 cells. For 15 boron heterocycles, resistant colonies were observed within the zones of inhibition only on the inducing plates in TIPA II assays. DNA sequencing confirmed that resistant clones harbor plasmids with fabI gene as insert, indicating that these boron heterocycles all target enoyl ACP reductase. Additionally, cell-based assays and dose response curved obtained indicated that for two boron heterocycle inhibitors, the fabI cell clone in AG1 (wild-type) host cells exhibited at least 11 fold more resistance under induced conditions than under non-induced conditions. Moreover, TIPA II also identified cellular targets of known antibacterial inhibitors triclosan, phosphomycin, trimethoprim, diazaborine and thiolactomycin, further validating the utility of the new system.
Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's ...disease (AD).
Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD Mini-Mental State Examination (MMSE) score 10-27 were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures).
At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients.
In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.
Enoyl‐ACP reductase, the last enzyme of the fatty‐acid biosynthetic pathway, is the molecular target for several successful antibiotics such as the tuberculosis therapeutic isoniazid. It is currently ...under investigation as a narrow‐spectrum antibiotic target for the treatment of several types of bacterial infections. The diazaborine family is a group of boron heterocycle‐based synthetic antibacterial inhibitors known to target enoyl‐ACP reductase. Development of this class of molecules has thus far focused solely on the sulfonyl‐containing versions. Here, the requirement for the sulfonyl group in the diazaborine scaffold was investigated by examining several recently characterized enoyl‐ACP reductase inhibitors that lack the sulfonyl group and exhibit additional variability in substitutions, size and flexibility. Biochemical studies are reported showing the inhibition of Escherichia coli enoyl‐ACP reductase by four diazaborines, and the crystal structures of two of the inhibitors bound to E. coli enoyl‐ACP reductase solved to 2.07 and 2.11 Å resolution are reported. The results show that the sulfonyl group can be replaced with an amide or thioamide without disruption of the mode of inhibition of the molecule.
With the advancement of high throughput screening, it has become easier and faster to discover hit compounds that inhibit proliferation of bacterial cells. However, development in technologies used ...to identify cellular targets of potent antibacterial inhibitors has lagged behind. Here, we describe a novel strategy of target identification for antibacterial inhibitors using an array of
Escherichia coli clones each over-expressing one essential protein. In a proof-of-concept study, eight essential genes were cloned into pLex5BA vector under the control of an inducible promoter. Over-expression of target proteins was confirmed. For two clones, one over-expressing FabI and the other over-expressing MurA enzymes, the host cells became 17- and 139-fold more resistant to the specific inhibitors triclosan and phosphomycin, respectively, while the susceptibility of other clones towards these inhibitors remained unchanged after induction of gene expression. Target identification via target protein over-expression was demonstrated using both mixed clone and individual clone assay formats.
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