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关键词： Heart failure with preserved ejection fraction   Arterial stiffness   Left ventricular hypertrophy   L-T-type calcium channel blocker   Angiotensin receptor-neprilysin inhibitor  

摘要： Heart failure (HF) is an important health problem worldwide whose stages have traditionally been classified from A to D. In addition, HF can be categorized as that with preserved ejection fraction (HFpEF) and that with reduced ejection fraction (HFrEF). Hypertension and arterial stiffness in stage A HF are major drivers of the progression to left ventricular hypertrophy (LVH), a criterion of stage B HF. Although the pathogenesis of HFpEF is heterogeneous, affected patients tend to be older than HFrEF patients and have a greater prevalence of hypertension, which is closely associated with arterial stiffness and LVH. Thus, to treat HFpEF, the optimal intervention for improving prognosis is an aggressive approach to early-stage, i.e., Stage A and B, HF. This paper reviews the findings on arterial stiffness and LVH using conventional antihypertensive drugs such as angiotensin receptor II blockers (ARBs) and a new drug class for HF, ARB/neprilysin inhibitor (ARNi). Previous studies have suggested that the combination of an ARB with an L-T-type calcium channel blocker might be recommended for the improvement of arterial stiffness and regression of LVH. More recent research has shown that ARNi also improves central BP, which leads to a reduced afterload and a significant reduction in LVH. For optimal treatment of HFpEF, drug therapy should directly address arterial stiffness as well as hypertension.

关键词： Logistic differential equation   Fractional calculus   Fractional derivative   Non-singular kernel   Fractional differential equation  

摘要： We solve the logistic differential equation of fractional order and non-singular kernel. The analytical solution is obtained. (C) 2021 The Author(s). Published by Elsevier Ltd.

关键词： Streptococcus pneumoniae   K48-ubiquitination   K63-ubiquitination   autophagy   proteasomal degradation   blood-brain barrier   proteasome   ubiquitin topology   ubiquitination  

摘要： The protective mechanisms of blood-brain barrier (BBB) prohibiting entry of pathogens into central nervous system (CNS) are critical for maintenance of brain homeostasis. These include various intracellular defense mechanisms that are vital to block transcytosis of neurotropic pathogens into the CNS. However, mechanistic details of coordination between these defense pathways remain unexplored. In this study, we established that BBB-driven ubiquitination acts as a major intracellular defense mechanism for clearance of Streptococcus pneumoniae, a critical neurotropic pathogen, during transit through BBB. Our findings suggest that the BBB employs differential ubiquitination with either K48- or K63-ubiquitin (Ub) chain topologies as an effective strategy to target S. pneumoniae toward diverse killing pathways. While K63-Ub decoration triggers autophagic killing, K48-Ub directs S. pneumoniae exclusively toward proteasomes. Timelapse fluorescence imaging involving proteasomal marker LMP2 revealed that in the BBB, the majority of the ubiquitinated S. pneumoniae was cleared by proteasome. Fittingly, inhibition of proteasome and autophagy pathway led to accumulation of K48Ub- and K63-Ub-marked S. pneumoniae, respectively, and triggered significant increases in intracellular S. pneumoniae burden. Moreover, genetic impairment of either K48- or K63-Ub chain formation demonstrated that although both chain types are key in disposal of intracellular S. pneumoniae, K48-Ub chains and subsequent proteasomal degradation have more pronounced contributions to intracellular S. pneumoniae killing in the BBB. Collectively, these observations, for the first time, illustrated a pivotal role of differential ubiquitination deployed by BBB in orchestrating a symphony of intracellular defense mechanisms for interception and degradation of S. pneumoniae, blocking its entry into the brain, which could be exploited to prevent bacterial CNS infections. IMPORTANCE The blood-brain barrier (BBB) repres

关键词： photovoltaic strings   switching frequencies   photovoltaic power systems   PV-to-PV architecture   partial shading   power-electronics-based methods   photovoltaic systems   soft switching   zero voltage switching   power electronics   bypass diode method   zero current switching   power engineering computing   differential power processing topology   energy harvesting   MATLAB-Simulink environment  

摘要： Energy harvesting from photovoltaic (PV) strings is significantly affected by partial shading. To address this problem, several power-electronics-based methods have been proposed in the literature. In this context, this letter presents an enhanced differential power processing topology. This novel solution allows obtaining soft switching, as well as the operation at lower switching frequencies, considering good trade-offs between the number of modules of the string and component count. The proposed differential power processing approach is thoroughly analysed and compared with both the traditional bypass diode method and the PV-to-PV architecture through simulations carried out in MATLAB/Simulink environment.

关键词： Atrial flutter   Cavo-tricuspid isthmus block   Catheter ablation  

摘要： Purpose Bidirectional block of the cavo-tricuspid isthmus (CTI) is an established endpoint of CTI-dependent atrial flutter (AFl) ablation. Differential pacing has been used to evaluate the CTI block. The purpose of this study is to describe a modified differential pacing technique to evaluate the CTI block. Methods Sixty-two patients underwent radiofrequency (RF) ablation of CTI-dependent AFl. The acute endpoints were non-inducibility of the AFl, and verification of the bidirectional CTI block by our methodology. Pacing was performed in the CS with an ablation catheter positioned immediately lateral to the CTI ablation line, and then 1-2 cm more laterally. The stimulus-to-ablation catheter atrial electrogram intervals were measured at these sites (Stim(CS)-Abl(1) and Stim(CS)-Abl(2), respectively). Pacing with the ablation catheter also was performed at these 2 sites, and the stimulus-to-CS electrogram intervals (Stim(ABL1)-CS and Stim(ABL2)-CS) were measured. The criteria for the bidirectional block were Stim(CS)-Abl(1) > Stim(CS)-Abl(2), and Stim(ABL1)-CS > Stim(ABL2)-CS. Clinical efficacy was defined as freedom from recurrent AFl during follow-up. Results Following 12.2 +/- 3.7 min of RF delivery across the CTI, intervals were Stim(CS)-Abl(1) = 181.2 +/- 22.7 ms and Stim(ABL1)-CS = 181.0 +/- 23.6 ms, and Stim(CS)-Abl(2) = 152.2 +/- 26.5 ms and Stim(ABL2)-CS = 151.2 +/- 22.7 (P < 0.001). Atrial flutter was rendered not inducible in all patients, and no procedural complications were encountered. During the next 15.9 +/- 0.7 months, two patients were lost to follow-up, and among the 62 other patients, one (1.7%) had flutter recurrence. Conclusions The bidirectional CTI block can be assessed quickly and easily using only the ablation and CS catheters for differential pacing.

关键词： prostate cancer   metallothionein   androgen receptor   ralaniten   off-target   sintokamide   MTF1  

摘要： Simple Summary Inhibition of the androgen receptor (AR) remains the mainstay treatment for prostate cancer. All current therapies involving AR inhibition either directly or indirectly target its ligand-binding domain (LBD). We have developed the first novel compounds which target the N-terminal domain, (NTD) a region which is essential for AR transcriptional activity. First-generation ralaniten (NCT02606123), and second-generation EPI-7386 (NCT04421222) remain the only AR-NTD inhibitors to progress to clinical trials. Here we aim to characterize differences between different classes of AR antagonists targeting the AR-LBD and the AR-NTD, as well as next generation AR-NTD inhibitors. An incidental finding was that ralaniten was uniquely associated with increased metallothionein expression which was independent of AR activity. Instead, expression of metallothionein genes was driven by MTF-1 indicating a potential off-target effect. Neither AR-LBD inhibitor enzalutamide nor second-generation AR-NTD inhibitor EPI-7170 had this effect. This work has important implications for the development of novel AR-NTD inhibitors. Hormonal therapies for prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD). Clinical development for inhibitors that bind to the N-terminal domain (NTD) of AR has yielded ralaniten and its analogues. Ralaniten acetate is well tolerated in patients at 3600 mgs/day. Clinical trials are ongoing with a second-generation analogue of ralaniten. Binding sites on different AR domains could result in differential effects on AR-regulated gene expression. Here, we provide the first comparison between AR-NTD inhibitors and AR-LBD inhibitors on androgen-regulated gene expression in prostate cancer cells using cDNA arrays, GSEA, and RT-PCR. LBD inhibitors and NTD inhibitors largely overlapped in the profile of androgen-induced genes that they each inhibited. However, androgen also represses gene expression by various mechanisms, many of which in

关键词： Wireless communication   Training   Servers   Computational modeling   Wireless sensor networks   Data models   Interference   Federated learning   differential privacy   multi-agent multi-armed bandit   max-min bipartite matching  

摘要： In federated learning (FL), model training is distributed over clients and local models are aggregated by a central server. The performance of uploaded models in such situations can vary widely due to imbalanced data distributions, potential demands on privacy protections, and quality of transmissions. In this paper, we aim to minimize FL training delay over wireless channels, constrained by overall training performance as well as each client's differential privacy (DP) requirement. We solve this problem in a multi-agent multi-armed bandit (MAMAB) framework to deal with the situation where there are multiple clients confronting different unknown transmission environments, e.g., channel fading and interference. Specifically, we first transform long-term constraints on both training performance and each client's DP into a virtual queue based on the Lyapunov drift technique. Then, we convert the MAMAB to a max-min bipartite matching problem at each communication round, by estimating rewards with the upper confidence bound (UCB) approach. More importantly, we propose two efficient solutions to this matching problem, i.e., a modified Hungarian algorithm and greedy matching with a better alternative (GMBA), of which the former can achieve the optimal solution with high complexity while the latter approaches a better trade-off by enabling verified low-complexity with little performance loss. In addition, we develop an upper bound on the expected regret of this MAMAB based FL framework, which shows a linear growth over the logarithm of communication rounds, justifying its theoretical feasibility. Extensive experimental results are conducted to validate the effectiveness of our proposed algorithms, and the impacts of various parameters on the FL performance over wireless edge networks are also discussed.

关键词： Psoriasis   Secukinumab   Ustekinumab   Nail involvement   Prognostic factor  

摘要： Introduction Patients with plaque psoriasis may experience varying levels of treatment response to different biologics, based on phenotypic characteristics and underlying genetic factors. Nail psoriasis is a common manifestation of psoriasis (approx. 50% of patients) and has been linked to the human leukocyte antigen-C*0602 (HLA-C*0602) allele, which in turn has been associated with differential treatment responses to certain drugs. Here we investigate whether nail involvement in patients with psoriasis can predict differential skin responses to two biologics with different modes of action, namely secukinumab (anti-interleukin-17A) and ustekinumab (anti-interleukin-12/23), to ultimately guide treatment choice. Methods Data were pooled from the CLEAR and CLARITY studies and stratified post hoc by nail involvement status at baseline. Psoriasis Area and Severity Index (PASI) 75 and 90 responses over 52 weeks and absolute PASI <= 3, <= 1, and 0 values at weeks 16 and 52, were assessed. Results Based on the medical history, 30.4% (269/886) of the patients in the secukinumab arm and 29.7% (265/891) of patients in the ustekinumab arm presented with nail involvement. Nail involvement status had little to no impact on the efficacy of secukinumab, as comparable responses were achieved for patients with and without nail involvement in terms of PASI 75/90, <= 3, and 0 responses;slightly lower PASI <= 1 reponses were achieved in patients with nail involvement. In the ustekinumab arm, patients with nail involvement achieved lower responses across all endpoints. Conclusions These findings indicate that nail involvement can serve as an observable prognostic factor for efficacy in skin psoriasis treatment and guide the choice between secukinumab and ustekinumab.

关键词： comorbidities   COVID-19   duration   olfaction   outcomes   SARS-CoV2   severity   smell loss   SNOT22   taste loss  

关键词： Radiofrequency identification   Trajectory planning   Drones   Approximation algorithms   Statistics   Sociology   Mathematical model   Complex industrial product warehouse   differential evolution (DE) algorithm   3-D trajectory planning   UAV stocktaking  

摘要： Tobacco industry companies need to conduct a regular inventory of finished products and raw and auxiliary materials, and drones with radio frequency identification (RFID) readers are becoming a major application trend of inventory. Under the condition of ensuring the accuracy of inventory, this article considers the physical performance constraints of the drone, the constraints of the RFID reader, etc., and introduces the force of the drone into the model establishment, and a task planning model for UAV inventory library equipped with RFID reader is proposed. Then, in view of the problem that the greedy strategy in the traditional differential evolution (DE) algorithm will cause the location information retained by other individuals to be lost, a hybrid DE algorithm based on the lion swarm optimization is proposed. Finally, the proposed algorithm was verified by environmental modeling based on the data of the tobacco enterprise warehouse.