Tip110 Control of HIV-1 Gene Expression and Replication

Indiana University-Purdue University Indianapolis (IUPUI)Transcription and alternative splicing play important roles in HIV-1 gene expression and replication and mandate complicated but coordinated interactions between the host and the virus. Studies from our group have shown that a HIV-1 Tat-interacting protein of 110 kDa, Tip110 synergies with Tat in Tat-mediated HIV-1 gene transcription and replication. However, the underlying molecular mechanisms were not fully understood and are the focus of the dissertation research. In the study, we first demonstrated that Tip110 bound to unphosphorylated RNA polymerase II (RNAPII) in a direct and specific manner. We then showed that Tip110 was detected at the HIV-1 long terminal repeat (LTR) promoter and associated with increased phosphorylation of serine 2 within the RNAPII C-terminal domain (CTD) and increased recruitment of positive transcription elongation factor b (P-TEFb) to the LTR promoter. Consistent with these findings, we demonstrated that Tip110 interaction with Tat directly enhanced transcription elongation of the LTR promoter. During these studies, we also found that Tip110 altered HIV-1 mRNA alternative splicing and increased tat mRNA production. Subsequent analysis indicated that Tip110 selectively increased tat exons 1-2 splicing by activating HIV-1 A3 splice site but had no function in tat exons 2-3 splicing. We then showed that the preferential splicing activity of Tip110 resulted from Tip110 complex formation with hnRNP A1 protein, a negative splicing regulator that binds to the ESS2 element within tat exon 2, and as a result, blocked the complex formation of hnRNP A1 with ESS2 and subsequently activated HIV-1 A3 splice site. Taken together, these results show that Tip110 functions to regulate HIV-1 transcription elongation and HIV-1 RNA alternative splicing. These findings not only add to our understanding of Tip110 biology and function but also uncover a new potential target for development of anti-HIV intervention and therapeutic strategies

Impact of agricultural insurance on green agricultural production in China: Based on the mediation effect of agricultural technology progress

[Objective] Under the background of comprehensive green transformation of economic and social development, encouraging and developing agricultural insurance plays an important role in promoting green agricultural production, realizing high-quality agricultural development, and promoting rural revitalization and construction in China. [Methods] Firstly, we try to construct a research framework of Cobb-Douglas production function including agricultural insurance, agricultural technology progress and green agricultural production, and theoretically analyze the channels of agricultural insurance on green agricultural production. Secondly, based on the panel data of 31 provinces in China from 2011 to 2021, the index of green agricultural production level is constructed by entropy weight method, and the mixed regression, fixed effect and random effect and two-stage least squares method are used to empirically investigate the effect of agricultural insurance on green agricultural production by promoting agricultural technology progress. [Results] The study found that: (1) Agricultural insurance to promote agricultural technological progress is an important mechanism to promote green agricultural production ; the security of agricultural insurance can disperse the risks faced by agriculture, optimize the input of technical elements, eliminate traditional technologies with high pollution and high emissions, and produce substitution effects; the policy of agricultural insurance encourages farmers to pay for insurance through financial subsidies, improves the enthusiasm of farmers to grow crops, promotes the scale and mechanization of agriculture, and produces peer effects; (2) The effect of agricultural insurance on green agricultural production by promoting agricultural technological progress will show significant differences due to the different degrees of technological development in various provinces. Compared with regions with low agricultural green total factor productivity, agricultural insurance has a better effect on green agricultural production by promoting agricultural technology progress in regions with high agricultural green total factor productivity. Compared with areas with higher total power of agricultural machinery, the effect of agricultural insurance on green agricultural production by promoting agricultural technological progress is better in areas with lower total power of agricultural machinery. [Conclusion] The substitution effect and peer effect of agricultural insurance encourage farmers to adopt green low-carbon production technologies and facilitate agricultural green production. This article also put forward some policy recommendations, including government agencies leading the development, broadening and optimizing the participation of various parties in the development of green agriculture, and strengthening the professional and science and technology training of farmers

Modulation of Type III Secretion System in Pseudomonas aeruginosa: Involvement of the PA4857 Gene Product

Pseudomonas aeruginosais an opportunistic pathogen that causes serious acute or chronic infections in humans.Acute infections typically involve the type Ш secretion systems (T3SS) and bacterial motility,whereas chronic infectionsare often associated with biofilm formation and the type VI secretion system (T6SS). To identifynew genes required for pathogenesis, a transposon mutagenesis library was constructed and the gene PA4857, named tspR, was found to modulateT3SS gene expression. Deletion of P. aeruginosa tspRreduced the virulence in a mouse acute lung infection model and diminished cytotoxicity. Suppression of T3SS gene expression in the tspR mutant resulted from compromised translation of the T3SS master regulator ExsA. TspR negatively regulated two small RNAs, RsmYand RsmZ, which control RsmA. Our data demonstrated that defects inT3SS expression and biofilm formation in retS mutant could be partially restored by overexpression of tspR. Taken together, our results demonstrated thatthe newly identifiedretS-tspRpathway is coordinated with the retS-gacSsystem, which regulates the genes associated with acute and chronic infections andcontrols the lifestyle choice of P. aeruginosa

Human factors quantification via boundary identification of flight performance margin

AbstractA systematic methodology including a computational pilot model and a pattern recognition method is presented to identify the boundary of the flight performance margin for quantifying the human factors. The pilot model is proposed to correlate a set of quantitative human factors which represent the attributes and characteristics of a group of pilots. Three information processing components which are influenced by human factors are modeled: information perception, decision making, and action execution. By treating the human factors as stochastic variables that follow appropriate probability density functions, the effects of human factors on flight performance can be investigated through Monte Carlo (MC) simulation. Kernel density estimation algorithm is selected to find and rank the influential human factors. Subsequently, human factors are quantified through identifying the boundary of the flight performance margin by the k-nearest neighbor (k-NN) classifier. Simulation-based analysis shows that flight performance can be dramatically improved with the quantitative human factors

Florofangchinoline inhibits proliferation of osteosarcoma cells via targeting of histone H3 lysine 27 trimethylation and AMPK activation

Purpose: To investigate the effect of florofangchinoline on osteosarcoma cell growth in vitro, and the underlying mechanism of action.Methods: Changes in the viability of KHOS and Saos-2 cells were measured using water soluble tetrazolium salt (WST) assay, while apoptosis was determined using Annexin V/PI staining and flow cytometry. Increases in mtDNA, and expressions of PGC-1α and TFAM were assayed with immunoblot analysis and quantitative real-time polymerase chain reaction (qPCR), respectively.Results: Microscopic examination of florofangchinoline-treated cells showed significant decrease in cell density, relative to control cells (p < 0.05). Treatment with 10 μM florofangchinoline increased apoptosis in KHOS and Saos-2 cells to 56.32 and 63.75 %, respectively (p < 0.05). Florofangchinoline treatment markedly enhanced cleavage of caspase-3, caspase-8, caspase-9 and PARP. It elevated Bax level and reduced Bcl-2 in KHOS and Saos-2 cells. Moreover, florofangchinoline increased p21 and p-AMPKα levels, and mtDNA counts in KHOS and Saos-2 cells (p < 0.05). Moreover, in florofangchinoline-treated KHOS cells, the expressions of EED, EZH2 and SUZ12 were significantly suppressed (p < 0.05).Conclusion: Florofangchinoline inhibits osteosarcoma cell viability by activation of apoptosis. Moreover, it activates AMPK and down-regulates  histone H3 lysine 27 trimethylation in osteosarcoma cells. Therefore, florofangchinoline has potentials for development as a therapeutic drug forosteosarcoma. Keywords: Osteosarcoma, Histone H3, Florofangchinoline, Apoptosis, Chemotherapeuti

Portfolio-Based Incentive Mechanism Design for Cross-Device Federated Learning

In recent years, there has been a significant increase in attention towards designing incentive mechanisms for federated learning (FL). Tremendous existing studies attempt to design the solutions using various approaches (e.g., game theory, reinforcement learning) under different settings. Yet the design of incentive mechanism could be significantly biased in that clients' performance in many applications is stochastic and hard to estimate. Properly handling this stochasticity motivates this research, as it is not well addressed in pioneering literature. In this paper, we focus on cross-device FL and propose a multi-level FL architecture under the real scenarios. Considering the two properties of clients' situations: uncertainty, correlation, we propose FL Incentive Mechanism based on Portfolio theory (FL-IMP). As far as we are aware, this is the pioneering application of portfolio theory to incentive mechanism design aimed at resolving FL resource allocation problem. In order to more accurately reflect practical FL scenarios, we introduce the Federated Learning Agent-Based Model (FL-ABM) as a means of simulating autonomous clients. FL-ABM enables us to gain a deeper understanding of the factors that influence the system's outcomes. Experimental evaluations of our approach have extensively validated its effectiveness and superior performance in comparison to the benchmark methods

Ginkgolide K potentiates the protective effect of ketamine against intestinal ischemia/reperfusion injury by modulating NF-κB/ERK/JNK signaling pathway

Purpose: To investigate the effect of ginkgolide K and ketamine treatments, alone and in combination, on intestinal  ischemia/reperfusion injury (I/R)-induced injury in rats, as well as the mechanism involved. Methods: Rats were treated with ginkgolide K (GK, 15 mg/kg i.v) and ketamine (KTM, 100 mg/kg i.p.), either alone or in combination 30 min before the induction of intestinal I/R. The effects of GK and KTM were determined by assessing the levels of cytokines in serum, and parameters of oxidative stress and ROS production in the intestinal tissues of I/R rats. Moreover, intestinal mRNA expressions of JNK, ERK, p38 and NF-kB were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: GK and KTM treatments, alone and in combination, reduced cytokine levels in serum and oxidative stress parameters in intestinal tissues, when compared to I/R group of rats. Treatments with GK and KTM, alone and in combination, mitigated the altered mRNA expressions of JNK, ERK, p38 and NF-kB in intestinal tissues of I/R-injured rats. Conclusion: These results reveal that GK potentiates the protective effect of KTM100 on I/R-induced intestinal injury in rats by regulating the NF-kB/ERK/JNK signaling pathway. Therefore, GK and KTM may find use in the management of I/R Keywords: Ginkgolide K, Ketamine, Intestinal injury, Ischemia/Reperfusion, Inflammatio

Modeling of Causes of Sina Weibo Continuance Intention with Mediation of Gender Effects

Sina Weibo is a Twitter-like social networking site and one of the most popular microblogging services in China. This study aims to examine the factors that influence the intentions of users to continue using this site. This paper synthesizes the expectation confirmation model (ECM), constructs of habit and perceived critical mass, and the gender effect to construct a theoretical model to explain and predict these user intentions. The model is then tested via an online survey of 498 Sina Weibo users and partial least squares (PLS) modeling. The results indicate that the continuance intention of users is directly predicted by their perceived usefulness of the service (β=0.299), their satisfaction (β=0.208), and their habits (β=0.389), which jointly explain 65.9% of the variance in intention. In addition to the effects of these predictors on the continuance intentions of Sina Weibo users, an assessment of the moderating effect of gender suggests that habit plays a more important role for females than for males in continuance intention, but perceived usefulness seems to be more important for males than for females. The implications of these findings are then discussed

Conjoint and dissociated structural and functional abnormalities in first-episode drug-naive patients with major depressive disorder: a multimodal meta-analysis

Published MRI evidence of structural and resting-state functional brain abnormalities in MDD has been inconsistent. To eliminate interference by repeated disease episodes and antidepressant treatment, we conducted the first multimodal voxel-wise meta-analysis of studies of voxel-based morphometry (VBM) and the amplitude of low-frequency fluctuation (ALFF) in first-episode drug-naive MDD patients, using the Seed-based d Mapping method (SDM). Fifteen VBM data sets and 11 ALFF data sets were included. SDM-based multimodal meta-analysis was used to highlight brain regions with both structural and functional abnormalities. This identified conjoint structural and functional abnormalities in left lateral orbitofrontal cortex and right supplementary motor area, and also dissociated abnormalities of structure (decreased grey matter in right dorsolateral prefrontal cortex and right inferior temporal gyrus; increased grey matter in right insula, right putamen, left temporal pole, and bilateral thalamus) and function (increased brain activity in left supplementary motor area, left parahippocampal gyrus, and hippocampus; decreased brain activity in right lateral orbitofrontal cortex). This study reveals a complex pattern of conjoint and dissociated structural and functional abnormalities, supporting the involvement of basal ganglia-thalamocortical circuits, representing emotional, cognitive and psychomotor abnormalities, in the pathophysiology of early-stage MDD. Specifically, this study adds to Psychoradiology, an emerging subspecialty of radiology, which seems primed to play a major clinical role in guiding diagnostic and treatment planning decisions in patients with mental disorder

Effects of synthetic colloids on oxidative stress and inflammatory response in hemorrhagic shock: comparison of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin

INTRODUCTION: This study compared the effects of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model. METHODS: Sodium pentobarbital-anesthetized adult male Wistar rats (200 g to 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg to 33 mL/kg) and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured two hours after resuscitation. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 in the intestine were also measured. RESULTS: Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs and brain, and it also inhibited the production of TNF-α in the intestine two hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed. CONCLUSIONS: Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 or succinylated gelatin administration at doses of approximately 33 mL/kg