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Background: Viral infection elicits the type I interferon (IFN-I) response in host cells and subsequently inhibits viral infection through inducing hundreds of IFN-stimulated genes (ISGs) that counteract many steps in the virus life cycle. However, most of ISGs have unclear functions and mechanisms in viral infection. Thus, more work is required to elucidate the role and mechanisms of individual ISGs against different types of viruses. Results: Herein, we demonstrate that poliovirus receptor-like protein4 (PVRL4) is an ISG strongly induced by IFN-I stimulation and various viral infections. Overexpression of PVRL4 protein broadly restricts growth of enveloped RNA and DNA viruses, including vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whereas deletion of PVRL4 in host cells increases viral infections. Mechanistically, it suppresses viral entry by blocking viral-cellular membrane fusion through inhibiting endosomal acidification. The vivo studies demonstrate that Pvrl4-deficient mice were more susceptible to the infection of VSV and IAV. Conclusion: Overall, our studies not only identify PVRL4 as an intrinsic broad-spectrum antiviral ISG, but also provide a candidate host-directed target for antiviral therapy against various viruses including SARS-CoV-2 and its variants in the future. [ABSTRACT FROM AUTHOR]

Introduction: The HIV response has long recognized that certain "key populations" such as individuals in detention, adolescent girls and young women, sex workers, people who use drugs, LGBTQ individuals, migrants and others face higher barriers to access to, uptake of, and retention in HIV prevention and treatment services. One approach to addressing these barriers is the training of community paralegals to advocate for the rights of individuals and to address discrimination in health settings. Discussion: Community paralegal programmes have been able to successfully address rights violations that impact access to health services and underlying determinants of health across a range of countries and populations, focusing upon issues such as discrimination and the denial of health services; unlawful detention of outreach workers, sex workers, persons who use drugs and men who have sex with men; and harmful traditional practices and gender‐based violence. In addition to resolving specific cases, evaluations of paralegal programmes have found that these programmes increased legal literacy among key populations at risk of HIV and increased understanding of human rights among healthcare providers, resulting in improved access to HIV services. Some evaluations have noted challenges related to the sustainability of paralegal programmes similar to those raised with community health worker programmes more broadly. Conclusions: To achieve global HIV goals, funding for legal literacy and paralegal programmes should be increased and interventions should be rigorously evaluated. Efforts should target discrimination in access to HIV prevention and treatment and criminalization of key populations, two key barriers to ensuring access to HIV prevention and treatment services. [ABSTRACT FROM AUTHOR]

Background: Non‐small cell lung cancer (NSCLC) accounts for 85% of lung cancer which is the most frequently diagnosed malignancy in China. Colon cancer associated transcript 1 (CCAT1) acts as an oncogene in enhancing tumor progression. However, the effects of CCAT1 in NSCLC remain unclear. The purpose of this study was to explore the role of CCAT1 in NSCLC. Methods: Wound healing and transwell assays were performed to measure cell migration. RT‐qPCR was employed to calculate the mRNA level of CCAT1 and miR‐490. Results: High expression of CCAT1 was observed in NSCLC tissues and cells, with low expression of miR‐490. CCAT1 promoted the proliferation and metastasis of H1299 and A549 cells, while miR‐490 had the opposite effect. CCAT1 could specifically bind to miR‐490 and regulate its expression. MiR‐490 partially reversed the inhibitory effect of CCAT1 on cell proliferation and metastasis. Conclusions: The CCAT1/miR‐490 molecular axis has been shown to be important for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

The imbalance of Th17/Treg cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Caveolin-1 (Cav-1) has been regarded as a potential critical regulatory protein in pathological mechanisms of chronic inflammatory respiratory diseases. Therefore, we investigated whether the loss of Cav-1 is involved in the homeostasis of Th17/Treg cells in COPD. We examined the expressions of plasma Cav-1 and circulating Th17, Treg cells, and the related cytokines in patients with COPD. Enzyme-linked immunosorbent assay (ELISA) analyses showed a significant reduction of plasma Cav-1 levels in patients with stable COPD (SCOPD) and acutely exacerbated COPD (AECOPD) compared to smokers without COPD. This loss was associated with an increase in frequency of Treg and decreased in frequency of Th17 cells. To further identify the role of Cav-1, we studied the effects of Cav-1 overexpression or downregulation on frequencies of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects. Interestingly, small interfering RNA (siRNA) downregulation of Cav-1 was accompanied by an augmentation of Treg and reduction of Th17 expression. Together, our study demonstrated that the loss of Cav-1 contributed to the imbalance of Th17/Treg cells in patients with COPD. [ABSTRACT FROM AUTHOR]

Metabolic intermediates, such as succinate and citrate, regulate important processes ranging from energy metabolism to fatty acid synthesis. Cytosolic concentrations of these metabolites are controlled, in part, by members of the SLC13 gene family. The molecular mechanism underlying Na+-coupled di- and tricarboxylate transport by this family is understood poorly. The human Na+/dicarboxylate cotransporter NaDC3 (SLC13A3) is found in various tissues, including the kidney, liver, and brain. In addition to citric acid cycle intermediates such as α-ketoglutarate and succinate, NaDC3 transports other compounds into cells, including N-acetyl aspartate, mercaptosuccinate, and glutathione, in keeping with its dual roles in cell nutrition and detoxification. In this study, we construct a homology structural model of NaDC3 on the basis of the structure of the Vibrio cholerae homolog vcINDY. Our computations are followed by experimental testing of the predicted NaDC3 structure and mode of interaction with various substrates. The results of this study show that the substrate and cation binding domains of NaDC3 are composed of residues in the opposing hairpin loops and unwound portions of adjacent helices. Furthermore, these results provide a possible explanation for the differential substrate specificity among dicarboxylate transporters that underpin their diverse biological roles in metabolism and detoxification. The structural model of NaDC3 provides a framework for understanding substrate selectivity and the Na+-coupled anion transport mechanism by the human SLC13 family and other key solute carrier transporters. [ABSTRACT FROM AUTHOR]

The SdcF transporter from Bacillus licheniformis (gene BL02343) is a member of the divalent anion sodium symporter (DASS)/SLC13 family that includes Na/dicarboxylate transporters from bacteria to humans. SdcF was functionally expressed in Escherichia coli (BL21) and assayed in right side out membrane vesicles. ScdF catalyzed the sodium-coupled transport of succinate and α-ketoglutarate. Succinate transport was strongly inhibited by malate, fumarate, tartrate, oxaloacetate and l-aspartate. Similar to the other DASS transporters, succinate transport by SdcF was inhibited by anthranilic acids, N-( p-amylcinnamoyl) anthranilic acid and flufenamate. SdcF transport was cation-dependent, with a K for sodium of ~1.5 mM and a K for Li of ~40 mM. Succinate transport kinetics by SdcF were sigmoidal, suggesting that SdcF may contain two cooperative substrate binding sites. The results support an ordered binding mechanism for SdcF in which sodium binds first and succinate binds last. We conclude that SdcF is a secondary active transporter for four- and five-carbon dicarboxylates that can use Na or Li as a driving cation. [ABSTRACT FROM AUTHOR]

The Na+/dicarboxylate symporter from Staphylococcus aureus, named SdcS, is a member of the divalent anion sodium symporter (DASS) family that also includes the mammalian SLC13 Na+/dicarboxylate cotransporters, NaDC1 and NaCT. The mammalian members of the family are sensitive to inhibition by anthranilic acid derivatives such as N-(p-amylcinnamoyl)anthranilic acid (ACA), which act as slow inhibitors. This study shows that SdcS is inhibited by ACA as well as the fenamate nonsteroidal anti-inflammatory drugs, flufenamate and niflumate. The inhibition was rapid and reversible. The IC50 for ACA was approximately 55 μM. Succinate kinetics by SdcS were sigmoidal, with a K0.5 of 9 μM and a Hill coefficient of 1.5. Addition of ACA decreased the Vmax and increased the Hill coefficient without affecting the K0.5, consistent with its activity as a negative modulator of SdcS activity. ACA inhibition was not correlated with the K0.5 for succinate in SdcS mutants, and ACA did not affect the reactivity of the N108C mutant to the cysteine reagent, MTSET. We conclude that ACA and other anthranilic acid derivatives are effective allosteric inhibitors of SdcS. Furthermore, the mechanism of inhibition appears to be distinct from the mechanism observed in human NaDC1. [ABSTRACT FROM AUTHOR]

Abstract: Citric acid cycle intermediates, including succinate and citrate, are absorbed across the apical membrane by the NaDC1 Na+/dicarboxylate cotransporter located in the kidney and small intestine. The secondary structure model of NaDC1 contains 11 transmembrane helices (TM). TM7 was shown previously to contain determinants of citrate affinity, and Arg-349 at the extracellular end of the helix is required for transport. The present study involved cysteine scanning mutagenesis of 26 amino acids in TM7 and the associated loops. All of the mutants were well expressed on the plasma membrane, but many had low or no transport activity: 6 were inactive and 7 had activity less than 25% of the parental. Three of the mutants had notable changes in functional properties. F336C had increased transport activity due to an increased V max for succinate. The conserved residue F339C had very low transport activity and a change in substrate selectivity. G356C in the putative extracellular loop was the only cysteine mutant that was affected by the membrane-impermeant cysteine reagent, MTSET. However, direct labeling of G356C with MTSEA-biotin gave a weak signal, indicating that this residue is not readily accessible to more bulky reagents. The results suggest that the amino acids of TM7 are functionally important because their replacement by cysteine had large effects on transport activity. However, most of TM7 does not appear to be accessible to the extracellular fluid and is likely to be an outer helix in contact with the lipid bilayer. [Copyright &y& Elsevier]

The sodium-couple transport of citric acid cycle intermediates in the intestine and kidney is mediated by the Na+-dicarboxylate cotransporter, NaDCI. In the kidney, NaDC1 plays an important role in regulating succinate and citrate concentrations in the urine, which may have physiological consequences including the development of kidney stones. In the present study, the impact of nonsynonymous single nucleotide polymorphisms (SNPs) on NaDCI expression and function was characterized using the COS-7 cell heterologous expression system. The 1550V variant had an increased sensitivity to lithium inhibition although there were no significant effects on protein abundance. The L44F variant had no significant effects on expression or function. The membrane protein abundance of the M45L, VII71, and F254L variants was decreased, with corresponding decreases in transport activity. The A310P variant had decreased protein abundance as well as a change in substrate selectivity. The P385S variant had a large decrease in succinate transport Vmax, as well as altered substrate selectivity, and a change in the protein glycosylation pattern. The most damaging variant was V477M, which had decreased affinity for both succinate and sodium. The V477M variant also exhibited stimulation by lithium, indicating a change in the high-affinity cation binding site. We conclude that most of the naturally occurring nonsynonymous SNPs affect protein processing of NaDC1, and several also affect functional properties. All of these mutations are predicted to decrease transport activity in vivo, which would result in decreased intestinal and renal absorption of citric acid cycle intermediates. [ABSTRACT FROM AUTHOR]

Neprilysin ( NEP) is a key cell surface peptidase in the maintenance of airway homeostasis and the development of pulmonary disorders. However, little information is available about the effect of particulate matter (PM) on airway NEP. In this controlled human exposure study, changes in induced sputum were measured in 11 subjects at baseline, overshot (OS) mucking, and diesel exhaust (DE) exposure days. Neither OS condition nor DE exposure was found to induce significant changes in total protein, but DE induced significant increases in cell numbers of macrophages and epithelium. Moreover, significant increases in soluble NEP were observed following OS mining dust particulates (0.43 ± 0.06 nmol/μg protein/min; p = .023) and DE exposure (0.40 ± 0.03 nmol/μg protein/min; p = .035) when compared with the baseline control (0.30 ± 0.04 nmol/μg protein/min), with 42% and 31% average net increase, respectively. Pearson’s correlation analyses indicated that sputum NEP activity was significantly associated with personal exposure product (elemental carbon concentration [mg/m3] × time [min]; C × T). The data suggest that changes in NEP activity may be an early, accurate endpoint for airway epithelial injury and provide a new insight into the mechanism of airway effects following particulate exposure. [ABSTRACT FROM AUTHOR]

The effects of JP-8 on pro-inflammatory cytokine interleukin (IL)-1α,β and nitric oxide (NO) secretion as well as the role of substance P (SP) in these processes were examined in cultured alveolar macrophages (AM), type II epithelial cells (AIIE), and AM/AIIE co-cultures. Exposure of AM to JP-8 for 24 hr exhibited release of IL-1α,β, whereas exposure to AIIE showed a concentration-dependent NO overproduction. Data indicate that there are cell-dependent inflammatory mechanisms responsible for the actual level of JP-8 exposure in alveoli. However, treatment with substance P significantly attenuated JP-8 induced the IL-1α,β secretion. This finding was confirmed by using [Sar9 Met (O2)11] SP (10- 10 M), an agonist of substance P, suggesting that substance P may have signal pathway(s) to AM in the inflammatory response mediated by IL-1. Moreover, AM/AIIE co-culture obviously reduced NO overproduction observed in AIIE alone, suggesting that there may be cell interactions or communications between AM and AIIE in response to the JP-8 exposure. [ABSTRACT FROM AUTHOR]

To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time- course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability. [ABSTRACT FROM AUTHOR]

To evaluate the role of substance P (SP)-containing C-fiber nerves in the development of the inflammatory responses to sidestream cigarette smoke (SSCS), female Fischer 344 rats were randomly assigned into vehicle and capsaicin groups, respectively. Then, half the number in each group (N=24) was nose-only exposed to air or 0.4 mg/m3 total particulate matter of SSCS for 4 h/day for 7 days. Exposure of the vehicle rats to SSCS induced obvious pulmonary neurogenic inflammation as indicated by elevations in plasma extravasation and proinflammatory cytokine secretions [interieukin (IL)-1β and IL-12]. In addition, except for SP release, SSCS exposure significantly induced the tachykininergic toxicities at the gene level: upregulation of β-preprotachykinin-I (β-PPT-I) mRNA. However, neither SSCS exposure nor capsaicin pretreatment affects the immunolabeling density of neurokinin-1 receptor (NK-1R) in airway epithelium. SSCS also significantly inactivated pulmonary neutral endopeptidase (NEP) in lung tissue. Moreover, pretreatment with capsaicin significantly exacerbated the SSCS-induced inflammatory responses mentioned above as well as the release of plasma protein. Considering that capsaicin did not affect the normal control baselines of these parameters except for a decrease in NK-1R mRNA, we conclude that the degree of SSCS-induced inflammatory response was exacerbated because of the depletion of stored SP and/or inactivation of capsaicin-sensitive C-fiber nerves. Our data suggest the loss of afferent tachykinin SP signaling may lead to dysfunction of the sensory C-fiber nerve reflexes during exposure to SSCS, suggesting that SP serves a protective role. [Copyright &y& Elsevier]

This study characterizes the molecular neurotoxicity of diesel exhaust (DE) on the tachykinin substance P (SP) signaling system in the lungs. A total of 96 female Fischer 344/NH rats (~175 g, ~4 weeks old) were randomly assigned to eight groups in a 2×4 factorial design: capsaicin versus non-capsaicin (vehicle) pretreatment, and filtered room air versus two exposure levels of DE with diesel engine room control. The rats were exposed nose-only to room air or low (35.3 µg/m3) and high concentrations (669.3 µg/m3) particulates directly from a Cummins N14 research engine at 75% throttle for 4 h/day, 5 days/week, for 3 weeks. The findings showed that exposure to DE dose-dependently induced bronchopulmonary neurogenic inflammation, both in capsaicin- and vehicle-pretreated rats, as measured by plasma extravasation, edema, and inflammatory cells. DE inhalation affected the SP signaling processes, including stored SP depletion and the gene/protein overexpression for neurokinin-1 receptor. DE also significantly reduced the activity of neutral endopeptidase, a main degradation enzyme for SP. Consequently, these changes may be regarded as critical factors that switched neurogenic pulmonary responses from their protective functions to a detrimental role that perpetuates lung inflammation. These changes may possibly be associated with the mass concentration of DE particles due to their physico-chemical characteristics. Moreover, capsaicin-pretreated rats had more sensitivity to these levels of DE exposure due to stimulation of bronchopulmonary C-fibers. However, the effects of capsaicin treatment were not consistent and apparent in this study. Taken together, our findings suggest that neurokininergic mechanisms may possibly be involved in DE-induced lung inflammation, but that bronchopulmonary C-fibers did not dominate DE-induced inflammatory abnormalities. [ABSTRACT FROM AUTHOR]

The increased morbidity of childhood leukemia in Fallon, Nevada and Sierra Vista, Arizona has prompted great health concern. The main characteristic that these two towns share is the environmental pollution attributed to metal ore from abandoned mining operations. Consequently, we have investigated the transcriptome effects of metal ores from these endemic areas using a human T-cell acute lymphoblastic leukemia cell line (T-ALL). Metal ore from Fallon significantly increased cell growth after 24, 48 and 72 h of incubation at 1.5 μg/mL concentration, as measured by trypan-blue. Sierra Vista ore significantly increased cell growth with 0.15 and 1.5 μg/mL following 72 h of incubation. From human cDNA microarray, results indicate that in total, eight genes, mostly metallothionein (MT) genes, were up-regulated and 10 genes were down-regulated following treatment of the T-ALL cells with 0.15 and 1.5 μg/mL of metal ores at 72 h, in comparison with untreated cells. Twenty-eight metals of both ores were quantified and their presence may be associated with the cell growth rate and dose-dependent activation of transcriptomes in immature T-cells. [ABSTRACT FROM AUTHOR]

Neurokinin-1 receptor (NK-1R), a high-affinity plasma membrane-bound receptor for neurokinin substance P, plays important roles in the onset of the pathophysiological responses. To test whether the transcript levels of gene encoding NK-1R in organs are affected by sidestream cigarette smoke (SSCS) exposure, the C57BL/6 mice were randomly assigned to five groups (six/group) in a study of the dose-effect relationship. The mice were exposed to 0 (filtered room air), 2, 4, 8 and 16 mg total particulate matter (TPM) of SSCS/exposure/day, respectively, for seven days through a nose-only exposure chamber (IN-TOX, Albuquerque, NM, USA). The levels of NK-1R mRNA in the lung, heart, liver, kidney and spleen tissues were detected by reverse transcription-polymerase chain reaction (RT-PCR) techniques and normalized against GAPDH expression. NK-1R mRNA in heart tissue showed SSCS-induced dose-dependent downregulation, with minimum expression at a dose of 8.0 mg TPM. Whereas, the levels of NK-1R mRNA in the liver were upregulated to 2.86 and 5.13- fold after exposure to 2.0 and 4.0 mg TPM of SSCS respectively, then returned to 4.19 and 3.93-fold at the exposure doses of 8.0 and 16.0 mg TPM, respectively, when compared to that of the control. In the kidney, SSCS exposure at a dose of 2.0 TPM, but not higher than that level, induced significant elevation of NK-1R mRNA expression. These findings suggest that there are the paracrine and/or autocrine signalling mechanisms through receptor-ligand interactions. No alteration of NK-1R gene expression was observed in the lungs and spleen tissues in this study.The tissue-specific patterns by which SSCS affect NK-1R gene expression in these organs may partially explain dissimilarity of NK-1R activation and the associated toxicity caused by environmental tobacco smoke. [ABSTRACT FROM AUTHOR]

Several recent epidemiological investigations raise serious questions about the health effects of high-dose supplements of Vitamin E (VE) in cigarette smokers. To examine these findings, a total of 96 C57BL/6 mice were randomly assigned to eight groups in a 2×4 factorial design (smoke vs. sham smoke and normal diet vs. 3 VE supplements). The mice were exposed to sidestream cigarette smoke (SSCS), at 0.4 mg total particulate matter/m3 air, from standard research cigarettes (1R4)/day or filtered room air at 30 min/day, 5 days/week, for 9 weeks through a nose-only exposure chamber. The American Institute of Nutrition 93G purified rodent diet was modulated with 75 (regular diet, 1-fold), 1050 (15-fold), 5550 (75-fold), and 11 175 (150-fold) IU dl-α-tocopherol acetate (α-TA)/kg as VE supplementation and provided ad libitum at an average intake rate of 4.11 g diet/mouse/day. This result demonstrated that SSCS exposure results in lung dysfunction, as indicated by a decrease of pulmonary dynamic compliance (Cdyn) and increase of lung resistance (RL), and body weight loss in mice fed with regular diet. These changes accompanied with increases of bronchoalveolar lavage (BAL) concentrations of cytokines interleukin (IL)-1β, IL-4 and IFN-γ, as well as hepatic lipid peroxidation. However, supplemental α-TA at the doses of ⩾1050 IU/kg diet prevented the SSCS-induced body weight loss and lung dysfunction. α-TA at ⩾5550 IU/kg significantly increased BAL levels of IL-2 and IL-4 in both the sham SSCS and the SSCS groups. Given at 5550 IU α-TA/kg, but not higher, mice elevated BAL IL-1β level if they were exposed to SSCS. Hepatic lipid peroxidation was decreased in a dose-dependent fashion with different α-TA supplements in both the sham SSCS and SSCS groups. Neither SSCS nor α-TA had an effect on lung permeability, BAL IL-6, splenic T and B lymphocyte proliferation and their T helper (Th)1 and Th2 cytokines measured among all groups. Data suggest that supplemental α-TA may be needed to counteract SSCS-induced oxidative stress, but that potential side effects introduced by high dosage of this synthetic compound should be considered. [Copyright &y& Elsevier]

Examines the molecular cloning, chromosomal organization, and functional characterization of the sodium-dicarboxylate cotransporter mNaDC-1 from the mouse kidney. Exon/intron organization of the mouse Slc13a2 gene; Substrate kinetics in oocytes expressing mNaDC-1; Functional characterization of mNADC-1.

Presents a study which discussed the gene structure and functional properties of the sodium-dicarboxylate cotransporter of a mouse renal proximal tubule. Methodology; Results; Discussion.

In an environment fraught with uncertainty, supply chains encounter disruptions in supply. Amidst the dual challenges posed by the global technological revolution and the frequent emergence of public emergencies, the significance of emergency response capability within industrial internet projects has become increasingly pronounced. Due to the influence of uncertain factors, the implementation of strategies for building emergency capacity is subject to randomness. Therefore, taking into account the impact of random factors, this paper establishes three cooperation models for enhancing emergency response capability in vertical, horizontal, and collaborative scenarios using a stochastic differential game model. Subsequently, it explores the effects of different cooperation modes and random factors on the enhancement of emergency response capability. The findings indicate that the most effective approach to improving emergency capacity involves the participation, resource sharing, and collaborative efforts of all major stakeholders in the industrial internet supply chain. However, varying risk preferences and specific circumstances may lead to the adoption of different cooperation modes, suggesting that collaboration may not always be the optimal choice. Decision-makers can leverage the insights from this study to identify suitable cooperation modes and devise emergency capacity-building strategies for enhancing supply chain emergency response capability during crises, thereby ensuring the smooth implementation of industrial internet projects. [ABSTRACT FROM AUTHOR]

They were intended to provide a framework for a rights-based response to the HIV epidemic and recognized that an extensive array of human rights are critical to a successful HIV response (Box). Twenty-three years later, as is often the case in the fight for human rights, much has changed, but much still needs to change to ensure respect for human rights, to uphold the principles outlined in the Guidelines, and to bring to scale rights-based HIV programmes. Yet, recognition within the HIV response of the scale and the specific contribution of violence against women to HIV vulnerability is sometimes missing, even though women who have experienced physical or sexual intimate partner violence are estimated to be 50% more likely to be living with HIV [14]. The success of the HIV response to date has been founded on human rights principles, such as recognizing the equal dignity and worth of all persons, as well as the meaningful involvement of affected communities and people living with HIV (GIPA). [Extracted from the article]

Most of the existing virtual scenarios built for the digital protection of Chinese classical private gardens are too modern in expression style to show the aesthetic significance of their historical period. Considering the aesthetic commonality between traditional Chinese landscape paintings and classical private gardens and referring to image style transfer, here, a deep neural network was proposed to transfer the aesthetic style from landscape paintings to the virtual scenario of classical private gardens. The network consisted of two parts: style prediction and style transfer. The style prediction network was used to obtain style representation from style paintings, and the style transfer network was used to transfer style representation to the content scenario. The pre-trained network was then embedded into the scenario rendering pipeline and combined with the screen post-processing method to realise the stylised expression of the virtual scenario. To verify the feasibility of this methodology, a virtual scenario of the Humble Administrator's Garden was used as the content scenario and five garden landscape paintings from different time periods and painting styles were selected for the case study. The results demonstrated that this methodology could effectively achieve the aesthetic style transfer of a virtual scenario. [ABSTRACT FROM AUTHOR]

Our study has demonstrated that epithelial neutral endopeptidase (NEP) was down-regulated transcriptionally by diesel exhaust particulate (DEP) exposure. To further understand the impact of NEP loss in epithelial response to DEP, we collected transcriptome profiles of the concentration-effects of DEP in BEAS-2B cells through a 2 X 3 factorial design [NEP siRNA transfected vs. mock cells and controls vs. low, high DEP exposure]. Microarray data clearly indicated that DEP exposure induced numerous gene up- or down-regulation involving transcription factor activities, DNA/protein binding, and intracellular signaling cascade of chemokines, and cytokines. DEP also disturbed many gene transcriptions relating to cellular monooxygenase, GTPase, and protein kinase activities. Moreover, the integration of microarray with RNAi technique helped us to find that NEP plays an important role in the particulate relevant cellular response or the genetic susceptibility to particulate exposure. These identified genes include signal transduction of interleukin (IL)-6, IL-8, and chemokine(C-X-C motif) legend 1. NEP expression was also associated with the metabolic capability of cytochrome P450 family (CYP1A1, CYP1B1) for DEP. Collectively, the data revealed that there exists a complex molecular cascade mediated by NEP in different subcellular compartments, further influencing normal cellular functions. [ABSTRACT FROM AUTHOR]

Background: Recognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions. Results: Here we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV). Conclusion: Thus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins. [ABSTRACT FROM AUTHOR]

Introduction Evidence suggests that people who inject drugs often begin their drug use and injecting practices in adolescence, yet there are limited data available on the HIV epidemic and the responses for this population. The comprehensive package of interventions for the prevention, treatment and care of HIV infection among people who inject drugs first laid out in 2009 (revised in 2012) by World Health Organization, United Nations Office of Drugs and Crime and Joint United Nations Programme on HIV/AIDS, does not consider the unique needs of adolescent and young people. In order to better understand the values and preferences of young people who inject drugs in accessing harm reduction services and support, we undertook a series of community consultations with young people with experience of injecting drugs during adolescence. Methods Community consultations (4-14 persons) were held in 14 countries. Participants were recruited using a combined criterion and maximum variation sampling strategy. Data were analyzed using collaborative qualitative data analysis. Frequency analysis of themes was conducted. Results Nineteen community consultations were organized with a total of 132 participants. All participants had experienced injecting drugs before the age of 18. They had the following age distribution: 18-20 (37%), 21-25 (48%) and 26-30 (15%). Of the participants, 73.5% were male while 25.7% were female, with one transgender participant. Barriers to accessing the comprehensive package included: lack of information and knowledge of services, age restrictions on services, belief that services were not needed, fear of law enforcement, fear of stigma, lack of concern, high cost, lack of outreach, lack of knowledge of HCV/TB and lack of youth friendly services. Conclusions The consultations provide a rare insight into the lived experiences of adolescents who inject drugs and highlight the dissonance between their reality and current policy and programmatic approaches. Findings suggest that harm reduction and HIV policies and programmes should adapt the comprehensive package to reach young people and explore linkages to other sectors such as education and employment to ensure they are fully supported and protected. Continued participation of the community of young people who inject drugs can help ensure policy and programmes respond to the social exclusion and denial of rights and prevent HIV infection among adolescents who inject drugs. [ABSTRACT FROM AUTHOR]

Introduction: Evidence suggests that people who inject drugs often begin their drug use and injecting practices in adolescence, yet there are limited data available on the HIV epidemic and the responses for this population. The comprehensive package of interventions for the prevention, treatment and care of HIV infection among people who inject drugs first laid out in 2009 (revised in 2012) by World Health Organization, United Nations Office of Drugs and Crime and Joint United Nations Programme on HIV/AIDS, does not consider the unique needs of adolescent and young people. In order to better understand the values and preferences of young people who inject drugs in accessing harm reduction services and support, we undertook a series of community consultations with young people with experience of injecting drugs during adolescence. Methods: Community consultations (4–14 persons) were held in 14 countries. Participants were recruited using a combined criterion and maximum variation sampling strategy. Data were analyzed using collaborative qualitative data analysis. Frequency analysis of themes was conducted. Results: Nineteen community consultations were organized with a total of 132 participants. All participants had experienced injecting drugs before the age of 18. They had the following age distribution: 18–20 (37%), 21–25 (48%) and 26–30 (15%). Of the participants, 73.5% were male while 25.7% were female, with one transgender participant. Barriers to accessing the comprehensive package included: lack of information and knowledge of services, age restrictions on services, belief that services were not needed, fear of law enforcement, fear of stigma, lack of concern, high cost, lack of outreach, lack of knowledge of HCV/TB and lack of youth friendly services. Conclusions: The consultations provide a rare insight into the lived experiences of adolescents who inject drugs and highlight the dissonance between their reality and current policy and programmatic approaches. Findings suggest that harm reduction and HIV policies and programmes should adapt the comprehensive package to reach young people and explore linkages to other sectors such as education and employment to ensure they are fully supported and protected. Continued participation of the community of young people who inject drugs can help ensure policy and programmes respond to the social exclusion and denial of rights and prevent HIV infection among adolescents who inject drugs. [ABSTRACT FROM AUTHOR]

To examine the hypothesis that Jet Propulsion Fuel (JP-8) inhalation potentiates influenza virus-induced inflammatory responses, we randomly divided female C57BL/6 mice (4-weeks old, weighing approximately 24.6 g) into the following groups: air control, JP-8 alone (1023 mg/m3 of JP-8 for 1 h/day for 7 days), A/Hong Kong/8/68 influenza virus (HKV) alone (a 10 μl aliquot of 2000 viral titer in the nasal passages), and a combination of JP-8 with HKV (JP-8 + HKV). The HKV alone group exhibited significantly increased total cell number/granulocyte differential in bronchoalveolar lavage fluid (BALF) compared to controls whereas the JP-8 alone group did not. The JP-8 + HKV group further exacerbated the HKV alone-induced response. However, increases in pulmonary microvascular permeability and pathological alterations in JP-8 + HKV just matched the sum of JP-8 alone- and HKV alone-induced response. Increases in BALF substance P in the JP-8 alone group and BALF leukotriene B4 or total lung compliance in the HKV alone group, respectively were similar to the changes in the JP-8 + HKV group. These findings suggest that changes in the JP-8 + HKV group may be attributed to either JP-8 inhalation or HKV treatment and indicate the different physiological responses to either JP-8 or HKV exposure. Taken together, most of the data did not provide supporting evidence that JP-8 inhalation synergizes influenza virus-induced inflammatory responses. [Copyright &y& Elsevier]

Alveolar type II epithelial cells (AIIE) and pulmonary alveolar macrophages (PAM) are involved in pulmonary toxicity of JP-8 jet fuel exposure. To further elucidate their inflammatory mechanisms, the effect(s) of JP-8 jet fuel on cytokine secretion were examined in a transformed rat AIIE cell line (RLE-6TN) culture alone, primary PAM (from Fischer 344 rats) culture alone, and the co-culture of AIIE and primary PAM. A series of JP-8 jet fuel concentrations (0–0.8 μg/ml), which may actually be encountered in alveolar space of lungs exposed in vivo, were placed in cell culture for 24 h. Cultured AIIE alone secreted spontaneously interleukin (IL)-1β and -6 [below detectable limits for IL-10 and tumor necrosis factor-α (TNF-α)], whereas cultured PAM alone secreted IL-1β, -10, and TNF-α, in a concentration-dependent manner. These data suggest that the release of cytokines, not only from PAM but also from AIIE cells, may contribute to JP-8 jet fuel-induced inflammatory response in the alveolar space. However, the co-cultures of AIIE and PAM showed no significant changes in IL-1β, -6, and TNF-α at any JP-8 jet fuel concentration compared to control values. These cytokine levels in co-cultures of AIIE and PAM were inversely related to these of cultured AIIE or PAM alone. Interestingly, IL-10 levels in the co-culture system were concentration-dependently increased up to 1058% at JP-8 concentrations of 0.8 μg/ml, although under detectable limits in cultured AIIE alone and no significant concentration change in cultured PAM alone. It appears that PAM may possibly act via paracrine and/or autocrine pathways to signal AIIE cells to regulate cytokine release. [Copyright &y& Elsevier]

Background: Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Methods: The study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11−/−, PARP12−/− and PARP11−/−PARP12−/− HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12. Results: Both mRNA and protein levels of PARP11 were induced in WT but not IFNAR1−/− cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11−/− cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation. Conclusion: We identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection. [ABSTRACT FROM AUTHOR]

Dickkopf-related protein 1 (DKK1) is essential to gastric cancer as an inhibitor of Wnt signaling. Gastric intestinal metaplasia (GIM) is an important precancerous lesion of gastric cancer that can be activated by bile acid reflux and chronic inflammation. However, the exact mechanism of DKK1 in bile acid-induced GIM has not been completely elucidated. We aimed to explore the epigenetic alterations and biological functions of DKK1 in the development of GIM. In the present study, bile acid was found to induce the expression of intestinal markers in gastric epithelial cells, whereas DKK1 was downregulated in response to bile acid stimulation. The mRNA and protein expression levels of DKK1 were decreased in GIM tissues as evidenced by qRT-PCR and immunohistochemical staining. Surprisingly, the methylation of the DKK1 promoter increased in GIM tissues, and we discovered 28 differential methylation sites of the DKK1 promoter in GIM tissues. Bile acid was able to induce the partial methylation of the DKK1 promoter, while 5-aza could increase DKK1 expression as well as decrease intestinal markers expression in gastric epithelial cells. In conclusion, the promoter methylation and downregulation of DKK1 might play important roles in the development of GIM, especially bile acid-induced GIM. A schematic diagram of the bile acids/DKK1/GIM pathway in gastric cells. Suitable concentrations of bile acid could promote the methylation of the DKK1 promoter region, which could be partially inhibited by 5-azacytidine. Image 1 • DKK1 was decreased in intestinal metaplasia and methylation of its promoter was increased, which were reversely correlated. • DKK1 could down-regulate expression of intestinal markers in gastric epithelial cells. • Bile acids could reduce DKK1 and increase the intestinal markers by inducing methylation of the DKK1 promoter. • 28 differential methylation sites were detected in the DKK1 promoter region in the intestinal metaplasia tissues. [ABSTRACT FROM AUTHOR]

Heterotrimeric G proteins are key molecular switches that control cell behavior. The canonical activation of G proteins by agonistoccupied G protein-coupled receptors (GPCRs) has recently been elucidated from the structural perspective. In contrast, the structural basis for GPCR-independent G protein activation by a novel family of guanine-nucleotide exchange modulators (GEMs) remains unknown. Here, we present a 2.0-Å crystal structure of Gαi in complex with the GEM motif of GIV/Girdin. Nucleotide exchange assays, molecular dynamics simulations, and hydrogen- deuterium exchange experiments demonstrate that GEM binding to the conformational switch II causes structural changes that allosterically propagate to the hydrophobic core of the Gαi GTPase domain. Rearrangement of the hydrophobic core appears to be a common mechanism by which GPCRs and GEMs activate G proteins, although with different efficiency. Atomic-level insights presented here will aid structure-based efforts to selectively target the noncanonical G protein activation. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to test whether serum vitamin D levels affected Helicobacter pylori (H. pylori) infection and eradication rates. Methods: A multicenter observational prospective cohort study was conducted. A total of 496 H. pylori− positive (H. pylori+) and 257 H. pylori‐negative (H. pylori−) patients were enrolled from four hospitals in China. Baseline serum vitamin D levels were measured and a 13C‐urea breath test (UBT) was performed for all the participants. The H. pylori+ patients were divided into two subgroups based on their serum vitamin D levels (<10 or ≥10 ng/mL). A second 13C‐UBT was performed between 4 and 8 weeks after 14‐day bismuth‐containing quadruple eradication therapies. Factors potentially affecting H. pylori eradication were determined using a questionnaire survey. Results: Serum vitamin D levels were significantly lower in the H. pylori+ group than in the H. pylori− group ([17.0 ± 6.9] ng/mL vs [19.2 ± 8.0] ng/mL, P = 0.000). H. pylori eradication rate significantly differed between patients with serum vitamin D levels of <10 ng/mL and ≥10 ng/mL (71.7% vs 87.3%, P = 0.005). A multivariate analysis showed that having serum vitamin D level ≥10 ng/mL was an independent risk factor for a successful H. pylori eradication (odds ratio 0.381, 95% confidence interval 0.183‐0.791, P = 0.010). Conclusions: Serum vitamin D level may affect H. pylori infection and its eradication. Randomized controlled trials are needed to find out whether vitamin D supplements may increase the H. pylori eradication rate. [ABSTRACT FROM AUTHOR]

Using the compiled human genome sequence, we systematically cataloged all tandem repeats with periods between 20 and 2000 bp and defined two subsets whose consensus sequences were found at either single-locus tandem repeats (slTRs) or multilocus tandem repeats (mlTRs). Parameters compiled for these subsets provide insights into mechanisms underlying the creation and evolution of tandem repeats. Both subsets of tandem repeats are nonrandomly distributed in the genome, being found at higher frequency at many but not all chromosome ends and internal clusters of mlTRs were also observed. Despite the integral role of recombination in the biology of tandem repeats, recombination hotspots colocalized only with shorter microsatellites and not the longer repeats examined here. An increased frequency of slTRs was observed near imprinted genes, consistent with a functional role, while both slTRs and mlTRs were found more frequently near genes implicated in triplet expansion diseases, suggesting a general instability of these regions. Using our collated parameters, we identified 2230 slTRs as candidates for highly informative molecular markers. [ABSTRACT FROM AUTHOR]

Background: Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer. Both animal and clinical studies have revealed that bile acid reflux and subsequent chronic inflammation are key causal factors of IM. Previous studies indicated that SOX2, the key transcription factor in gastric differentiation, was downregulated during IM development while CDX2, the pivotal intestine-specific transcription factor was upregulated significantly. However, it remains unclear whether the downregulation of SOX2 promotes gastric IM emergence or is merely a concomitant phenomenon. In addition, the underlying mechanisms of SOX2 downregulation during IM development are unclear. Methods: Gastric cell lines were treated with deoxycholic acid (DCA) in a dose-dependent manner. The expression of CDX2 and miR-21 in gastric tissue microarray were detected by immunohistochemistry and in situ hybridization. Coimmunoprecipitation and immunofluorescence were performed to ascertain the interaction of SOX2 and CDX2. Luciferase reporter assays were used to detect the transcriptional activity of CDX2, and confirm miR-21 binding to SOX2 3′-UTR. The protein level of SOX2, CDX2 and downstream IM-specific genes were investigated using western blotting. mRNA level of miR-21, SOX2, CDX2 and downstream IM-specific genes were detected by qRT-PCR. Results: Bile acid treatment could suppress SOX2 expression and simultaneously induce expression of CDX2 in gastric cell lines. Furthermore, we demonstrated that SOX2 overexpression could significantly inhibit bile acid- and exogenous CDX2-induced IM-specific gene expression, including KLF4, cadherin 17 and HNF4α expression. In contrast, SOX2 knockdown had the opposite effect. A dual-luciferase reporter assay demonstrated that SOX2 overexpression could significantly suppress CDX2 transcriptional activity in HEK293T cells. CDX2 and SOX2 could form protein complexes in the nucleus. In addition, bile acid induced the expression of miR-21. The inhibition of SOX2 in bile acid-treated gastric cell lines was rescued by miR-21 knockdown. Conclusions: These findings suggested that SOX2 can interfere with the transcriptional activity of CDX2 in bile acid-induced IM and that miR-21 might play a key role in this process, which shed new lights in the prevention of gastric cancer. [ABSTRACT FROM AUTHOR]