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In Taiwan, the pesticides dimethomorph and imidacloprid are recommended for pest control in vineyards. Therefore, tank-mixing of these two pesticides is usually a routine practice before application. This study analyzed the influence of vineyard soil microbial flora under the recommended and high dosages (100 times the recommended dosage) of dimethomorph and imidacloprid. Individual and combined applications of pesticides were also tested through batches of soil incubation experiments. Four treatments-control (C), dimethomorph (DT), imidacloprid (IM), and mixed application of dimethomorph and imidacloprid (ID)-were used in the experimental design. From the soil metabolism, no significant reaction was observed after 2 months in the recommended dosage group, regardless of whether the pesticides were being applied individually or combined. For the high dosage, imidacloprid showed a higher effect than the co-exposure treatments, showing a possible prolonged effect after its repetitive application. From PCoA analysis, pesticide treatments altered the soil ecology after 2 months, and the effect of imidacloprid can be explicitly observed at high dosages. At the phylum level, Acidobacteria can indicate pesticide application around the recommended dosage. It was inhibited by ID on day 7 and was augmented by all pesticides on day 63. The effect of the recommended dosage of pesticide mixtures after 2 months of incubation was revealed in the minor families Gemmataceae and Pirellulaceae, while the high dosage treatments affected both the core and the minor families. Our findings verified the changes in the composition of microbial communities upon pesticide application, which would affect carbon, nitrogen, sulfur, phosphorous cycles, and contaminant removal ability within the vineyard.
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Single-cell omics research has the power to leave a deep impact on modern healthcare. Sharing data widely and freely advances this progress in both the academic and clinical spheres. We developed the Single Cell Portal (SCP) to maximize the impact of this work. SCP enables data sharing, supports dynamic results visualization, and facilitates scientific exploration across a large repository of single-cell datasets. SCP's data contributors maintain full control over how their data are shared and presented, without requiring web development expertise. Finally, SCP supports the entire lifecycle of a research project, from sparking an idea, to fine-tuning the data with collaborators, to sharing results in an accessible and interactive way. This paper highlights the most valuable ways in which SCP helps to advance single-cell research.
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With the urgent need to implement the EU countries pledges and to monitor the effectiveness of Green Deal plan, Monitoring Reporting and Verification tools are needed to track how emissions are changing for all the sectors. Current official inventories only provide annual estimates of national CO2 emissions with a lag of 1+ year which do not capture the variations of emissions due to recent shocks including COVID lockdowns and economic rebounds, war in Ukraine. Here we present a near-real-time country-level dataset of daily fossil fuel and cement emissions from January 2019 through December 2021 for 27 EU countries and UK, which called Carbon Monitor Europe. The data are calculated separately for six sectors: power, industry, ground transportation, domestic aviation, international aviation and residential. Daily CO2 emissions are estimated from a large set of activity data compiled from different sources. The goal of this dataset is to improve the timeliness and temporal resolution of emissions for European countries, to inform the public and decision makers about current emissions changes in Europe.
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Background: Titanium (Ti) is one of the most popular implant materials, and its surface titanium dioxide (TiO2) provides good biocompatibility. The coagulation of blood on Ti implants plays a key role in wound healing and cell growth at the implant site; however, researchers have yet to fully elucidate the mechanism underlying this process on TiO2. Methods: This study examined the means by which blood coagulation was affected by the crystal structure of TiO2 thin films (thickness < 50 nm), including anatase, rutile, and mixed anatase/rutile. The films were characterized in terms of roughness using an atomic force microscope, thickness using an X-ray photoelectron spectrometer, and crystal structure using transmission electron microscopy. The surface energy and dielectric constant of the surface films were measured using a contact angle goniometer and the parallel plate method, respectively. Blood coagulation properties (including clotting time, factor XII contact activation, fibrinogen adsorption, fibrin attachment, and platelet adhesion) were then assessed on the various test specimens. Results: All of the TiO2 films were similar in terms of surface roughness, thickness, and surface energy (hydrophilicity); however, the presence of rutile structures was associated with a higher dielectric constant, which induced the activation of factor XII, the formation of fibrin network, and platelet adhesion. Conclusions: This study provides detailed information related to the effects of TiO2 crystal structures on blood coagulation properties on Ti implant surfaces.
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Factor XII , Titanio , Coagulación Sanguínea , Fibrina , Propiedades de Superficie , Titanio/químicaRESUMEN
Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.
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Vacunas contra el SIDA , Infecciones por Citomegalovirus , Vacunas contra Citomegalovirus , Vacunas contra el SIDAS , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Linfocitos T CD8-positivos , Citomegalovirus/genética , Interleucina-15 , Macaca fascicularis , Macaca mulattaRESUMEN
Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.
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Linfocitos T CD8-positivos/inmunología , Interleucina-15/inmunología , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Citomegalovirus , Femenino , Vectores Genéticos , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & controlRESUMEN
COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2.
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COVID-19/virología , Células Madre Pluripotentes Inducidas/virología , Miocitos Cardíacos/virología , SARS-CoV-2/patogenicidad , Células Cultivadas , Humanos , Empalme del ARN/genética , ARN Mensajero/genética , SARS-CoV-2/genética , Internalización del VirusRESUMEN
Polysorbates (also known as "Tween") are common components of protein formulations used to minimize protein adsorption and stabilize the protein. These nonionic surfactants are heterogenous mixtures of fatty acids with a complex reversed-phase profile due to the inhomogeneity of the polymers present. Polysorbates can be oxidized, which can be hard to detect in the complex polymer profile. Further adding to the analytical challenge is the lack of a chromophore for the detection of these polymers. The routine analysis of polysorbates in protein formulations was greatly improved through the introduction of online solid-phase extraction (SPE) to simplify the polysorbate profile for quantification. However, this method combines many of the polysorbate polymers into a single peak for detection, thus limiting its effectiveness for detecting degradation. To address the need for a stability indicating method without the complexity of the reversed-phase profile, an optimized online SPE method was developed and investigated. Using polysorbate 80, this investigation shows that further expanding the step gradient can yield a profile that is stability indicating and available for routine testing of protein formulation.
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Polisorbatos , Extracción en Fase Sólida , Cromatografía Líquida de Alta Presión , Oxidación-Reducción , Polisorbatos/análisis , Proteínas , TensoactivosRESUMEN
Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.
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The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14+ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14+ cells and/or their gene expression correlates with blood Type 1 CD4+ T helper cells, α4ß7+ plasmablasts, and vaginal cytocidal NKG2A+ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4+Ki67+CD38+ and CD4+Ki67+α4ß7+ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A+ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.
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Células Asesinas Naturales/inmunología , Monocitos/inmunología , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Células TH1/inmunología , Vacunación , Vagina/inmunología , Vacunas Virales/inmunología , Animales , Femenino , Células Asesinas Naturales/patología , Macaca mulatta , Monocitos/patología , Células TH1/patologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine-induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.
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Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Linfocitos T CD8-positivos/inmunología , Colon/patología , Femenino , Perfilación de la Expresión Génica , Interferón gamma/metabolismo , Recuento de Linfocitos , Macaca mulatta , Masculino , Membrana Mucosa/patología , Receptores CCR5/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Resultado del Tratamiento , Vacunación , Vagina/inmunología , Vagina/virologíaRESUMEN
Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-ß and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.
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Fibronectinas/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Factor de Crecimiento Transformador beta/inmunología , Cicatrización de Heridas/inmunología , Animales , Chlorocebus aethiops/genética , Chlorocebus aethiops/inmunología , Progresión de la Enfermedad , Fibronectinas/metabolismo , Mucosa Intestinal/metabolismo , Macaca mulatta/genética , Macaca mulatta/inmunología , Macrófagos/metabolismo , Recto/inmunología , Recto/metabolismo , Virus de la Inmunodeficiencia de los Simios , Biología de Sistemas , Transcriptoma , Factor de Crecimiento Transformador beta/genética , Cicatrización de Heridas/genéticaRESUMEN
Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-ß induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca2+ influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the N-terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.
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Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions.
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Colon/inmunología , Microbioma Gastrointestinal/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Inflamación/inmunología , Neutrófilos/inmunología , Recto/inmunología , Colon/microbiología , Colon/patología , Femenino , Infecciones por VIH/virología , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Recto/microbiología , Recto/patologíaRESUMEN
Liver disease is a leading contributor to morbidity and mortality during HIV infection, despite the use of combination antiretroviral therapy (cART). The precise mechanisms of liver disease during HIV infection are poorly understood partially due to the difficulty in obtaining human liver samples as well as the presence of confounding factors (e.g. hepatitis co-infection, alcohol use). Utilizing the simian immunodeficiency virus (SIV) macaque model, a controlled study was conducted to evaluate the factors associated with liver inflammation and the impact of cART. We observed an increase in hepatic macrophages during untreated SIV infection that was associated with a number of inflammatory and fibrosis mediators (TNFα, CCL3, TGFß). Moreover, an upregulation in the macrophage chemoattractant factor CCL2 was detected in the livers of SIV-infected macaques that coincided with an increase in the number of activated CD16+ monocyte/macrophages and T cells expressing the cognate receptor CCR2. Expression of Mac387 on monocyte/macrophages further indicated that these cells recently migrated to the liver. The hepatic macrophage and T cell levels strongly correlated with liver SIV DNA levels, and were not associated with the levels of 16S bacterial DNA. Utilizing in situ hybridization, SIV-infected cells were found primarily within portal triads, and were identified as T cells. Microarray analysis identified a strong antiviral transcriptomic signature in the liver during SIV infection. In contrast, macaques treated with cART exhibited lower levels of liver macrophages and had a substantial, but not complete, reduction in their inflammatory profile. In addition, residual SIV DNA and bacteria 16S DNA were detected in the livers during cART, implicating the liver as a site on-going immune activation during antiretroviral therapy. These findings provide mechanistic insights regarding how SIV infection promotes liver inflammation through macrophage recruitment, with implications for in HIV-infected individuals.
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Antirretrovirales/administración & dosificación , Inflamación/patología , Hígado/patología , Macrófagos/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Carga Viral , Animales , Antirretrovirales/farmacología , Recuento de Células , Células Cultivadas , Quimioterapia Combinada , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Hígado/inmunología , Hígado/virología , Macaca mulatta , Macrófagos/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral/efectos de los fármacos , Carga Viral/inmunologíaRESUMEN
INTRODUCTION: Zinc finger-like protein that regulates apoptosis (Zfra) is a naturally occurring 31-amino-acid protein. Synthetic peptides Zfra1-31 and Zfra4-10 are known to effectively block the growth of many types of cancer cells. METHODS: Ten-month-old triple-transgenic (3×Tg) mice for Alzheimer's disease (AD) received synthetic Zfra peptides via tail vein injections, followed by examining restoration of memory deficits. RESULTS: Zfra significantly downregulated TRAPPC6AΔ, SH3GLB2, tau, and amyloid ß (Αß) aggregates in the brains of 3×Tg mice and effectively restored their memory capabilities. Zfra inhibited melanoma-induced neuronal death in the hippocampus and plaque formation in the cortex. Mechanistically, Zfra blocked the aggregation of amyloid ß 42 and many serine-containing peptides in vitro, suppressed tumor necrosis factor-mediated NF-κB activation, and bound cytosolic proteins for accelerating their degradation in ubiquitin/proteasome-independent manner. DISCUSSION: Zfra peptides exhibit a strong efficacy in blocking tau aggregation and amyloid Αß formation and restore memory deficits in 3×Tg mice, suggesting its potential for treatment of AD.
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This paper describes a community coalition-university partnership to address health needs in an underserved US-Mexico border, community. For approximately 15 years, this coalition engaged in community-based participatory research with community organizations, state/local health departments, and the state's only accredited college of public health. Notable efforts include the systematic collection of health-relevant data 12 years apart and data that spawned numerous health promotion activities. The latter includes specific evidence-based chronic disease-preventive interventions, including one that is now disseminated and replicated in Latino communities in the US and Mexico, and policy-level changes. Survey data to evaluate changes in a range of health problems and needs, with a specific focus on those related to diabetes and access to health-care issues-identified early on in the coalition as critical health problems affecting the community-are presented. Next steps for this community and lessons learned that may be applicable to other communities are discussed.
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The unprecedented 2013-2016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS-/- mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.