Miracle-dz/UniFAR-FTUs huggingface dataset:
CD4+ T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination

ABSTRACT Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4+ T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4+ T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4+ T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4+ T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4+ T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4+ T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals. IMPORTANCE NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.
Herpes Simplex Virus Is Equipped with RNA- and Protein-Based Mechanisms To Repress Expression of ATRX, an Effector of Intrinsic Immunity

ABSTRACT Intrinsic immunity is a first-line intracellular defense against virus infection, and viruses have evolved mechanisms to counteract it. During herpes simplex virus (HSV) infection, nuclear domain 10 (ND10) components localize adjacent to incoming viral genomes and generate a repressive environment for viral gene expression. Here, we found that the ND10 component, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) protein, is predicted to be a target of HSV-1 miR-H1 and HSV-2 miR-H6. These microRNAs (miRNAs) share a seed sequence and are abundant during lytic infection. Mimics of both miRNAs could deplete endogenous ATRX, and an miR-H1 mimic could repress the expression of a reporter linked to the 3′ untranslated region of ATRX mRNA, identifying a cellular mRNA targeted by an HSV miRNA. Interestingly, ATRX protein and its mRNA were depleted in cells lytically infected with HSV, and ATRX protein was also depleted in cells infected with human cytomegalovirus. However, infection with an HSV-1 mutant lacking miR-H1 still resulted in ATRX depletion. This depletion was sensitive to a proteasome inhibitor and was largely ablated by a deletion of the gene encoding the immediate-early ICP0 protein. Additionally, a deletion of the gene encoding the tegument protein Vhs ablated most of the depletion of ATRX mRNA. Thus, HSV is equipped with multiple mechanisms to limit the expression of ATRX. As ATRX is implicated in repression of lytic viral gene expression, our results suggest roles for these different mechanisms during various phases of HSV infection.
Interaction of Adenovirus Type 5 E4orf4 with the Nuclear Pore Subunit Nup205 Is Required for Proper Viral Gene Expression

ABSTRACT Adenovirus type 5 E4orf4 is a multifunctional protein that regulates viral gene expression. The activities of E4orf4 are mainly mediated through binding to protein phosphatase 2A (PP2A). E4orf4 recruits target phosphoproteins into complexes with PP2A, resulting in dephosphorylation of host factors, such as SR splicing factors. In the current study, we utilized immunoprecipitation followed by mass spectrometry to identify novel E4orf4-interacting proteins. In this manner we identified Nup205, a component of the nuclear pore complex (NPC) as an E4orf4 interacting partner. The arginine-rich motif (ARM) of E4orf4 was required for interaction with Nup205 and for nuclear localization of E4orf4. ARMs are commonly found on viral nuclear proteins, and we observed that Nup205 interacts with three different nuclear viral proteins containing ARMs. E4orf4 formed a trimolecular complex containing both Nup205 and PP2A. Furthermore, Nup205 complexed with E4orf4 was hypophosphorylated, suggesting that the protein is specifically targeted for dephosphorylation. An adenovirus mutant that does not express E4orf4 (Orf4−) displayed elevated early and reduced late gene expression relative to that of the wild type. We observed that knockdown of Nup205 resulted in the same phenotype as that of the Orf4− virus, suggesting that the proteins function as a complex to regulate viral gene expression. Furthermore, knockdown of Nup205 resulted in a more than a 4-fold reduction in the replication of wild-type adenovirus. Our data show for first time that Ad5 E4orf4 interacts with and modifies the NPC and that Nup205-E4orf4 binding is required for normal regulation of viral gene expression and viral replication. IMPORTANCE Nuclear pore complexes (NPCs) are highly regulated conduits in the nuclear membrane that control transport of macromolecules between the nucleus and cytoplasm. Viruses that replicate in the nucleus must negotiate the NPC during nuclear entry, and viral DNA, mRNA, and proteins must then be exported from the nucleus. Several types of viruses restructure the NPC to facilitate replication, and the current study shows that adenovirus type 5 (Ad5) utilizes a novel mechanism to modify NPC function. We demonstrate that a subunit of the NPC, Nup205, is a phosphoprotein that is actively dephosphorylated by the Ad5-encoded protein E4orf4. Moreover, Nup205 is required by Ad5 to regulate viral gene expression and efficient viral replication. Nup205 is a nonstructural subunit that is responsible for the gating functions of the NPC, and this study suggests for the first time that the NPC is regulated by phosphorylation both during normal physiology and viral infection.
Glycosylation of Simian Immunodeficiency Virus Influences Immune-Tissue Targeting during Primary Infection, Leading to Immunodeficiency or Viral Control

ABSTRACT Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Δ5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4+ T cells reside. The results showed that Δ5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Δ5G-infected animals deplete CXCR3+ CCR5+ transitional memory (TrM) CD4+ T cells. An early robust Δ5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6+ CXCR3− CCR5+ effector memory CD4+ T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4+ T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively.
Recovery Beverages: A Review of Two Recent Studies

CHOCOLATE MILK AS A RECOVERY DRINK Jason R. Karp, M.S., et al (1) studied the effects of chocolate milk on recovery. The purpose of their study was to ‘‘test the efficacy of chocolate milk as a recovery drink following glycogen-depleting exercise. ’’ They determined this by assessing time to exhaustion and total power output. They compared low-fat chocolate milk to a fluid replacement drink and a carbohydrate replacement drink. There were nine healthy trained cyclists who participated in this crossover designed study, which means that each subject went through all the treatments (in this case, they consumed each of the beverages for each trial). A crossover design is a good design because that means that each subject acts as his or her own control. They had an average maximal oxygen consumption (V̇O2max) of 65 T 9 mL/kg/min. Each cyclist participated in four testing sessions. The first session consisted of incremental exercise to determine their V̇O2max and maximum power output (Pmax). The remaining three testing trials consisted of a randomized crossover design where the subjects cycled to ‘‘glycogen depletion,’’ which was followed by a 4-hour recovery period. Participants consumed one of the three drinks during recovery time after each session immediately, postexercise, and 2 hours into the recovery period. Although the participants could not be blinded by the taste of each drink, the investigators were blinded to each trial. After consumption of the drink and the 4-hour recovery period, participants performed the second exercise bout at 70% of their V̇O2max until exhaustion. Each testing session was separated by 1 week. The investigators also collected 3-day dietary records before each testing session. The participants’ diets did not differ before each session, with respect to carbohydrate, protein, and fat intake. Karp et al (1) reported a significantly greater time to exhaustion (minutes) and a significantly greater total work (kilojoules) in the chocolate milk and fluid replacement drink trials as compared with the carbohydrate replacement drink R4 trial. Although this study showed some interesting results, some limitations to consider are the following: its small sample size (although it was a crossover design, which strengthens the results); the participants were all men, women may respond differently; they were all trained cyclists, other athletes may respond differently; the participants began each session A Nutritionist’s View
Cost-effectiveness of endobronchial percutaneous biopsy compared with transthoracic biopsy for diagnosis of peripheral lung lesions

SUMMARY: Aim: This study compares the cost–effectiveness of radial endobronchial ultrasound (R-EBUS; Olympus Medical Systems Group, Tokyo, Japan) and electromagnetic navigation (ENB) to transthoracic needle biopsy (TTNB) to attain a confirmative diagnosis of the suspect lung lesions(s). Methods: The National Lung Screening Trial enrolled over 50,000 people aged 55–74 years with at least a 30-pack/year smoking history, in fairly good health and not symptomatic of lung disease. The study found low-dose computed tomography of the chest resulted in a 20% lower chance of dying from lung cancer compared with those who had chest x-rays. Approximately 25% of the low-dose computed tomography-screened patients had a positive screen requiring confirmation of the lung lesion. Using an estimate of 5.2 million annual chest CT scans in the USA as a basis for the number of patients seeking a confirmative result before being recommended for surgery for possible benign lung lesions our study seeks to identify the most cos.
Faster Segmentation-Free Handwritten Chinese Text Recognition with Character Decompositions

Recently, segmentation-free methods for handwritten Chinese text were proposed. They do not require character-level annotations to be trained, and avoid character segmentation errors at decoding time. However, segmentation-free methods need to make at least as many predictions as there are characters in the image, and often a lot more. Combined with the fact that there are many characters in Chinese, these systems are too slow to be suited for industrial applications. Inspired by the input methods for typing Chinese characters, we propose a sub-character-level recognition that achieves a 4x speedup over the baseline Multi-Dimensional Long Short-Term Memory Recurrent Neural Network (MDLSTM-RNN).
Adolescents misusing prescription drugs: who’s the riskiest users of them all?

Early age of onset of alcohol use or prescription drug misuse (PDM) is associated with later alcohol or prescription drug-related substance use disorders. While the prevalence of PDM among youth continues to increase at an alarming rate, relatively little research attention has been given to the study of adolescent PDM. The present study examined differences in risky behaviors (hazardous drinking and externalizing symptoms) and impulsivity among adolescents (N = 111) who reported current PDM and underage alcohol use (i.e. PDM and alcohol use in past 30 days; n = 37), current underage alcohol use only (i.e. past-30-day alcohol use but no PDM in past 30 days; n = 37) and those who reported no alcohol or drug use in past 30 days (n = 37). Findings indicated that adolescents who reported current PDM also reported highest levels of hazardous alcohol use and impulsivity compared to adolescents in the current alcohol-only and current non-user groups. Adolescents who reported current PDM also reported higher levels of externalizing symptoms than did non-current using adolescents. Overall, the results of the present study suggest that adolescents who misuse prescription drugs could be at high risk for involvement in other types of problem behaviors.
Recovery of an HMWP/hmwBP (pUL48/pUL47) Complex from Virions of Human Cytomegalovirus: Subunit Interactions, Oligomer Composition, and Deubiquitylase Activity

ABSTRACT We report that the human cytomegalovirus (HCMV) high-molecular-weight tegument protein (HMWP, pUL48; 253 kDa) and the HMWP-binding protein (hmwBP, pUL47; 110 kDa) can be recovered as a complex from virions disrupted by treatment with 50 mM Tris (pH 7.5), 0.5 M NaCl, 0.5% NP-40, and 10 mM dithiothreitol [DTT]. The subunit ratio of the complex approximates 1:1, with a shape and structure consistent with an elongated heterodimer. The HMWP/hmwBP complex was corroborated by reciprocal coimmunoprecipitation experiments using antipeptide antibodies and lysates from both infected cells and disrupted virus particles. An interaction of the amino end of pUL48 (amino acids [aa] 322 to 754) with the carboxyl end of pUL47 (aa 693 to 982) was identified by fragment coimmunoprecipitation experiments, and a head-to-tail self-interaction of hmwBP was also observed. The deubiquitylating activity of pUL48 is retained in the isolated complex, which cleaves K11, K48, and K63 ubiquitin isopeptide linkages. IMPORTANCE Human cytomegalovirus (HCMV, or human herpesvirus 5 [HHV-5]) is a large DNA-containing virus that belongs to the betaherpesvirus subfamily and is a clinically important pathogen. Defining the constituent elements of its mature form, their organization within the particle, and the assembly process by which it is produced are fundamental to understanding the mechanisms of herpesvirus infection and developing drugs and vaccines against them. In this study, we report isolating a complex of two large proteins encoded by HCMV open reading frames (ORFs) UL47 and UL48 and identifying the binding domains responsible for their interaction with each other and of pUL47 with itself. Our calculations indicate that the complex is a rod-shaped heterodimer. Additionally, we determined that the ubiquitin-specific protease activity of the ORF UL48 protein was functional in the complex, cleaving K11-, K48-, and K63-linked ubiquitin dimers. This information builds on and extends our understanding of the HCMV tegument protein network that is required to interface the HCMV envelope and capsid.
Customer-Satisfaction-Aware Optimal Multiserver Configuration for Profit Maximization in Cloud Computing

Along with the development of cloud computing, an increasing number of enterprises start to adopt cloud service, which promotes the emergence of many cloud service providers. For cloud service providers, how to configure their cloud service platforms to obtain the maximum profit becomes increasingly the focus that they pay attention to. In this paper, we take customer satisfaction into consideration to address this problem. Customer satisfaction affects the profit of cloud service providers in two ways. On one hand, the cloud configuration affects the quality of service which is an important factor affecting customer satisfaction. On the other hand, the customer satisfaction affects the request arrival rate of a cloud service provider. However, few existing works take customer satisfaction into consideration in solving profit maximization problem, or the existing works considering customer satisfaction do not give a proper formalized definition for it. Hence, we first refer to the definition of customer satisfaction in economics and develop a formula for measuring customer satisfaction in cloud computing. And then, an analysis is given in detail on how the customer satisfaction affects the profit. Lastly, taking into consideration customer satisfaction, service-level agreement, renting price, energy consumption, and so forth, a profit maximization problem is formulated and solved to get the optimal configuration such that the profit is maximized.
Cell Susceptibility to Baculovirus Transduction and Echovirus Infection Is Modified by Protein Kinase C Phosphorylation and Vimentin Organization

ABSTRACT Some cell types are more susceptible to viral gene transfer or virus infection than others, irrespective of the number of viral receptors or virus binding efficacy on their surfaces. In order to characterize the cell-line-specific features contributing to efficient virus entry, we studied two cell lines (Ea.hy926 and MG-63) that are nearly nonpermissive to insect-specific baculovirus (BV) and the human enterovirus echovirus 1 (EV1) and compared their characteristics with those of a highly permissive (HepG2) cell line. All the cell lines contained high levels of viral receptors on their surfaces, and virus binding was shown to be efficient. However, in nonpermissive cells, BV and its receptor, syndecan 1, were unable to internalize in the cells and formed large aggregates near the cell surface. Accordingly, EV1 had a low infection rate in nonpermissive cells but was still able to internalize the cells, suggesting that the postinternalization step of the virus was impaired. The nonpermissive and permissive cell lines showed differential expression of syntenin, filamentous actin, vimentin, and phosphorylated protein kinase C subtype α (pPKCα). The nonpermissive nature of the cells could be modulated by the choice of culture medium. RPMI medium could partially rescue infection/transduction and concomitantly showed lower syntenin expression, a modified vimentin network, and altered activities of PKC subtypes PKCα and PKCε. The observed changes in PKCα and PKCε activation caused alterations in the vimentin organization, leading to efficient BV transduction and EV1 infection. This study identifies PKCα, PKCε, and vimentin as key factors affecting efficient infection and transduction by EV1 and BV, respectively.
Cytokine Profiles in Nasal Fluid in Patients with Nasal Polyps: A Flow Cytometric Study

Cytokine Profiles in Nasal Fluid in Patients with Nasal Polyps: A Flow Cytometric Study Biological markers in nasal fluid provide valuable information on nasal pathophysiology. The aims of this study were to compare the cytokine profiles of nasal fluid in subjects with nasal polyps (NP) and co-morbid asthma and NP patients without asthma and to determine the role of these cytokines in the development of NP. Thirty patients with NP (15 asthmatic and 15 non asthmatic) were included in this prospective study. Nasal secretion samples were collected from nasal cavities of all 30 subjects. The levels of eleven cytokines (TNF-α, TNF-β, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IFN-γ) were measured using flow cytometry. The concentrations of Th2 cytokines IL-5, IL-6 and IL-10 were significantly higher in patients with NP and asthma compared with subjects with NP without asthma. We also found significantly higher levels of IFN-α, IL-4, IL-6 and IL-10 in allergic patients with NP and asthma compared with those without asthma. In nonallergic patients with NP and asthma, the concentrations of TNF-α, IL-5 and IL-6 were significantly higher than in nonallergic patients with NP without asthma. Our results show that the presence of Th2 cytokines, especially IL-5 and IL-6 in patients with NP and asthma is a more prominent feature than in those without asthma that relates to the increased eosinophilic inflammation. We have also found a significant influence of allergy on the cytokine profiles both in asthmatic and nonasthmatic patients. Profili Citokina u Nosnom Sekretu kod Pacijenata s Nosnim Polipima: Ispitivanje Protočnom Citometrijom Biološki markeri u nosnom sekretu mogu pružiti dragocene podatke o patofiziologiji bolesti nosa i paranazalnih sinusa. Cilj studije je bio da se uporede profili citokina u nosnom sekretu kod obolelih od nosne polipoze (NP) udružene sa astmom i pacijenata obolelih od NP bez astme i ispita uloga tih citokina u razvoju NP. Trideset pacijenata sa NP (15 sa astmom i 15 bez astme) uključeno je u ovu prospektivnu studiju. Uzorci nosnog sekreta su uzeti iz nosne šupljine svakom od 30 pacijenata. Koncentracije jedanaest citokina (TNF-α, TNF-β, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL 12 i IFN-γ) merene su flow-citometrijom. Koncentracije Th2-citokina IL-5, IL-6 i IL-10 bile su statistički značajno više kod pacijenata sa NP i astmom u poređenju sa obolelima od NP bez astme. Takođe smo našli značajno više vrednosti IFN-γ, IL-4, IL-6 i IL-10 kod alergičnih pacijenata sa NP i astmom u poređenju sa onima bez astme. Kon nealergičnih pacijenata sa NP i astmom, koncentracije TNF-α, IL-5 i IL-6 bile su značajno više nego kod nealergičnih pacijenata sa NP bez astme. Rezultati su pokazali da je koncentracija Th2-citokina, naročito IL-5 i IL-6, kod pacijenata sa NP i astmom izraženija karakteristika nego kod onih bez astme, povezana sa pojačanom eozinofilnom inflamacijom. Takođe je otkriven značajan uticaj alergije na profile citokina i kod astmatičnih i kod neastmatičnih pacijenata.