Miracle-dz/UniFAR-FTUs huggingface dataset:
Ets-1 Is Required for the Activation of VEGFR3 during Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma (KS), is present in the predominant tumor cells of KS, the spindle cells. Spindle cells express markers of lymphatic endothelium and, interestingly, KSHV infection of blood endothelial cells reprograms them to a lymphatic endothelial cell phenotype. KSHV-induced reprogramming requires the activation of STAT3 and phosphatidylinositol 3 (PI3)/AKT through the activation of cellular receptor gp130. Importantly, KSHV-induced reprogramming is specific to endothelial cells, indicating that there are additional host genes that are differentially regulated during KSHV infection of endothelial cells that contribute to lymphatic reprogramming. We found that the transcription factor Ets-1 is highly expressed in KS spindle cells and is upregulated during KSHV infection of endothelial cells in culture. The KSHV latent vFLIP gene is sufficient to induce Ets-1 expression in an NF-κB-dependent fashion. Ets-1 is required for KSHV-induced expression of VEGFR3, a lymphatic endothelial-cell-specific receptor important for lymphangiogenesis, and Ets-1 activates the promoter of VEGFR3. Ets-1 knockdown does not alter the expression of another lymphatic-specific gene, the podoplanin gene, but does inhibit the expression of VEGFR3 in uninfected lymphatic endothelium, indicating that Ets-1 is a novel cellular regulator of VEGFR3 expression. Knockdown of Ets-1 affects the ability of KSHV-infected cells to display angiogenic phenotypes, indicating that Ets-1 plays a role in KSHV activation of endothelial cells during latent KSHV infection. Thus, Ets-1 is a novel regulator of VEGFR3 and is involved in the induction of angiogenic phenotypes by KSHV.
VSV-GP: a Potent Viral Vaccine Vector That Boosts the Immune Response upon Repeated Applications

ABSTRACT Antivector immunity limits the response to homologous boosting for viral vector vaccines. Here, we describe a new, potent vaccine vector based on replication-competent vesicular stomatitis virus pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (VSV-GP), which we previously showed to be safe in mice. In mice, VSV and VSV-GP encoding ovalbumin (OVA) as a model antigen (VSV-OVA and VSV-GP-OVA) induced equal levels of OVA-specific humoral and cellular immune responses upon a single immunization. However, boosting with the same vector was possible only for VSV-GP-OVA as neutralizing antibodies to VSV limited the immunogenicity of the VSV-OVA boost. OVA-specific cytotoxic T-lymphocyte (CTL) responses induced by VSV-GP-OVA were at least as potent as those induced by an adenoviral state-of-the-art vaccine vector and completely protected mice in a Listeria monocytogenes challenge model. VSV-GP is so far the only replication-competent vaccine vector that does not lose efficacy upon repeated application. IMPORTANCE Although there has been great progress in treatment and prevention of infectious diseases in the past several years, effective vaccines against some of the most serious infections, e.g., AIDS, malaria, hepatitis C, or tuberculosis, are urgently needed. Here, several approaches based on viral vector vaccines are under development. However, for all viral vaccine vectors currently in clinical testing, repeated application is limited by neutralizing antibodies to the vector itself. Here, we have exploited the potential of vesicular stomatitis virus pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (VSV-GP) as a vaccine platform. VSV-GP is the first replication-competent viral vector vaccine that does not induce vector-specific humoral immunity, i.e., neutralizing antibodies, and therefore can boost immune responses against a foreign antigen by repeated applications. The vector allows introduction of various antigens and therefore can serve as a platform technology for the development of novel vaccines against a broad spectrum of diseases.
The Use of Strain-Counterstrain in the Treatment of Patients with Low Back Pain

Abstract Strain-Counterstrain (S-CS) is a manipulative technique routinely used by manual practitioners to treat somatic dysfunction. However, no peer-reviewed literature to support or refute its use has been reported. In the four clinical cases reported, S-CS was initially provided as the sole treatment for low back pain. The S-CS intervention phase for each case took approximately one week and consisted of 2 to 3 treatment sessions to resolve perceived “aberrant neuromuscular activity. ” Outcome measures were derived from the McGill Pain Questionnaire and the Oswestry Low Back Pain Disability Questionnaire. All patients registered reductions in pain and disability following S-CS intervention. No experimental evidence for the effectiveness of S-CS is offered, although outcomes do suggest that a controlled study is warranted to examine the effectiveness of S-CS for the treatment of low back pain.
Diagnosing the Periphery: Using the Rey–Osterrieth Complex Figure Drawing Test to Characterize Peripheral Visual Function

Peripheral vision is strongly limited by crowding, the deleterious influence of neighboring stimuli on target perception. Many quantitative aspects of this phenomenon have been characterized, but the specific nature of the perceptual degradation remains elusive. We utilized a drawing technique to probe the phenomenology of peripheral vision, using the Rey–Osterrieth Complex Figure, a standard neuropsychological clinical instrument. The figure was presented at 12° or 6° in the right visual field, with eye tracking to ensure that the figure was only presented when observers maintained stable fixation. Participants were asked to draw the figure with free viewing, capturing its peripheral appearance. A foveal condition was used to measure copying performance in direct view. To assess the drawings, two raters used standard scoring systems that evaluated feature positions, spatial distortions, and omission errors. Feature scores tended to decrease with increasing eccentricity, both within and between conditions, reflecting reduced resolution and increased crowding in peripheral vision. Based on evaluation of the drawings, we also identified new error classes unique to peripheral presentation, including number errors for adjacent similar features and distinctive spatial distortions. The multifaceted nature of the Rey–Osterrieth Complex Figure—containing configural elements, detached compound features, and texture-like components—coupled with the flexibility of the free-response drawing paradigm and the availability of standardized scoring systems, provides a promising method to probe peripheral perception and crowding.
Sequences Related to SUMO Interaction Motifs in Herpes Simplex Virus 1 Protein ICP0 Act Cooperatively To Stimulate Virus Infection

ABSTRACT Herpes simplex virus type 1 immediate-early protein ICP0 is an E3 ubiquitin ligase of the RING finger class that degrades several cellular proteins during infection. This activity is essential for its functions in stimulating efficient lytic infection and productive reactivation from latency. ICP0 targets a number of proteins that are modified by the small ubiquitin-like SUMO family of proteins, and it includes a number of short sequences that are related to SUMO interaction motifs (SIMs). Therefore, ICP0 has characteristics that are related to those of cellular SUMO-targeted ubiquitin ligase enzymes. Here, we analyze the impact of mutation of a number of SIM-like sequences (SLSs) within ICP0 on HSV-1 replication and gene expression and their requirement for ICP0-mediated degradation of both sumoylated and unmodified promyelocytic leukemia (PML) and other sumoylated cellular proteins. One SLS in the central portion of the ICP0 sequence (SLS4) was found to be absolutely required for targeting cellular sumoylated species in general and sumoylated forms of PML other than those of PML isoform I. Mutation of a group of SLSs in the C-terminal quarter of ICP0 also reduced ICP0-mediated degradation of sumoylated PML in a cooperative manner. Although mutation of individual SLSs caused only modest decreases in viral replication, combined mutation of SLS4 with SLS sequences in the C-terminal quarter of the protein reduced plaque formation efficiency by up to two orders of magnitude. These results provide further evidence that the biological activities of ICP0 are connected with host cell sumoylation events. IMPORTANCE Herpes simplex virus type 1 protein ICP0 plays important roles in regulating the initial stages of lytic infection and productive reactivation from latency. ICP0 mediates its effects through inducing the degradation of cellular proteins that have repressive effects on viral gene expression. An increasing number of cellular proteins are known to be sensitive to ICP0-mediated degradation; therefore, it is important to understand how ICP0 selects its substrates for degradation. This study identifies sequence motifs within ICP0 that are involved in targeting cellular proteins that are modified by the SUMO family of ubiquitin-like proteins and describes how mutation of combinations of these motifs causes a 100-fold defect in viral infectivity.
The Majority of CD4+ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

ABSTRACT Untreated human immunodeficiency virus (HIV) infection is characterized by depletion of CD4+ T cells, ultimately leading to the impairment of host immune defenses and death. HIV-infected CD4+ T cells die from direct virus-induced apoptosis and CD8 T-cell-mediated elimination, but a broader and more profound depletion occurs in uninfected CD4+ T cells via multiple indirect effects of infection. We fit mathematical models to data from experiments that tested an HIV eradication strategy in which five macaques with a proportion of CD4+ T cells resistant to simian-human immunodeficiency virus (SHIV) entry were challenged with SHIV89.6P, a highly pathogenic dual-tropic chimeric SIV-HIV viral strain that results in rapid loss of both SHIV-susceptible and SHIV-resistant CD4+ T cells. Our results suggest that uninfected (bystander) cell death accounts for the majority of CD4+ T-lymphocyte loss, with at least 60% and 99% of CD4+ T cell death occurring in uninfected cells during acute and established infection, respectively. Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival. IMPORTANCE HIV infection induces a massive depletion of CD4+ T cells, leading to profound immunodeficiency, opportunistic infections, and eventually death. While HIV induces apoptosis (programmed cell death) by directly entering and replicating in CD4+ T cells, uninfected CD4+ T cells also undergo apoptosis due to ongoing toxic inflammation in the region of infection. In this paper, we use mathematical models in conjunction with data from simian-human immunodeficiency virus SHIV89.6P infection in macaques (a model of HIV infection in humans) to estimate the percentage of cell death that occurs in uninfected cells during the initial period of infection. We reveal that the vast majority of cell death occurs in these cells, which are not infected. The “bystander effects” that lead to enormous reductions in the number of uninfected CD4+ T cells may be a target for future interventions that aim to limit the extent of damage caused by HIV.
Behavioral Treatment of Depression in Predominantly African-American Medical Patients

The efficacy of behavioral treatment for depression in older adult medical rehabilitation inpatients was tested by comparing two groups that received behavioral treatment with a no treatment control group. In one treatment group an experienced geropsychologist provided behavioral treatment, whereas in the other treatmcnt group trained occupational therapists provided the behavioral treatment (n = 13 in each group). Compared to the no treatment group (n = 11) depression was significantly reduced in both treatment groups. In addition, functional recovery of ADL skills was significantly better in the occupational therapy led treatment group than in the no treatment group. The behavioral treatment protocol, method of training occupational therapists and significance of the results are discussed.
Conceptualizing How Usability of Mobile Services Affects Business Performance

Usability of business services can have wide- ranging effects on the business performance of the company using the service. In the fields where mobility is a crucial part of the business, such as in transportation, it is beneficial if the services are also mobile - allowing the employees to process information where appropriate. However, mobility also introduces challenges as the context of use is changing and the information input and output is more troublesome. This paper presents a case study from the field of passenger transport and provides an analysis for understanding the relationship between the usability of mobile business services and business performance. The results indicate that both tangible and intangible effects of usability can be identified at individual, organizational, and customer levels.
Interventions for the metabolic syndrome in schizophrenia: a review

The metabolic syndrome (MetS) is an increasingly prevalent condition in people with schizophrenia. It remains highly prevalent in the general population in developed countries, but recently health promotion campaigns and greater awareness of the high associated mortality rates have resulted in improvements in the rates of cardiovascular risk factors. This is not the case for people with schizophrenia who continue to have more than twice the rates of MetS and significantly higher mortality rates than the general population. Various behavioural and pharmacological interventions have been used to improve conditions that are linked to MetS, mainly smoking and obesity. This review aims to provide an update of the latest knowledge about the behavioural, pharmacological and other interventions that might help to combat this life-threatening problem in people with schizophrenia.
Diuretic effects of fenoldopam in healthy cats

Objective: To determine the effect of fenoldopam infusion on urine output, sodium excretion, creatinine clearance, and indirect blood pressure in healthy cats. Design: Prospective study. Setting: Veterinary medical teaching hospital. Animals: Eight purpose-bred cats, 2–4 years old. Interventions: None. Measurements: Urine output was measured hourly for 12 hours before and after fenoldopam administration. Sodium excretion, modified creatinine clearance, and fractional sodium excretion were measured before and following fenoldopam administration. Urine specific gravity, central venous pressure, and systolic blood pressure were measured every 4 hours during the experiment. Main results: Compared with pre-infusion values, urine output, sodium excretion, and fractional excretion of sodium increased significantly 6 hours after initiation of fenoldopam infusion. This increase was sustained throughout the observation period. The modified creatinine clearance decreased significantly following 2 hours of fenoldopam infusion, but increased significantly by 6 hours after infusion, the time of peak urine output. Changes in urine specific gravity mirrored changes in fractional sodium excretion, whereas the central venous pressure mirrored changes in modified creatinine clearance. The diuretic effect in cats was prevented when a dopamine receptor blocking agent was administered before fenoldopam infusion. Conclusion: Fenoldopam at a dose of 0.5 μg/kg/min induces diuresis in cats in a delayed manner. This increase appears to be due, in part, to dopamine receptor-induced natriuresis. Changes in glomerular filtration rate may also occur.
Human Cell Tropism and Innate Immune System Interactions of Human Respiratory Coronavirus EMC Compared to Those of Severe Acute Respiratory Syndrome Coronavirus

ABSTRACT Infections with human coronavirus EMC (HCoV-EMC) are associated with severe pneumonia. We demonstrate that HCoV-EMC resembles severe acute respiratory syndrome coronavirus (SARS-CoV) in productively infecting primary and continuous cells of the human airways and in preventing the induction of interferon regulatory factor 3 (IRF-3)-mediated antiviral alpha/beta interferon (IFN-α/β) responses. However, HCoV-EMC was markedly more sensitive to the antiviral state established by ectopic IFN. Thus, HCoV-EMC can utilize a broad range of human cell substrates and suppress IFN induction, but it does not reach the IFN resistance of SARS-CoV.
Evasion of Antiviral Immunity through Sequestering of TBK1/IKKε/IRF3 into Viral Inclusion Bodies

ABSTRACT Cells are equipped with pattern recognition receptors (PRRs) such as the Toll-like and RIG-I-like receptors that mount innate defenses against viruses. However, viruses have evolved multiple strategies to evade or thwart host antiviral responses. Viral inclusion bodies (IBs), which are accumulated aggregates of viral proteins, are commonly formed during the replication of some viruses in infected cells, but their role in viral immune evasion has rarely been explored. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging febrile illness caused by a novel phlebovirus in the Bunyaviridae. The SFTS viral nonstructural protein NSs can suppress host beta interferon (IFN-β) responses. NSs can form IBs in infected and transfected cells. Through interaction with tank-binding kinase 1 (TBK1), viral NSs was able to sequester the IKK complex, including IKKε and IRF3, into IBs, although NSs did not interact with IKKε or IRF3 directly. When cells were infected with influenza A virus, IRF3 was phosphorylated and active phosphorylated IRF3 (p-IRF3) was translocated into the nucleus. In the presence of NSs, IRF3 could still be phosphorylated, but p-IRF3 was trapped in cytoplasmic IBs, resulting in reduced IFN-β induction and enhanced viral replication. Sequestration of the IKK complex and active IRF3 into viral IBs through the interaction of NSs and TBK1 is a novel mechanism for viral evasion of innate immunity.
TRIM5α and TRIM22 Are Differentially Regulated According to HIV-1 Infection Phase and Compartment

ABSTRACT The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = −0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4+ lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo. IMPORTANCE Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5α and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5α and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4+ lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined.
Financial burden of diabetic foot ulcers to world: a progressive topic to discuss always

Diabetic foot complications are the most common occurring problems throughout the globe, resulting in devastating economic crises for the patients, families and society. Diabetic foot ulcers (DFUs) have a neuropathic origin with a progressive prevalence rate in developing countries compared with developed countries among diabetes mellitus patients. Diabetic patients that are of greatest risk of ulcers may easily be diagnosed with foot examination. Economic burden may be carefully examined. The budget costing must include both the clinical and social impact of the patients.
Boosting Functional Avidity of CD8+ T Cells by Vaccinia Virus Vaccination Depends on Intrinsic T-Cell MyD88 Expression but Not the Inflammatory Milieu

ABSTRACT T-cell functional avidity is a crucial determinant for efficient pathogen clearance. Although recombinant DNA priming coupled with a vaccinia-vectored vaccine (VACV) boost has been widely used to mount robust CD8+ T-cell responses, how VACV boost shapes the properties of memory CD8+ T cells remains poorly defined. Here, we characterize the memory CD8+ T cells boosted by VACV and demonstrate that the intrinsic expression of MyD88 is critical for their high functional avidity. Independent of selection of clones with high-affinity T-cell receptor (TCR) or of enhanced proximal TCR signaling, the VACV boost significantly increased T-cell functional avidity through a decrease in the activation threshold. VACV-induced inflammatory milieu is not sufficient for this improvement, as simultaneous administration of the DNA vaccine and mock VACV had no effects on the functional avidity of memory CD8+ T cells. Furthermore, reciprocal adoptive transfer models revealed that the intrinsic MyD88 pathway is required for instructing the functional avidity of CD8+ T cells boosted by VACV. Taking these results together, the intrinsic MyD88 pathway is required for the high functional avidity of VACV-boosted CD8+ T cells independent of TCR selection or the VACV infection-induced MyD88-mediated inflammatory milieu. IMPORTANCE Functional avidity is one of the crucial determinants of T-cell functionality. Interestingly, although it has been demonstrated that a DNA prime-VACV boost regimen elicits high levels of T-cell functional avidity, how VACV changes the low avidity of CD8+ T cells primed by DNA into higher ones in vivo is less defined. Here, we proved that the enhancement of CD8+ T cell avidity induced by VACV boost is mediated by the intrinsic MyD88 pathway but not the MyD88-mediated inflammatory milieu, which might provide prompts in vaccine design.