Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8+ dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.
CD160 Activation by Herpesvirus Entry Mediator Augments Inflammatory Cytokine Production and Cytolytic Function by NK Cells

Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage herpesvirus entry mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells. Human CD56dim NK cells were costimulated specifically by HVEM but not by other receptors that share the HVEM ligands LIGHT, Lymphotoxin-α, or BTLA. HVEM enhanced human NK cell activation by type I IFN and IL-2, resulting in increased IFN-γ and TNF-α secretion, and tumor cell–expressed HVEM activated CD160 in a human NK cell line, causing rapid hyperphosphorylation of serine kinases ERK1/2 and AKT and enhanced cytolysis of target cells. In contrast, HVEM activation of BTLA reduced cytolysis of target cells. Together, our results demonstrate that HVEM functions as a regulator of immune function that activates NK cells via CD160 and limits lymphocyte-induced inflammation via association with BTLA.
Protective CD8 T Cell–Mediated Immunity against Influenza A Virus Infection following Influenza Virus–like Particle Vaccination

The development of influenza A virus (IAV) vaccines capable of inducing cytotoxic CD8 T cell responses could potentially provide superior, long-term protection against multiple, heterologous strains of IAV. Although prior studies demonstrated the effectiveness of baculovirus-derived virus-like particle (VLP) vaccination in generating Ab-mediated protection, the role that CD8 T cell immunity plays in overall VLP-mediated protection is less-well understood. In this article, we demonstrate that intranasal vaccination of mice with a VLP containing the hemagglutinin and matrix 1 proteins of IAV/PR/8/34 leads to a significant increase in hemagglutinin 533–specific CD8 T cells in the lungs and protection following subsequent homologous challenge with IAV. VLP-mediated protection was significantly reduced by CD8 T cell depletion, indicating a critical role for CD8 T cells in protective immunity. Importantly, our results show that VLP vaccine–induced CD8 T cell–mediated protection is not limited to homologous IAV strains. VLP vaccination leads to an increase in protection following heterosubtypic challenge with a strain of IAV that avoids vaccine-induced neutralizing Abs but contains conserved, immunodominant CD8 T cell epitopes. Overall, our results demonstrate the ability of influenza protein–containing VLPs to prime IAV-specific CD8 T cell responses that contribute to protection from homo- and heterosubtypic IAV infections. These results further suggest that vaccination strategies focused on the development of cross-protective CD8 T cell responses may contribute to the development of “universal” IAV vaccines.
Role for σ38 in Prolonged Survival of Escherichia coli in Drosophila melanogaster

Bacteria adapt themselves to host environments by altering the pattern of gene expression. The promoter-recognizing subunit σ of bacterial RNA polymerase plays a major role in the selection of genes to be transcribed. Among seven σ factors of Escherichia coli, σ38 is responsible for the transcription of genes in the stationary phase and under stressful conditions. We found a transient increase of σ38 when E. coli was injected into the hemocoel of Drosophila melanogaster. The loss of σ38 made E. coli rapidly eliminated in flies, and flies infected with σ38-lacking E. coli stayed alive longer than those infected with the parental strain. This was also observed in fly lines defective in humoral immune responses, but not in flies in which phagocytosis was impaired. The lack of σ38 did not influence the susceptibility of E. coli to phagocytosis, but made them vulnerable to killing after engulfment. The changes caused by the loss of σ38 were recovered by the forced expression of σ38-encoding rpoS as well as σ38-regulated katE and katG coding for enzymes that detoxify reactive oxygen species. These results collectively suggested that σ38 contributes to the prolonged survival of E. coli in Drosophila by inducing the production of enzymes that protect bacteria from killing in phagocytes. Considering the similarity in the mechanism of innate immunity against invading bacteria between fruit flies and humans, the products of these genes could be new targets for the development of more effective antibacterial remedies.
Prevalence and correlates for tobacco smoking among persons aged 25 years or older in Lusaka urban district, Zambia

for 18.5 to 24.9 BMI; AOR = 0.12 (95% CI [0.05, 0.31]) for 25.0 to 29.9 BMI; and AOR = 0.03 (95% CI [0.00, 0.26]) for 30+ BMI. We conclude that the tobacco smoking epidemic is in its early stage in Zambia. Zambia must act now to curtail the epidemic. The association between smoking and body mass index should further be explored so that an intervention can be designed that addresses both smoking and nutrition.
Off-premise alcohol outlet characteristics and violence

Abstract Background: There is considerable evidence of an association between alcohol outlet density and violence. Although prior research reveals the importance of specific characteristics of bars on this association and that the relationship between bar density and violence may be moderated by these characteristics, there are few similar studies of the characteristics of off-premise outlets (e.g. liquor and convenience stores). Objectives: We examined whether immediate environment, business practice, staff, and patron characteristics of off-premise alcohol outlets are associated with simple and aggravated assault density. Methods: Cross-sectional design using aggregate data from 65 census block groups in a non-metropolitan college town, systematic social observation, and spatial modeling techniques. Results: We found limited effects of immediate environment, business practice, staff, and patron characteristics on simple assault density and no effect on aggravated assault density. Only two out of 17 characteristics were associated with simple assault density (i.e. nearby library and male patrons). Conclusion: This is the first study to examine the association between several off-premise alcohol outlet characteristics and assault. Our findings suggest that where the off-premise outlets are located, how well the immediate environment is maintained, what types of beverages the outlets sell, who visits them, and who works there matter little in their association with violence. This suggests the importance of outlet density itself as a primary driver of any association with violence. Public policies aimed at reducing alcohol outlet density or clustering may be useful for reducing violence.
Placental Macrophages Are Impaired in Chorioamnionitis, an Infectious Pathology of the Placenta

Pregnancy is dependent on maternal–fetal tolerance that may be compromised because of infections or inflammation of the placenta. In this study, we examined whether the context of placental immune tolerance affected the functions of resident macrophages and if their functions were altered during chorioamnionitis, an infectious pathology of the placenta. Macrophages from at-term placentas expressed CD14, exhibited macrophage microbicidal functions, but were less inflammatory than monocyte-derived macrophages. Moreover, placental macrophages spontaneously matured into multinucleated giant cells (MGCs), a property not exhibited by monocyte-derived macrophages, and we detected MGCs of myeloid origin in placental tissue. Compared with placental macrophages, MGCs exhibited a specific phenotype and gene expression signature, consisting of increased cytoskeleton-associated gene expression along with depressed expression of inflammatory response genes. Furthermore, placental macrophages from patients with chorioamnionitis were unable to form MGCs, but this defect was partially corrected by incubating these placental macrophages with control trophoblast supernatants. MGCs formation likely serves to regulate their inflammatory and cytocidal activities in a context that imposes semiallograft acceptance and defense against pathogens.
Omega-3 Fatty Acids and Cognitive Decline

The brain is a lipid-rich organ and thus it is reasonable to question the role of fatty acids in normal brain function, including cognition. The purpose of this article is to examine our current knowledge on the relationship between omega-3 fatty acids (ω3FA) and cognitive function and explore the therapeutic implications of ω3FA in the prevention and treatment of cognitive impairment. Published cross-sectional and prospective observational research, though not fully consistent, predominantly support the role of ω3FA in decreasing the risk of cognitive decline. However, to date, the results from randomized controlled trials have been predominantly null, with the exception of supplementation in individuals with mild cognitive impairment. Whether lack of evidence is a result of insufficient study design or absence of actual benefit warrants further clinical research. Given the low side effect profile, high accessibility, and relatively low cost, it is reasonable to recommend, at minimum, the dietary intake of ω3FA or supplementation of fish oil in alignment with the 2010 Department of Health and Human Services Dietary Guidelines for Americans.
ANTHROPOMETRIC AND STRENGTH CHARACTERISTICS OF TENPIN BOWLERS WITH DIFFERENT PLAYING ABILITIES

The primary purpose of this study was to investigate the strength and anthropometric characteristics of elite and semi-elite tenpin bowlers as compared to non-bowlers, and to establish whether it was possible to discriminate playing level through selected predictor variables. Elite and semi-elite bowlers were distinguished by their bowling score average (BSave), with participants scoring 200 pin falls and above assigned to the elite group. Eighteen elite bowlers (M=10, F=8; BSave 213.2±6.80), 12 semi-elite bowlers (M=7, F=5; BSave 181.3±9.36) and 33 sedentary university students (M=14, F=19) were recruited. Anthropometric measurements were taken and isometric arm strength was recorded. Between-group differences were identified through a two-way ANOVA, while discriminant analysis was used to predict group membership. For anthropometric characteristics, the results indicated that the elite bowlers were heavier, had longer lower leg and hand length and had a wider arm span as compared to the non-bowlers. The elite group also had stronger forearm/wrist internal rotation compared to non-bowlers. In addition, the male elite group were stronger than the non-bowling group for arm flexion. There appeared to be a 54% success rate for predicting group membership from selected anthropometric and strength discriminating variables, with forearm/wrist internal rotation strength being the best discriminating variable. It is suggested that coaches should benefit by selecting larger built bowlers with long limbs. Furthermore, bowlers could potentially gain by paying extra attention to increasing the strength levels of forearm/wrist internal rotators and arm flexors during training. These findings also provide normative data for elite and semi-elite bowlers.
Double Positive Thymocytes Select Mucosal-Associated Invariant T Cells

NKT and mucosal-associated invariant T (MAIT) cells express semi-invariant TCR and restriction by nonclassical MHC class Ib molecules. Despite common features, the respective development of NKT and MAIT subsets is distinct. NKTs proliferate extensively and acquire effector properties prior to thymic export. MAIT cells exit the thymus as naive cells and acquire an effector/memory phenotype in a process requiring both commensal flora and B cells. During thymic development, NKTs are selected by CD1d-expressing cortical thymocytes; however, the hematopoietic cell type responsible for MAIT cell selection remains unresolved. Using reaggregated thymic organ culture and bone marrow chimeras, we demonstrate that positive selection of mouse iVα19 transgenic and Vβ6 transgenic MAIT cell progenitors requires MHC-related 1–expressing CD4+CD8+ double positive thymocytes, whereas thymic B cells, macrophages, and dendritic cell subsets are dispensable. Preincubation of double positive thymocytes with exogenous bacterial ligand increases MHC-related 1 surface expression and enhances mature MAIT cell activation in the in vitro cocultures. The revelation of a common cell type for the selection of both NKT and MAIT subsets raises questions about the mechanisms underlying acquisition of their specific features.
The antioxidant advantage of the Mediterranean diet in cardiovascular disease

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress. com/permissions.php Nutrition and Dietary Supplements 2014:6 35–40 Nutrition and Dietary Supplements Dovepress
Munc18-2 and Syntaxin 3 Control Distinct Essential Steps in Mast Cell Degranulation

Mast cell degranulation requires N-ethylmaleimide–sensitive factor attachment protein receptors (SNARE) and mammalian uncoordinated18 (Munc18) fusion accessory proteins for membrane fusion. However, it is still unknown how their interaction supports fusion. In this study, we found that small interfering RNA–mediated silencing of the isoform Munc18-2 in mast cells inhibits cytoplasmic secretory granule (SG) release but not CCL2 chemokine secretion. Silencing of its SNARE-binding partner syntaxin 3 (STX3) also markedly inhibited degranulation, whereas combined knockdown produced an additive inhibitory effect. Strikingly, while Munc18-2 silencing impaired SG translocation, silencing of STX3 inhibited fusion, demonstrating unique roles of each protein. Immunogold studies showed that both Munc18-2 and STX3 are located on the granule surface, but also within the granule matrix and in small nocodazole-sensitive clusters of the cytoskeletal meshwork surrounding SG. After stimulation, clusters containing both effectors were detected at fusion sites. In resting cells, Munc18-2, but not STX3, interacted with tubulin. This interaction was sensitive to nocodazole treatment and decreased after stimulation. Our results indicate that Munc18-2 dynamically couples the membrane fusion machinery to the microtubule cytoskeleton and demonstrate that Munc18-2 and STX3 perform distinct, but complementary, functions to support, respectively, SG translocation and membrane fusion in mast cells.
The effect of alcohol priming on neural markers of alcohol cue-reactivity

Abstract Background: Priming doses of alcohol are associated with increased desire to drink and disinhibitory effects on subsequent control over drinking. Despite the importance of alcohol priming in the cue-reactivity literature, the effects of priming on brain responses to alcohol cues remains unclear. Furthermore, evidence suggests this relationship may be moderated by OPRM1 genotype. Methods: Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent two functional magnetic resonance imaging (fMRI) sessions, before and after a priming dose of alcohol, each including a gustatory alcohol cue reactivity paradigm and self-reported craving measures. Results: Self-reported alcohol craving generally increased and remained higher for alcohol versus water cue presentations across pre- and post-priming scans. Compared to alcohol cues delivered during the post-priming scan, alcohol cues delivered pre-priming were associated with greater activation in regions including the hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex. Controlling for alcoholism severity increased statistical significance of activation in these regions. Follow-up analyses revealed a positive correlation between alcoholism severity and pre- versus post-priming alcohol cue-reactivity primarily in frontal regions. OPRM1 genotype was also found to moderate alcohol cue-reactivity across scans. Conclusion: This study provides initial evidence of alcohol cue-elicited habituation in fronto-temporal regions, despite continued craving, following a priming dose of alcohol. Further, it provides preliminary evidence for moderating roles of alcoholism severity and OPRM1 genotype on priming-related changes in cue-reactivity, adding to our understanding of the function of alcohol priming in alcohol dependence.
Development of glomerulonephritis during anti-TNF-α therapy for rheumatoid arthritis

BACKGROUND Treatment of rheumatoid arthritis with anti-tumour necrosis factor alpha (TNFalpha) agents may lead to autoantibody formation and flares of vasculitis, but renal complications are rare. METHODS We report the clinical and pathologic findings in five patients with longstanding rheumatoid arthritis (duration of rheumatoid arthritis, 10-30 years; mean, 23 years) who developed new onset of glomerular disease after commencing therapy with anti-TNFalpha agents (duration of therapy, 3-30 months; median, 6 months). RESULTS At presentation, three patients were receiving etanercept, one adalimumab and one infliximab. Two subjects presented with acute renal insufficiency, haematuria, nephrotic-range proteinuria, positive lupus serologies, and hypocomplementemia, and renal biopsies showed proliferative lupus nephritis. Two individuals presented with new onset renal insufficiency, haematuria and proteinuria, and renal biopsies showed pauci-immune necrotizing and crescentic glomerulonephritis. One of these subjects, who had anti-myeloperoxidase autoantibodies, also developed pulmonary vasculitis. The fifth patient presented with nephrotic syndrome and renal biopsy findings of membranous glomerulonephritis, associated with immune complex renal vasculitis. A pathogenic role for anti-TNFalpha therapy is suggested by the close temporal relationship with development of glomerular disease, and by the improvement in clinical and laboratory abnormalities after drug withdrawal and initiation of immunosuppressive therapy in most cases. CONCLUSIONS Rheumatoid arthritis patients receiving anti-TNFalpha agents may develop glomerulonephritis via the induction of rheumatoid arthritis-related nephropathy or de novo autoimmune disorders.
IPS-1 Is Essential for Type III IFN Production by Hepatocytes and Dendritic Cells in Response to Hepatitis C Virus Infection

Hepatitis C virus (HCV) is a major cause of liver disease. The innate immune system is essential for controlling HCV replication, and HCV is recognized by RIG-I and TLR3, which evoke innate immune responses through IPS-1 and TICAM-1 adaptor molecules, respectively. IL-28B is a type III IFN, and genetic polymorphisms upstream of its gene are strongly associated with the efficacy of polyethylene glycol–IFN and ribavirin therapy. As seen with type I IFNs, type III IFNs induce antiviral responses to HCV. Recent studies established the essential role of TLR3–TICAM-1 pathway in type III IFN production in response to HCV infection. Contrary to previous studies, we revealed an essential role of IPS-1 in type III IFN production in response to HCV. First, using IPS-1 knockout mice, we revealed that IPS-1 was essential for type III IFN production by mouse hepatocytes and CD8+ dendritic cells (DCs) in response to cytoplasmic HCV RNA. Second, we demonstrated that type III IFN induced RIG-I but not TLR3 expression in CD8+ DCs and augmented type III IFN production in response to cytoplasmic HCV RNA. Moreover, we showed that type III IFN induced cytoplasmic antiviral protein expression in DCs and hepatocytes but failed to promote DC-mediated NK cell activation or cross-priming. Our study indicated that IPS-1–dependent pathway plays a crucial role in type III IFN production by CD8+ DCs and hepatocytes in response to HCV, leading to cytoplasmic antiviral protein expressions.
Nurses’ Experiences of Providing Care to Dementia Patients Through Home Health Care

Most Western countries aim to enable dementia sufferers to live at home for as long as possible. Person centeredness, continuity of care, and competence level are all important for the quality of home health care (HHC). The aim of this qualitative study is to describe staff’s experiences of providing care to home-dwelling dementia clients through HHC services. The study used a phenomenological-hermeneutic interpretation of focus group interviews. This study supports the value of continuous interpersonal relationships in HHC services. The findings show that specialized teams facilitate continuity and person-centered care, and that after training, staff become more holistically oriented, involve clients in daily care, and experience greater job confidence.