Miracle-dz/UniFAR-FTUs huggingface dataset:
Innate IFN‐γ Production by Subsets of Natural Killer Cells, Natural Killer T Cells and γδ T Cells in Response to Dying Bacterial‐Infected Macrophages

Interferon‐γ (IFN‐γ) activation of macrophages is a crucial step in the early innate defence against bacterial infection. This innate IFN‐γ is thought to be produced mainly by natural killer (NK) cells through activation with interleukin (IL)‐12p70 secreted by macrophages and dendritic cells (DCs) that have sensed bacterial products. However, a number of reports have shown that bacterial stimuli are unable to induce macrophages and/or DCs to produce sufficient amounts of IL‐12p70 unless these cells are primed by IFN‐γ. It remains, therefore, unsettled how initial IFN‐γ is produced. In a previous study, we reported a novel IFN‐γ production pathway that was associated with cell death in macrophages caused by intracellular bacteria like Listeria monocytogenes (LM) and Shigella flexneri. In this study, we showed that cell death of bone‐marrow‐derived macrophage (BMM) cells following in vitro infection with Staphylococcus aureus (SA), an extracellular bacterium, can also stimulate this IFN‐γ production pathway. We also unequivocally demonstrated by using BMM cells from IL‐12‐deficient mice that the bacterial‐infected macrophage cell death‐mediated IFN‐γ production can occur without IL‐12 although the magnitude of the response is much smaller than that in the presence of IL‐12. The enhancing effect of IL‐12 on this response proved to be attributable to the negligible amounts (0.5∼1.5 pg/ml) of IL‐12p70 but not to the large amounts of IL‐12p40 that were both secreted by SA‐ and LM‐infected macrophages. Taken all together, we propose that macrophage cell death caused by bacteria may trigger the initial IFN‐γ production at an early stage of bacterial infection.
Functionalization of P4 using a Lewis acid stabilized bicyclo[1.1.0]tetraphosphabutane anion.

Reacting white phosphorus (P4 ) with sterically encumbered aryl lithium reagents (aryl=2,6-dimesitylphenyl or 2,4,6-tBu3 C6 H2 ) and B(C6 F5 )3 gives the unique, isolable Lewis acid stabilized bicyclo[1.1. 0]tetraphosphabutane anion. Subsequent alkylation of the nucleophilic site of the RP4 anion gives access to non-symmetrical disubstituted bicyclic tetraphosphorus compounds. This novel method enables PC bond formation in a controlled fashion using white phosphorus as starting material.
In vivo residue-specific dopa-incorporated engineered mussel bioglue with enhanced adhesion and water resistance.

Misaminoacylation of 3,4-dihydroxyphenylalanine (Dopa) molecules to tRNA(Tyr) by endogenous tyrosyl-tRNA synthetase allowed the quantitative replacement of tyrosine residues with a yield of over 90 % by an in vivo residue-specific incorporation strategy, to create, for the first time, engineered mussel adhesive proteins (MAPs) in Escherichia coli with a very high Dopa content, close to that of natural MAPs. The Dopa-incorporated MAPs exhibited a superior surface adhesion and water resistance ability by assistance of Dopa-mediated interactions including the oxidative Dopa cross-linking, and furthermore, showed underwater adhesive properties comparable to those of natural MAPs. These results propose promising use of Dopa-incorporated engineered MAPs as bioglues or adhesive hydrogels for practical underwater applications.
Safety of hormonal and intrauterine methods of contraception for women with HIV/AIDS: a systematic review

Objective:To determine from the literature whether HIV-infected women who use hormonal or intrauterine contraception are at increased risk of HIV disease progression, other adverse health outcomes, or HIV transmission to uninfected sexual partners. Design:A systematic review. Methods:We searched PubMed for articles published in peer-reviewed journals through August 2009 for evidence relevant to all hormonal and intrauterine contraceptive methods and HIV/AIDS. Results:Eight observational studies reported no increased risk of HIV disease progression with hormonal or intrauterine contraceptive use, whereas one randomized controlled trial found increased risks of declining CD4 cell count and death for hormonal contraceptive users compared with intrauterine device users. Women with HIV who used hormonal contraception had increased risks of acquiring sexually transmitted infections compared with women not using hormonal contraception, similar to the risks reported among uninfected women. One study found no association between hormonal or intrauterine contraceptive use and increased risk of HIV transmission to uninfected partners, whereas findings from nine studies examining contraceptive use and viral shedding from the genital tract were inconsistent. Conclusion:Evidence regarding the safety of hormonal and intrauterine contraceptive use among women with HIV remains limited, but generally reassuring regarding adverse health effects, disease transmission to uninfected partners, and disease progression; however, one randomized trial raised concerns about enhanced disease progression among women using hormonal contraception. Preventing unintended pregnancy among women with HIV remains a high priority in public health, both for the health of the woman as well as for the prevention of mother-to-child transmission of HIV.
Hormonal contraception and HIV disease progression: a multicountry cohort analysis of the MTCT-Plus Initiative

Objective:HIV-infected women need access to safe and effective contraception. Recent animal and human data suggest that hormonal contraception may accelerate HIV disease progression. Methods:We compared the incidence of HIV disease progression among antiretroviral therapy-naive women with and without exposure to hormonal contraception at 13 sites in Africa and Asia. Disease progression was defined as becoming eligible for antiretroviral therapy or death. Results:Between 1 August 2002 and 31 December 2007, the MTCT-Plus programs enrolled 7846 women. In total, 4109 (52%) women met eligibility criteria for this analysis and contributed 5911 person-years of follow-up (median follow-up, 379 days; interquartile range, 121–833). At baseline, 3064 (75%) women reported using either no contraception or a nonhormonal method, whereas 823 (20%) reported using implants/injectables and 222 (5%) reported using oral contraceptive pills. The disease progression outcome was met by 944 (29%) women (rate, 18.3/100 woman-years). Neither implants/injectables (adjusted hazard ratio 1.0, 95% confidence interval 0.8–1.1) nor oral contraceptive pills (adjusted hazard ratio 0.8, 95% confidence interval 0.6–1.1) were associated with disease progression. Treating contraceptive method as a time-varying exposure did not change this negative finding. Conclusion:This multicountry cohort analysis provides some reassurance that hormonal contraception is not associated with HIV disease progression. Further research is needed to address the contraceptive needs of HIV-infected women.
Small Islets are Essential for Successful Intraportal Transplantation in a Diabetes Mouse Model

Optimization of islet transplantation protocols is necessary for improved success of treatment for type 1 diabetes. Here, we investigated whether the size of islets transplanted into the portal vein (PV) of the liver can affect engraftment in the early post‐transplantation in an experimental mouse model. Small (average diameter < 250 μm, group A) or large (average diameter > 250 μm, group B) islets (400 islet equivalents/recipient) purified from normal BALB/c mice were transplanted into syngenic recipients with diabetes induced by STZ. The percentage of mice returning to a non‐diabetic status was higher in group A (100%) than that of group B (62.5%). Focal areas of liver necrosis associated with the islets emboli were observed in both groups, but the pathology in group B was significantly worse. Multiple proinflammatory cytokines were significantly higher in group B than that of A at 3 h post‐transplantation. Our study determined that the size of islets plays a critical role in the success of intraportal islet transplantation (IPIT) and should be taken into account in future IPIT protocols for the treatment of diabetes.
Feasibility and effectiveness of integrating provider-initiated testing and counselling within family planning services in Kenya

Objective:To assess an intervention for increasing access to and use of HIV testing among family planning clients through provider-initiated testing and counselling for HIV. Design:Two versions of the intervention were prospectively compared using a prepost intervention only design. Health facilities were purposively selected and family planning consultations randomly selected. Setting:Twenty-three public-sector hospitals, health centres and dispensaries in two districts of Central Province, Kenya. Participants:One group of 28 family planning providers were trained in the integrated family planning–HIV counselling intervention and in providing HIV testing and counselling to family planning clients requesting a test during the consultation and another group of 47 family planning providers were trained in the intervention and in referring clients interested in an HIV test. Samples of family planning clients willing to be observed and interviewed were randomly selected (538 preintervention, 520 postintervention) and their informed consent obtained to observe their consultation. Intervention:All family planning providers were trained in an algorithm that integrates HIV/sexually transmitted infection prevention counselling, including offering HIV testing and counselling, with family planning counselling. Clients choosing to be tested were either referred or tested during the consultation by a trained family planning provider. Main outcome measures:The proportion of family planning clients with whom HIV testing was discussed; the proportion offered HIV testing; and the proportion choosing to have a test. Results:The proportion of consultations in which HIV prevention counselling was provided and HIV testing offered increased significantly. The proportion of clients requesting an HIV test increased from 1 to 26%; approximately one third of these had never been tested previously. Conclusion:Provider-initiated testing and counselling is feasible and acceptable in family planning services, does not adversely affect the quality of the family planning consultation and increases access to and use of HIV testing in a population who would benefit from knowing their status.
Violent deaths in Port Harcourt, Nigeria

Background: Accidental, homicidal and suicidal deaths together form a category of deaths referred to as violent deaths. There is a need to for adequate characterization of these deaths, particularly for control measures. Method: A retrospective study of violent deaths in Port Harcourt, Nigeria 1995 - 1999. Results: Five hundred and seventy seven cases were analysed during the period, which makes up 72% of all medicolegal autopsies. Accidental deaths accounted for 63% of violent deaths, homicidal deaths 35.2% and suicidal deaths 1.6%. The majority of the victims (37.2%) were aged 39 years or less. Motorcycle accidents formed the commonest cause of vehicular accidents in Port Harcourt given (55%) Conclusion: The commonest method of homicidal death is by firearms and the commonest method of suicide is by hanging. Key Words: Violent death, Port Harcourt, suicides, homicides, accidents Nigerian Journal of Surgical Research Vol.5(1&2) 2003: 124-128
Assessing subtype and drug-resistance-associated mutations among antiretroviral-treated HIV-infected patients

Background:Several studies have reported an increasing number of therapeutic failures with antiretroviral drugs in HIV-infected patients. The emergence of viral-resistant strains is a major problem for the medical management of infected individuals. The aim of this study is to determine viral subtypes and drug-resistance mutations among antiretroviral-treated HIV-infected patients. Methods:A total of 42 antiretroviral-treated but still viremic HIV-infected patients were enrolled. The HIV pol regions were amplified and sequenced to determine subtypes and antiretroviral-resistant mutations. Results:The subtype distribution was 48% A/D recombinants, 43% subtype B, 5% subtype A and 5% CRF01-AE recombinants. Drug-resistant mutations were most common in subtype B (53%) and A/D recombinant strains (44%). Virus samples from 19% of participants had no drug-resistant mutations; 2, 2 and 76% of samples carried one, two and at least three drug-resistant mutations, respectively. The prevalence of nucleoside transcriptase inhibitor mutations was 76%, with M184V and L74V present in 60 and 38% of samples, respectively. The prevalence of nonnucleoside transcriptase inhibitor mutations was 74%, with P225H present in 55% of study specimens. The prevalence of protease inhibitor mutations was 45%, with major mutation L90M seen in 33% and minor mutation A71V in 36% of samples. Of note, the P225H and A71V are ‘minor’ drug-resistance mutations conferring only minimal drug-resistance phenotypes in the absence of major mutations. Conclusion:Our study found a high prevalence of drug-resistant mutations in Iranian HIV-infected patients. Our data support the need for continued surveillance of resistance patterns to help guide therapeutic approaches and limit transmission of these variants.
Rifampin monoresistant tuberculosis and HIV comorbidity in California, 1993–2008: a retrospective cohort study

Objective:Rifampin monoresistant tuberculosis (RMR-TB) is increasingly identified because of scale-up of rapid molecular tests. The longitudinal association of RMR-TB, multidrug-resistant TB (MDR-TB), and HIV/AIDS is incompletely described. Methods:We examined clinical characteristics and treatment outcomes of patients with RMR-TB, isoniazid monoresistant TB (IMR-TB), MDR-TB, and drug-susceptible TB during a 16-year period (1993–2008) in California. TB cases were cross-matched with the state HIV/AIDS registry, and HIV prevalence denominators modeled using nonparametric backcalculation. Results:Of 42 582 TB cases, 178 (0.4%), 3469 (8.1%), and 635 (1.5%) were RMR-TB, IMR-TB, and MDR-TB, respectively. From the pre-HAART (1993–1996) to HAART (2005–2008) era, RMR-TB rates declined rapidly (12.0 vs. 0.5 per 100 000) among patients with HIV infection. The proportion of patients for whom rifampin resistance indicated RMR-TB (rather than MDR-TB) decreased from 31% [95% confidence interval (CI) 26–38%] to 11% (95% CI 5–19%). In multivariate analysis controlling for HIV coinfection and other covariates, patients with RMR-TB were twice as likely to die as patients with drug-sensitive TB (relative risk 1.94, 95% CI 1.40–2.69). Conclusion:RMR-TB/HIV rates declined substantially over time in association with improved TB control and HIV control in California. Mortality among patients with RMR-TB was high, even after adjusting for HIV status.
Promoting hearing health and the combined risk of noise-induced hearing loss and ototoxicity

The ototoxicity of therapeutic drugs has been a concern in the field of audiology for many years. In comparison, only recently has the ototoxicity of chemicals found in the environment from contaminants in air, food or water, and in the workplace become a concern for audiologists and other health professionals. Studies have shown that some toxins can reach the inner ear through the bloodstream. They were found in the inner ear fluids and have caused damage to some of the inner ear structures and functions. The damage, however, is not always restricted to the cochlea. The onset, site, mechanism and extent of ototoxic damage caused by these toxins vary according to risk factors that include type of chemical, interactions, exposure level and duration of exposure as is the case with therapeutic drugs. Noise exposure has been reported to potentiate or interact synergistically with several toxins. Moreover, it makes the detection and diagnosis of the ototoxicity effect more challenging. The new evidence has prompted the proposal of new guidelines and standards on hearing loss prevention. In this paper, the implications of the studies on the effect of environmental and occupational toxins exposure on the auditory system are discussed. Recent guidelines and legislative developments and alternative strategies for preventing auditory effects of exposure to ototoxic chemicals are examined.
Disruption of the Chaperonin Containing TCP-1 Function Affects Protein Networks Essential for Rod Outer Segment Morphogenesis and Survival*

Type II Chaperonin Containing TCP-1 (CCT, also known as TCP-1 Ring Complex, TRiC) is a multi-subunit molecular machine thought to assist in the folding of ∼10% of newly translated cytosolic proteins in eukaryotes. A number of proteins folded by CCT have been identified in yeast and cultured mammalian cells, however, the function of this chaperonin in vivo has never been addressed. Here we demonstrate that suppressing the CCT activity in mouse photoreceptors by transgenic expression of a dominant-negative mutant of the CCT cofactor, phosducin-like protein (PhLP), results in the malformation of the outer segment, a cellular compartment responsible for light detection, and triggers rapid retinal degeneration. Investigation of the underlying causes by quantitative proteomics identified distinct protein networks, encompassing ∼200 proteins, which were significantly affected by the chaperonin deficiency. Notably among those were several essential proteins crucially engaged in structural support and visual signaling of the outer segment such as peripherin 2, Rom1, rhodopsin, transducin, and PDE6. These data for the first time demonstrate that normal CCT function is ultimately required for the morphogenesis and survival of sensory neurons of the retina, and suggest the chaperonin CCT deficiency as a potential, yet unexplored, cause of neurodegenerative diseases.
Associations between immune depression and cardiovascular events in HIV infection

Objective:To consider associations between the latest/nadir CD4+ cell count, and time spent with CD4+ cell count less than 200 cells/&mgr;l (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals. Design:Longitudinal cohort study. Methods:Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included stroke-like events and rejected strokes into the stroke endpoint. Results:Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4+ cell counts after adjustment [current CD4+ <100 cells/&mgr;l: relative rate (95% confidence interval) 0.96 (0.62–1.50) for MI, 0.89 (0.30–2.36) for CHD; nadir CD4+ <100 cells/&mgr;l: 1.36 (0.57–3.23) for MI, 0.98 (0.45–2.16) for CHD], stroke and CVD rates were higher in those with a latest CD4+ cell count less than 100 cells/&mgr;l [2.26 (1.29–3.94) and 1.14 (0.84–1.56), respectively]. All events occurred less frequently in those who had not experienced immune depression, although evidence for a linear association with duration of immune depression was weak. The association between stroke risk and the latest CD4+ cell count strengthened as stroke-like and rejected strokes were included; conversely, associations with established stroke risk factors weakened. Conclusion:We do not find strong evidence that HIV-positive individuals with a low CD4+ cell count are more likely to experience MI/CHD. Although strokes appear to occur more commonly at low CD4+ cell counts, this may be partly explained by misclassification or other biases.
Human leukocyte antigen B*57 does not fully explain hepatitis C clearance in HIV controllers

Objective:HIV controllers demonstrate high rates of spontaneous clearance of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the role of human leukocyte antigen (HLA) B*57 and other genetic polymorphisms on HCV clearance in HIV controllers. Design:This is a prospective cohort study. Methods:Patients in the Study of the Consequences of Protease Inhibitor Era (SCOPE) were tested for anti-HCV using enzyme immunoassay (EIA3) and HCV RNA using discriminatory HCV transcription-mediated amplification assay (Norvatis). We compared the proportion of HIV controllers and noncontrollers demonstrating HCV clearance and fitted multivariable Poisson regression models with robust standard errors to estimate adjusted prevalence ratios (APRs) and assessed genetic and immunologic predictors of HCV clearance. Results:Of 279 HIV/HCV seropositive individuals, 48 were HIV controllers. HIV controllers compared to HIV noncontrollers, were significantly more likely to have HLA B*57 (33 vs. 10%, P < 0.01). In multivariate analyses, adjusting for HLAB57, IL28B genotype, age, sex and race/ethnicity, HCV clearance was significantly more likely in HIV controllers than HIV noncontrollers [APR 1.78; 95% confidence interval (CI) 1.06–3.0; P = 0.03]. HLA B*57 did not explain the increased proportion of HCV clearance in HIV controllers, but IL28B CC genotype was independently associated with spontaneous HCV clearance (APR 2.76; 95% CI 1.85–4.11; P < 0.001). Conclusion:Although enriched in HIV controllers, HLA B*57 does not explain the increased HCV clearance. Further identification of host immunologic or genetic factors that contribute to control of HIV and HCV may support the development of novel treatments for and effective vaccines against both viruses.
An Informatics-assisted Label-free Approach for Personalized Tissue Membrane Proteomics: Case Study on Colorectal Cancer

We developed a multiplexed label-free quantification strategy, which integrates an efficient gel-assisted digestion protocol, high-performance liquid chromatography tandem MS analysis, and a bioinformatics alignment method to determine personalized proteomic profiles for membrane proteins in human tissues. This strategy provided accurate (6% error) and reproducible (34% relative S.D.) quantification of three independently purified membrane fractions from the same human colorectal cancer (CRC) tissue. Using CRC as a model, we constructed the personalized membrane protein atlas of paired tumor and adjacent normal tissues from 28 patients with different stages of CRC. Without fractionation, this strategy confidently quantified 856 proteins (≥2 unique peptides) across different patients, including the first and robust detection (Mascot score: 22,074) of the well-documented CRC marker, carcinoembryonic antigen 5 by a discovery-type proteomics approach. Further validation of a panel of proteins, annexin A4, neutrophils defensin A1, and claudin 3, confirmed differential expression levels and high occurrences (48–70%) in 60 CRC patients. The most significant discovery is the overexpression of stomatin-like 2 (STOML2) for early diagnostic and prognostic potential. Increased expression of STOML2 was associated with decreased CRC-related survival; the mean survival period was 34.77 ± 2.03 months in patients with high STOML2 expression, whereas 53.67 ± 3.46 months was obtained for patients with low STOML2 expression. Further analysis by ELISA verified that plasma concentrations of STOML2 in early-stage CRC patients were elevated as compared with those of healthy individuals (p < 0.001), suggesting that STOML2 may be a noninvasive serological biomarker for early CRC diagnosis. The overall sensitivity of STOML2 for CRC detection was 71%, which increased to 87% when combined with CEA measurements. This study demonstrated a sensitive, label-free strategy for differential analysis of tissue membrane proteome, which may provide a roadmap for the subsequent identification of molecular target candidates of multiple cancer types.