Miracle-dz/UniFAR-FTUs huggingface dataset:
Mesoderm‐specific transcript localization in the ER and ER‐lipid droplet interface supports a role in adipocyte hypertrophy

Highly variable expression of mesoderm‐specific transcript (Mest) in adipose tissue among genetically homogeneous mice fed an obesogenic diet, and its positive association with fat mass expansion, suggests that Mest is an epigenetic determinant for the development of obesity. Although the mechanisms by which MEST augments fat accumulation in adipocytes have not been elucidated, it has sequence homology and catalytic peptide motifs which suggests that it functions as an epoxide hydrolase or as a glycerol‐ or acylglycerol‐3‐phosphate acyltransferase. To better understand MEST function, detailed studies were performed to precisely define the intracellular organelle localization of MEST using immunofluorescence confocal microscopy. Lentiviral‐mediated expression of a C‐terminus Myc‐DDK‐tagged MEST fusion protein expressed in 3T3‐L1 preadipocytes/adipocytes, and ear‐derived mesenchymal stem cells (EMSC) from mice was observed in the endoplasmic reticulum (ER) membranes and is consistent with previous studies showing endogenous MEST in the membrane fraction of adipose tissue. MEST was not associated with the Golgi apparatus or mitochondria; however, frequent contacts were observed between MEST‐positive ER and mitochondria. MEST‐positive domains were also shown on the plasma membrane (PM) of non‐permeabilized cells but they did not co‐localize with ER‐PM bridges. Post‐adipogenic differentiated 3T3‐L1 adipocytes and EMSC showed significant co‐localization of MEST with the lipid droplet surface marker perilipin at contact points between the ER and lipid droplet. Identification of MEST as an ER‐specific protein that co‐localizes with lipid droplets in cells undergoing adipogenic differentiation supports a function for MEST in the facilitation of lipid accumulation and storage in adipocytes.
Interleukin-6 as a Potential Indicator for Prevention of High-Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial

Serum interleukin-6 (IL-6), a proinflammatory cytokine, is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis. Flavonols, which can be found in fruits and vegetables, may inhibit colorectal carcinogenesis partly by inhibiting inflammation. We estimated odds ratios and 95% confidence intervals (95% CI) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and thus may serve as a risk indicator and as a response indicator to dietary flavonols. Serum IL-6 concentrations at baseline, year 1, and year 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Intake of flavonols, especially of isorhamnetin, kaempferol, and quercetin, was inversely associated with serum IL-6 concentrations (highest versus lowest flavonol intake quartile, 1.80 versus 2.20 pg/mL) and high-risk (OR, 0.51; 95% CI, 0.26-0.98) and advanced adenoma recurrence (OR, 0.17; 95% CI, 0.06-0.50). A decrease in IL-6 concentration during the trial was inversely associated with high-risk (OR, 0.44; 95% CI, 0.23-0.84) and advanced adenoma recurrence (OR, 0.47; 95% CI, 0.19-1.18). Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high-risk and advanced adenoma. Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention. Cancer Prev Res; 3(6); 764–75. ©2010 AACR.
Kinetic brain analysis and whole-body imaging in monkey of [11C]MNPA, a dopamine agonist radioligand

With a view to future extension of the use of the agonist radioligand [11C]MNPA ([O‐methyl‐11C]2‐methoxy‐N‐propylnorapomorphine) from animals to humans, we performed two positron emission tomography (PET) studies in monkeys. First, we assessed the ability to quantify the brain uptake of [11C]MNPA with compartmental modeling. Second, we estimated the radiation exposure of [11C]MNPA to human subjects based on whole‐body imaging in monkeys. Brain PET scans were acquired for 90 min and included concurrent measurements of the plasma concentration of unchanged radioligand. Time‐activity data from striatum and cerebellum were quantified with two methods, a reference tissue model and distribution volume. Whole‐body PET scans were acquired for 120 min using four bed positions from head to mid thigh. Regions of interest were drawn on compressed planar whole‐body images to identify organs with the highest radiation exposures. After injection of [11C]MNPA, the highest concentration of radioactivity in brain was in striatum, with lowest levels in cerebellum. Distribution volume was well identified with a two‐tissue compartmental model and was quite stable from 60 to 90 min. Whole‐body PET scans showed the organ with the highest radiation burden (μSv/MBq) was the urinary bladder wall (26.0), followed by lungs (22.5), gallbladder wall (21.9), and heart wall (16.1). With a 2.4‐h voiding interval, the effective dose was 6.4 μSv/MBq (23.5 mrem/mCi). In conclusion, brain uptake of [11C]MNPA reflected the density of D2/3 receptors, quantified relative to serial arterial measurements, and caused moderate to low radiation exposure. Synapse 62:700–708, 2008. Published 2008 Wiley‐Liss, Inc.
Sociocultural factors related to parents' and caregivers' decisions to vaccinate children against HPV

Human Papillomavirus (HPV) is the most common sexually transmitted infection in the U.S and can lead to several types of cancers. A better understanding of the variables impacting HPV vaccination will help inform the development of effective disease prevention interventions. This study aims to describe factors that impact parents’ and caregivers’ decisions to vaccinate their children against HPV by examining sociocultural factors and behavioral change theory among parents or caretakers of sons and daughters (ages 9-18) from diverse socioeconomic, racial, and ethnic backgrounds. A national sample was recruited and participants completed demographic questions and measures related to their attitudes and beliefs about the vaccine and measures based on the transtheoretical model. These variables were used to predict child vaccine initiation and to validate existing measures using a novel sample. Health care provider recommendation, perceived vaccine effectiveness, pros for vaccination, and self-efficacy increased the likelihood that children had initiated the HPV vaccine. While no significant differences were found for race/ethnicity and gender on vaccine initiation, some disparities were noted. There were regional differences in perceived cons for vaccination, socioeconomic differences in selfefficacy and perceived effectiveness, and gender differences in health care provider recommendation and parent perception of cons, vaccine harm, and barriers. These findings may inform future, tailored interventions aimed at increasing HPV vaccine initiation among children and adolescents.
Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

AIMS To investigate the effects of two single nucleotide polymorphisms (SNPs) in the human P2X₇ receptor gene (P2RX7)--1068G>A (A348T) and 1513A>C (E496A)--on P2X₇ receptor function, using a specific receptor antagonist (GSK1370319A) and prospective genetic stratification. METHODS Lipopolysaccharide- and ATP-stimulated interleukin-1β production was determined in the presence or absence of GSK1370319A in blood culture from 32 prospectively genotyped subjects. RESULTS There was approximately 6.7-fold difference (P < 0.0001) in IC₅₀ for inhibition of ATP-stimulated interleukin-1β release by GSK1370319A between individuals with the homozygous gain--(1068A) and loss-of-function (1513C) genotypes (expressing the 348T, 496E and 348A, 496A alleles, respectively). CONCLUSIONS Leukocyte P2X₇ receptors had significantly altered pharmacodynamic responses to a specific antagonist (GSK1370319A), directly related to SNP genotype.
The PAS domain‐containing histidine kinase RpfS is a second sensor for the diffusible signal factor of Xanthomonas campestris

A cell–cell signalling system mediated by the fatty acid signal DSF controls the virulence of Xanthomonas campestris pv. campestris (Xcc) to plants. The synthesis and recognition of the DSF signal depends upon different Rpf proteins. DSF signal generation requires RpfF whereas signal perception and transduction depends upon the sensor RpfC and regulator RpfG. Detailed analyses of the regulatory roles of different Rpf proteins have suggested the occurrence of further sensors for DSF. Here we have used a mutagenesis approach coupled with high‐resolution transcriptional analysis to identify XC_2579 (RpfS) as a second sensor for DSF in Xcc. RpfS is a complex sensor kinase predicted to have multiple Per/Arnt/Sim (PAS) domains, a histidine kinase domain and a C‐terminal receiver (REC) domain. Isothermal calorimetry showed that DSF bound to the isolated N‐terminal PAS domain with a Kd of 1.4 μM. RpfS controlled expression of a sub‐set of genes distinct from those controlled by RpfC to include genes involved in type IV secretion and chemotaxis. Mutation of XC_2579 was associated with a reduction in virulence of Xcc to Chinese Radish when assayed by leaf spraying but not by leaf inoculation, suggesting a role for RpfS‐controlled factors in the epiphytic phase of the disease cycle.
Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are rare, autosomal recessive disorders of the connective tissue caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2) located on chromosome 4q21. Characteristically, these conditions present with overlapping clinical features, such as nodules and/or pearly papules, gingival hyperplasia, flexion contractures of the joints, and osteolytic bone defects. The present report describes a pair of sibs and three other JHF/ISH patients whose diagnoses were based on typical clinical manifestations and confirmed by histopathologic analyses and/or molecular analysis. A comparison of ISH and JHF, additional thoughts about new terminology (hyaline fibromatosis syndrome) and a modified grading system are also included. © 2012 Wiley Periodicals, Inc.
Essays on the Impacts of Education Policies

Author(s): Dotter, Dallas Dwight | Abstract: This dissertation evaluates the impacts of education policies affecting students early in their educational careers. The first chapter studies the impacts of universally free school breakfast programs on student achievement. I study the staggered implementation of an in -classroom breakfast program in San Diego elementary schools, which provides meals to all students during class time, to determine the impacts of universally free school breakfasts on student attendance rates, classroom behavior and academic performance. Introducing universally free breakfasts increases math and reading test score gains by roughly 15 and 10 percent of a standard deviation on average, respectively. The results suggest that offering universally free breakfast increases participation-- perhaps by reducing associated social stigmas--and that the resulting positive impacts on academic achievement are at least partly driven by year round benefits rather than only consumption at the time of testing. Chapter two investigates the long-term effects of school entry age on student achievement and educational attainment. Using finely detailed longitudinal data on students in San Diego, I exploit the discontinuity in student ages resulting from school-entry cutoff dates to investigate the relationships between relative age, classroom environment, differentiated curricula and long-run educational outcomes. I find that achievement premiums from entering school relatively older persist well through the high school years. Older entrants are also more likely to enroll in four-year postsecondary institutions after high school, have higher levels of postsecondary persistence, but not higher levels of attainment. These differences can be partially explained by large and lasting differences in classroom behavior during elementary grades and access to higher level course placements beginning in grade eight. Finally, chapter three studies the impacts of high ability tracking on overall educational attainment for students just on the margin of inclusion in "gifted and talented" classrooms. Using a regression discontinuity design, I find GATE participation for these students increases rates of postsecondary degree attainment by roughly 8 percentage points. The results suggest that expanding high ability tracking programs to include students of slightly lower levels of ability may benefit overall educational attainment through more advanced curricula and higher quality peers
Epidemiology of HIV-associated tuberculosis

Purpose of reviewWe review literature concerning the epidemiology of HIV-associated tuberculosis (HIV-TB), focusing on articles published between 2007 and 2008. Recent findingsAn estimated 1.37 million new cases of HIV-TB occurred in 2007, representing 15% of the total global burden of TB. In addition, an estimated 456 000 HIV-TB deaths accounted for 23% of global HIV/AIDS mortality. Sub-Saharan Africa is the worst affected region with 79% of the disease burden. The epicentre of the coepidemic lies in the south of the continent, with South Africa alone accounting for over one quarter of all cases. A critical overlap between HIV and the global multidrug-resistant TB epidemics is emerging. Although it is as yet unclear whether HIV is driving a disproportionate increase in multidrug-resistant TB cases at a population level, HIV has nevertheless been a potent risk factor for institutional outbreaks, especially in South Africa and eastern Europe. Increasing data have highlighted the risk of TB among HIV-infected healthcare workers in resource-limited settings. However, many studies also show the major benefits to be derived from antiretroviral therapy in high-income and low-income countries. SummaryHIV-TB remains a major challenge to global health that requires substantial increases in resource allocation and concerted international action.
Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa.

More than 80% of the world's HIV-infected adults live in sub-Saharan Africa, where heterosexual transmission is the predominant mode of spread. The virologic and immunologic correlates of female-to-male (FTM) and male-to-female (MTF) transmission are not well understood. A total of 1022 heterosexual couples with discordant HIV-1 serology results (one partner HIV infected, the other HIV uninfected) were enrolled in a prospective study in Lusaka, Zambia and monitored at 3-month intervals. A nested case-control design was used to compare 109 transmitters and 208 nontransmitting controls with respect to plasma HIV-1 RNA (viral load, VL), virus isolation, and CD4(+) cell levels. Median plasma VL was significantly higher in transmitters than nontransmitters (123,507 vs. 51,310 copies/ml, p < 0.001). In stratified multivariate Cox regression analyses, the risk ratio (RR) for FTM transmission was 7.6 (95% CI: 2.3, 25.5) for VL > or = 100,000 copies/ml and 4.1 (95% CI: 1.2, 14.1) for VL between 10,000 and 100,000 copies/ml compared with the reference group of <10,000 copies/ml. Corresponding RRs for MTF transmission were 2.1 and 1.2, respectively, with 95% CI both bounding 1. Only 3 of 41 (7%) female transmitters had VL < 10,000 copies/ml compared with 32 of 93 (34%) of female nontransmitters (p < 0.001). The transmission rate within couples was 7.7/100 person-years and did not differ from FTM (61/862 person-years) and MTF (81/978 person-years) transmission. We conclude that the association between increasing plasma viral load was strong for female to male transmission, but was only weakly predictive of male to female transmission in Zambian heterosexual couples. FTM and MTF transmission rates were similar. These data suggest gender-specific differences in the biology of heterosexual transmission.
Centrosome amplification induced by the antiretroviral nucleoside reverse transcriptase inhibitors lamivudine, stavudine, and didanosine

In cultured cells, exposure to the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) induces genomic instability, cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated AZT‐induced centrosome amplification (>2 centrosomes/cell). Here, we investigate centrosome amplification in cells exposed to other commonly used NRTIs. Experiments were performed using Chinese Hamster ovary (CHO) cells, and two normal human mammary epithelial cell (NHMEC) strains: M99005 and M98040, which are high and low incorporators of AZT into DNA, respectively. Cells were exposed for 24 hr to lamivudine (3TC), stavudine (d4T), didanosine (ddI), and thymidine, and stained with anti‐pericentrin antibody. Dose response curves were performed to determine cytotoxicity and a lower concentration at near plasma levels and a 10 fold higher concentration were chosen for the experiments. In CHO cells, there was a concentration‐dependent, significant (P < 0.05) increase in centrosome amplification for each of the NRTIs. In NHMEC strain M99005, an NRTI‐induced increase (P < 0.05) in centrosome amplification was observed for the high concentrations of each NRTI and the low doses of 3TC and ddI. In NHMEC strain M98040, the high doses of ddI and d4T showed significant increases in centrosome amplification. Functional viability of amplified centrosomes was assessed by arresting microtubule nucleation with nocodazole. In cells with more than two centrosomes, the ability to recover microtubule nucleation was similar to that of unexposed cells. We conclude that centrosome amplification is a consequence of exposure to NRTIs and that cells with centrosome amplification are able to accomplish cell division. Environ. Mol. Mutagen. , 2009. © 2009 Wiley‐Liss, Inc.
Prognostic factors for patients with cervical cancer treated with concurrent chemoradiotherapy: a retrospective analysis in a Japanese cohort

Objective Concurrent chemoradiotherapy (CCRT) is the primary treatment for locally advanced cervical cancer. We studied prognostic factors for patients treated with CCRT. Methods We retrospectively reviewed records of 85 consecutive patients with cervical cancer who were treated with CCRT between 2002 and 2011, with external beam radiation therapy, intracavitary brachytherapy, and platinum-based chemotherapy. Survival data were analyzed with Kaplan-Meier methods and Cox proportional hazard models. Results Of the 85 patients, 69 patients (81%) had International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease; 25 patients (29%) had pelvic lymph node enlargement (based on magnetic resonance imaging), and 64 patients (75%) achieved clinical remission following treatment. Median maximum tumor diameter was 5.5 cm. The 3- and 5-year overall survival rates were 60.3% and 55.5%, respectively. Cox regression analysis showed tumor diameter >6 cm (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2 to 4.6), pelvic lymph node enlargement (HR, 2.2; 95% CI, 1.1 to 4.5), and distant metastasis (HR, 10.0; 95% CI, 3.7 to 27.0) were significantly and independently related to poor outcomes. Conclusion New treatment strategies should be considered for locally advanced cervical cancers with tumors >6 cm and radiologically enlarged pelvic lymph nodes.
β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo

ABSTRACT The expression of β-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic β-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic β-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic β-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. β-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53−/− mice. They are CD4− CD8−, while p53-dependent lymphomas are largely CD4+ CD8+, and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic β-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic β-catenin.
Cutaneous Infection with Leishmania major Mediates Heterologous Protection against Visceral Infection with Leishmania infantum

Visceral leishmaniasis (VL) is a fatal disease of the internal organs caused by the eukaryotic parasite Leishmania. Control of VL would best be achieved through vaccination. However, this has proven to be difficult partly because the correlates of protective immunity are not fully understood. In contrast, protective immunity against nonfatal cutaneous leishmaniasis (CL) is well defined and mediated by rapidly recruited, IFN-γ–producing Ly6C+CD4+ T cells at the dermal challenge site. Protection against CL is best achieved by prior infection or live vaccination with Leishmania major, termed leishmanization. A long-standing question is whether prior CL or leishmanization can protect against VL. Employing an intradermal challenge model in mice, we report that cutaneous infection with Leishmania major provides heterologous protection against visceral infection with Leishmania infantum. Protection was associated with a robust CD4+ T cell response at the dermal challenge site and in the viscera. In vivo labeling of circulating cells revealed that increased frequencies of IFN-γ+CD4+ T cells at sites of infection are due to recruitment or retention of cells in the tissue, rather than increased numbers of cells trapped in the vasculature. Shortly after challenge, IFN-γ–producing cells were highly enriched for Ly6C+T-bet+ cells in the viscera. Surprisingly, this heterologous immunity was superior to homologous immunity mediated by prior infection with L. infantum. Our observations demonstrate a common mechanism of protection against different clinical forms of leishmaniasis. The efficacy of leishmanization against VL may warrant the introduction of the practice in VL endemic areas or during outbreaks of disease.
Common Patterns of Prediction of Literacy Development in Different Alphabetic Orthographies

Previous studies have shown that phoneme awareness, letter-sound knowledge, rapid automatized naming (RAN), and verbal memory span are reliable correlates of learning to read in English. However, the extent to which these different predictors have the same relative importance in different languages remains uncertain. In this article, we present the results from a 10-month longitudinal study that began just before or soon after the start of formal literacy instruction in four languages (English, Spanish, Slovak, and Czech). Longitudinal path analyses showed that phoneme awareness, letter-sound knowledge, and RAN (but not verbal memory span) measured at the onset of literacy instruction were reliable predictors, with similar relative importance, of later reading and spelling skills across the four languages. These data support the suggestion that in all alphabetic orthographies, phoneme awareness, letter-sound knowledge, and RAN may tap cognitive processes that are important for learning to read.