Cross Section Measurements Using the Zero Degree Detector

The Zero Degree Detector (ZDD) is an instrument that has been used in accelerator exposures to measure the angular dependence of particles produced in heavy ion fragmentation experiments. The ZDD uses two identical layers of pixelated silicon detectors that make coincident measurements over the active area of the instrument. The angular distribution of secondary particle produced in nuclear interactions for several heavy ions: and target materials will be presented along with performance characteristic of the instrument

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Risk factors for pre-term birth in Iraq: a case-control study

BACKGROUND: Preterm birth (PTB)is a major clinical problem associated with perinatal mortality and morbidity. The aim of the present study is to identify risk factors associated with PTB in Mosul, Iraq. METHODS: A case-control study was conducted in Mosul, Iraq, from 1(st )September, 2003 to 28(th )February, 2004. RESULTS: A total of 200 cases of PTB and 200 controls of full-term births were screened and enrolled in the study. Forward logistic regression analysis was used in the analysis. Several significant risk associations between PTB and the following risk factors were identified: poor diet (OR = 4.33), heavy manual work (OR = 1.70), caring for domestic animals (OR = 5.06), urinary tract infection (OR = 2.85), anxiety (OR = 2.16), cervical incompetence (OR = 4.74), multiple pregnancies (OR = 7.51), direct trauma to abdomen (OR = 3.76) and abortion (OR = 6.36). CONCLUSION: The main determinants of PTB in Iraq were low socio-economic status and factors associated with it, such as heavy manual work and caring for domestic animals, in addition to urinary tract infections and poor obstetric history

Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR

BACKGROUND: The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes. METHODS: We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures. RESULTS: Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores. CONCLUSIONS: Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function. TRIAL REGISTRATION: ClinicialTrials.gov, NCT01521338. FUNDING: CFF Therapeutics (GOAL11K1)

The role of Prenatal Care and Social Risk Factors in the relationship between immigrant status and neonatal morbidity: A retrospective cohort study

Background and Aim Literature evaluating association between neonatal morbidity and immigrant status presents contradictory results. Poorer compliance with prenatal care and greater social risk factors among immigrants could play roles as major confounding variables, thus explaining contradictions. We examined whether prenatal care and social risk factors are confounding variables in the relationship between immigrant status and neonatal morbidity. Methods Retrospective cohort study: 231 pregnant African immigrant women were recruited from 2007–2010 in northern Spain. A Spanish population sample was obtained by simple random sampling at 1:3 ratio. Immigrant status (Spanish, Sub-Saharan and Northern African), prenatal care (Kessner Index adequate, intermediate or inadequate), and social risk factors were treated as independent variables. Low birth weight (LBW < 2500 grams) and preterm birth (< 37 weeks) were collected as neonatal morbidity variables. Crude and adjusted odds ratios (OR) were estimated by unconditional logistic regression with 95% confidence intervals (95% CI). Results Positive associations between immigrant women and higher risk of neonatal morbidity were obtained. Crude OR for preterm births in Northern Africans with respect to nonimmigrants was 2.28 (95% CI: 1.04–5.00), and crude OR for LBW was 1.77 (95% CI: 0.74–4.22). However, after adjusting for prenatal care and social risk factors, associations became protective: adjusted OR for preterm birth = 0.42 (95% CI: 0.14–1.32); LBW = 0.48 (95% CI: 0.15–1.52). Poor compliance with prenatal care was the main independent risk factor associated with both preterm birth (adjusted OR inadequate care = 17.05; 95% CI: 3.92–74.24) and LBW (adjusted OR inadequate care = 6.25; 95% CI: 1.28–30.46). Social risk was an important independent risk factor associated with LBW (adjusted OR = 5.42; 95% CI: 1.58– 18.62). Conclusions Prenatal care and social risk factors were major confounding variables in the relationship between immigrant status and neonatal morbidity

Partial Loss of Ataxin-1 Function Contributes to Transcriptional Dysregulation in Spinocerebellar Ataxia Type 1 Pathogenesis

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1). Molecular and genetic data indicate that SCA1 is mainly caused by a gain-of-function mechanism. However, deletion of wild-type ATXN1 enhances SCA1 pathogenesis, whereas increased levels of an evolutionarily conserved paralog of ATXN1, Ataxin 1-Like, ameliorate it. These data suggest that a partial loss of ATXN1 function contributes to SCA1. To address this possibility, we set out to determine if the SCA1 disease model (Atxn1154Q/+ mice) and the loss of Atxn1 function model (Atxn1−/− mice) share molecular changes that could potentially contribute to SCA1 pathogenesis. To identify transcriptional changes that might result from loss of function of ATXN1 in SCA1, we performed gene expression microarray studies on cerebellar RNA from Atxn1−/− and Atxn1154Q/+ cerebella and uncovered shared gene expression changes. We further show that mild overexpression of Ataxin-1-Like rescues several of the molecular and behavioral defects in Atxn1−/− mice. These results support a model in which Ataxin 1-Like overexpression represses SCA1 pathogenesis by compensating for a partial loss of function of Atxn1. Altogether, these data provide evidence that partial loss of Atxn1 function contributes to SCA1 pathogenesis and raise the possibility that loss-of-function mechanisms contribute to other dominantly inherited neurodegenerative diseases