Prediction of line shape parameters and their temperature dependences for CO2-N2 using molecular dynamics simulations.

We show in this paper that requantized classical molecular dynamics simulations (rCMDSs) are capable of predicting various refined spectral-shape parameters of absorption lines of CO2 broadened by N2 with high precision. Combining CMDSs and a requantization procedure, we computed the auto-correlation function of the CO2 dipole moment responsible for the absorption transition. Its Fourier-Laplace transform directly yields the spectrum. Calculations were made for two temperatures, 200 and 296 K, at 1 atm and for a large range of Doppler widths, from the near-Doppler to the collision-dominant regimes. For each temperature and each line, the spectra calculated for various Doppler widths were simultaneously fit with the Hartmann-Tran (HT) profile. This refined profile, which takes into account the effects of the speed dependent collisional line broadening, the Dicke narrowing, and the collisional line mixing, was recommended as a reference model to be used in high-resolution spectroscopy (instead of the simplified Voigt model). The HT parameters retrieved from the rCMDS-calculated spectra were then directly compared with those deduced from high-precision measurements [J. S. Wilzewski et al., J. Quant. Spectrosc. Radiat. Transfer 206, 296-305 (2018)]. The results show a very good agreement, even for those parameters whose influence on the spectra is very small. Good agreement is also obtained between measured and predicted temperature dependences of these parameters. This demonstrates that rCMDS is an excellent tool, highly competitive with respect to high quality measurements for precise line-shape studies.

The effects of transboundary air pollution following major events in China on air quality in the U.S.: Evidence from Chinese New Year and sandstorms.

Transboundary air pollution is a global environmental and public health problem including in the U.S., where pollution emissions from China, the largest emitter of anthropogenic air pollution in the world, can travel across the Pacific Ocean and reach places like California and Oregon. We examine the effects of transboundary air pollution following major events in China, specifically sandstorms, a natural-occurring source of air pollution, and Chinese New Year, a major 7-day holiday, on background air quality in the U.S. We focus on high elevation sites on the west coast between 2000 and 2013. We use regression analysis and a natural experiment to exploit the variation in the timing of these events in China, which are plausibly uncorrelated to other factors that affect air quality in China and the U.S. We find that sandstorms are associated with statistically significant increases in background coarse and fine particulate matter (PM) in the U.S., representing between 16 and 39% of average weekly PM levels. We also find Chinese New Year is associated with modest reductions in background air quality in the U.S., representing between 0.4 and 2.5% of PM levels. Findings are robust to different models and falsification tests. These results suggest that regression analysis could be a powerful tool to complement other, more widely used techniques in the environmental sciences that study this problem. This also has important implications for policymakers, who could track major sandstorms in China and prepare for possible increased foreign pollution emissions in the U.S.

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation.

GABAergic interneurons are essential for neural circuit function, and their loss or dysfunction is implicated in human neuropsychiatric disease. In vitro methods for interneuron generation hold promise for studying human cellular and functional properties and, ultimately, for therapeutic cell replacement. Here we describe a protocol for generating cortical interneurons from hESCs and analyze the properties and maturation time course of cell types using single-cell RNA-seq. We find that the cell types produced mimic in vivo temporal patterns of neuron and glial production, with immature progenitors and neurons observed early and mature cortical neurons and glial cell types produced late. By comparing the transcriptomes of immature interneurons to those of more mature neurons, we identified genes important for human interneuron differentiation. Many of these genes were previously implicated in neurodevelopmental and neuropsychiatric disorders.

A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development.

During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/ß-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.

Why participation matters for air quality studies: risk perceptions, understandings of air pollution and mobilization in a poor neighborhood in Nairobi, Kenya.

OBJECTIVES: With high urbanization rates, Sub-Saharan Africa is facing growing problems of poor air quality in its cities. We make a case for participatory approaches in air quality studies especially including those living in poor neighborhoods who may be particularly at risk from this trend. STUDY DESIGN: We used collaboration with a community based organization, interviews, focus group discussions and a community forum. METHODS: We conducted a pilot study to assess health risk perceptions of air pollution for civic-minded residents in Mathare, an informal settlement in Nairobi, Kenya. Simultaneously, we involved Mathare residents in measuring levels of PM2.5 and later presented these data at a community forum with the participants of the monitoring study and the focus group discussions. RESULTS: We found that participation in conducting and interpreting air quality studies helped residents improve their understanding of air pollution and also helped them develop responses to it. Initially, participants associated air pollution with a bad odor or discomfort rather than their health, but once the connection to health was made through participation, they sought more information about air quality data and its hazards. Some residents also came up with strategies for coping with their environment and its risks. CONCLUSIONS: These results point to the potential of including participation in air quality monitoring as a way to increase awareness and support local action to address it. Discussion and sharing of results at the local level as well as at a wider policy level will be critical for advocacy to improve air quality.

Structural essentials for ß-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids.

This paper explores the computer modelling aided design and synthesis of ß-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure-activity relationships along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that ß-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.

Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes.

AIM: To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP-531, designed to improve glycaemic control and reduce weight. METHODS: Assessments, including glucose measurements, were performed in a three-part randomized study. In Part A, healthy subjects [n = 44, age 18-50 years, body mass index (BMI) 20-28 kg/m(2) ] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP-531 or placebo. In Part B, overweight/obese subjects (n = 32, age 18-65 years, BMI 28-38 kg/m(2) ) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18-65 years, BMI 20-40 kg/m(2) , glycated haemoglobin (HbA1c) 7-10%] received AZP-531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively). RESULTS: AZP-531 was well tolerated. Single- and multiple-dose pharmokinetic variables were similar. Maximum AZP-531 concentrations were typically reached at 1 h post-dose. Observed maximum concentration (Cmax ) and area under the curve were dose-proportional. The mean terminal half-life (t1/2 ) was 2-3 h. In Part B, AZP-531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin-sensitizing effect. AZP-531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In Part C, glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP-531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo). CONCLUSIONS: AZP-531 was well tolerated in this first-in-human study. Its pharmacokinetic profile, suitable for once-daily dosing, and metabolic effects support further clinical development for T2D.

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.

Human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus-infected cells in vitro.

We previously reported that exosomal transfer of hepatitis C virus (HCV) positive-strand RNA from human Huh-7 hepatoma cells to human plasmacytoid dendritic cells (pDCs) triggers pDC alpha/beta interferon (IFN-α/ß) production in a Toll-like receptor 7 (TLR7)-dependent, virus-independent manner. Here we show that human pDCs are also activated by a TLR7-dependent, virus-independent, exosomal RNA transfer mechanism by human and mouse hepatoma and nonhepatoma cells that replicate the negative-strand lymphocytic choriomeningitis virus (LCMV).

Velocity effects on the shape of pure H2O isolated lines: complementary tests of the partially correlated speed-dependent Keilson-Storer model.

Complementary tests of the partially correlated speed-dependent Keilson-Storer (pCSDKS) model for the shape of isolated transition of pure water vapor [N. H. Ngo et al., J. Chem. Phys. 136, 154310 (2012)] are made using new measurements. The latter have been recorded using a high sensitivity cavity ring down spectrometer, for seven self-broadened H(2)O lines in the 1.6 µm region at room temperature and for pressures from 0.5 to 15 Torr. Furthermore, the H(2) (18)O spectra of [M. D. De Vizia et al., Phys. Rev. A 83, 052506 (2011)] in the 1.38 µm region, measured at 273.15 K and for pressures from 0.3 to 3.75 Torr have also been used for comparison with the model. Recall that the pCSDKS model takes into account the collision-induced velocity changes, the speed dependences of the broadening and shifting coefficients as well as the partial correlation between velocity and rotational-state changes. All parameters of the model have been fixed at values previously determined, except for a scaling factor applied to the input speed-dependent line broadening. Comparisons between predictions and experiments have been made by looking at the results obtained when fitting the calculated and measured spectra by Voigt profiles. The good agreement obtained for all considered lines, at different temperature and pressure conditions, confirms the consistency and the robustness of the model. Limiting cases of the model have been then derived, showing the influence of different contributions to the line shape.

Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations.

BACKGROUND: There are no reliable markers of malignancy in phaeochromocytomas (PCC) and paragangliomas (PGL). We investigated the relevance of the mammalian target of rapamycin (mTOR)/AKT and hypoxic pathways as novel immunohistochemical markers of malignancy. METHODS: Tissue microarray blocks were constructed with a total of 100 tumours (10 metastatic) and 20 normal adrenomedullary samples. Sections were immunostained for hypoxia-inducible factor 1α (Hif-1α), vascular endothelial growth factor A (VEGF-A), mTOR, carbonic anhydrase IX (CaIX) and AKT. The predictive performance of these markers was studied using univariate, multivariate and receiver operating characteristic analyses. RESULTS: In all, 100 consecutive patients, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Univariate analyses showed Hif-1α overexpression, tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1α, necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1α was the most discriminatory biomarker for the presence of metastatic diffusion. Strong membranous CaIX expression was seen in von Hippel-Lindau (VHL) PCC as opposed to other subtypes. CONCLUSION: Lack of vascular invasion, tumour necrosis and low Hif-1α expression identify tumours with lower risk of malignancy. We propose membranous CaIX expression as a potential marker for VHL disease in patients presenting with PCC.

Influence of velocity effects on the shape of N2 (and air) broadened H2O lines revisited with classical molecular dynamics simulations.

The modeling of the shape of H(2)O lines perturbed by N(2) (and air) using the Keilson-Storer (KS) kernel for collision-induced velocity changes is revisited with classical molecular dynamics simulations (CMDS). The latter have been performed for a large number of molecules starting from intermolecular-potential surfaces. Contrary to the assumption made in a previous study [H. Tran, D. Bermejo, J.-L. Domenech, P. Joubert, R. R. Gamache, and J.-M. Hartmann, J. Quant. Spectrosc. Radiat. Transf. 108, 126 (2007)], the results of these CMDS show that the velocity-orientation and -modulus changes statistically occur at the same time scale. This validates the use of a single memory parameter in the Keilson-Storer kernel to describe both the velocity-orientation and -modulus changes. The CMDS results also show that velocity- and rotational state-changing collisions are statistically partially correlated. A partially correlated speed-dependent Keilson-Storer model has thus been used to describe the line-shape. For this, the velocity changes KS kernel parameters have been directly determined from CMDS, while the speed-dependent broadening and shifting coefficients have been calculated with a semi-classical approach. Comparisons between calculated spectra and measurements of several lines of H(2)O broadened by N(2) (and air) in the ν(3) and 2ν(1) + ν(2) + ν(3) bands for a wide range of pressure show very satisfactory agreement. The evolution of non-Voigt effects from Doppler to collisional regimes is also presented and discussed.

Pressure effects on water vapour lines: beyond the Voigt profile.

A short overview of recent results on the effects of pressure (collisions) regarding the shape of isolated infrared lines of water vapour is presented. The first part of this study considers the basic collisional quantities, which are the pressure-broadening and -shifting coefficients, central parameters of the Lorentzian (and Voigt) profile and thus of any sophisticated line-shape model. Through comparisons of measured values with semi-classical calculations, the influences of the molecular states (both rotational and vibrational) involved and of the temperature are analysed. This shows the relatively unusual behaviour of H(2)O broadening, with evidence of a significant vibrational dependence and the fact that the broadening coefficient (in cm(-1) atm(-1)) of some lines increases with temperature. In the second part of this study, line shapes beyond the Voigt model are considered, thus now taking 'velocity effects' into account. These include both the influence of collisionally induced velocity changes that lead to the so-called Dicke narrowing and the influence of the dependence of collisional parameters on the speed of the radiating molecule. Experimental evidence of deviations from the Voigt shape is presented and analysed. The interest of classical molecular dynamics simulations, to model velocity changes, together with semi-classical calculations of the speed-dependent collisional parameters for line-shape predictions from 'first principles', are discussed.

A pure H2O isolated line-shape model based on classical molecular dynamics simulations of velocity changes and semi-classical calculations of speed-dependent collisional parameters.

It is well known that the Voigt profile does not well describe the (measured) shapes of isolated lines. This is due to the neglect of the intermolecular collision-induced velocity changes and of the speed dependence of the collisional parameters. In this paper, we present a new line profile model for pure H(2)O which takes both of these effects into account. The speed dependence of the collisional parameters has been calculated by a semi-classical method. The velocity changes have been modeled by using the Keilson-Storer collision kernel with two characteristic parameters. The latter have been deduced from classical molecular dynamics simulations which also indicate that, for pure H(2)O, the correlation between velocity-changing and state-changing collisions is not negligible, a result confirmed by the analysis of measured spectra. A partially correlated speed-dependent Keilson-Storer model has thus been adopted to describe the line-shape. Comparisons between simulated spectra and measurements for four self-broadened lines in the near-infrared at various pressures show excellent agreements.

Natural radioactivity and external dose assessment of surface soils in Vietnam.

In this study, natural radioactivity in surface soils of Vietnam and external dose assessment to human population, deduced from activities of (226)Ra, (232)Th and (40)K nuclides, were determined. From 528 soil samples collected in 63 provinces of Vietnam, including five centrally governed cities, the average activities were obtained and equal to 42.77 ± 18.15 Bq kg(-1) for (226)Ra, 59.84 ± 19.81 Bq kg(-1) for (232)Th and 411.93 ± 230.69 Bq kg(-1) for (40)K. The outdoor absorbed dose rates (OADRs) in air at 1 m above the ground level for 63 provinces were calculated, and their average value was 71.72 ± 24.72 nGy h(-1), with a range from 17.45 to 149.40 nGy h(-1). The population-weighted OADR of Vietnam was 66.70 nGy h(-1), which lies in the range of 18-93 nGy h(-1) found in the World. From the OADRs obtained, it was estimated that the outdoor annual effective dose and indoor annual effective dose to the population were 0.082  and 0.458 mSv, which are higher than the corresponding values 0.07 and 0.41 mSv, respectively, of the World. The radium equivalent activity Ra(eq) and the external hazard index H(ex) of surface soils of Vietnam are lower than the corresponding permissible limits of 370 Bq kg(-1) and 1, respectively. Therefore, soil from Vietnam is safe for the human population when it is used as a building material.

The significance of tumour cell immunophenotype in myeloma and its impact on clinical outcome.

BACKGROUND AND AIMS: Antigen expression of multiple myeloma (MM) cells is heterogeneous. We have investigated the clinical impact of expression of some of the commonly used immunohistochemical markers in the diagnostic work-up of bone marrow trephine biopsy (BMTB) samples in MM. PATIENTS AND METHODS: BMTB samples from 107 MM patients who had received an autologous stem cell transplant (ASCT) following chemotherapy were evaluated. In 75 cases, the immunophenotype had been evaluated on two or more occasions on further follow-up. RESULTS: In the cases evaluated, 32%, 79%, 73%, 39% and 60% of cases had been scored positive for CD20, CD79a, CD56, cyclin D1 and epithelial membrane antigen (EMA) respectively. Absence of CD79a was predictive of poor overall survival (OS) from the time of transplant (p = 0.029) and poor event-free survival (EFS) from the time of transplant (p = 0.003). Absence of EMA (p = 0.02) was predictive of poor EFS from the time of diagnosis. Presence of CD56 was predictive of poor EFS from the time of diagnosis (p = 0.026). On multivariate analysis, only CD79a expression (OS and EFS from the time of transplant) and EMA expression (EFS from the time of diagnosis) maintained their significance. 13 of 75 patients showed an immunophenotypic drift during the disease course. Loss of CD20 (four cases) during the disease course in cases that were previously scored positive correlated with significant worsening both, of OS (p = 0.02) and EFS (p = 0.009) from the time of diagnosis. CONCLUSION: Immunophenotype impacts on clinical outcome in MM.

Correlation of cyclin D1 transcript levels, transcript type and protein expression with proliferation and histology among mantle cell lymphoma.

BACKGROUND: Cyclin D1 expression is central to mantle cell lymphoma (MCL) biology. The cyclin D1 gene produces two forms of mRNA: long (D1L) and short (D1S) versions. AIMS: To study the relationship between histology, cyclin D1 mRNA (transcript) levels, cyclin D1 transcript type, cyclin D1 protein expression by immunohistochemistry (IHC), and proliferation (Ki-67%). METHODS: 17 MCLs were initially studied for: levels of expression of cyclin D1 transcripts and for cyclin D1 transcript type by reverse-transcriptase PCR; intensity and percentage cyclin D1 protein expression by IHC; and Ki-67% by IHC. The relationship between cyclin D1 protein expression and proliferation was further validated on an independent set of 23 MCLs. RESULTS: MCLs expressed variable levels of cyclin D1 at both transcript and protein levels. Furthermore, D1L and D1S were the predominant transcripts in 69% and 31% of cases, respectively. While only 9% of cases with dominance of D1L had blastoid histology, 60% of the cases with dominance of the D1S had blastoid features. Furthermore, the levels of D1L showed direct correlation with cyclin D1 protein expression and Ki-67%. Among these cases, and in the independent set of MCLs (n = 40), the level of cyclin D1 protein expression directly correlated with Ki-67%. CONCLUSIONS: MCLs express variable levels of cyclin D1 transcripts and protein, and have variable proliferation (Ki-67%). Cases with dominance of D1S transcripts are more likely to be of blastoid morphology. There is correlation between D1L transcripts levels, cyclin D1 protein expression and Ki-67%.

Down modulation of TNF-alpha mRNA placental expression by AZT used for the prevention of HIV-1 mother-to-child transmission.

Mechanisms of HIV-1 in utero mother-to-child transmission (MTCT) protection provided by AZT are not completely understood. The placental cytokine network is involved in the control of HIV-1 in utero transmission but the effect of AZT on this network is unknown. To evaluate the effects of AZT on placental cytokine expression, the chorionic villi from HIV-1 uninfected women term placentae were cultured with 0, 100, and 2,000 ng/ml AZT. Tissue fragments were harvested at days 1, 4, and 7 to determine the level of cytokine mRNA by real-time RT-PCR. The viability and morphology of the placental histocultures were monitored by the expression of beta-human chorionic gonadotropin (beta-hCG) gene, lipopolysaccharide (LPS) activation, and microscopic examination. AZT at 2,000 ng/ml significantly down-regulated TNF-alpha mRNA expression at day 1 and day 4, but had no effect on beta-hCG, stromal cell-derived factor 1 (SDF-1), and IL-10 gene expression. AZT did not induce any deleterious impact on placental tissue structure. Furthermore, activation of chorionic villi by LPS for 24 h up-regulated IL-10 and TNF-alpha mRNA expression. Down-regulation of TNF-alpha mRNA could represent a mechanism through which AZT can decrease the risk of HIV-1 MTCT, in addition to its direct effect on HIV-1 replication.