Improving Productivity of Multiphase Flow Aerobic Oxidation Using a Tube-in-Tube Membrane Contactor

The application of flow reactors in multiphase catalytic reactions represents a promising approach for enhancing the efficiency of this important class of chemical reactions. We developed a simple approach to improve the reactor productivity of multiphase catalytic reactions performed using a flow chemistry unit with a packed bed reactor. Specifically, a tube-in-tube membrane contactor (sparger) integrated in-line with the flow reactor has been successfully applied to the aerobic oxidation of benzyl alcohol to benzaldehyde utilizing a heterogeneous palladium catalyst in the packed bed. We examined the effect of sparger hydrodynamics on reactor productivity quantified by space time yield (STY). Implementation of the sparger, versus segmented flow achieved with the built in gas dosing module (1) increased reactor productivity 4-fold quantified by space time yield while maintaining high selectivity and (2) improved process safety as demonstrated by lower effective operating pressures

The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants of POL2 (Pol ϵ) do not elevate deletions. Further support for the conclusion that met18 strains result in impaired DNA synthesis by Pol δ are the observations that Pol δ isolated from met18 strains has less bound iron and is less processive in vitro than the wild-type holoenzyme

Biochromoendoscopy: molecular imaging with capsule endoscopy for detection of adenomas of the GI tract

Current capsule endoscopy (CE) provides minimally invasive technology for gastrointestinal imaging, but has limited ability to discriminate different polyp types. Near Infrared Fluorescent (NIRF) probes activated by biomarkers upregulated in adenomas (e.g., cathepsin B) are potentially powerful tools to distinguish premalignant or malignant lesions from benign or inflammatory lesions

The THO Complex Regulates Pluripotency Gene mRNA Export and Controls Embryonic Stem Cell Self-Renewal and Somatic Cell Reprogramming

Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, post-transcriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5, and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, as its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of post-transcriptional regulation in stem cell fate specification

ORIO (Online Resource for Integrative Omics): a web-based platform for rapid integration of next generation sequencing data

Abstract Established and emerging next generation sequencing (NGS)-based technologies allow for genome-wide interrogation of diverse biological processes. However, accessibility of NGS data remains a problem, and few user-friendly resources exist for integrative analysis of NGS data from different sources and experimental techniques. Here, we present Online Resource for Integrative Omics (ORIO; https://orio.niehs.nih.gov/), a web-based resource with an intuitive user interface for rapid analysis and integration of NGS data. To use ORIO, the user specifies NGS data of interest along with a list of genomic coordinates. Genomic coordinates may be biologically relevant features from a variety of sources, such as ChIP-seq peaks for a given protein or transcription start sites from known gene models. ORIO first iteratively finds read coverage values at each genomic feature for each NGS dataset. Data are then integrated using clustering-based approaches, giving hierarchical relationships across NGS datasets and separating individual genomic features into groups. In focusing its analysis on read coverage, ORIO makes limited assumptions about the analyzed data; this allows the tool to be applied across data from a variety of experiments and techniques. Results from analysis are presented in dynamic displays alongside user-controlled statistical tests, supporting rapid statistical validation of observed results. We emphasize the versatility of ORIO through diverse examples, ranging from NGS data quality control to characterization of enhancer regions and integration of gene expression information. Easily accessible on a public web server, we anticipate wide use of ORIO in genome-wide investigations by life scientists

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. CONCLUSIONS: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts

Opioid medication use and blood DNA methylation:epigenome-wide association meta-analysis

Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate \u3c0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use