Congenital diaphragmatic hernia and retinoids: searching for an etiology

Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of respiratory failure in the newborn. Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the epidemiology and pathophysiology of human CDH, the metabolism of retinoids and the implications of retinoids in the development of the diaphragm and lung. Finally, we describe the existing evidence of a disruption of the retinoid-signaling pathway in CDH

Rapid dissection and model-based optimization of inducible enhancers in human cells using a massively parallel reporter assay

Learning to read and write the transcriptional regulatory code is of central importance to progress in genetic analysis and engineering. Here we describe a massively parallel reporter assay (MPRA) that facilitates the systematic dissection of transcriptional regulatory elements. In MPRA, microarray-synthesized DNA regulatory elements and unique sequence tags are cloned into plasmids to generate a library of reporter constructs. These constructs are transfected into cells and tag expression is assayed by high-throughput sequencing. We apply MPRA to compare >27,000 variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon-β enhancer. We first show that the resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution. We then use the data to train quantitative sequence-activity models (QSAMs) of the two enhancers. We show that QSAMs from two cellular states can be combined to design enhancer variants that optimize potentially conflicting objectives, such as maximizing induced activity while minimizing basal activity.National Human Genome Research Institute (U.S.) (grant R01HG004037)National Science Foundation (U.S.) ((NSF) grant PHY-0957573)National Science Foundation (U.S.) (NSF grant PHY-1022140)Broad Institut

Structural and Sequence Analysis of Imelysin-Like Proteins Implicated in Bacterial Iron Uptake

Imelysin-like proteins define a superfamily of bacterial proteins that are likely involved in iron uptake. Members of this superfamily were previously thought to be peptidases and were included in the MEROPS family M75. We determined the first crystal structures of two remotely related, imelysin-like proteins. The Psychrobacter arcticus structure was determined at 2.15 Å resolution and contains the canonical imelysin fold, while higher resolution structures from the gut bacteria Bacteroides ovatus, in two crystal forms (at 1.25 Å and 1.44 Å resolution), have a circularly permuted topology. Both structures are highly similar to each other despite low sequence similarity and circular permutation. The all-helical structure can be divided into two similar four-helix bundle domains. The overall structure and the GxHxxE motif region differ from known HxxE metallopeptidases, suggesting that imelysin-like proteins are not peptidases. A putative functional site is located at the domain interface. We have now organized the known homologous proteins into a superfamily, which can be separated into four families. These families share a similar functional site, but each has family-specific structural and sequence features. These results indicate that imelysin-like proteins have evolved from a common ancestor, and likely have a conserved function

Invasive fungal infections in neutropenic enterocolitis: A systematic analysis of pathogens, incidence, treatment and mortality in adult patients

BACKGROUND: Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis. METHODS: Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature. RESULTS: Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy. CONCLUSION: In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis

Contemporary management of primary parapharyngeal space tumors

The parapharyngeal space is a complex anatomical area. Primary parapharyngeal tumors are rare tumors and 80% of them are benign. A variety of tumor types can develop in this location; most common are salivary gland neoplasm and neurogenic tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques, surgery, and radiotherapy. Most tumors can be removed with a low rate of complications and recurrence. The transcervical approach is the most frequently used. In some cases, minimally invasive approaches may be used alone or in combination with a limited transcervical route, allowing large tumors to be removed by reducing morbidity of expanded approaches. An adequate knowledge of the anatomy and a careful surgical plan is essential to tailor management according to the patient and the tumor. The purpose of the present review was to update current aspects of knowledge related to this more challenging area of tumor occurrence.Peer reviewe

Precision top-quark mass measurement in the lepton plus jets topology in p(p)over-bar collisions at root s=1.96 TeV

We report two measurements of the top-quark mass M-top using the CDF II detector at the Fermilab Tevatron in a 318 pb(-1) data sample of t (t) over bar events in the lepton+jets final state. One method uses an event-based likelihood technique resulting in M-top=173.2(-2.4)(+2.6)(stat)+/- 3.2(syst) GeV/c(2) or 173.2(-4.0)(+4.1) GeV/c(2). The second method reconstructs a top-quark mass in each event using the measured invariant mass of the hadronically decaying W boson to constrain the jet energy scale to obtain a value for M-top of 173.5(-3.6)(+3.7)(stat)+/- 1.3(syst) GeV/c(2) or 173.5(-3.8)(+3.9) GeV/c(2). We take the latter, which is more precise, as our result

Measurement of the Ratio of b Quark Production Cross Sections in Antiproton-Proton Collisions at 630 GeV and 1800 GeV

We report a measurement of the ratio of the bottom quark production cross section in antiproton-proton collisions at 630 GeV to 1800 GeV using bottom quarks with transverse momenta greater than 10.75 GeV identified through their semileptonic decays and long lifetimes. The measured ratio sigma(630)/sigma(1800) = 0.171 +/- .024 +/- .012 is in good agreement with next-to-leading order (NLO) quantum chromodynamics (QCD)

The respiratory response to carbon dioxide in humans with unilateral and bilateral resections of the carotid bodies

The acute hypercapnic ventilatory response (AHCVR) arises from both peripheral and central chemoreflexes. In humans, one technique for identifying the separate contributions of these chemoreflexes to AHCVR has been to associate the rapid component of AHCVR with the peripheral chemoreflex and the slow component with the central chemoreflex. Our first aim was to validate this technique further by determining whether a single slow component was sufficient to describe AHCVR in patients with bilateral carotid body resections (BR) for glomus cell tumours. Our second aim was to determine whether the slow component of AHCVR was diminished following carotid body resection as has been suggested by studies in experimental animals. Seven BR subjects were studied together with seven subjects with unilateral resections (UR) and seven healthy controls. A multifrequency binary sequence in end-tidal PCO2 was employed to stimulate ventilation dynamically under conditions of both euoxia and mild hypoxia. Both two- and one-compartment models of AHCVR were fitted to the data. For BR subjects, the two-compartment model fitted significantly better on 1 out of 13 occasions compared with 22 out of 28 occasions for the other subjects. Average values for the chemoreflex sensitivity of the slow component of AHCVR differed significantly (P < 0.05) between the groups and were 0.95, 1.38 and 1.50 l min−1 Torr−1 for BR, UR and control subjects, respectively. We conclude that, without the peripheral chemoreflex, AHCVR is adequately described by a single slow component and that BR subjects have sensitivities for the slow component that are lower than those of control subjects