Quantifying lung fissure integrity using a three-dimensional patch-based convolutional neural network on CT images for emphysema treatment planning.

Purpose: Evaluation of lung fissure integrity is required to determine whether emphysema patients have complete fissures and are candidates for endobronchial valve (EBV) therapy. We propose a deep learning (DL) approach to segment fissures using a three-dimensional patch-based convolutional neural network (CNN) and quantitatively assess fissure integrity on CT to evaluate it in subjects with severe emphysema. Approach: From an anonymized image database of patients with severe emphysema, 129 CT scans were used. Lung lobe segmentations were performed to identify lobar regions, and the boundaries among these regions were used to construct approximate interlobar regions of interest (ROIs). The interlobar ROIs were annotated by expert image analysts to identify voxels where the fissure was present and create a reference ROI that excluded non-fissure voxels (where the fissure is incomplete). A CNN configured by nnU-Net was trained using 86 CT scans and their corresponding reference ROIs to segment the ROIs of left oblique fissure (LOF), right oblique fissure (ROF), and right horizontal fissure (RHF). For an independent test set of 43 cases, fissure integrity was quantified by mapping the segmented fissure ROI along the interlobar ROI. A fissure integrity score (FIS) was then calculated as the percentage of labeled fissure voxels divided by total voxels in the interlobar ROI. Predicted FIS (p-FIS) was quantified from the CNN output, and statistical analyses were performed comparing p-FIS and reference FIS (r-FIS). Results: The absolute percent error mean (±SD) between r-FIS and p-FIS for the test set was 4.0% (±4.1%), 6.0% (±9.3%), and 12.2% (±12.5%) for the LOF, ROF, and RHF, respectively. Conclusions: A DL approach was developed to segment lung fissures on CT images and accurately quantify FIS. It has potential to assist in the identification of emphysema patients who would benefit from EBV treatment.

Polar Layered Intermetallic LaCo2P2 as a Water Oxidation Electrocatalyst.

We investigate LaCo2P2 as an electrocatalytic material for oxygen evolution reaction (OER) under alkaline and acidic conditions. This layered intermetallic material was prepared via Sn-flux high-temperature annealing. The electrocatalytic ink, prepared with the ball-milled LaCo2P2 catalyst at the mass loading of 0.25 mg/cm2, shows OER activity at pH = 14, reaching current densities of 10, 50, and 100 mA/cm2 under the overpotential of 400, 440, and 460 mV, respectively. Remarkably, the electrocatalytic performance remains constant for at least 4 days. Transmission electron microscopy reveals the formation of a catalytically active CoOx shell around the pre-catalyst LaCo2P2 core during the alkaline OER. The core serves as a robust support for the in situ-formed electrocatalytic system. Similar studies under pH = 0 reveal the rapid deterioration of LaCo2P2, with the formation of LaPO4 and amorphous cobalt oxide. This study shows the viability of layered intermetallics as stable OER electrocatalysts, although further developments are required to improve the electrocatalytic performance and increase the stability at lower pH values.

Microwave Synthesis and Magnetocaloric Effect in AlFe2B2.

A promising magnetic refrigerant, AlFe2B2, has been prepared for the first time by microwave (MW) melting of a mixture of constituent elements. For comparison, samples of AlFe2B2 have been also prepared by arc-melting, traditionally used for the synthesis of this material, and by induction (RF) melting, which was used in the very first report on the synthesis of AlFe2B2. Although an excess of Al has to be used to suppress the formation of ferromagnetic FeB, the other byproduct, Al13Fe4, is easily removed by acid treatment, affording phase-pure samples of AlFe2B2. Our analysis indicates that the equimolar Fe/B ratio typically used for the preparation of AlFe2B2 might not provide the best synthetic conditions, as it does not account for the full reaction stoichiometry. Furthermore, we find that the initial Al/Fe loading ratio strongly influences magnetic properties of the sample, as judged by the range of ferromagnetic ordering temperatures (TC = 280-293 K) observed in our experiments. The TC value increases with the decrease in the Al/Fe ratio, due to the change in the Al/Fe antisite disorder. The use of the same Al/Fe loading ratio in the arc-, RF-, and MW-melting experiments leads to samples with a more consistent TC of 286-287 K and similar values of the magnetocaloric effect.

Electrocatalytic water oxidation over AlFe2B2.

We report excellent electrocatalytic performance by AlFe2B2 in the oxygen-evolution reaction (OER). The inexpensive catalytic material, prepared simply by arc-melting followed by ball-milling, exhibits high stability and sustained catalytic performance under alkaline conditions. The overpotential value of 0.24 V observed at the current density of 10 mA cm-2 remained constant for at least 10 days. Electron microscopy and electron energy loss spectroscopy performed on the initial ball-milled material and on the material activated under electrocatalytic conditions suggest that the catalytic mechanism involves partial leaching of Al from the layered structure of AlFe2B2 and the formation of Fe3O4 nanoclusters on the exposed [Fe2B2] layers. Thus, the AlFe2B2 structure serves as a robust supporting material and, more importantly, as a pre-catalyst to the in situ formed active electrocatalytic sites. Comparative electrochemical measurements demonstrate that the electrocatalytic performance of the AlFe2B2-supported Fe3O4 nanoclusters substantially exceeds the results obtained with unsupported nanoparticles of Fe3O4, FeB, or such benchmark OER catalysts as IrO2 or RuO2. The excellent catalytic performance and long-term stability of this system suggests that AlFe2B2 can serve as a promising and inexpensive OER electrocatalyst.

The association between varicocoeles and vascular disease: an analysis of U.S. claims data.

S‪tudies have suggested an association between varicocele, hypogonadism, and elevated oxidative stress markers, but no other health risks have been associated with varicoceles. ‬‬‬‬We sought to determine the association between varicocele and incident medical comorbidities. ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬Using the Truven Health MarketScan® claims database from 2001 to 2009, we identified 4459 men with varicoceles, and 100,066 controls based on ICD-9 and CPT codes, with an average follow-up of 3.1 person years. Men with varicoceles were classified as symptomatic or asymptomatic based on co-existing diagnoses. Men with medical comorbidities present before or within 1 year of index diagnosis were excluded. Metabolic and cardiovascular outcome variables were identified via ICD-9 codes. A Cox regression analysis was used to assess incident risk of metabolic and cardiovascular disease amongst the different groups. Men with varicoceles had a higher incidence of heart disease compared to men who underwent infertility testing (HR 1.22, 95% CI: 1.03-1.45), and men who underwent vasectomy (HR 1.32, 95% CI 1.13-1.54). The varicoceles group also had a higher risk of diabetes (HR 1.73, 95% CI: 1.37-2.18) and hyperlipidemia (HR 1.15, 95% CI: 1.03-1.28) compared to the vasectomy group. Furthermore, men with symptomatic varicoceles (n = 3442) had a higher risk of heart disease, diabetes, and hyperlipidemia following diagnosis, while men with asymptomatic varicoceles (n = 1017) did not. Given the prevalence of varicoceles, further research is needed to understand the implications of a varicocele to a man's overall health.

Comparative variation within the genome of Campylobacter jejuni NCTC 11168 in human and murine hosts.

Campylobacteriosis incited by C. jejuni is a significant enteric disease of human beings. A person working with two reference strains of C. jejuni National Collection of Type Cultures (NCTC) 11168 developed symptoms of severe enteritis including bloody diarrhea. The worker was determined to be infected by C. jejuni. In excess of 50 isolates were recovered from the worker's stool. All of the recovered isolates and the two reference strains were indistinguishable from each other based on comparative genomic fingerprint subtyping. Whole genome sequence analysis indicated that the worker was infected with a C. jejuni NCTC 11168 obtained from the American Type Culture Collection; this strain (NCTC 11168-GSv) is the genome sequence reference. After passage through the human host, major genetic changes including indel mutations within twelve contingency loci conferring phase variations were detected in the genome of C. jejuni. Specific and robust single nucleotide polymorphism (SNP) changes in the human host were also observed in two loci (Cj0144c, Cj1564). In mice inoculated with an isolate of C. jejuni NCTC 11168-GSv from the infected person, the isolate underwent further genetic variation. At nine loci, mutations specific to inoculated mice including five SNP changes were observed. The two predominant SNPs observed in the human host reverted in mice. Genetic variations occurring in the genome of C. jejuni in mice corresponded to increased densities of C. jejuni cells associated with cecal mucosa. In conclusion, C. jejuni NCTC 11168-GSv was found to be highly virulent in a human being inciting severe enteritis. Host-specific mutations in the person with enteritis occurred/were selected for in the genome of C. jejuni, and many were not maintained in mice. Information obtained in the current study provides new information on host-specific genetic adaptation by C. jejuni.

Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.

GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.

Molecular methods to measure intestinal bacteria: a review.

The intestine is an exceptionally rich ecosystem encompassing a complex interaction among microorganisms, influenced by host factors, ingested food, and liquid. Characterizing the intestinal microbiota is currently an active area of research. Various molecular-based methods are available to characterize the intestinal microbiota, but all methods possess relative strengths, as well as salient weaknesses. It is important that researchers are cognizant of the limitations of these methods, and that they take the appropriate steps to mitigate weaknesses. Here, we discuss methodologies used to monitor intestinal bacteria including: (i) traditional clone libraries; (ii) direct sequencing using next-generation parallel sequencing technology; (iii) denaturing gradient gel electrophoresis and temperature gradient gel electrophoresis; (iv) terminal restriction fragment length polymorphism analysis; (v) fluorescent in situ hybridization; and (vi) quantitative PCR. In addition, we also discuss experimental design, sample collection and storage, DNA extraction, gene targets, PCR bias, and methods to reduce PCR bias.

New rhodamine nitroxide based fluorescent probes for intracellular hydroxyl radical identification in living cells.

The synthesis, characteristics, and biological applications of a series of new rhodamine nitroxide fluorescent probes that enable imaging of hydroxyl radicals (•OH) in living cells are described. These probes are highly selective for •OH in aqueous solution, avoiding interference from other reactive oxygen species (ROS), and they facilitate •OH imaging in biologically active samples. The robust nature of these probes (high specificity and selectivity, and facile synthesis) offer distinct advantages over previous methods for •OH detection.

spyder, a new method for in silico design and assessment of 16S rRNA gene primers for molecular microbial ecology.

Molecular microbial ecology studies are heavily reliant on 'Universal' 16S rRNA gene primers for elucidating microbial community structure and composition, and yet primer design and optimization is often overlooked. Primers that exhibit minor biases due to primer-template mismatches can substantially alter the pool of amplicons from a community DNA sample, resulting in inaccurate conclusions. As a result, it is important that primers are critically evaluated against the most comprehensive data sets available before commencing molecular microbial community studies. We present a user-friendly, multi-platform (e.g. Windows, Linux, Mac) method named spyder for the in silico design and assessment of 16S rRNA gene primers. The method utilizes the Ribosomal Database Project's Probe Match feature coupled with a compact program (available at http://people.uleth.ca/~selibl/Spyder/Spyder.html) that aligns and identifies mismatches between primers and templates. To demonstrate the value of spyder, we assessed commonly used 'Universal' and phyla-specific primers and identified primer modifications that improved the coverage of target organisms by 5-42% as well as removed excessive degeneracies.

Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments.

Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P<0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r=0.92) and glucagon-like peptide-1 levels (r=-0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.

Simple thiazocine-2-acetic acid derivatives via ring-closing metathesis.

A new protocol for synthesis of 2-heterocylylacetic acid derivatives involving conjugate addition of allyl mercaptan to an acrylate containing a tethered olefinic site followed by RCM (ring-closing metathesis) is described. In this series, sulfanyl derivatives were unreactive, while sulfoxide and sulfone analogues provided the corresponding thiazocines in fair to excellent yields. Use of the sulfoxide oxidation state as a protecting group for sulfides inert to RCM is demonstrated also. Thus, oxidation of sulfide 9 [N-allyl-N-[2-(allylthio)-4-(1H-indol-1-yl)-4-oxobutyl]-4-methylbenzenesulfonamide] followed by cyclization yielded the corresponding thiazocine sulfoxide 12. Deprotection (deoxygenation) of 12 was accomplished using Lawesson's reagent, producing 1-[[4-[4-(methylphenyl)sulfonyl]-3,4,5,8-tetrahydro-2H-1,4-thiazocin-2-yl]acetyl]-1H-indole (21) in 67% unoptimized yield.

A redox-mediated molecular brake: dynamic NMR study of 2-[2-(methylthio)phenyl]isoindolin-1-one and S-oxidized counterparts.

A redox-mediated molecular brake based on the sulfide-sulfoxide redox cycle is illustrated by modulation of the rotation rate of an N-Ar "shaft" by varying the oxidation state of sulfur in 2-[2-(sulfur-substituted)phenyl]isoindolin-1-ones. N-Ar rotational barriers in methylsulfinyl (2) and methylsulfonyl (3) derivatives (13.6 kcal mol(-1)) are approximately 5 kcal mol(-1) higher than sulfide 1. Rate reduction for N-Ar rotation is approximately 10(4) s(-1) (280 K) upon oxidation. Correlated N-pyramidalization/N-Ar rotation reduces the effectiveness of the brake by decreasing the energy barrier to N-Ar bond rotation.

Stannous chloride-mediated reductive cyclization-rearrangement of nitroarenyl ketones.

Cyclization products are produced in excellent yields from using standard reaction conditions for nitroarene reduction to aminoarene with SnCl2. Thus, 4-methyl-2-(2-nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treatment with SnCl2 in ethanol did not produce the expected aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-quino[3,2-b][1,4]benzothiazine (3) was produced in excellent yield, presumably via novel Sn (IV)-mediated amidine formation from the initial aniline reduction product. Under identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate (7). A novel semipinacol rearrangement is proposed to account for this extensive skeletal rearrangement. Aniline derivative (14) (from 6 treated with FeSO4.7H2O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodibenzo[b,f][1,5]thiazocine (15) upon treatment with SnCl2 in ethanol. Thiophene analogues of 6 and 14 (18 and 19, respectively) react similarly, forming the analogous thiazepine (20) and cyclic N,O-acetals (21), respectively.