bluuebunny/crossref_metadata_2025 huggingface dataset:
ChemInform Abstract: PHEROMONE SYNTHESIS. XLII. SYNTHESIS OF OPTICALLY ACTIVE FORMS OF METHYL (E)‐2,4,5‐TETRADECATRIENOATE, THE PHEROMONE OF THE MALE DRIED BEAN BEETLE
Authors: MORI K. , NUKADA T. , EBATA T.
Published: April 2016

Veresterung des Alkohols (i)‐(I) mit Phthalsäureanhydrid (II) gibt den Halbester (i)‐(III), dessen Spaltung in die enantiomeren Alkohole (Va) bzw. (Vb) durch Umsetzen mit den Aminen (IVa) bzw. (IVb), HC1‐Hydrolyse der gebildeten (R)‐ bzw. (S)‐Halbesteraminsalze und ihre NaOH‐Verseifung durchgeführt wird.
ChemInform Abstract: SYNTHESIS OF MEGAPHONE
Authors: BUECHI G. + , CHU P.‐S.
Published: April 2016

Das Ausgangsprodukt (VI) für die Synthese von Megaphon (XI) wird wie im Schema aufgezeichnet dargestellt.
ChemInform Abstract: NEWS IN STEROID CHEMISTRY
Authors: KREISER W.
Published: April 2016

Review: Kurzer Überblick.
The Importance of Heterolepticity in Improving the Antibacterial Activity of Bismuth(III) Thiolates
Authors: Luqman Ahmad , Blair Victoria L. , Brammananth Rajini , Crellin Paul K. , Coppel Ross L. , Andrews Philip C.
Published: April 2016

Five mixed thiolatobismuth(III) complexes [BiPh(5‐MMTD)2{4‐MMT(H)}] (1), [Bi(1‐MMTZ)2{(PYM)(PYM(H))2}] (2), [Bi(MBT)2(5‐MMTD)] (3), [Bi(4‐BrMTD)3{2‐MMI(H)}] (4) and [Bi(1‐MMTZ)2{1‐MMTZ(H)}(2‐MMI){2‐MMI(H)2}] (5) were synthesised from imidazole‐, thiazole‐, thiadiazole‐, triazole‐, tetrazole‐ and pyrimidine‐based heterocyclic thiones. Four of these complexes 1–4 were synthesized from BiPh3, while complex 5 was obtained from Bi[4‐(MeO)Ph]3. Complexes 1–5 were structurally characterised by XRD. Evaluation of the antibacterial properties against Mycobacterium smegmatis, Staphylococcus aureus, Methicillin‐resistant S. aureus (MRSA), Vancomycin‐resistant Enterococcus (VRE), Enterococcus faecalis and Escherichia coli showed that mixed thiolato complexes containing the anionic thiazole‐based ligands MBT and 4‐BrMTD are most effective. The mixed thiolato complexes [Bi(MBT)2(5‐MMTD)] (3) having thiazole‐ and thiadiazole‐ and [Bi(4‐BrMBT)3{2‐MMI(H)}] (4) containing thiazole‐ and imidazole‐based ligands proved to be more efficient, with low minimum inhibitory concentrations of 1.73 and 3.45 µm for 3 against VRE and E. faecalis, respectively, and 2.20 µm for 4 against M. smegmatis and E. faecalis. All complexes showed little or no toxicity towards mammalian COS‐7 cell lines at 20 µg mL–1.
Electronic Control of RuII Complexes with Proximal Oxophilic Phenylselenium Tethers: Synthesis, Characterization, and Activation of Molecular Oxygen
Authors: Shen Kaiji , Ben‐David Haviv , Laskavy Alexander , Leitus Gregory , Simon Linda J. W. , Neumann Ronny
Published: April 2016

Various ruthenium(II) complexes with proximal oxophilic phenylselenium groups of the general formula [RuIILALB]X2 {LA = LB = 6,6′‐bis[(4‐methoxyphenyl)selanyl]‐2,2′‐bipyridine; 6,6′‐bis[(nitrophenyl)selanyl]‐2,2′‐bipyridine; 3,6‐bis(phenylselanyl)dipyrido[3,2‐a:2′,3′‐c]phenazine; LA = 6,6′‐bis(phenylselanyl)‐2,2′‐bipyridine, LB = terpyridine} were prepared. The substitution patterns of these compounds were designed to have different electron‐withdrawing/‐donating properties or different binding motifs in comparison to the previously reported compound with LA = LB = 6,6′‐bis(phenylselanyl)‐2,2′‐bipyridine. The research objective was to evaluate the potential of these compounds to activate ground‐state molecular oxygen to form higher‐valent Ru–O–Se bonds by cleavage of the O–O bond of O2. All of the compounds prepared indeed activated O2 to form Ru–O–Se moieties, as observable by UV/Vis spectroscopy, mass spectrometry, or X‐ray crystallography.
Paddlewheel‐Type Dirhodium Tetrapivalate Based Coordination Polymer: Synthesis, Characterization, and Self‐Assembly and Disassembly Transformation Properties
Authors: Kataoka Yusuke , Yano Natsumi , Shimodaira Takashi , Yan Yin‐Nan , Yamasaki Mikio , Tanaka Hidekazu , Omata Kohji , Kawamoto Tatsuya , Handa Makoto
Published: April 2016

An extended one‐dimensional chain‐type coordination polymer, [Rh2(piv)4(tpy)]n (1; piv = pivalate, tpy = 2,2′:6′,2′′‐terpyridine), has been synthesized and characterized by single‐crystal and powder X‐ray diffraction analyses, elemental analysis, IR spectrosopy, thermogravimetric analysis, UV/Vis diffuse reflectance spectroscopy, and magnetic measurements at 300 K. This complex shows unique repeatable self‐assembly and disassembly transformation properties. Polymer 1 readily decomposed to its constituent building blocks, that is, [Rh2(piv)4] and tpy, in organic solvents at 300 K, but the disassembly product of 1 readily re‐self‐assembled to give 1 as a crystalline product in aqueous ethanol solution at 373 K. In addition, 1 was obtained as a crystalline powder by a water‐assisted mechanochemical synthesis route.
A Convenient Route to Monoalkyl‐Substituted Phosphanylboranes (HRP–BH2–NMe3): Prospective Precursors to Poly[(alkylphosphino)boranes]
Authors: Stauber Andreas , Jurca Titel , Marquardt Christian , Fleischmann Martin , Seidl Michael , Whittell George R. , Manners Ian , Scheer Manfred
Published: April 2016

A simple method to access borylphosphonium iodides [RH2P–BH2·NMe3]I (1a: R = Me; 1b: R = Et; 1c: R = nPr) by the addition of iodoalkanes to PH2–BH2·NMe3 was developed. Complexes 1a–c were characterized by multinuclear NMR spectroscopy, and 1a and 1b additionally by single‐crystal X‐ray diffraction. It was possible to synthesize the Lewis‐base‐stabilized organosubstituted phosphanylborane MePH–BH2·NMe3 (2) from [MePH2–BH2·NMe3]I (1a). Thermolysis of 2 generated a soluble, low‐molecular‐mass poly(alkylphosphinoborane) consisting of at least 40 repeat units, as identified by ESI‐MS. These results are promising for the future preparation of a wide range of Lewis‐base‐stabilized phosphanylboranes, which are of interest as precursors to poly[(alkylphosphino)boranes] and are otherwise difficult to access by conventional metal‐catalyzed methods.
Double‐Decker Coordination Cages
Authors: Bandi Sreenivasulu , Samantray Sagarika , Chakravarthy Rajan Deepan , Pal Amlan K. , Hanan Garry S. , Chand Dillip Kumar
Published: April 2016

Bis(pyridin‐3‐ylmethyl) pyridine‐3,5‐dicarboxylate (L) possessing one internal and two terminal pyridine moieties displayed differential coordination ability when combined with suitable PdII components. The compound L acted as a bidentate chelating ligand to form mononuclear complexes when combined with cis‐[Pd(tmeda)(NO3)2] or Pd(NO3)2 in calculated ratios. The combination of Pd(NO3)2 with L in a ratio of 3:4, however, afforded the trinuclear “double‐decker” cage [(NO3)2⊂Pd3(L)4](NO3)4, in which L acts as a nonchelating tridentate ligand and the counter anion (i.e., NO3–) acts as template. The encapsulated NO3– can be replaced by F–, Cl–, or Br– but not by I–. The F–‐encapsulated cage could not be isolated due to its reactivity, whereas the Cl– or Br– encapsulated cages could be isolated. Although anionic guests such as NO3–, Cl–, or Br– stabilized the cages, the presence of excess Cl– or Br– (not NO3–) facilitated decomplexation reactions releasing the ligand. The complexation of Pd(Y)2 (Y = BF4–, PF6–, CF3SO3–, or ClO4–) with L afforded the corresponding mononuclear complexes under appropriate conditions. However, these counter anions could not act as templates for the construction of double‐decker cages.
Polymethine Dyes in Hybrid Photovoltaics: Structure–Properties Relationships
Authors: Saccone Davide , Galliano Simone , Barbero Nadia , Quagliotto Pierluigi , Viscardi Guido , Barolo Claudia
Published: April 2016

Polymethine dyes as photosensitizers for dye‐sensitized solar cells (DSCs) are reviewed. The review provides a summary of design strategies, the main synthetic routes, and the optical and photovoltaic properties of polymethine dyes applied in hybrid photovoltaics. In particular, we focus on cyanine and squaraine dyes and their structure–properties relationships, highlighting the role of the active molecule design on device performance.
Production of Csp3–Csp3 Bonds through Palladium‐Catalyzed Tsuji–Trost‐Type Reactions of (Hetero)Benzylic Substrates
Authors: Le Bras Jean , Muzart Jacques
Published: April 2016

This review covers the formation of Csp3–Csp3 bonds through Pd‐catalyzed reactions of benzylic and heterobenzylic substrates bearing acetate, carbonate, phosphonate, or halide leaving groups, with malonate‐type compounds, oxazoles, aldehydes, α,β‐unsaturated aldehydes, oxindoles, or azlactones. Some of these coupling reactions have been carried out efficiently under enantioselective conditions. In most cases the reaction involves nucleophilic addition to the η3‐benzylpalladium intermediate formed by elimination of the leaving group. Before the nucleophilic attack, however, this intermediate can equilibrate with another benzylpalladium complex, leading to the isomeric coupling product. Because the nucleophilic addition can lead to the dearomatization of the aryl unit, subsequent rearomatization can transform the Csp3–Csp3 bond into a Csp2–Csp3 bond. Intramolecular reactions between benzylic and nucleophilic units have been reported, as well as decarboxylative benzylations from substrates in which the leaving group contains a potential nucleophilic species.
Synthesis of Alkenylboronic Esters: An Alternative Route to Trisubstituted Homoallylic Alcohols
Authors: Gehrke Yvonne , Berg Christina Annette , Vahabi Roza , Pietruszka Jörg
Published: April 2016

New alkenylboronic esters were synthesised from halo‐substituted alkenylboronic esters through cross‐coupling reactions. Upon Johnson rearrangement, enantiomerically pure allylboronates bearing a stereogenic centre in the position α to the boron moiety were obtained in moderate yield (53 %; 29 % over six steps from the protected propargylic alcohols). The products of these reactions were separable by medium‐pressure liquid chromatography, and could be used in highly stereoselective allylation reactions to synthesise enantiomerically enriched homoallylic alcohols containing a 1,1,2‐trisubstituted (Z)‐configured double bond.
A Comparative Ancillary Ligand Survey in Palladium‐Catalyzed C–O Cross‐Coupling of Primary and Secondary Aliphatic Alcohols
Authors: Sawatzky Ryan S. , Hargreaves Breanna K. V. , Stradiotto Mark
Published: April 2016

The utility of RockPhos, Ad‐BippyPhos, JosiPhos (CyPF‐tBu), and Mor‐DalPhos in palladium‐catalyzed C–O cross‐coupling reactions involving aliphatic alcohols and (hetero)aryl halides under analogous conditions was examined, both at room temperature and at elevated temperature (90 °C). In general, the RockPhos‐based catalyst system proved superior, especially at room temperature, but catalysts based on the other ligands examined also proved effective across a range of C–O cross‐couplings, in some cases providing better catalytic performance than RockPhos. New reactivity was established in terms of the scope of room temperature reactions. Proof‐of‐principle examples of such cross‐couplings involving aryl mesylates were also demonstrated.
Sc(OTf)3‐Catalyzed Diastereoselective Formal [3+2] Cycloaddition Reactions of Alkynylcyclopropane Ketones with Electron‐Rich Aromatic Aldehydes To Yield 2,5‐trans‐Tetrahydrofurans
Authors: Zhang Chi , Xu Muyun , Ren Jun , Wang Zhongwen
Published: April 2016

In contast to the general [4+2] cycloaddition reactions of alkynylcyclopropane ketones reported in the literature, we report herein a Sc(OTf)3‐catalyzed formal intermolecular [3+2] cycloaddition reaction of alkynylcyclopropane ketones with electron‐rich aromatic aldehydes. 2,3,3,5‐Tetrasubstituted tetrahydrofurans were obtained by this method, and the tetrahydrofuran skeleton was diastereoselectively constructed with a 2,5‐trans configuration. This is also quite different to the 2,5‐cis configuration usually obtained from typical [3+2] cycloaddition reactions of most donor–acceptor cyclopropanes. Additionally, the cycloadducts were subjected to a domino carbopalladation/C–H activation/C–C bond‐formation process for the highly efficient construction of polycyclic skeletons.
Synthesis and Characterization of Amidato Divalent Lanthanide Complexes and Their Use in Forming 2,4‐Quinazolidinones from CO2 and 2‐Aminobenzonitriles
Authors: Wang Qianyu , Lu Chengrong , Zhao Bei , Yao Yingming
Published: April 2016

Four amidato divalent lanthanide complexes, {LnLn[N(TMS)2]THF}2 [n = 1, Ln = Eu (1); n = 2, Ln = Eu (3), Yb (4); HL1 = tBuC6H4CONHC6H3(iPr)2; HL2 = C6H5CONHC6H3(iPr)2] and {L3Eu[N(TMS)2]THF}{L32Eu(THF)2} (2) [HL3 = ClC6H4CONHC6H3(iPr)2], were synthesized and extensively characterized. This is the first time that the amidato lanthanide amides 1–4 were used to catalyze the reactions of CO2 and 2‐aminobenzonitriles to form quinazoline‐2,4(1H,3H)‐diones at atmospheric pressure. All the complexes efficiently catalyzed the transformation, with complex 3 showing the highest activity. This catalytic system gave good to excellent yields, and good functional group tolerance. Preliminary studies were conducted to investigate the reaction mechanism.
Expedient Synthesis of Large‐Ring trans‐Enamide Macrolides by CuI‐Mediated Intramolecular Coupling of Vinyl Iodide with Amide: Total Synthesis of Palmyrolide A
Authors: Yadav Jhillu Singh , Suresh Borra , Srihari Pabbaraja
Published: April 2016

An efficient and improved procedure for copper‐catalyzed coupling of vinyl iodide with amide in an intramolecular fashion is described. The protocol utilizes a combination of copper iodide, CsF and (±)‐1,2‐diaminocyclohexane as ligand. The vinyl iodide couples efficiently with the amide to generate an enamide macrolide without any alteration in the double ‐bond geometry. The developed method was applied in the synthesis of several large‐ring enamide macrolides, and for the total synthesis of natural product palmyrolide A and homologated sanctolide A.
An Introverted Bis‐Au Cavitand and Its Catalytic Dimerization of Terminal Alkynes
Authors: Endo Naoki , Kanaura Mao , Schramm Michael P. , Iwasawa Tetsuo
Published: April 2016

A preparative synthesis of an inwardly oriented phosphoramidite‐Au dinuclear resorcinarene cavitand complex is described, including a description of potent catalytic abilities. The cavitand structure was determined by crystallographic analysis, which revealed that the phosphoramidite P–N bonds point outside placing the two Au atoms inside. We explored the catalytic proclivity of the cavitand and found that it effeciently catalyzes selective and direct dimerization of terminal alkynes to afford conjugated enynes. Mixed dimerizations give rise to chemoselective products, and macrocyclization by intramolecular dimerization are both trademark capabilities of the method.
Streamflow response to the rapid retreat of a lake‐calving glacier
Authors: Moyer Alexis N. , Moore R. D. , Koppes Michele N.
Published: April 2016

There has been increasing attention over the last decade to the potential effects of glacier retreat on downstream discharge and aquatic habitat. This study focused on streamflow variability downstream of Bridge Glacier in the southern Coast Mountains of BC between 1979 and 2014, prior to and during a period in which the glacier experienced enhanced calving and rapid retreat across a lake‐filled basin. Here we combined empirical trend detection and a conceptual‐parametric hydrological model to address the following hypotheses: (1) streamflow trends in late summer and early autumn should reflect the opposing influences of climatic warming (which would tend to increase unit‐area meltwater production) and the reduction in glacier area (which would tend to reduce the total volume of meltwater generated), and (2) winter streamflow should increase because of displacement of lake water as ice flows past the grounding line and calves into the lake basin. In relation to the first hypothesis, we found no significant trends in monthly discharge during summer. However, applying regression analysis to account for air temperature and precipitation variations, weak but statistically significant negative trends were detected for August and melt season discharge. The HBV‐EC model was applied using time‐varying glacier cover, as derived from Landsat imagery. Relative to simulations based on constant glacier extent, model results indicated that glacier recession caused a decline in mean monthly streamflow of 9% in August and 11% in September. These declines in late‐summer streamflow are consistent with the results from our empirical analysis. The second hypothesis is supported by the finding of positive trends for December, January, and February discharge. Despite the modelled declines in late‐summer mean monthly streamflow, recorded discharge data exhibited neither positive nor negative trends during the melt season, suggesting that Bridge Glacier may currently be at or close to the point of peak water. Further analysis of the impact of lake‐terminating glaciers on downstream discharge is needed to refine the peak water model. Copyright © 2016 John Wiley & Sons, Ltd.
Prediagnostic body size and breast cancer survival in the E3N cohort study
Authors: His Mathilde , Fagherazzi Guy , Mesrine Sylvie , Boutron‐Ruault Marie‐Christine , Clavel‐Chapelon Françoise , Dossus Laure
Published: April 2016

Obesity has been associated with poor breast cancer prognosis, however most studies have focused on body mass index (BMI) and few have considered the distribution of adipose tissue. We investigated associations between prediagnostic adiposity and breast cancer survival, considering BMI, waist and hip circumferences (WC and HC), and waist‐to‐hip ratio (WHR). Analyses included 3,006 women from the French E3N prospective cohort study diagnosed with primary invasive breast cancer between 1995 and 2008. We investigated overall, breast cancer‐specific, and disease‐free survival, overall and according to stage, menopausal and hormonal status and year of diagnosis, using Cox proportional hazard models adjusted for tumor characteristics and lifestyle risk factors. Women with a prediagnostic HC > 100 cm were at increased risk of death from all causes (hazard ratio (HR)>100vs < 95 cm = 1.38, 95% Confidence Interval (CI) = 1.02–1.86, Ptrend = 0.02) and from breast cancer (HR>100vs < 95 cm = 1.50, CI = 1.03–2.17, Ptrend = 0.03), and of second invasive cancer event (HR>100vs < 95 cm = 1.36, CI = 1.11–1.67, Ptrend = 0.002), compared to those with HC <95 cm. Associations were stronger after adjustment for BMI. BMI, WC and WHR were not associated with survival after breast cancer. Our study underlines the importance of going beyond BMI when studying the association between adiposity and breast cancer survival. Further studies should be conducted to confirm our results on hip circumference.
Detrimental graft survival of size‐mismatched graft for high model for end‐stage liver disease recipients in liver transplantation
Authors: Fukazawa Kyota , Nishida Seigo , Pretto Ernesto A. , Vater Youri , Reyes Jorge D.
Published: April 2016

Background

In orthotopic liver transplantation (OLT) size‐mismatch may cause adverse outcomes. We previously reported on a method to predict donor‐recipient size‐mismatch using the body surface area index (BSAi). In this study, we hypothesized that graft survival of size‐mismatch transplantation deteriorates with higher model for end‐stage liver disease (MELD) score at transplantation.

Methods

We evaluated non‐parametrically the association of BSAi and MELD with 1‐year graft survival with a generalized additive model. For derivation, transplantations performed between 2005 and 2010 were used. The associations were then validated by comparing Kaplan–Meier estimates between patient groups stratified according to estimated risk, using transplantations from 2011–2013.

Results

A total of 30,870 OLT were included in the study with 16,466 in the validation group. The derivation model revealed that graft survival significantly decreased with higher or lower BSAi, and with higher MELD (P < 0.0001). Validation confirmed the correlation of observed graft survival with estimated risk categories.

Conclusions

We found that there is an interactive effect between MELD score and size‐mismatch. Also high MELD recipient has a narrower safety margin for size‐mismatched graft. The risk calculated from our nonparametric model with MELD and BSAi well predicts outcome in liver transplantation.
Elevation‐dependent reductions in wind speed over and around the Tibetan Plateau
Authors: Guo Xiaoyu , Wang Lei , Tian Lide , Li Xiuping
Published: April 2016

The Tibetan Plateau (TP) affects its surroundings significantly through thermal and dynamic processes. Reductions in near‐surface wind speed (Ws) have been observed from ground measurements but how the trends of Ws vary with the elevation is less clear. Trends of Ws with respect to elevation were investigated using long‐term daily records taken from 1970 to 2012 of Ws and maximum (Tmax), minimum (Tmin), and mean (Tmean) air temperatures from 139 stations over and around the TP. The major findings are as follows. (1) Pronounced reductions in Ws can be observed in all seasons and annually across the TP. Spring demonstrates the most prominent weakening. The rate of reductions in Ws was amplified with elevation, and higher‐elevation environments experienced greater changes in Ws than lower‐elevation areas. Elevation‐dependent reductions in Ws have intensified from 1970 to 2012. (2) Statistically significant negative correlations between Ws and corresponding near‐surface temperatures were detected. We suggested that the elevation‐dependent warming and thereby the increased surface roughness at higher‐elevation environments may contribute to the elevation‐dependent reductions in Ws over and around the TP. More detailed mechanisms causing this pattern are to be further explored.
Reliability of office‐based narrow‐band imaging–guided flexible laryngoscopic tissue samplings
Authors: Chang Catherine , Lin Wan‐Ni , Hsin Li‐Jen , Lee Li‐Ang , Lin Chien‐Yu , Li Hsueh‐Yu , Liao Chun‐Ta , Fang Tuan‐Jen
Published: April 2016

Objectives/Hypothesis

Direct suspension laryngoscopic biopsy performed under general anesthesia is the conventional management for obtaining pathological diagnosis for neoplasms of the larynx, oropharynx, and hypopharynx. Since the development of distal chip laryngoscopy and digital imaging systems, transnasal flexible laryngoscopy tissue sampling has gained popularity as an office‐based procedure. Additional assessment with narrow‐band imaging (NBI) can help to increase the diagnostic yield. The aim of the study was to evaluate the accuracy, sensitivity, and specificity of a novel diagnostic tool: office‐based NBI (OB‐NBI) flexible laryngoscopic tissue sampling.

Study Design

Retrospective chart review performed in a tertiary referral medical center in Taiwan.

Methods

From January 2010 to February 2013, 90 consecutive patients received OB‐NBI biopsies. The accuracies of the OB‐NBI biopsies were compared among locations, tumor sizes, head and neck cancer histories, and other factors.

Results

All patients had completed the procedure without life‐threatening complications. The overall sensitivity and specificity were 97.2% and 100%, respectively, with a diagnostic accuracy of 98.9%. Accuracy was not affected by tumor size, location, learning curves, or previous head and neck cancer history.

Conclusions

We present an integrated technique that merges the safety and versatility of flexible laryngoscopy with the diagnostic power of NBI to produce a promising method of high accuracy and minimal morbidity.

Level of Evidence

4 Laryngoscope, 126:2764–2769, 2016
Supramolecular Hydrogel from Nanoparticles and Cyclodextrins for Local and Sustained Nanoparticle Delivery
Authors: Xu Shuxin , Yin Li , Xiang Yuzhang , Deng Hongzhang , Deng Liandong , Fan Hongxia , Tang Hua , Zhang Jianhua , Dong Anjie
Published: April 2016

Injectable and biodegradable supramolecular hydrogel mPECT NP/α‐CDgel composed of high‐concentration nanoparticle dispersion (≤20% W/V) and α‐cyclodextrins (α‐CD) are prepared by a two‐level physical cross‐linking using amphiphilic block polymer methoxy poly(ethylene glycol)‐b‐poly(ε‐caprolactone‐co‐1,4,8‐trioxa[4.6]spiro‐9‐undecanone) (mPECT) and α‐CD. The gelation behavior depends on the concentration of nanoparticles and α‐CD. The viscoelasticity and shear thinning of mPECT NP/α‐CDgel are confirmed. In vitro hydrogel erosion is demonstrated to be mainly a concentration‐dependent dissociation process with general release of discrete mPECT nanoparticles about 50 nm that can be easily taken up by cells. The in vitro release behavior can be modulated by changing the concentration of nanoparticles or α‐CD. In vitro and in vivo cytotoxicity study demonstrates its biocompatibility and biosafety. Gel formation after subcutaneous injection is also confirmed and mPECT NP/α‐CDgel shows about 2 weeks retention time. This work validates the potential application for this supramolecular hydrogel in local and sustained delivery of nanoparticles.

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Egg consumption and risk of incident type 2 diabetes: a dose–response meta-analysis of prospective cohort studies
Authors: Tamez Martha , Virtanen Jyrki K. , Lajous Martin
Published: April 2016

Experimental data suggest that egg intake could have a beneficial impact on several risk factors for type 2 diabetes. In contrast, some recent epidemiological studies have concluded that egg consumption may increase diabetes risk. We performed a dose–response meta-analysis of prospective cohorts on the relation of egg consumption with incident type 2 diabetes. We searched for cohort studies that assessed egg consumption and diabetes risk up to June 2015. We identified 416 articles and extracted data independently and in duplicate from ten eligible studies. We used random-effects generalised least squares models for pooled dose–response estimation based on thirteen estimates. Our study included 251 213 individuals and 12 156 incident type 2 diabetes cases. Egg intake was associated with incident type 2 diabetes (risk ratio (RR)/egg per d 1·13; 95 % CI 1·04, 1·22). We identified study location as a major source of heterogeneity. For studies conducted in the USA, we observed a stronger association (RR 1·47; 95 % CI 1·32, 1·64), whereas results were null for studies conducted elsewhere. Studies considered to be of high quality yielded null findings (RR 0·94; 95 % CI 0·74, 1·19). The association of egg intake with increased risk of incident type 2 diabetes may be restricted to US cohort studies. There are limited data to support a biological mechanism that could underlie this association; thus, the possibility that these results may be due to residual confounding by dietary behaviours restricted to certain populations cannot be excluded.
SAMFIRE: multi-locus variant calling for time-resolved sequence data
Authors: Illingworth C. J. R.
Published: April 2016

Summary: An increasingly common method for studying evolution is the collection of time-resolved short-read sequence data. Such datasets allow for the direct observation of rapid evolutionary processes, as might occur in natural microbial populations and in evolutionary experiments. In many circumstances, evolutionary pressure acting upon single variants can cause genomic changes at multiple nearby loci. SAMFIRE is an open-access software package for processing and analyzing sequence reads from time-resolved data, calling important single- and multi-locus variants over time, identifying alleles potentially affected by selection, calculating linkage disequilibrium statistics, performing haplotype reconstruction and exploiting time-resolved information to estimate the extent of uncertainty in reported genomic data.

Availability and Implementation: C ++ code may be found at https://github.com/cjri/samfire/.

Contact:  chris.illingworth@gen.cam.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Pasha: a versatile R package for piling chromatin HTS data
Authors: Fenouil Romain , Descostes Nicolas , Spinelli Lionel , Koch Frederic , Maqbool Muhammad Ahmad , Benoukraf Touati , Cauchy Pierre , Innocenti Charlène , Ferrier Pierre , Andrau Jean-Christophe
Published: April 2016

Summary: We describe an R package designed for processing aligned reads from chromatin-oriented high-throughput sequencing experiments. Pasha (preprocessing of aligned sequences from HTS analyses) allows easy manipulation of aligned reads from short-read sequencing technologies (ChIP-seq, FAIRE-seq, MNase-Seq, …) and offers innovative approaches such as ChIP-seq reads elongation, nucleosome midpoint piling strategy for positioning analyses, or the ability to subset paired-end reads by groups of insert size that can contain biologically relevant information.

Availability and implementation: Pasha is a multi-platform R package, available on CRAN repositories under GPL-3 license (https://cran.r-project.org/web/packages/Pasha/).

Contacts:  rfenouil@gmail.com or jean-christophe.andrau@igmm.cnrs.fr

Supplementary information:  Supplementary data are available at Bioinformatics online.
Partitioning and correlating subgroup characteristics from Aligned Pattern Clusters
Authors: Lee En-Shiun Annie , Whelan Fiona J. , Bowdish Dawn M. E. , Wong Andrew K. C.
Published: April 2016

Motivation: Evolutionarily conserved amino acids within proteins characterize functional or structural regions. Conversely, less conserved amino acids within these regions are generally areas of evolutionary divergence. A priori knowledge of biological function and species can help interpret the amino acid differences between sequences. However, this information is often erroneous or unavailable, hampering discovery with supervised algorithms. Also, most of the current unsupervised methods depend on full sequence similarity, which become inaccurate when proteins diverge (e.g. inversions, deletions, insertions). Due to these and other shortcomings, we developed a novel unsupervised algorithm which discovers highly conserved regions and uses two types of information measures: (i) data measures computed from input sequences; and (ii) class measures computed using a priori class groupings in order to reveal subgroups (i.e. classes) or functional characteristics.

Results: Using known and putative sequences of two proteins belonging to a relatively uncharacterized protein family we were able to group evolutionarily related sequences and identify conserved regions, which are strong homologous association patterns called Aligned Pattern Clusters, within individual proteins and across the members of this family. An initial synthetic demonstration and in silico results reveal that (i) the data measures are unbiased and (ii) our class measures can accurately rank the quality of the evolutionarily relevant groupings. Furthermore, combining our data and class measures allowed us to interpret the results by inferring regions of biological importance within the binding domain of these proteins. Compared to popular supervised methods, our algorithm has a superior runtime and comparable accuracy.

Availability and implementation: The dataset and results are available at www.pami.uwaterloo.ca/∼ealee/files/classification2015 .

Contact:  akcwong@uwaterloo.ca

Supplementary information:  Supplementary data are available at Bioinformatics online.
Bayesian nonparametrics in protein remote homology search
Authors: Margelevičius Mindaugas
Published: April 2016

Motivation: Wide application of modeling of three-dimensional protein structures in biomedical research motivates developing protein sequence alignment computer tools featuring high alignment accuracy and sensitivity to remotely homologous proteins. In this paper, we aim at improving the quality of alignments between sequence profiles, encoded multiple sequence alignments. Modeling profile contexts, fixed-length profile fragments, is engaged to achieve this goal.

Results: We develop a hierarchical Dirichlet process mixture model to describe the distribution of profile contexts, which is able to capture dependencies between amino acids in each context position. The model represents an attempt at modeling profile fragments at several hierarchical levels, within the profile and among profiles. Even modeling unit-length contexts leads to greater improvements than processing 13-length contexts previously. We develop a new profile comparison method, called COMER, integrating the model. A benchmark with three other profile-to-profile comparison methods shows an increase in both sensitivity and alignment quality.

Availability and Implementation: COMER is open-source software licensed under the GNU GPLv3, available at https://sourceforge.net/projects/comer.

Contact:  mindaugas.margelevicius@bti.vu.lt

Supplementary information:  Supplementary data are available at Bioinformatics online.
ARACNe-AP: gene network reverse engineering through adaptive partitioning inference of mutual information
Authors: Lachmann Alexander , Giorgi Federico M. , Lopez Gonzalo , Califano Andrea
Published: April 2016

Summary: The accurate reconstruction of gene regulatory networks from large scale molecular profile datasets represents one of the grand challenges of Systems Biology. The Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) represents one of the most effective tools to accomplish this goal. However, the initial Fixed Bandwidth (FB) implementation is both inefficient and unable to deal with sample sets providing largely uneven coverage of the probability density space. Here, we present a completely new implementation of the algorithm, based on an Adaptive Partitioning strategy (AP) for estimating the Mutual Information. The new AP implementation (ARACNe-AP) achieves a dramatic improvement in computational performance (200× on average) over the previous methodology, while preserving the Mutual Information estimator and the Network inference accuracy of the original algorithm. Given that the previous version of ARACNe is extremely demanding, the new version of the algorithm will allow even researchers with modest computational resources to build complex regulatory networks from hundreds of gene expression profiles.

Availability and Implementation: A JAVA cross-platform command line executable of ARACNe, together with all source code and a detailed usage guide are freely available on Sourceforge (http://sourceforge.net/projects/aracne-ap). JAVA version 8 or higher is required.

Contact:  califano@c2b2.columbia.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
rnaQUAST: a quality assessment tool for de novo transcriptome assemblies
Authors: Bushmanova Elena , Antipov Dmitry , Lapidus Alla , Suvorov Vladimir , Prjibelski Andrey D.
Published: April 2016

Summary: Ability to generate large RNA-Seq datasets created a demand for both de novo and reference-based transcriptome assemblers. However, while many transcriptome assemblers are now available, there is still no unified quality assessment tool for RNA-Seq assemblies. We present rnaQUAST—a tool for evaluating RNA-Seq assembly quality and benchmarking transcriptome assemblers using reference genome and gene database. rnaQUAST calculates various metrics that demonstrate completeness and correctness levels of the assembled transcripts, and outputs them in a user-friendly report.

Availability and Implementation: rnaQUAST is implemented in Python and is freely available at http://bioinf.spbau.ru/en/rnaquast.

Contact:  ap@bioinf.spbau.ru

Supplementary information:  Supplementary data are available at Bioinformatics online.
Incorporating organelle correlations into semi-supervised learning for protein subcellular localization prediction
Authors: Xu Ying-Ying , Yang Fan , Shen Hong-Bin
Published: April 2016

Motivation: Bioimages of subcellular protein distribution as a new data source have attracted much attention in the field of automated prediction of proteins subcellular localization. Performance of existing systems is significantly limited by the small number of high-quality images with explicit annotations, resulting in the small sample size learning problem. This limitation is more serious for the multi-location proteins that co-exist at two or more organelles, because it is difficult to accurately annotate those proteins by biological experiments or automated systems.

Results: In this study, we designed a new protein subcellular localization prediction pipeline aiming to deal with the small sample size learning and multi-location proteins annotation problems. Five semi-supervised algorithms that can make use of lower-quality data were integrated, and a new multi-label classification approach by incorporating the correlations among different organelles in cells was proposed. The organelle correlations were modeled by the Bayesian network, and the topology of the correlation graph was used to guide the order of binary classifiers training in the multi-label classification to reflect the label dependence relationship. The proposed protocol was applied on both immunohistochemistry and immunofluorescence images, and our experimental results demonstrated its efficiency.

Availability and implementation: The datasets and code are available at: www.csbio.sjtu.edu.cn/bioinf/CorrASemiB.

Contact:  hbshen@sjtu.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.
An efficient approach for surveillance of childhood diabetes by type derived from electronic health record data: the SEARCH for Diabetes in Youth Study
Authors: Zhong Victor W , Obeid Jihad S , Craig Jean B , Pfaff Emily R , Thomas Joan , Jaacks Lindsay M , Beavers Daniel P , Carey Timothy S , Lawrence Jean M , Dabelea Dana , Hamman Richard F , Bowlby Deborah A , Pihoker Catherine , Saydah Sharon H , Mayer-Davis Elizabeth J
Published: April 2016

Objective To develop an efficient surveillance approach for childhood diabetes by type across 2 large US health care systems, using phenotyping algorithms derived from electronic health record (EHR) data.

Materials and Methods Presumptive diabetes cases <20 years of age from 2 large independent health care systems were identified as those having ≥1 of the 5 indicators in the past 3.5 years, including elevated HbA1c, elevated blood glucose, diabetes-related billing codes, patient problem list, and outpatient anti-diabetic medications. EHRs of all the presumptive cases were manually reviewed, and true diabetes status and diabetes type were determined. Algorithms for identifying diabetes cases overall and classifying diabetes type were either prespecified or derived from classification and regression tree analysis. Surveillance approach was developed based on the best algorithms identified.

Results We developed a stepwise surveillance approach using billing code–based prespecified algorithms and targeted manual EHR review, which efficiently and accurately ascertained and classified diabetes cases by type, in both health care systems. The sensitivity and positive predictive values in both systems were approximately ≥90% for ascertaining diabetes cases overall and classifying cases with type 1 or type 2 diabetes. About 80% of the cases with “other” type were also correctly classified. This stepwise surveillance approach resulted in a >70% reduction in the number of cases requiring manual validation compared to traditional surveillance methods.

Conclusion EHR data may be used to establish an efficient approach for large-scale surveillance for childhood diabetes by type, although some manual effort is still needed.
An informatics research agenda to support precision medicine: seven key areas
Authors: Tenenbaum Jessica D , Avillach Paul , Benham-Hutchins Marge , Breitenstein Matthew K , Crowgey Erin L , Hoffman Mark A , Jiang Xia , Madhavan Subha , Mattison John E , Nagarajan Radhakrishnan , Ray Bisakha , Shin Dmitriy , Visweswaran Shyam , Zhao Zhongming , Freimuth Robert R
Published: April 2016

The recent announcement of the Precision Medicine Initiative by President Obama has brought precision medicine (PM) to the forefront for healthcare providers, researchers, regulators, innovators, and funders alike. As technologies continue to evolve and datasets grow in magnitude, a strong computational infrastructure will be essential to realize PM’s vision of improved healthcare derived from personal data. In addition, informatics research and innovation affords a tremendous opportunity to drive the science underlying PM. The informatics community must lead the development of technologies and methodologies that will increase the discovery and application of biomedical knowledge through close collaboration between researchers, clinicians, and patients. This perspective highlights seven key areas that are in need of further informatics research and innovation to support the realization of PM.
A bioinformatics approach for precision medicine off-label drug drug selection among triple negative breast cancer patients
Authors: Cheng Lijun , Schneider Bryan P , Li Lang
Published: April 2016

Background Cancer has been extensively characterized on the basis of genomics. The integration of genetic information about cancers with data on how the cancers respond to target based therapy to help to optimum cancer treatment.

Objective The increasing usage of sequencing technology in cancer research and clinical practice has enormously advanced our understanding of cancer mechanisms. The cancer precision medicine is becoming a reality. Although off-label drug usage is a common practice in treating cancer, it suffers from the lack of knowledge base for proper cancer drug selections. This eminent need has become even more apparent considering the upcoming genomics data.

Methods In this paper, a personalized medicine knowledge base is constructed by integrating various cancer drugs, drug-target database, and knowledge sources for the proper cancer drugs and their target selections. Based on the knowledge base, a bioinformatics approach for cancer drugs selection in precision medicine is developed. It integrates personal molecular profile data, including copy number variation, mutation, and gene expression.

Results By analyzing the 85 triple negative breast cancer (TNBC) patient data in the Cancer Genome Altar, we have shown that 71.7% of the TNBC patients have FDA approved drug targets, and 51.7% of the patients have more than one drug target. Sixty-five drug targets are identified as TNBC treatment targets and 85 candidate drugs are recommended. Many existing TNBC candidate targets, such as Poly (ADP-Ribose) Polymerase 1 (PARP1), Cell division protein kinase 6 (CDK6), epidermal growth factor receptor, etc., were identified. On the other hand, we found some additional targets that are not yet fully investigated in the TNBC, such as Gamma-Glutamyl Hydrolase (GGH), Thymidylate Synthetase (TYMS), Protein Tyrosine Kinase 6 (PTK6), Topoisomerase (DNA) I, Mitochondrial (TOP1MT), Smoothened, Frizzled Class Receptor (SMO), etc. Our additional analysis of target and drug selection strategy is also fully supported by the drug screening data on TNBC cell lines in the Cancer Cell Line Encyclopedia.

Conclusions The proposed bioinformatics approach lays a foundation for cancer precision medicine. It supplies much needed knowledge base for the off-label cancer drug usage in clinics.
Data quality of electronic medical records in Manitoba: do problem lists accurately reflect chronic disease billing diagnoses?
Authors: Singer Alexander , Yakubovich Sari , Kroeker Andrea L , Dufault Brenden , Duarte Roberto , Katz Alan
Published: April 2016

Objective To determine problem list completeness related to chronic diseases in electronic medical records (EMRs) and explore clinic and physician factors influencing completeness.

Methods A retrospective analysis of primary care EMR data quality related to seven chronic diseases (hypertension, diabetes, asthma, congestive heart failure, coronary artery disease, hypothyroidism, and chronic obstructive pulmonary disorder) in Manitoba, Canada. We included 119 practices in 18 primary care clinics across urban and rural Manitoba. The main outcome measure was EMR problem list completeness. Completeness was measured by comparing the number of EMR-documented diagnoses to the number of billings associated with each disease. We calculated odds ratios for the effect of clinic patient load and salary type on EMR problem list completeness of the 7 chronic diseases.

Results Completeness of EMR problem list for each disease varied widely among clinics. Factors that significantly affected EMR problem list completeness included the primary care provider, the patient load, and the clinic’s funding and organization model (ie, salaried, fee-for-service, or residency training clinics). Average rates of completeness were: hypertension, 72%; diabetes, 80%; hypothyroidism, 63%; asthma, 56%; chronic obstructive pulmonary disorder, 43%; congestive heart failure, 54%; and coronary artery disease, 64%.

Conclusion This study demonstrates the high variability but generally low quality of problem lists (health condition records) related to 7 common chronic diseases in EMRs. There are systematic physician- and clinic-level factors associated with low data quality completeness. This information may be useful to support improvement in EMR data quality in primary care.
Quality improvement teams, super-users, and nurse champions: a recipe for meaningful use?
Authors: Shea Christopher M , Reiter Kristin L , Weaver Mark A , Albritton Jordan
Published: April 2016

Objective This study assessed whether having an electronic health record (EHR) super-user, nurse champion for meaningful use (MU), and quality improvement (QI) team leading MU implementation is positively associated with MU Stage 1 demonstration.

Methods Data on MU demonstration of 596 providers in 37 ambulatory care clinics came from the clinical data warehouse and administrative systems of UNC Health Care. We surveyed the 37 clinics about champions, super-users, and QI teams. We used generalized estimating equation methods with an independence working correlation matrix to account for clustering within clinics and to weight contributions from each clinic according to clinic size.

Results Having a QI team lead MU implementation was significantly associated with MU demonstration (odds ratio, OR = 3.57, 95% CI, 1.83-6.96, P < .001, Table 2 ). Having neither a nurse champion nor an EHR super-user was significant.

Conclusion Our findings support the alignment of MU with QI efforts by having the QI team lead MU implementation.