bluuebunny/crossref_metadata_2025 huggingface dataset:
Extreme group sizes in a colonial bird favored during a rare climatic event
Authors: Brown Charles R. , Brown Mary Bomberger
Published: September 2018

What maintains stasis in animal group‐size distributions is an unresolved problem in behavioral ecology. One potential driver could be rare climatic events that favor certain group sizes in ways that do not occur in normal conditions. We investigated mortality among colonially nesting cliff swallows (Petrochelidon pyrrhonota) during a rare climatic event in western Nebraska in 1996 that led to the starvation of thousands of adult birds. Colonies at the extreme end of the size distribution exhibited less size reduction (higher adult survival) than those of intermediate size. That this event resulted in disruptive selection on colony size was suggested by an underrepresentation of locally produced yearling birds that recruited into colonies of intermediate size the following year. There was no evidence that the colony‐size‐related mortality could be explained by differential sorting of birds among colonies based on body size or differing patterns of selection on morphology. The selection on colony size was likely driven by lower competition for food in the smallest colonies and better quality foraging habitat associated with the largest colonies, with these advantages enhanced in severe weather. Selection on colony size during rare climatic events can reinforce or oppose selection occurring during other times of the annual cycle. Whether such selection results in long‐term change in the colony‐size distribution may depend on the frequency and severity of these climatic events.
Telemedical Interventional Management in Heart Failure II (TIM‐HF2), a randomised, controlled trial investigating the impact of telemedicine on unplanned cardiovascular hospitalisations and mortality in heart failure patients: study design and description of the intervention
Authors: Koehler Friedrich , Koehler Kerstin , Deckwart Oliver , Prescher Sandra , Wegscheider Karl , Winkler Sebastian , Vettorazzi Eik , Polze Andreas , Stangl Karl , Hartmann Oliver , Marx Almuth , Neuhaus Petra , Scherf Michael , Kirwan Bridget‐Anne , Anker Stefan D.
Published: September 2018

Background

Heart failure (HF) is a complex, chronic condition that is associated with debilitating symptoms, all of which necessitate close follow‐up by health care providers. Lack of disease monitoring may result in increased mortality and more frequent hospital readmissions for decompensated HF. Remote patient management (RPM) in this patient population may help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and care before a manifestation of HF decompensation.

Objective

The objective of the present article is to describe the design of a new trial investigating the impact of RPM on unplanned cardiovascular hospitalisations and mortality in HF patients.

Methods

The TIM‐HF2 trial is designed as a prospective, randomised, controlled, parallel group, open (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. Eligible patients with HF are randomised (1:1) to either RPM + usual care or to usual care only and are followed for 12 months. The primary outcome is the percentage of days lost due to unplanned cardiovascular hospitalisations or all‐cause death. The main secondary outcomes are all‐cause and cardiovascular mortality.

Conclusion

The TIM‐HF2 trial will provide important prospective data on the potential beneficial effect of telemedical monitoring and RPM on unplanned cardiovascular hospitalisations and mortality in HF patients.

Trial registration:
ClinicalTrials.gov Identifier NCT01878630.
Two‐Photon Excitable Iridium Complex Containing Dipyrazolyltriazine as Cellular Imaging Dyes
Authors: Zheng Poonnapa , Chaibuth Pawittra , Lo Wai‐Sum , Jin Weiweij , Sun Xinyang , Meksawangwong Sureemas , Punyain Wikorn , Gál Miraoslav , Gu Yanjuan , Chan Wesley Ting Kwok , Kielar Filip , Law Ga‐Lai
Published: September 2018

In this work, the synthesis, stability studies, and photophysical properties of a bis‐cyclometalated iridium(III) complex with a push‐pull ancillary ligand are presented. The complex was found to localize in mitochondria and could be excited by a two‐photon excitation process under a confocal laser scanning microscope.
Controlling Size‐Dispersion of Single Walled Carbon Nanotubes by Interaction with Polyoxometalates Armed with a Tryptophan Tweezer
Authors: Syrgiannis Zois , Trautwein Guido , Calvaresi Matteo , Modugno Gloria , Zerbetto Francesco , Carraro Mauro , Prato Maurizio , Bonchio Marcella
Published: September 2018

A bis‐tryptophan tweezer was installed on a polyoxometalate (POM) surface via a bis‐amide covalent bond, yielding the enantiopure hybrid POM with C2 symmetry, as a result of the regioselective functionalization of decatungosilicate [γ‐SiW10O36]8– at the lacunary site. The combined polyanionic and receptor properties are instrumental for a POM‐driven solubilization and enrichment of single walled carbon nanotubes (SWCNTs) with diameter <1.1 nm, as demonstrated by Raman and UV/Vis‐NIR evidence, in agreement with the calculated energetics of the tryptophan tweezer–SWCNT interaction.
High Open Circuit Voltage for Perovskite Solar Cells with S,Si‐Heteropentacene‐Based Hole Conductors
Authors: Dar M. Ibrahim , Arora Neha , Steck Christopher , Mishra Amaresh , Alotaibi Mohammad Hayal , Bäuerle Peter , Zakeeruddin Shaik Mohammed , Grätzel Michael
Published: September 2018

High photovoltage in perovskite solar cells (PSCs) can be achieved by designing new hole transporting materials (HTMs) with relatively deeper energy levels of the highest occupied molecular orbital (HOMO). Here, we report on the synthesis of a new heteroacene‐based HTM (HTM‐1) and demonstrate its potential in the fabrication of FAPbBr3 [FA = CH(NH2)2] PSCs yielding VOC as high as 1.55 V, a record value for this light harvester. The energetic position of the frontier orbitals of HTM‐1 was estimated using electrochemical measurements, and the charge transport across the interfaces was studied using steady‐state and time‐resolved photoluminescence. When spiro‐OMeTAD (HOMO = –5.1 eV) is replaced with HTM‐1 (HOMO = –5.3 eV), the VOC increases from 1.51 to 1.55 V, whereas the JSC value decreases from 7.0 to 5.7 mA cm–2. The similar trade‐off between JSC and VOC is observed for efficient iodide‐based PSCs, suggesting that there is a critical energy level for the HOMO below which overall photovoltaic performance will suffer. After probing at a maximum power point under full‐sun illumination at 60 °C for a duration of 120 h, the FAPbBr3 PSCs based on HTM‐1 retained ≈ 95 % of their initial efficiency, which demonstrates their robust operational stability.
Trifluoromethylated Thiopyranoid Glycals: Synthesis and Ferrier (I) Type Reactions
Authors: Siry Serhii A. , Shermolovich Yurii G. , Kinzhybalo Vasyl V. , Bednarchuk Tamara J. , Timoshenko Vadim M.
Published: September 2018

The synthesis of a single diastereomer of 3‐acetoxy‐2‐(trifluoromethyl)‐4‐hydroxy‐3,4‐dihydro‐2H‐thiopyran from the mixture of diastereomeric cycloadducts of p‐tolyl trifluorodithioacetate and 1‐acetoxybutadiene is described. Its acetylation and nucleophilic chlorination provides glycosylating agents with different leaving groups have been prepared. Their reactions with various O‐, S‐, N‐ and C‐nucleophiles have been studied. Depending on the conditions of the experiments, the reactions proceed as Ferrier (I) reactions affording 3‐acetoxy‐2‐(trifluoromethyl)‐6‐substituted‐3,6‐dihydro‐2H‐thiopyrans or as formal direct replacement of the leaving group in the position 4 giving 3‐acetoxy‐2‐(trifluoromethyl)‐4‐substituted‐3,4‐dihydro‐2H‐thiopyrans. The stereochemistry of the resulting products and all their precursors is discussed.
The Diels–Alder Reaction from the EDA‐NOCV Perspective: A Re‐Examination of the Frontier Molecular Orbital Model
Authors: Fernández Israel , Frenking Gernot
Published: September 2018

We report calculated activation barriers for the Diels–Alder reaction between substituted butadienes and ethenes with density functional theory at the M06–2X level using a basis set with TZ2P quality. The interactions between the dienes and dienophiles at the transition state are analyzed with the EDA‐NOCV method. There is a modest correlation between the activation barriers and the strength of the frontier‐orbital interactions. The calculations suggest that the effect of the substituents on the reactivity of the Diels–Alder reactions depends on both, the deformation (“strain”) energies of the reactants and the intrinsic orbital interactions at the transition states. Surprisingly, the frontier‐orbital interactions exhibit a better correlation with the reaction barriers than the total orbital interactions.
Mechanisms in Frustrated Lewis Pair‐Catalyzed Reactions
Authors: Paradies Jan
Published: September 2018

This review summarizes the principle reaction mechanisms of frustrated Lewis pairs (FLP) in hydrogenations and carbon–nitrogen and carbon–carbon bond forming reactions. The fundamental mechanism of hydrogen activation by FLPs is reviewed and the influence of the FLP's nature on hydrogenation reactions is discussed, leading to a structure‐reactivity relationship in phosphine/borane or amine/borane derived FLPs. This reactivity concept is validated for a series of FLP‐catalyzed reactions. Furthermore, alternative reaction mechanisms e.g. protodeborylations or σ‐bond metathesis are discussed.
Intramolecular Reaction of tert‐Butyl‐NNO‐Azoxy and Cyano Groups – Novel Synthesis of Pyridazine, 1,2,3‐Triazepine, and Furan Rings
Authors: Anikin Oleg V. , Klenov Michael S. , Churakov Aleksandr M. , Guskov Alexey A. , Strelenko Yurii A. , Lyssenko Konstantin A. , Tartakovsky Vladimir A.
Published: September 2018

A reaction of (tert‐butyl‐NNO‐azoxy)acetonitrile with N,N‐dimethylacetamide dimethylacetal afforded 2,4‐bis(tert‐butyl‐NNO‐azoxy)‐3‐methylpent‐2‐enedinitrile 9 as a main product. This compound cyclized on silica gel surface with the loss of isobutylene to give 6‐amino‐5‐(tert‐butyl‐NNO‐azoxy)‐4‐methylpyridazine‐3‐carbonitrile 2‐oxide 10. On the contrary, the cyclization of dinitrile 9 in protic solvents resulted in quite different products: furan, 1,2,3‐triazepine, and pyridazine derivatives were among them. These reactions are the first examples of intramolecular reactions of (tert‐butyl‐NNO‐azoxy) and cyano groups. The structures of products under investigation were confirmed by X‐ray diffraction analysis.
Solvent‐Controlled α‐Monobromination, α,α‐Dibromination or Imidation of 1,3‐Diketones with N‐Bromosuccinimide
Authors: Zou Liang‐Hua , Li Yan‐Chun , Li Ping‐Gui , Zhou Jing , Wu Zhimeng
Published: September 2018

In this work, we present a solvent‐controlled regioselective method for α‐monobromination, dibromination or imidation of 1,3‐diketones with N‐bromosuccinimide under simple reaction conditions. The employment of solvents plays a key role on the reaction selectivity providing α‐monobrominated, dibrominated and imidated products. Visible light irradiation accelerates the dibromination reaction of 1,3‐diketones. In particular, one important solvent was found to be highly effective for the imidation of 1,3‐diketones under base‐free condition.
Rapid One‐Pot Access to Unique 3,4‐Dihydrothiopyrano[3,4‐b]indol‐1(9H)‐imines via Bi(OTf)3‐Catalysed Tandem Friedel–Crafts Alkylation/Thia‐Michael Addition
Authors: Dethe Dattatraya H. , Boda Vijay Kumar , Mandal Anupam
Published: September 2018

A highly efficient and atom economical one‐pot annulation strategy for novel tetrahydrothiopyrano[3,4‐b]indoles is presented. This protocol involves a Bi(OTf)3 catalyzed tandem Friedel–Crafts alkylation and intramolecular thia‐Michael addition reactions to furnish target molecules in an efficient manner. The method works effectively on substrates with unprotected indoles and also it is successfully employed to make tetrahydrothiepino[3,4‐b]indoles. The scaffolds synthesized are diverse and first of the kind. The reaction is practically simple with broad substrate scope and vast functional group compatibility.
N‐Thiophosphorylthioureas RNHC(S)NHP(S)(OiPr)2 as an Excellent Platform for Studying the Synergy between Hydrogen‐Hydrogen Bonding and Other Families of Non‐Covalent Interactions
Authors: Mitoraj Mariusz P. , Sagan Filip , Babashkina Maria G. , Isaev Alexey Y. , Chichigina Yana M. , Safin Damir A.
Published: September 2018

A family of thiourea based derivatives, RNHC(S)NHP(S)(OiPr)2 [R = Ph (YEZNUN), 2‐MeC6H4 (AQOYAH), 2,5‐Me2C6H3 (WARREO), 2,6‐Me2C6H3 (GUJGUO), 2,4,6‐Me3C6H2 (AQOYEL), PhNH (QORXUR), 1‐naphthyl (MOWPEU)], has been studied to understand the synergy between dihydrogen and other (non)conventional non‐covalent interactions. It was established that all monomers are stabilized through intramolecular dihydrogen C–H···H–C interactions. Additionally, C–H···π interactions are noted in AQOYAH, WARREO, and MOWPEU; N–H···O interactions in AQOYAH, and WARREO; C–H···S interactions in GUJGUO, YEZNUN, and AQOYEL; N–H···S interactions in GUJGUO, AQOYEL, MOWPEU, and YEZNUN; and N–H···N interactions in QORXUR. The crystal structures of all the thioureas are further stabilized by the most pronounced intermolecular C–H···H–C interactions followed by N–H···S and C–H···S with the formation of centrosymmetric R22(8) dimers. These non‐covalent interactions are augmented by the π···π stacking in YEZNUN and MOWPEU; C–H···π in WARREO, GUJGUO, AQOYEL and MOWPEU; N–H···π in QORXUR. The synergy between intra‐ and intermolecular C–H···H–C and other types of non‐covalent interactions lead to the extraordinary stability of these systems as indicated by the ETS‐NOCV Scheme Although the London dispersion forces cover ≈ 70–80 % of the overall C–H···H–C stabilization, the covalent‐like charge delocalization based on depletion of electron charge from the σ(C–H) orbitals to the inter‐atomic H···H region contributes notably up to 15 %.
Divergent Palladium‐ and Platinum‐Catalyzed Intramolecular Hydroamination/Hydroarylation of O‐Propargyl‐2‐aminophenols
Authors: Christodoulou Michael S. , Giofrè Sabrina , Broggini Gianluigi , Mazza Alberto , Sala Roberto , Beccalli Egle M.
Published: September 2018

A fruitful divergent cyclization of terminal alkynes arising from 2‐aminophenols depending on the transition metal employed is reported. Under palladium‐ and platinum‐catalysis, the total regioselective carbon–nitrogen or carbon–carbon bonds formation afforded 1,4‐benzoxazines or benzopyrans, through different reaction pathways. The subsequent functionalization of the benzopyran scaffold paved the way for a new synthesis of the tricyclic pyrano[3,2‐h]quinolines.
Hydroxylation of Eleuthoside Synthetic Intermediates by P450BM3 (CYP102A1)
Authors: Syntrivanis Leonidas‐Dimitrios , Wong Luet Lok , Robertson Jeremy
Published: September 2018

A seven‐step synthesis of the first tricyclic intermediate in Danishefsky's total synthesis of eleutherobin is reported with Wittig homologation and sequential additions of metallated furan derivatives to aldehydes as key steps. Aiming to prepare hydroxylated eleutherobin analogues for cytotoxicity screening, the furan diol epimers 6 and precursors 1 and 2 were exposed to a 48‐member panel of engineered cytochrome P450BM3 variants. Both furan‐containing substrates reacted solely at the furan ring, one resulting in overall biocatalytic Achmatowicz reaction. Selective hydroxylation at four separate sp3 C–H centres was achieved in the substrates lacking the furan component. P450BM3‐catalysed hydroxylation of racemic substrates can proceed with kinetic resolution; in the case reported here, the 2°‐allylic alcohol product 10 was generated with an 82:18 enantiomeric ratio.
Trapping DNA with a high throughput microfluidic device
Authors: Montes Ryan J. , Butler Jason E. , Ladd Anthony J. C.
Published: September 2018

Long strands of DNA can be trapped and concentrated near the inlet of a microfluidic channel by applying a pressure gradient and an opposing electric field. The mechanism for trapping involves a migration of DNA perpendicular to both the fluid flow and the electric field. Migration leads to a highly nonuniform distribution of DNA within a cross section of the channel, with the bulk of the DNA concentrated in a thin (10 μm) layer next to the walls of the channel. This highly concentrated layer generates an electrophoretic flux toward the inlet to the device, despite the much larger fluid flow in the opposite direction. In this paper, the extent to which DNA can be trapped and concentrated by this means has been characterized by fluorescence measurements. At short times (<2 hours) nearly all the incoming DNA remains trapped within the device until the electric field is turned off. The DNA largely accumulates near the inlet, but after 30–60 minutes additional DNA starts to accumulate deeper into the channel. Eventually DNA leaks from the device itself, but ≈80% of the incoming DNA can be retained for up to 5 hours. Optimizing the electric field strength can increase the amount of DNA that can be trapped, but the efficiency is not affected by the channel cross‐section.
Dielectric relaxation spectroscopy of aqueous micellar electrolyte solutions: A novel application to infer Dukhin number and zeta potential of a micelle
Authors: Khademi Mahmoud , Barz Dominik P. J.
Published: September 2018

The complex permittivities of aqueous SDS solutions, with and without the addition of sodium chloride (NaCl), are measured in the frequency range from 200 MHz to 14 GHz. The SDS concentrations are chosen such that the SDS molecules aggregate to micelles. In this frequency range, the measured spectra allow for the identification of two different relaxation processes. That is, the relaxation of the water molecules at frequencies above 1 GHz and the micellar relaxation at frequencies lower than 1 GHz. It is found that the addition of NaCl to the system mostly affects the micellar relaxation process. In detail, the time constant as well as the amplitude of the relaxation decrease by adding NaCl. These effects are attributed to the change in the solution conductivity that changes the properties of the micelle's electrical double layer. We also extract the Dukhin number of the micelles as a function of surfactant and electrolyte content from the measurements. The Dukhin number is a dimensionless group that describes the influence of the surface conductivity on a phenomena. A regression between Dukhin numbers and free sodium ions is found so that all data collapses on a single curve independent of the surfactant concentration. The surface conductivity is a manifestation of the electrical double layer and we use the Bikerman equation to infer the zeta potential of the micelles. Comparison to literature data shows very good agreement and proves that dielectric relaxation spectroscopy can be engaged to infer the zeta potential of micelles. Abbreviations: CMC critical micelle concentration, DRS dielectric relaxation spectroscopy, EDL electrical double layer
Model aggregation using optimal transport and applications in wind speed forecasting
Authors: Papayiannis G. I. , Galanis G. N. , Yannacopoulos A. N.
Published: September 2018

In several environmental affected socio‐economic activities, including renewable energy site assessment, search and rescue operations, and local microclimate modeling, the need of very local wind speed prediction is critical and not completely covered by the use of numerical weather prediction models. In meteorology and, particularly, in wind speed prediction, the spatial location of the prediction does not coincide with the spatial locations where numerical models provide estimates of the relevant quantity (which are typically grid points used for the numerical resolution of the wind transport equations). Hence, the important problem of constructing a predictive model for the wind speed at the required location using a combination of actual measurements and model predictions arises. This problem is far from trivial on account of the fact that measurements and predictions do not refer to the same quantity for the reason that typical grid points for the numerical scheme that provide model predictions and the location of the meteorological stations that provide measurements do not coincide. In this work, a new approach is proposed based on optimal transportation theory for the aggregation of model predictions and measurements for the construction of an optimal predictor for wind speed at the location of interest. Our model provides a linear predictive model in the space of probability distributions of the predictors (Wasserstein space), which is then mapped into observation space using a generalized quantile regression technique. Importantly, the proposed scheme allows also for the construction of zone monitoring the extremes, which when applied to real data, provides superior results with respect to other existing methods.
What controls submarine channel development and the morphology of deltas entering deep‐water fjords?
Authors: Gales Jenny A. , Talling Peter J. , Cartigny Matthieu J.B. , Hughes Clarke John , Lintern Gwyn , Stacey Cooper , Clare Michael A.
Published: September 2018

River deltas and associated turbidity current systems produce some of the largest and most rapid sediment accumulations on our planet. These systems bury globally significant volumes of organic carbon and determine the runout distance of potentially hazardous sediment flows and the shape of their deposits. Here we seek to understand the main factors that determine the morphology of turbidity current systems linked to deltas in fjords, and why some locations have well developed submarine channels while others do not. Deltas and associated turbidity current systems are analysed initially in five fjord systems from British Columbia in Canada, and then more widely. This provides the basis for a general classification of delta and turbidity current system types, where rivers enter relatively deep (>200 m) water. Fjord‐delta area is found to be strongly bimodal. Avalanching of coarse‐grained bedload delivered by steep mountainous rivers produces small Gilbert‐type fan deltas, whose steep gradient (11°–25°) approaches the sediment's angle of repose. Bigger fjord‐head deltas are associated with much larger and finer‐grained rivers. These deltas have much lower gradients (1.5°–10°) that decrease offshore in a near exponential fashion. The lengths of turbidity current channels are highly variable, even in settings fed by rivers with similar discharges. This may be due to resetting of channel systems by delta‐top channel avulsions or major offshore landslides, as well as the amount and rate of sediment supplied to the delta front by rivers. © 2018 John Wiley & Sons, Ltd.
Improved method for implementing contact angle condition in simulation of liquid sloshing under microgravity
Authors: Tang Yong , Yue Baozeng , Yan Yulong
Published: September 2018

The finite element simulation of liquid sloshing under microgravity is focused on in this paper. For this class of flows, an important issue is to implement the contact angle boundary condition appropriately. A novel method of adding infinitely small free‐surface mesh just adjacent to the contact line is proposed here, which coincides with the physical definition of the contact angle. This free‐surface mesh has its orientation determined according to the contact angle, and the mean curvature at the contact line can be computed using this orientation. Hence, surface tension force can be computed and incorporated as an essential boundary condition into the pressure solve. This method is convenient to be applied in three‐dimensional simulations, and the use of relatively coarse meshes near the contact line is allowed. In order to validate the proposed method, several numerical simulations of flows in two‐dimensional circular and three‐dimensional cylindrical and spherical containers are presented, including calculation of equilibrium positions of the free surfaces, unsteady flows of liquid reorientation, and large‐amplitude nonlinear liquid sloshing under lateral excitation in microgravity. Parts of the numerical results are compared with the theoretical and published experimental results.
Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study
Authors: Volckmar Anna‐Lena , Endris Volker , Gaida Matthias M. , Leichsenring Jonas , Stögbauer Fabian , Allgäuer Michael , von Winterfeld Moritz , Penzel Roland , Kirchner Martina , Brandt Regine , Neumann Olaf , Sültmann Holger , Schirmacher Peter , Rudi Jochen , Schmitz Daniel , Stenzinger Albrecht
Published: September 2018

Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty‐two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)‐guided fine‐needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow‐up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.
Prevalence rates of arthritis among US older adults with varying degrees of depression: Findings from the 2011 to 2014 National Health and Nutrition Examination Survey
Authors: Brooks Jessica M. , Titus Alexander J. , Polenick Courtney A. , Orzechowski Nicole M. , Reid Manney Carrington , MacKenzie Todd A. , Bartels Stephen J. , Batsis John A.
Published: September 2018

Objective

Arthritis and depressive symptoms often interact and negatively influence one another to worsen mental and physical health outcomes. Better characterization of arthritis rates among older adults with different levels of depressive symptoms is an important step toward informing mental health professionals of the need to detect and respond to arthritis and related mental health complications. The primary objective is to determine arthritis rates among US older adults with varying degrees of depression.

Methods

Using National Health and Nutrition Examination Survey 2011 to 2014 data (N = 4792), we first identified participants aged ≥50 years. Measures screened for depressive symptoms and self‐reported doctor‐diagnosed arthritis. Weighted logistic regression models were conducted.

Results

Prevalence of arthritis was 55.0%, 62.9%, and 67.8% in participants with minor, moderate, and severe depression, respectively. In both unadjusted and adjusted regression models, a significant association between moderate depression and arthritis persisted. There were also significant associations between minor and severe depression with arthritis.

Conclusions

Arthritis is commonly reported in participants with varying degrees of depression. This study highlights the importance of screening for and treating arthritis‐related pain in older adults with depressive symptoms and the need for future geriatric psychiatry research on developing integrated biopsychosocial interventions for these common conditions.
Intraoperative hypotension and flap loss in free tissue transfer surgery of the head and neck
Authors: Kass Jason L. , Lakha Sameer , Levin Matthew A. , Joseph Thomas , Lin Hung‐Mo , Genden Eric M. , Teng Marita S. , Miles Brett A. , DeMaria Samuel
Published: September 2018

Background

In free flap head and neck reconstructions, hemodynamic management is complicated by the deleterious effects of excessive crystalloid administration. Patients may undergo periods of hypotension or excess fluid administration. The purpose of this study was to present our examination of the hypotheses that intraoperative hypotension and blood pressure lability are associated with increased fluid administration and flap failure.

Methods

We reviewed the records of 445 patients undergoing head and neck surgery involving free tissue transfer. We used multivariate logistic regression to examine the relationship between hemodynamic variables and flap loss (primary outcome) and other complications.

Results

On multivariate analysis, intraoperative hypotension and large‐volume fluid administration were associated with flap loss. Neither blood pressure lability nor vasopressor administration was significantly associated to our primary outcome.

Conclusions

Intraoperative hypotension is associated to flap failure in head and neck free tissue transfer surgeries, as is large‐volume fluid administration.
Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease
Authors: Blokker Britt A. , Maijo Monica , Echeandia Marta , Galduroz Mikel , Patterson Angela M. , Ten Anna , Philo Mark , Schungel Rebecca , Gutierrez‐de Juan Virginia , Halilbasic Emina , Fuchs Claudia , Le Gall Gwenaelle , Milkiewicz Malgorzata , Milkiewicz Piotr , Banales Jesus M. , Rushbrook Simon M. , Mato José M. , Trauner Michael , Müller Michael , Martínez‐Chantar María Luz , Varela‐Rey Marta , Beraza Naiara
Published: September 2018

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1‐overexpressing (SIRToe) and hepatocyte‐specific SIRT1‐KO (knockout) mice (SIRThep–/–
) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24‐norursodeoxycholic acid) was tested in BDL/SIRToe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2–/–
) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep–/–
mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRToe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRThep–/–
hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRToe mice. Interestingly, both SIRT1 overexpression and hepatocyte‐specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine‐tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.
Single‐cell genetic analysis of clonal dynamics in colorectal adenomas indicates CDX2 gain as a predictor of recurrence
Authors: Fiedler David , Heselmeyer‐Haddad Kerstin , Hirsch Daniela , Hernandez Leanora S. , Torres Irianna , Wangsa Darawalee , Hu Yue , Zapata Luis , Rueschoff Josef , Belle Sebastian , Ried Thomas , Gaiser Timo
Published: September 2018

Colorectal adenomas are common precancerous lesions with the potential for malignant transformation to colorectal adenocarcinoma. Endoscopic polypectomy provides an opportunity for cancer prevention; however, recurrence rates are high. We collected formalin‐fixed paraffin‐embedded tissue of 15 primary adenomas with recurrence, 15 adenomas without recurrence, and 14 matched pair samples (primary adenoma and the corresponding recurrent adenoma). The samples were analysed by array‐comparative genomic hybridisation (aCGH) and single‐cell multiplex interphase fluorescence in situ hybridisation (miFISH) to understand clonal evolution, to examine the dynamics of copy number alterations (CNAs) and to identify molecular markers for recurrence prediction. The miFISH probe panel consisted of 14 colorectal carcinogenesis‐relevant genes (COX2, PIK3CA, APC, CLIC1, EGFR, MYC, CCND1, CDX2, CDH1, TP53, HER2, SMAD7, SMAD4 and ZNF217), and a centromere probe (CEP10). The aCGH analysis confirmed the genetic landscape typical for colorectal tumorigenesis, that is, CNAs of chromosomes 7, 13q, 18 and 20q. Focal aberrations (≤10 Mbp) were mapped to chromosome bands 6p22.1‐p21.33 (33.3%), 7q22.1 (31.4%) and 16q21 (29.4%). MiFISH detected gains of EGFR (23.6%), CDX2 (21.8%) and ZNF217 (18.2%). Most adenomas exhibited a major clone population which was accompanied by multiple smaller clone populations. Gains of CDX2 were exclusively seen in primary adenomas with recurrence (25%) compared to primary adenomas without recurrence (0%). Generation of phylogenetic trees for matched pair samples revealed four distinct patterns of clonal dynamics. In conclusion, adenoma development and recurrence are complex genetic processes driven by multiple CNAs whose evaluations by miFISH, with emphasis on CDX2, might serve as a predictor of recurrence.
Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo
Authors: Alimova Irina , Pierce Angela , Danis Etienne , Donson Andrew , Birks Diane K. , Griesinger Andrea , Foreman Nicholas K. , Santi Mariarita , Soucek Laura , Venkataraman Sujatha , Vibhakar Rajeev
Published: September 2018

Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long‐term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic subgroups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation. Here we show that MYC occupies distinct promoter loci in ATRT compared to embryonic stem (ES) cells. Furthermore, using human ATRT cell lines, patient‐derived cell culture, ex vivo patient‐derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1‐deleted tumors and that such inhibition effectively suppresses BMP and pluripotency‐associated genomic programs, attenuates tumor cell self‐renewal, promotes senescence, and inhibits ATRT tumor growth in vivo. Transgenic expression of Omomyc (a bona‐fide MYC dominant negative) or chemical inhibition of MYC transcriptomic programs with the BET inhibitor JQ1 phenocopy genetic depletion of MYC, effectively restricting ATRT tumor growth and opening a promising therapeutic avenue for rhabdoid tumors in children.
Assessing the effect of triethyleneglycol dimethacrylate on tissue repair in 3D organotypic cultures
Authors: Tigani Elise K. , Skrtic Drago , Valerio Michael S. , Kaufman Gili
Published: September 2018

Leachables from dental restoratives induce toxicity in gingival and pulp tissues and affect tissue regeneration/healing. Appropriate testing of these materials requires a platform that mimics the in vivo environment and allows the architectural self‐assembly of cells into tissue constructs. In this study, we employ a new 3D model to assess the impact of triethyleneglycol dimethacrylate (TEGDMA) on early organization and advanced recruitment/accumulation of immortalized mouse gingival fibroblasts (GFs) and dental papilla mesenchymal cells (DPMCs) in extracellular matrix. We hypothesize that TEGDMA (1) interferes with the developmental architecture of GFs and DPMCs, and (2) inhibits the deposition of mineral. To test these hypotheses, GFs and DPMCs were incubated with the soluble TEGDMA at concentrations (0‐2.5) mmol/L. Diameter and thickness of the constructs were determined by microscopic analysis. Cell differentiation was assessed by immunocytochemistry and the secreted mineral detected by alizarin‐red staining. TEGDMA interfered with the development of GFs and/or DPMCs microtissues in a dose‐dependent manner by inhibiting growth of inter‐spherical cell layers and decreasing spheroid size (four to six times). At low/moderate TEGDMA levels, GFs organoids retained their structures while reducing thickness up to 21%. In contrast, at low TEGDMA doses, architecture of DPMC organoids was altered and thickness decreased almost twofold. Overall, developmental ability of TEGDMA‐exposed GFs and DPMCs depended on TEGDMA level. GFs constructs were more resistant to structural modifications. The employed 3D platform was proven as an efficient tool for quantifying the effects of leachables on tissue repair capacities of gingiva and dental pulp.
Antibacterial 3D bone scaffolds for tissue engineering application
Authors: Pant Jitendra , Sundaram Jaya , Goudie Marcus J. , Nguyen Dieu Thao , Handa Hitesh
Published: September 2018

Open bone fractures are not only difficult to heal but also are at a high risk of infections. Annual cases of fractures which result from osteoporosis amount to approximately 9 million. Endogenously released nitric oxide (NO) has been shown to play a role in osteogenic differentiation in addition to eradicating infection against a wide variety of pathogens. In the current work, antimicrobial NO releasing 3D bone scaffolds were fabricated using S‐nitroso‐N‐acetyl‐penicillamine (SNAP) as the NO donor. During fabrication, nano‐hydroxyapatite (nHA) was added to each of the scaffolds in the concentration range of 10–50 wt % in nHA‐starch‐alginate and nHA‐starch‐chitosan scaffolds. The mechanical strength of the scaffolds increased proportionally to the concentration of nHA and 50 wt % nHA‐starch‐alginate possessed the highest load bearing capacity of 203.95 ± 0.3 N. The NO flux of the 50 wt % nHA‐starch‐alginate scaffolds was found to be 0.50 ± 0.06 × 10−10 mol/min/mg initially which reduced to 0.23 ± 0.02 × 10−10 over a 24 h period under physiological conditions. As a result, a 99.76% ± 0.33% reduction in a gram‐positive bacterium, Staphylococcus aureus and a 99.80% ± 0.62% reduction in the adhered viable colonies of gram‐negative bacterium, Pseudomonas aeruginosa were observed, which is a significant stride in the field of antibacterial natural polymers. The surface morphology and pore size were observed to be appropriate for the potential bone cell growth. The material showed no toxic response toward mouse fibroblast cells. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1068–1078, 2019.
A fibrin‐coated pericardial extracellular matrix prevented heart adhesion in a rat model
Authors: Funamoto Seiichi , Hashimoto Yoshihide , Kishida Akio , Negishi Jun
Published: September 2018

As most surgical treatments pose a risk of tissue adhesion, methods to prevent adhesion are needed across various surgical fields. In this study, we investigated the use of a decellularized pericardium with fibrin glue to prevent rat heart adhesion. Porcine pericardia were decellularized by a high‐hydrostatic pressure method. Cells adhered to the resulting pericardial extracellular matrix (ECM) during an in vitro cell‐seeding test, but fibrin‐coated pericardial ECM showed reduced cell adhesion. In a rat surgical model of heart adhesion, the fibrin‐coated pericardial ECM did not adhere to the heart and mesothelial cell adhesion was observed on the ECM surface. Notably, the anti‐adhesion effect of fibrin‐coated pericardial ECM was observed 4 weeks after surgery. These results support the utility of fibrin‐coated pericardial ECM as an adhesion prevention material for cardiovascular surgery. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1088–1094, 2019.
Identification and validation of l‐asparaginase as a potential metabolic target against Mycobacterium tuberculosis
Authors: Kataria Arti , Singh Jasdeep , Kundu Bishwajit
Published: September 2018

Multidrug‐resistant Mycobacterium tuberculosis (Mtb) has emerged as a major health challenge, necessitating the search for new molecular targets. A secretory amidohydrolase,
l‐asparaginase of Mtb (MtA), originally implicated in nitrogen assimilation and neutralization of acidic microenvironment inside human alveolar macrophages, has been proposed as a crucial metabolic enzyme. To investigate whether this enzyme could serve as a potential drug target, it was studied for structural details and active site–specific inhibitors were tested on cultured
Mycobacterial strain. The structural details of MtA obtained through comparative modeling and molecular dynamics simulations provided insights about the orchestration of an alternate reaction mechanism at the active site. This was contrary to the critical Tyr flipping mechanism reported in other asparaginases. We report the novel finding of Tyr to Val replacement in catalytic triad I along with the structural reorganization of a β‐hairpin loop upon substrate binding in MtA active site. Further, 5 MtA‐specific, active‐site–based inhibitors were obtained by following a rigorous differential screening protocol. When tested on
Mycobacterium culture, 3 of these, M3 (ZINC 4740895), M26 (ZINC 33535), and doxorubicin showed promising results with inhibitory concentrations (IC
50) of 431, 100, and 56 µM, respectively. Based on our findings and considering stark differences with human asparaginase, we project MtA as a promising molecular target against which the selected inhibitors may be used to counteract Mtb infection effectively.
DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence
Authors: Williams Kristin E. , Jawale Rahul M. , Schneider Sallie S. , Otis Christopher N. , Pentecost Brian T. , Arcaro Kathleen F.
Published: September 2018

DNA methylation plays a role in the etiology of primary breast cancers. We analyzed paired primary and second breast tumors to elucidate the role of methylation in recurrence. Methylation profiles from paired primary and second breast tumors of 23 women were assessed using the HumanMethylation450 BeadChip. Twelve women had estrogen receptor positive (ERpos) primary and second tumors, five had estrogen receptor negative (ERneg) primary and second tumors, and six had an ERpos primary tumor but an ERneg second tumor. Stratifying tumors by occurrence revealed that the greater methylation previously associated with ERpos tumors, is more pronounced in primary tumors than in second tumors. Further, ERneg second tumors are more methylated than ERpos second tumors among women who had ERpos primary tumors. Pathway analyses using gene lists generated from comparisons of methylation in ERpos primary tumors from the paired sets with ERpos tumors from six women without recurrences, identified differences between groups based on the ER status of the second tumor. Hypermethylated genes of significantly enriched pathways were differentially associated with survival. DNA methylation profiles of ERpos primary breast tumors support the development and use of tumor methylation profiles for stratifying women with breast cancer both for prognosis and therapy.
CCL17‐CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer
Authors: Zhao Hongda , Bo Qiyu , Wang Weifen , Wang Rui , Li Yan , Chen Shouzhen , Xia Yangyang , Wang Wenfu , Wang Yong , Zhu Kejia , Liu Lei , Cui Jianfeng , Wang Shuai , Liu Qinggang , Wu Zonglong , Guo Hu , Shi Benkang
Published: September 2018

As an important chemokine receptor, the role of CCR4 in the progression of bladder cancer (BC) remains unknown. In this study, we have shown that CCR4 expression was upregulated in bladder carcinoma tissues compared with adjacent nontumor tissues. Kaplan‐Meier survival analysis revealed that CCR4 expression was an independent prognostic risk factor in BC patients, and the addition of CCL17 induced CCR4 production and promoted migration and invasion of BC cells. In addition, CCR4 knockdown significantly attenuated the migratory and invasive capabilities of BC cells. Mechanistically, CCL17‐CCR4 axis is involved in ERK1/2 signaling and could mediate the migration and invasion of BC cells by regulating MMP13 activation. This study suggests that CCR4 might represent a promising prognostic biomarker and a potential therapeutic option for BC.
The regulatory roles of VEGF‐Notch signaling pathway on aplastic anemia with kidney deficiency and blood stasis
Authors: Deng Shu , Zeng Yuqing , Wu Liqiang , Hu Zhiping , Shen Jianping , Shen Yiping , Shen Yingying , Zhou Yuhong , Chen Jian , Lin Shengyun
Published: September 2018

Objective

Vascular endothelial growth factor (VEGF)‐Notch signaling pathway plays an important role in aplastic anemia (AA). This study aimed to evaluate the regulatory roles of VEGF‐Notch signaling pathway on mesenchymal stem cells (MSCs) isolated from AA patients with kidney deficiency and blood stasis (KB) (AA MSCs).

Methods

Expression of VEGF‐Notch signaling related factors, including VEGF, VEGFR, Notch‐1, Jagged1, Delta‐like1, and hes1 was detected in bone marrow (BM) tissues and AA MSCs by Western blot analysis. VEGF (100 ng/mL) and γ‐secretase inhibitor (DAPT) (10 μM) was used to active and inhibit VEGF‐Notch signaling in AA MSCs, respectively. After treatment, the proliferation, apoptosis, and adipogenic differentiation of AA MSCs was detected by Cell Counting Kit‐8, flow cytometry, and Oil red O staining, respectively. Lentivirus short hairpin RNA (shRNA) were constructed to downregulate Notch‐1 and VEGF in normal bone marrow mesenchymal stem cells (BMSCs), and the effects of VEGF/Notch‐1 shRNA transfected BMSCs on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated.

Results

Significantly lower expression of VEGF, VEGFR, Notch‐1, Jagged1, Delta‐like1, and hes1 was revealed in AA BM tissues and AA MSCs when compared with the normal control (P < 0.05). The intervention of DAPT significantly inhibited the proliferation, and promoted the apoptosis and adipogenic differentiation of AA MSCs, while VEGF intervention exhibited opposite results (P < 0.05). Meanwhile, the proliferation, migration, and angiogenesis of HUVECs were significantly promoted by normal BMSCs, while inhibited by VEGF/Notch‐1 shRNA transfected BMSCs (P < 0.05).

Conclusion

The activation of VEGF‐Notch signaling pathway may be a potential therapeutic target for AA with KB.