bluuebunny/crossref_metadata_2025 huggingface dataset:
Resident CAPS on dense-core vesicles docks and primes vesicles for fusion
Authors: Kabachinski Greg , Kielar-Grevstad D. Michelle , Zhang Xingmin , James Declan J. , Martin Thomas F. J.
Published: December 2015

The Ca2+-dependent exocytosis of dense-core vesicles in neuroendocrine cells requires a priming step during which SNARE protein complexes assemble. CAPS (aka CADPS) is one of several factors required for vesicle priming; however, the localization and dynamics of CAPS at sites of exocytosis in live neuroendocrine cells has not been determined. We imaged CAPS before, during, and after single-vesicle fusion events in PC12 cells by TIRF micro­scopy. In addition to being a resident on cytoplasmic dense-core vesicles, CAPS was present in clusters of approximately nine molecules near the plasma membrane that corresponded to docked/tethered vesicles. CAPS accompanied vesicles to the plasma membrane and was present at all vesicle exocytic events. The knockdown of CAPS by shRNA eliminated the VAMP-2–dependent docking and evoked exocytosis of fusion-competent vesicles. A CAPS(ΔC135) protein that does not localize to vesicles failed to rescue vesicle docking and evoked exocytosis in CAPS-depleted cells, showing that CAPS residence on vesicles is essential. Our results indicate that dense-core vesicles carry CAPS to sites of exocytosis, where CAPS promotes vesicle docking and fusion competence, probably by initiating SNARE complex assembly.
The casein kinases Yck1p and Yck2p act in the secretory pathway, in part, by regulating the Rab exchange factor Sec2p
Authors: Stalder Danièle , Novick Peter J.
Published: December 2015

Sec2p is a guanine nucleotide exchange factor that activates Sec4p, the final Rab GTPase of the yeast secretory pathway. Sec2p is recruited to secretory vesicles by the upstream Rab Ypt32p acting in concert with phosphatidylinositol-4-phosphate (PI(4)P). Sec2p also binds to the Sec4p effector Sec15p, yet Ypt32p and Sec15p compete against each other for binding to Sec2p. We report here that the redundant casein kinases Yck1p and Yck2p phosphorylate sites within the Ypt32p/Sec15p binding region and in doing so promote binding to Sec15p and inhibit binding to Ypt32p. We show that Yck2p binds to the autoinhibitory domain of Sec2p, adjacent to the PI(4)P binding site, and that addition of PI(4)P inhibits Sec2p phosphorylation by Yck2p. Loss of Yck1p and Yck2p function leads to accumulation of an intracellular pool of the secreted glucanase Bgl2p, as well as to accumulation of Golgi-related structures in the cytoplasm. We propose that Sec2p is phosphorylated after it has been recruited to secretory vesicles and the level of PI(4)P has been reduced. This promotes Sec2p function by stimulating its interaction with Sec15p. Finally, Sec2p is dephosphorylated very late in the exocytic reaction to facilitate recycling.
Meeting Art with Art: Arts-Based Methods Enhance Researcher Reflexivity in
Research with Mental Health Service Users
Authors: McCaffrey Tríona , Edwards Jane
Published: December 2015

This paper presents a rationale for arts-based practices in music therapy research, and provides an example of using ABR techniques in research. Arts-based materials are increasingly demonstrated to have the capacity to extend processes of reflexivity and analysis in a range of qualitative health research studies. By comparison, music therapy research studies have rarely employed arts-based methods or techniques. There is a need for more studies in music therapy that employ arts-based research to demystify and elaborate a wider range of creative approaches within music therapy inquiry. In the study described in this paper, ABR was used to reflect on the contribution of a service user in a community mental health context who participated in a focus group about his experiences of music therapy. ABR was found to offer a creative way to engage service users, and to deepen and extend the researcher’s reflexivity when responding to materials created by research participants.
Perineural Invasion Predicts for Distant Metastasis in Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiation and Surgery
Authors: Chablani Priyanka , Nguyen Phuong , Pan Xueliang , Robinson Andrew , Walston Steve , Wu Christina , Frankel Wendy L. , Chen Wei , Bekaii-Saab Tanios , Chakravarti Arnab , Wuthrick Evan , Williams Terence M.
Published: December 2015

Objectives:

The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients.

Materials and Methods:

We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling.

Results:

Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P<0.0001). The median DFS was 13.5 months for PNI+ and 39.8 months for PNI− (P<0.0001). In a multivariate model including 7 pathologic variables, type of surgery, time to surgery from end of nCRT, and use of adjuvant chemotherapy, PNI remained a significant independent predictor of DMFS (hazard ratio 9.79; 95% confidence interval, 3.48-27.53; P<0.0001) and DFS (hazard ratio 5.72; 95% confidence interval, 2.2-14.9; P=0.0001).

Conclusions:

For patients with LARC treated with nCRT, PNI found at the time of surgery is significantly associated with worse DMFS and DFS. Our data support testing the role of adjuvant chemotherapy in patients with PNI and perhaps other high-risk features.
Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy
Authors: Moraes Fabio Ynoe de , Leite Elton Trigo Teixeira , Hamstra Dan A. , Feng Felix Y. , Arruda Fernando Freire , Gadia Rafael , Abreu Carlos Eduardo Cintra Vita , Marta Gustavo Nader , Hanna Samir Abdallah , Silva João Luis Fernandes da , Carvalho Heloisa de Andrade , Spratt Daniel E.
Published: December 2015

Objectives:

To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy.

Materials and Methods:

The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression.

Results:

Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01).

Conclusions:

The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.
The Benefit of Adjuvant Radiotherapy in High-grade Nonmetastatic Retroperitoneal Soft Tissue Sarcoma
Authors: Bates James E. , Dhakal Sughosh , Mazloom Ali , Constine Louis S.
Published: December 2015

Objectives:

Controversy persists on the use of adjuvant radiotherapy (RT) in patients with retroperitoneal sarcoma (RPS). High-grade disease is known to be associated with decreased local control and overall survival (OS). Because RT has proven beneficial for local control and OS in patients with high-grade extremity soft tissue sarcoma, we evaluated the efficacy of adjuvant RT in high-grade RPS.

Methods:

The Surveillance, Epidemiology, and End Results database was used to identify patients with pathology-confirmed RPS from 1973 to 2010. Clinical characteristics and outcomes were analyzed.

Results:

Of 480 total patients, 144 (30.0%) received postoperative radiation. Patients who received adjuvant RT had improved median OS (36 mo) compared with those who did not (27 mo, hazard ratio [HR]=0.79,P=0.023). On multivariate analysis the use of adjuvant RT (HR=0.80; 95% confidence interval [CI], 0.65-0.98;P=0.029), male sex (HR=1.32; 95% CI, 1.10-1.59;P=0.003), age above 65 years (HR=1.38; 95% CI, 1.15-1.67;P=0.001), and increasing the Surveillance, Epidemiology, and End Results historical stage (HR=1.46; 95% CI, 1.21-1.76;P<0.001) were all prognostic factors for OS.

Conclusions:

In a large retrospective analysis, postoperative RT improved OS in high-grade RPS patients. As such, adjuvant RT should be strongly considered in all patients with high-grade RPS. The optimal timing of RT relative to surgery requires further study.
A Phase 2 Randomized, Double-Blind, Multicenter Trial of Imexon Plus Gemcitabine Versus Gemcitabine Plus Placebo in Patients With Metastatic Chemotherapy-naïve Pancreatic Adenocarcinoma
Authors: Cohen Steven J. , Zalupski Mark M. , Conkling Paul , Nugent Francis , Ma Wen Wee , Modiano Manuel , Pascual Rolan , Lee Fa Chyi , Wong Lucas , Hersh Evan
Published: December 2015

Background:

Imexon is a cyanoaziridine-derived iminopyrrolidone which has synergistic cytotoxicity with gemcitabine. A phase 1 study of the combination demonstrated good tolerance with encouraging clinical activity and thus we conducted this randomized phase II study.

Materials and Methods:

Patients with measurable, metastatic, treatment-naive pancreatic adenocarcinoma were randomized 1:1 to receive gemcitabine at 1000 mg/m2 days 1, 8, and 15 with either imexon, 875 mg/m2 or placebo days 1, 8, and 15 every 28 days. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and response rate.

Results:

A total of 142 patients were randomized, 72 to the imexon containing arm and 70 to the placebo arm. Patients in the imexon arm received an average of 3.6 cycles (range, 1 to 23) compared with 4.4 (range, 1 to 21) in the placebo arm. There was no increased rate of ≥grade 3 toxicity in the imexon arm. Seven patients had objective responses in the imexon arm (13.7%), whereas 9 did in the placebo arm (17%). In the imexon arm, 23 patients had ≥50% reduction in CA 19-9 from baseline (33%), whereas 22 did in the placebo arm (31.4%). The median progression-free survival was 2.8 months in the imexon arm (95% confidence interval [CI], 2.0-4.1 m) and 3.8 months in the placebo arm (95% CI, 2.2-4.7 m), P=0.504. The median overall survival time in the imexon arm was 5.2 months (95% CI, 4.2-6.7 m) as compared with 6.8 m (95% CI, 4.9-8.5 m) in the placebo arm, P=0.6822.

Conclusions:

The combination of imexon and gemcitabine does not result in improved outcome as initial therapy of metastatic pancreatic adenocarcinoma.
CRYSTALLINE RETINOPATHY FROM HYPEROXALURIA: LONG-TERM FOLLOW-UP
Authors: Sangave Amit A. , Gearinger Matthew D. , Diloreto David A.
Published: December 2015

Purpose:

To report long-term follow-up in a patient with retinal oxalosis from primary hyperoxaluria.

Methods:

Retrospective chart review was performed for this patient. Patients: A 6-year-old girl that presented to our clinic before and after combined kidney/liver transplant.

Results:

Optical coherence tomography and fundus findings consistent with oxalate crystal deposition.

Conclusion:

Progressive macular changes, including atrophy and fibrosis can occur in crystalline retinopathy, secondary to hyperoxaluria, after combined hepatorenal transplant.
Direct Costs of Acute Recurrent and Chronic Pancreatitis in Children in the INSPPIRE Registry
Authors: Ting Jie , Wilson Leslie , Schwarzenberg Sarah Jane , Himes Ryan , Barth Bradley , Bellin Melena D. , Durie Peter R. , Fishman Douglas S. , Freedman Steven D. , Gariepy Cheryl E. , Giefer Matthew J. , Gonska Tanja , Husain Sohail Z. , Kumar Soma , Morinville Veronique D. , Lowe Mark E. , Ooi Chee Y. , Pohl John F. , Troendle David , Usatin Danielle , Werlin Steven L. , Wilschanski Michael , Heyman Melvin B. , Uc Aliye
Published: December 2015

Objective:

To estimate selected direct medical care costs of children with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP).

Methods:

We performed a cross‐sectional study of data from International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE), a multinational registry of children with ARP or CP. We determined health care utilization and estimated costs of hospitalizations, surgical and endoscopic procedures, and medications in our study population. Health care utilization data were obtained from all subjects enrolled in the study, and costs were calculated using national United States costs.

Results:

We included 224 subjects (median age 12.7 years), 42% of whom had CP. Mean number of hospitalizations, including for surgery and endoscopic retrograde cholangiopancreatography, was 2.3 per person per year, costing an estimated average $38,755 per person per year. Including outpatient medications, estimated total mean cost was $40,589 per person per year. Subjects using surgical procedures or endoscopic retrograde cholangiopancreatography incurred mean annual costs of $42,951 per person and $12,035 per person, respectively. Estimated annual costs of pancreatic enzyme replacement therapy, diabetic medications, and pain medications were $4114, $1761, and $614 per person, respectively. In an exploratory analysis, patients with the following characteristics appear to accrue higher costs than those without them: more frequent ARP attacks per year, reported constant or episodic pain, family history of pancreatic cancer, and use of pain medication.

Conclusions:

ARP and CP are uncommon childhood conditions. The severe burden of disease associated with these conditions and their chronicity results in high health care utilization and costs. Interventions that reduce the need for hospitalization could lower costs for these children and their families.
Antioxidative Activity of Colostrum and Human Milk
Authors: Marinković Vesna , Ranković‐Janevski Milica , Spasić Snežana , Nikolić‐Kokić Aleksandra , Lugonja Nikoleta , Djurović Dijana , Miletić Srdjan , Vrvić Miroslav M. , Spasojević Ivan
Published: December 2015

Objectives:

Milk banks collect, pasteurize, and freeze/store human milk. The processing may alter redox properties of milk, but the effects have not been fully examined.

Methods:

We collected 10 mature milk and 10 colostrum samples and applied a battery of biochemical assays and electron paramagnetic resonance spectroscopy to inspect changes that milk undergoes with pasteurization and 30 days storage at −20°C.

Results:

Pasteurization and storage of raw milk did not affect total nonenzymatic antioxidative capacity, but specific components and features were altered. Urate radical and ascorbyl radical emerge as products of exposure of milk to hydroxyl radical‐generating system. Processing shifted the load of antioxidative activity from ascorbate to urate and lowered the capacity of milk to diminish hydroxyl radical. Pasteurization caused a significant drop in the activity of 2 major antioxidative enzymes—superoxide dismutase and glutathione peroxidase, whereas freezing/storage of raw milk affected only superoxide dismutase. Colostrum showed drastically higher total nonenzymatic antioxidative capacity, hydroxyl radical scavenging ability, and glutathione reductase activity compared with mature milk.

Conclusions:

Pasteurization and storage affect nonenzymatic and enzymatic antioxidative agents in human milk. It appears that nonenzymatic antioxidative systems in colostrum and milk are different. The effects of processing may be partially compensated by fortification/spiking with ascorbate before use.
Gastroesophageal Reflux Burden, Even in Children That Aspirate, Does Not Increase Pediatric Hospitalization
Authors: Duncan Daniel R. , Amirault Janine , Johnston Nikki , Mitchell Paul , Larson Kara , Rosen Rachel L.
Published: December 2015

Objectives:

Gastroesophageal reflux is common but remains a controversial disease to diagnose and treat and little is known about the role of reflux testing in predicting clinical outcomes, particularly in children at risk for extraesophageal reflux complications. The aim of this study was to determine if rates of hospitalization were affected by reflux burden even after adjusting for aspiration risk.

Methods:

We prospectively recruited, between 2009 and 2014, a cohort of pediatric patients with suspected extraesophageal reflux disease who were referred for reflux testing and underwent both multichannel intraluminal impedance with pH (pH‐MII) and modified barium swallow studies. A subset of patients also underwent bronchoalveolar lavage with pepsin analysis. We determined their rates of hospitalization for a minimum of 1 year following pH‐MII testing.

Results:

We prospectively enrolled 116 pediatric patients who presented for care at Boston Children's Hospital and underwent both pH‐MII and modified barium swallow studies. There was no statistically significant relationship between reflux burden measured by pH‐MII or bronchoalveolar pepsin and total number of admissions or number of admission nights even after adjusting for aspiration status (P > 0.2). There were no statistically significant relationships between reflux burden by any method and the number or nights of urgent pulmonary admissions before or after adjusting for aspiration risk (P > 0.08).

Conclusions:

Even in aspirating children, reflux burden did not increase the risk of hospitalization. Based on these results, routine reflux testing cannot be recommended even in aspirating children, because the results do not impact clinically significant outcomes.
Plasminogen Activator Inhibitor‐1 Predicts Quantity of Hepatic Steatosis Independent of Insulin Resistance and Body Weight
Authors: Holzberg Jeffrey R. , Jin Ran , Le Ngoc‐Anh , Ziegler Thomas R. , Brunt Elizabeth M. , McClain Craig J. , Konomi Juna V. , Arteel Gavin E. , Vos Miriam B.
Published: December 2015

Objective:

The aim of the present study was to examine the association between plasminogen activator inhibitor‐1 (PAI‐1), an acute phase protein strongly associated with cardiovascular disease risk, and adiposity, insulin resistance, and inflammation among overweight and obese children with a wide range of hepatic steatosis.

Methods:

Plasma PAI‐1 levels were measured in a prospectively recruited cohort of 39 overweight or obese children who underwent comprehensive anthropometric assessment and metabolic measurements. Hepatic steatosis was quantified using magnetic resonance spectroscopy and participants were divided into 3 groups based on whether they had normal hepatic steatosis (<5%), low hepatic steatosis (≥5%–10%), and high hepatic steatosis (>10%).

Results:

Plasma PAI‐1 levels significantly increased across the severity of hepatic steatosis in overweight and obese children, and this association was independent of body mass index z score, visceral fat, insulin resistance, and inflammatory markers (P < 0.05).

Conclusion:

Hepatic steatosis in children is positively associated with circulating levels of PAI‐1 independent of body mass index, insulin resistance, and inflammatory markers. Further studies are needed to clarify the potential role of PAI‐1 as a therapeutic target in pediatric nonalcoholic fatty liver disease.
Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort
Authors: Nimgaonkar Vishwajit L. , Yolken Robert H. , Wang Tianxiu , Chang Chung-Chou H. , McClain Lora , McDade Eric , Snitz Beth E. , Ganguli Mary
Published: December 2015

Background:

Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain.

Methods:

In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders.

Results:

The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection.

Conclusions:

Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age–related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment.
Distributed acoustic cues for caller identity in macaque vocalization
Authors: Fukushima Makoto , Doyle Alex M. , Mullarkey Matthew P. , Mishkin Mortimer , Averbeck Bruno B.
Published: December 2015

Individual primates can be identified by the sound of their voice. Macaques have demonstrated an ability to discern conspecific identity from a harmonically structured ‘coo’ call. Voice recognition presumably requires the integrated perception of multiple acoustic features. However, it is unclear how this is achieved, given considerable variability across utterances. Specifically, the extent to which information about caller identity is distributed across multiple features remains elusive. We examined these issues by recording and analysing a large sample of calls from eight macaques. Single acoustic features, including fundamental frequency, duration and Weiner entropy, were informative but unreliable for the statistical classification of caller identity. A combination of multiple features, however, allowed for highly accurate caller identification. A regularized classifier that learned to identify callers from the modulation power spectrum of calls found that specific regions of spectral–temporal modulation were informative for caller identification. These ranges are related to acoustic features such as the call’s fundamental frequency and FM sweep direction. We further found that the low-frequency spectrotemporal modulation component contained an indexical cue of the caller body size. Thus, cues for caller identity are distributed across identifiable spectrotemporal components corresponding to laryngeal and supralaryngeal components of vocalizations, and the integration of those cues can enable highly reliable caller identification. Our results demonstrate a clear acoustic basis by which individual macaque vocalizations can be recognized.
Geometric auxetics
Authors: Borcea Ciprian , Streinu Ileana
Published: December 2015

We formulate a mathematical theory of auxetic behaviour based on one-parameter deformations of periodic frameworks. Our approach is purely geome- tric, relies on the evolution of the periodicity lattice and works in any dimension. We demonstrate its usefulness by predicting or recognizing, without experiment, computer simulations or numerical approximations, the auxetic capabilities of several well-known structures available in the literature. We propose new principles of auxetic design and rely on the stronger notion of expansive behaviour to provide an infinite supply of planar auxetic mechanisms and several new three-dimensional structures.
A constitutive relationship for mechanical hysteresis of sandstone materials
Authors: Pecorari Claudio
Published: December 2015

Experimental results concerning mechanical hysteresis in sandstone samples, which were obtained by means of either dynamic acousto-elastic or quasi-static techniques, are mathematically modelled assuming that the critical stress at which hysteresis is activated is not an intrinsic material property, but decreases with increasing stress rate. A macroscopic strain–stress constitutive relationship is derived from this assumption, which leads the main features characterizing mechanical hysteresis in sandstones to be recovered, at least in a qualitative sense. In particular, for sinusoidal loading used in dynamic acousto-elastic experiments, the model predicts a vanishing anelastic strain and a continuous variation of the modulus defect during the entire loading cycle. Furthermore, hysteresis is shown to disappear when the frequency of the excitation approaches the static limit. Experimental results and theoretical models concerning other Earth materials and metal alloys are also considered. Although in some case, the latter results have been acquired under dramatically different experimental conditions, they are better understood, and, for this reason, are used as reference to discuss those obtained by exploiting acousto-elasticity of sandstones. The striking difference between reference findings and results in sandstone suggests that equally strikingly different mechanisms are responsible for hysteresis in the latter material system.
Stabilization mechanisms in the evolution of thin liquid-films
Authors: Kirkinis E. , Davis S. H.
Published: December 2015

In recent years, there has been great interest in using control theory to alter the stability regimes of fluid systems. A flow property is measured at a point and relayed back to a control that alters a condition that opposes the instability, thereby postponing its onset. Here, we discuss an alternative to postponing and even eliminating instabilities without the need for measuring properties or designing control strategies: a shear flow imposed upon a system produces an interfacial viscous-capillary wave which, in the nonlinear regime, is capable of postponing or even eliminating the incipient instability. The literature shows several examples, whereby Rayleigh break-up of capillary jets is eliminated, van der Waals dry-out of a film is removed and thermocapillary instability is avoided by the application of a suitable surface shear or an imposed fluid flow. The stabilization mechanism is closely linked to the behaviour of the lower-order terms governing the evolution of the liquid–gas interface profile, providing an estimate for the time scales and shear strength involved. Our intention here is to develop a unified theoretical framework for the study of a large number of thin liquid-film configurations and related systems.
Optimizing and evaluating the operational factors affecting the cyanide leaching circuit of the Aghdareh gold processing plant using a CCD model
Authors: Azizi Asghar , Ghaedrahmati Reza
Published: December 2015

A response surface method using a central composite design was employed to evaluate, model and optimize the influence of five main factors in the gold cyanidation process. These factors were pH, solid percentage, NaCN concentration, particle size and leaching time. A second-order equation was proposed and developed for the relationship between the gold recoveries and influential factors. The modelling results indicated that the factors influencing the degree of cyanide leaching of gold were in the order of leaching time > NaCN concentration
2
> particle size > pH > NaCN concentration > leaching time
2
> solid percentage × particle size > solid percentage × NaCN concentration > solid percentage. Also, we obtained a coefficient of determination (
R
2
) greater than 93%, which showed that the developed model was well fitted to the experimental data. In addition, the model equation was individually optimized by using quadratic programming to maximize gold recoveries within the experimental range. The optimum condition was found to be pH 10.11 for the solution, 36.07% for the solids content, 729.56 ppm for the NaCN concentration, 37.52 
μ
m for the particle size and 23.2 h for the leaching time. Under these conditions, the highest recovery of gold was achieved of approximately 91.5%.
Hybrid Systems Modeling for (Cancer) Systems Biology
Authors: Dobbe Roel , Tomlin Claire J.
Published: December 2015

The advent of biological data of increasingly higher resolution in space and time has triggered the use of dynamic models to explain and predict the evolution of biological systems over space and time. Computer-aided system modeling and analysis in biology has led to many new discoveries and explanations that would otherwise be intractable to articulate without the available data and computing power. Nevertheless, the complexity in biology still challenges many labs in capturing studied phenomena in models that are tractable and simple enough to analyze. Moreover, the popular use of ordinary differential equation models have their limitations in that they solely capture continuous dynamics, while we observe many discrete dynamic phenomena in biology such as gene switching or mutations. Hybrid systems modeling provides a framework in which both continuous and discrete dynamics can be simulated and analyzed. Moreover, it provides techniques to develop approximations and abstractions of complex dynamics that are tractable to analyze.
Exploiting variability of single cells to uncover the in vivo hierarchy of miRNA targets
Authors: Rzepiela Andrzej Jerzy , Vina-Vilaseca Arnau , Breda Jeremie , Ghosh Souvik , Syed Afzal P , Gruber Andreas J , Grandy William A , Eschbach Katja , Beisel Christian , van Nimwegen Erik , Zavolan Mihaela
Published: December 2015

MiRNAs are post-transcriptional repressors of gene expression that may additionally reduce the cell-to-cell variability in protein expression, induce correlations between target expression levels and provide a layer through which targets can influence each other's expression as 'competing RNAs' (ceRNAs). Here we combined single cell sequencing of human embryonic kidney cells in which the expression of two distinct miRNAs was induced over a wide range, with mathematical modeling, to estimate Michaelis-Menten (KM)-type constants for hundreds of evolutionarily conserved miRNA targets. These parameters, which we inferred here for the first time in the context of the entire network of endogenous miRNA targets, vary over ~2 orders of magnitude. They reveal an in vivo hierarchy of miRNA targets, defined by the concentration of miRNA-Argonaute complexes at which the targets are most sensitively down-regulated. The data further reveals miRNA-induced correlations in target expression at the single cell level, as well as the response of target noise to the miRNA concentration. The approach is generalizable to other miRNAs and post-transcriptional regulators and provides a deeper understanding of gene expression dynamics.
A protein truncating R179X variant inRNF186confers protection against ulcerative colitis
Authors: Rivas MA , Graham D , Sulem P , Stevens C , Desch AN , Goyette P , Gudbjartsson D , Jonsdottir I , Thorsteinsdottir U , Degenhardt F , Mucha S , Kurki MI , Li D , D’Amato M , Annese V , Vermeire S , Weersma R , Halfvarson J , Paavola-Sakki P , Lappalainen M , Lek M , Cummings B , Tukianen T , Haritunians T , Halme L , Koskinen LLE , Ananthakrishnan A , Luo Y , Heap GA , Visschedijk M ,   NIDDK IBD Genetics Consortium,   UK IBD Genetics Consortium, MacArthur DG , Neale BM , Ahmad T , Anderson CA , Brant SR , Duerr R , Silverberg M , Cho J , Palotie A , Saavalainen P , Kontula K , Färkkilä M , McGovern DPB , Franke A , Stefansson K , Rioux JD , Xavier RJ , Daly MJ
Published: December 2015

We conducted a search for protein truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. We found that a protein truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF = up to 0.78%) inRNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overallP= 6.89×10−7, odds ratio (OR) = 0.30). We further demonstrate that the truncated protein is expressed, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization or loss of an essential protein element.
Agent-based modeling of cancer stem cell driven solid tumor growth
Authors: Poleszczuk Jan , Macklin Paul , Enderling Heiko
Published: December 2015

Computational modeling of tumor growth has become an invaluable tool to simulate complex cell-cell interactions and emerging population-level dynamics. Agent-based models are commonly used to describe the behavior and interaction of individual cells in different environments. Behavioral rules can be informed and calibrated byin vitroassays, and emerging population-level dynamics may be validated with bothin vitroandin vivoexperiments. Here, we describe the design and implementation of a lattice-based agent-based model of cancer stem cell driven tumor growth.
A reference panel of 64,976 haplotypes for genotype imputation
Authors: McCarthy Shane , Das Sayantan , Kretzschmar Warren , Delaneau Olivier , Wood Andrew R. , Teumer Alexander , Kang Hyun Min , Fuchsberger Christian , Danecek Petr , Sharp Kevin , Luo Yang , Sidore Carlo , Kwong Alan , Timpson Nicholas , Koskinen Seppo , Vrieze Scott , Scott Laura J. , Zhang He , Mahajan Anubha , Veldink Jan , Peters Ulrike , Pato Carlos , van Duijn Cornelia M. , Gillies Christopher E. , Gandin Ilaria , Mezzavilla Massimo , Gilly Arthur , Cocca Massimiliano , Traglia Michela , Angius Andrea , Barrett Jeffrey , Boomsma Dorret I. , Branham Kari , Breen Gerome , Brummet Chad , Busonero Fabio , Campbell Hariy , Chan Andrew , Chen Sai , Chew Emily , Collins Francis S. , Corbin Laura , Smith George Davey , Dedoussis George , Dorr Marcus , Farmaki Aliki-Eleni , Ferrucci Luigi , Forer Lukas , Fraser Ross M. , Gabriel Stacey , Levy Shawn , Groop Leif , Harrison Tabitha , Hattersley Andrew , Holmen Oddgeir L. , Hveem Kristian , Kretzler Matthias , Lee James , McGue Matt , Meitinger Thomas , Melzer David , Min Josine , Mohlke Karen L. , Vincent John , Nauck Matthias , Nickerson Deborah , Palotie Aarno , Pato Michele , Pirastu Nicola , Mclnnis Melvin , Richards Brent , Sala Cinzia , Salomaa Veikko , Schlessinger David , Schoenheer Sebastian , Slagboom P Eline , Small Kerrin , Spector Timothy , Stambolian Dwight , Tuke Marcus , Tuomilehto Jaakko , Berg Leonard Van den , Van Rheenen Wouter , Volker Uwe , Wijmenga Cisca , Toniolo Daniela , Zeggini Eleftheria , Gasparini Paolo , Sampson Matthew G. , Wilson James F. , Frayling Timothy , Bakker Paul de , Swertz Morris A. , McCarroll Steven , Kooperberg Charles , Dekker Annelot , Altshuler David , Wilier Cristen , Iacono William , Ripatti Samuli , Soranzo Nicole , Walter Klaudia , Swaroop Anand , Cucca Francesco , Anderson Carl , Boehnke Michael , McCarthy Mark I. , Durbin Richard , Abecasis Gonçalo , Marchini Jonathan
Published: December 2015

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1%, a large increase in the number of SNPs tested in association studies and can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
Tunable protein synthesis by transcript isoforms in human cells
Authors: Floor Stephen N , Doudna Jennifer A
Published: December 2015

Eukaryotic genes generate multiple mRNA transcript isoforms though alternative transcription, splicing, and polyadenylation. However, the relationship between human transcript diversity and protein production is complex as each isoform can be translated differently. We fractionated a polysome profile and reconstructed transcript isoforms from each fraction, which we term Transcript Isoforms in Polysomes sequencing (TrIP-seq). Analysis of these data revealed regulatory features that control ribosome occupancy and translational output of each transcript isoform. We extracted a panel of 5′ and 3′ untranslated regions that control protein production from an unrelated gene in cells over a 100-fold range. Select 5′ untranslated regions exert robust translational control between cell lines, while 3′ untranslated regions can confer cell-type-specific expression. These results expose the large dynamic range of transcript-isoform-specific translational control, identify isoform-specific sequences that control protein output in human cells, and demonstrate that transcript isoform diversity must be considered when relating RNA and protein levels.
Analysis of stresses and crystal structure in the surface layer of hexagonal polycrystalline materials: a new methodology based on grazing incidence diffraction
Authors: Marciszko Marianna , Baczmański Andrzej , Braham Chedly , Wróbel Mirosław , Seiler Wilfrid , Wroński Sebastian , Berent Katarzyna
Published: December 2015

The multireflection grazing-incidence X-ray diffraction (MGIXD) method is commonly used to determine a stress gradient in thin surface layers (about 1–20 µm for metals). In this article, the development of MGIXD to enable the determination not only of stresses but also of thec/aratio and thea0strain-free lattice parameter in hexagonal polycrystalline materials is presented and tested. The new procedure was applied for the results of measurements performed using a laboratory X-ray diffractometer and synchrotron radiation. The evolution of stresses and lattice parameters with depth was determined for Ti and Ti-alloy samples subjected to different mechanical surface treatments. A very good agreement of the results obtained using three different wavelengths of synchrotron radiation as well as classical X-rays (CuKα radiation) was found.
Serum C‐reactive protein levels in Japanese patients with psoriasis and psoriatic arthritis: Long‐term differential effects of biologics
Authors: Asahina Akihiko , Umezawa Yoshinori , Yanaba Koichi , Nakagawa Hidemi
Published: December 2015

Psoriasis has been shown to accompany systemic inflammation. We aimed to examine serum C‐reactive protein (CRP) levels in Japanese psoriatic patients, and to elucidate their long‐term as well as short‐term changes by treatment with different biologics. A retrospective study was conducted in those who initiated and successfully continued the treatment for up to 24 months with either infliximab, adalimumab or ustekinumab, at the psoriasis special clinic of Jikei University School of Medicine. A total of 212 patients were included, 171 with plaque‐type psoriasis (PsV) and 41 with psoriatic arthritis (PsA). A statistically significant elevation of CRP values was found in the group with a Psoriasis Area and Severity Index (PASI) of 12 or more compared with the PASI of less than 12 for both PsV and PsA. The CRP‐positive patients had a higher proportion of PsA compared with the CRP‐negative patients, and they had significantly higher PASI scores. Serum CRP values declined as early as at 3 months after systemic treatment with biologics. Tumor necrosis factor (TNF)‐α antagonists did lead to a notable and sustained CRP decline up to 24 months. Infliximab showed rapid decline, while CRP decline by adalimumab treatment was time‐dependent. The interleukin‐12/23 p40 antagonist, ustekinumab, appeared to be less potent than TNF‐α antagonists in stabilizing CRP values at low levels despite good control of cutaneous lesions. In conclusion, serum CRP levels can be used to assess disease severity in Japanese psoriatic patients as a marker of systemic inflammation. TNF‐α antagonists may be more beneficial than ustekinumab in this regard.
Nutritional, muscular and metabolic characteristics in patients with neurofibromatosis type 1
Authors: Koga Monji , Yoshida Yuichi , Imafuku Shinichi
Published: December 2015

Neurofibromatosis type 1 (NF1) has many reported clinical characteristics. We previously found that NF1 patients (especially men) had lower body mass index (BMI) than controls, but the reason has not been elucidated. To address this issue, a retrospectively case–control study was conducted. Anthropometric and serum chemistry data that potentially relate to BMI were collected from medical records of NF1 patients and their age‐ and sex‐matched controls. Enrollment of 98 adult patients who underwent skin surgery with NF1 (41 men, 57 women) and 173 without NF1 (74 men, 99 women) were investigated. The median BMI in male NF1 patients was significantly lower than that of the controls. Triglycerides in male NF1 patients were significantly lower than male controls, creatine kinase and lactate dehydrogenase in NF1 patients were also lower than controls, aspartate aminotransferase and alanine aminotransferase showed a lower tendency in NF1 patients, but were significantly lower in female patients. With correlation analysis, lactate dehydrogenase was moderately correlated with BMI in male NF1 patients. Creatine kinase and creatinine showed no statistical correlation with BMI in either group. Triglycerides and alanine aminotransferase showed a positive correlation with BMI in both male and female controls, but not in NF1 patients. In conclusion, only lactate dehydrogenase was moderately correlated with BMI in male NF1 patients, although results of some nutritional and metabolic parameters suggest a specific metabolism in NF1.
Acquired dermal melanocytosis confined to the palm with a review of published cases of acquired dermal melanocytosis on the hands
Authors: Nakauchi Emi , Oka Masahiro , Fukumoto Takeshi , Sakaguchi Masanobu , Nishigori Chikako
Published: December 2015

Acquired dermal melanocytosis (ADM) classically occurs on the face. However, extrafacial ADM including palmar ADM has been reported on rare occasions. We present the first report of ADM confined to the palm without ADM lesions in other regions in a 30‐year‐old Japanese woman. The patient presented with several interspersed macules up to 1 cm in diameter with poorly defined margins, containing faint slate‐gray spots 1–2 mm in diameter, on the left palm near the first and second fingers and on the palmar side of the first finger near the metacarpophalangeal joint. These slate‐gray spots were prominent on and around palmar creases and on wrinkles on the metacarpophalangeal joint. The patient was right hand‐dominant. Histopathological examination revealed scattered spindle‐shaped cells with melanin granules and melanophages in the upper to middle dermis. Pigment‐bearing spindle‐shaped cells were demonstrated to be dermal melanocytes because of positive staining for Melan‐A after melanin removal. We review the published work for ADM on the hands.
Relation between endothelial progenitor cells and arterial stiffness in patients with psoriasis
Authors: Liu Ju‐Hua , Chen Yan , Zhen Zhe , Yeung Chi‐Keung , Chan Johnny , Chan Henry H. , Tse Hung‐Fat , Yiu Kai‐Hang
Published: December 2015

Patients with psoriasis are prone to premature atherosclerosis. We hypothesize that depletion of circulating endothelial progenitor cells (EPC) is related to patients with psoriasis and can contribute to the development of atherosclerosis. Thirty‐five plaque‐type psoriasis patients (41.9 ± 5.5 years, 30 men) and 20 age‐ and sex‐matched controls were studied. Four subpopulations of EPC, namely, CD34+ EPC, CD133+ EPC, CD34+/kinase insert domain‐containing receptor (KDR)+ EPC and CD133+/KDR+ EPC were measured by flow cytometry. Arterial stiffness in psoriasis patients was assessed by heart to ankle pulse wave velocity (haPWV), augmentation index (AI) and carotid intima media thickness (IMT). Patients with psoriasis had a lower level of CD34+ EPC (7.85 ± 2.49% vs 6.26 ± 2.13%, P = 0.02) compared with healthy controls. In patients with psoriasis, level of CD34+ EPC was negatively related with haPWV (r = −0.43 P = 0.01) and Psoriasis Area and Severity Index (r = −0.39 P = 0.02). Multivariate regression analysis further demonstrated that haPWV was independently associated with level of CD34+ EPC. Each percentage decrease in CD34+ EPC accounted for an increase in haPWV of +0.02 m/s. The result demonstrated that patients with psoriasis had reduced CD34+ EPC compared with controls. Importantly, CD34+ EPC was independently related with haPWV in these patients. This finding suggests that EPC reduction is associated with the development of arterial stiffness in patients with psoriasis.
Design Considerations for an Intensive Autism Treatment Centre
Authors: Deochand Neil , Conway Alissa A. , Fuqua R. Wayne
Published: December 2015

Individuals with autistic spectrum disorder (ASD) who display severe and challenging behaviour sometimes require centre‐based intensive applied behaviour analysis (ABA) therapy to meet their health, safety and educational needs. Unfortunately, despite the need for centre‐based treatment, there is a paucity of empirical research on building and programme design features that influence positive behavioural outcomes for individuals with ASD. We surveyed professionals who had experience providing services to the ASD population regarding the building design and policy features that could facilitate treatment. This article highlights the features that were highly endorsed as beneficial in the design of an intensive ASD treatment facility, with the intended purpose of discovering which features create an environment in which the individuals can more easily transition into an appropriate mainstream learning environment. It is hoped that the results of the survey will be helpful to those developing ASD treatment facilities and allow them to circumvent trial and error that could occur when building a centre from the ground up.
A prophet but not for profit: ethical value and character in Ghanaian Pentecostalism
Authors: Daswani Girish
Published: December 2015

The anthropological study of value has gained much currency in recent years. This article speaks to the importance of Pentecostal practices in understanding the qualitative aspects of value in Ghana. It demonstrates how practices relating to wealth accumulation and redistribution are in interaction with ethical evaluations about the character of charismatic Christian prophets. The moral evaluation of wealth of certain prophets, and the links perceived between their use of wealth and their character, tell us something about the moral climate in contemporary Ghanaian society, where wealth cannot simply be measured quantitatively (through acquiring riches), but also ought to be assessed qualitatively (discerned through the quality of one's acts).