bluuebunny/crossref_metadata_2025 huggingface dataset:
The mechanism of CIRP in inhibition of keratinocytes growth arrest and apoptosis following low dose UVB radiation
Authors: Liao Yi , Feng Jianguo , Zhang Yi , Tang Liling , Wu Shiyong
Published: November 2016

UV induces CIRP expression and subsequent Stat3 activation, but the biological function and mechanism of CIRP and Stat3 in mediating UVB‐induced skin carcinogenesis have not been fully elucidated. In this study, we demonstrate that CIRP is elevated in all tested melanoma and non‐melanoma skin cancer cell lines; and the expression of CIRP is upregulated in keratinocytes after being irradiated with relatively low dose (<5 mJ/cm2), but not high dose (50 mJ/cm2), UVB acutely and chronically. The increased expression of CIRP, either induced by UVB or through overexpression, leads to resistance of keratinocytes to UVB‐induced growth arrest and death; and reduced expression of CIRP by RNA knockdown sensitizes keratinocyte cells to the low dose UVB radiation. We also demonstrated that CIRP expression is required for the low dose UVB‐induced Tyr705‐phosphorylation, but not total amount, of Stat3. The p‐Stat3 level is correlated with the expression levels of cyclin D1 and VEGF, two known downstream cell growth regulators of Stat3, as well as Bag‐1/S, an apoptosis regulator. Inhibition of Stat3 DNA‐binding activity by S3I‐201 leads to a reduction of the p‐Stat3 and Bag‐1/S along with growth and survival of keratinocytes post‐UVB; and the effect of S3I‐201 on the UVB‐irradiated cells can be partially inhibited by overexpression of CIRP or Bag‐1/S. Furthermore, the overexpression of Bag‐1/S can totally inhibit UVB‐induced PARP cleavage and caspase 3 activation. The results presented above led us to propose that CIRP‐p(705)Stat3 cascade promotes cell proliferation and survival post‐UVB via upregulating the expression of cyclin D1 and Bag‐1/S, respectively. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Coupling dynamic behaviors of spatial flexible beam with weak damping
Authors: Hu Weipeng , Li Qingjun , Jiang Xianhong , Deng Zichen
Published: November 2016

As a typical high‐dimensional nonlinear dynamic problem, the difficulties of the dynamic analysis on the spatial flexible damping beam mostly result from the coupling between the spatial motion and the transverse vibration. Considering the coupling effect and the weak structure damping, the dynamic behaviors of the spatial flexible beam are investigated by a complex structure‐preserving method in this paper. Based on the variational principle, the dynamic model of the spatial flexible damping beam is established, which can be decoupled into two parts approximately, one controls the spatial motion and another mainly controls the transverse vibration. For the first part, the classic fourth‐order Runge–Kutta method can be used to discrete it expediently. For the latter part, based on the generalized multi‐symplectic idea, the approximate symmetric form as well as the generalized multi‐symplectic conservation law is formulated, and a 15‐point scheme equivalent to the Preissmann scheme is constructed. Numerical iterations are performed for six typical initial cases between the two parts to study the dynamic behaviors of the spatial flexible beam. In the numerical experiments, the effects of the damping factor and the initial conditions (including the initial radial velocity and the initial attitude angle) on the dynamic behaviors of the spatial flexible beam are investigated in detail. From the numerical results, it can be concluded that the damping effect on the long‐time dynamic behaviors of the spatial flexible beam could not be neglected even if it is weak; the numerical method proposed in this paper owns the tiny numerical dissipation as well as the excellent long‐time numerical stability. Copyright © 2016 John Wiley & Sons, Ltd.
Associations between feeding practices and maternal and child weight among mothers who do and do not correctly identify their child's weight status
Authors: Tabak R. G. , Schwarz C. D. , Haire‐Joshu D. L.
Published: November 2016

Objective

This study aimed to explore factors associated with accuracy of maternal weight perception and determine if maternal feeding practices are associated with weight status.

Methods

Overweight/obese mothers reported demographics and perception of their child's weight and completed a modified preschooler feeding questionnaire. Mother's and child's height and weight were measured. Logistic regression was used to explore associations between demographic factors and accuracy. Correlations between the preschooler feeding questionnaire scales and mom's body mass index (BMI) and child's BMI‐percentile were explored for the total sample and accurate and underestimating moms.

Results

Among mothers whose child was overweight or obese, only 20% of mothers correctly identified the child as overweight. Forty percent of moms were underestimaters. There was a positive correlation between concern the child was overweight/overeating and the child's BMI‐percentile among underestimating moms; in the total sample (r = 0.32, p < .001) and accurate moms (r = 0.52, p < .001). In underestimaters only, there was a negative relationship between child BMI‐percentile and pressure to eat (r = −0.30, p < .001) and concern about child underweight (r = −0.47, p < .001).

Conclusions

This study identified different associations between child weight and mother's feeding practices in mothers accurately and inaccurately perceiving her child's weight. Intervention studies should explore targeting education on feeding practices based on these perceptions.
Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme
Authors: Parker Lorien J. , Bocedi Alessio , Ascher David B. , Aitken Jade B. , Harris Hugh H. , Lo Bello Mario , Ricci Giorgio , Morton Craig J. , Parker Michael W.
Published: November 2016

Arsenic‐based compounds are paradoxically both poisons and drugs. Glutathione transferase (GSTP1‐1) is a major factor in resistance to such drugs. Here we describe using crystallography, X‐ray absorption spectroscopy, mutagenesis, mass spectrometry, and kinetic studies how GSTP1‐1 recognizes the drug phenylarsine oxide (PAO). In conditions of cellular stress where glutathione (GSH) levels are low, PAO crosslinks C47 to C101 of the opposing monomer, a distance of 19.9 Å, and causes a dramatic widening of the dimer interface by approximately 10 Å. The GSH conjugate of PAO, which forms rapidly in cancerous cells, is a potent inhibitor (Ki = 90 nM) and binds as a di‐GSH complex in the active site forming part of a continuous network of interactions from one active site to the other. In summary, GSTP1‐1 can detoxify arsenic‐based drugs by sequestration at the active site and at the dimer interface, in situations where there is a plentiful supply of GSH, and at the reactive cysteines in conditions of low GSH.
PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents
Authors: Mukherjee Jogeshwar , Majji Divya , Kaur Jasmeet , Constantinescu Cristian C. , Narayanan Tanjore K. , Shi Bingzhi , Nour Mohamed T. , Pan Min‐Liang
Published: November 2016

Imaging the high‐affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18F‐5‐OH‐FPPAT, and the newer 18F‐5‐OH‐FHXPAT and 18F‐7‐OH‐FHXPAT. Syntheses of 18F‐5‐OH‐FHXPAT and 18F‐7‐OH‐FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague‐Dawley rats were used with the 3 radiotracers (74‐111 kBq/cc). Competition with dopamine (1–100 nM) and Gpp(NH)p (10–50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA‐states and binding kinetics of 18F‐5‐OH‐FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18F‐5‐OH‐FHXPAT to ascertain HA‐state binding. PET/CT imaging in rats and wild type (WT) and D2 knock‐out mice were carried out using 18F‐7‐OH‐FHXPAT (2‐37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10−2 min−1 for 18F‐5‐OH‐FPPAT. Treatment with Gpp(NH)p significantly reduced 50–80% striatal binding with faster dissociation rates (5.0 × 10−2 min−1), suggesting HA‐state binding of 18F‐5‐OH‐FPPAT and 18F‐5‐OH‐FHXPAT. Striatal binding of 18F‐5‐OH‐FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA‐state binding in vivo. PET binding ratios of 18F‐7‐OH‐FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane‐bound HA‐state of the dopamine receptor.
Strain engineering and process optimization for enhancing the production of a thermostable steryl glucosidase in Escherichia coli
Authors: Eberhardt Florencia , Aguirre Andres , Menzella Hugo G , Peiru Salvador
Published: November 2016

Biodiesels produced from transesterification of vegetable oils have a major problem in quality due to the presence of precipitates, which are mostly composed of steryl glucosides (SGs). We have recently described an enzymatic method for the efficient removal of SGs from biodiesel, based on the activity of a thermostable β-glycosidase from Thermococcus litoralis. In the present work, we describe the development of an Escherichia coli-based expression system and a high cell density fermentation process. Strain and process engineering include the assessment of different promoters to drive the expression of a codon-optimized gene, the co-expression of molecular chaperones and the development of a high cell density fermentation process. A 200-fold increase in the production titers was achieved, which directly impacts on the costs of the industrial process for treating biodiesel.
Epidemiology of developmental dysplasia of the hip within the UK: Refining the risk factors
Authors: Woodacre Timothy , Ball Thomas , Cox Peter
Published: November 2016

Purpose

The epidemiology and risk factors for developmental dysplasia of the hip (DDH) are still being refined. We investigated the local epidemiology of DDH in order to define incidence, identify risk factors, and refine our policy on selective ultrasound screening.

Methods

With a cohort study design, data were prospectively recorded on all live births in our region from January 1998 to December 2008. We compared data on babies treated for DDH with data for all other children. Crude odds ratios (ORs) were calculated to identify potential risk factors. Logistic regression was then used to control for interactions between variables.

Results

There were 182 children born with DDH (with a total of 245 dysplastic hips) and 37,051 without. The incidence was 4.9 per 1000 live births. Female sex (adjusted OR 7.2, 95% confidence interval [CI] 4.6–11.2), breech presentation (adjusted OR 24.3, 95% CI 13.1–44.9), positive family history (adjusted OR 15.9, 95% CI 11.0–22.9) and first or second pregnancy (adjusted OR 1.8, 95% CI 1.5–2.3) were confirmed as risk factors ( p < 0.001). In addition, there was an increased risk with vaginal delivery (adjusted OR 2.7, 1.6–4.5, p < 0.001) and post-maturity (OR 1.7, 1.2–2.4, p < 0.002).

Conclusions

One in 200 children born within our region requires treatment for DDH. Using both established and novel risk factors, we can potentially calculate an individual child's risk. Our findings may contribute to the debate regarding selective versus universal ultrasound screening.

Level of Evidence

Prognostic Study: Level 1.
Applications of integrative OMICs approaches to gene regulation studies
Authors: Qin Jing , Yan Bin , Hu Yaohua , Wang Panwen , Wang Junwen
Published: November 2016

Background

Functional genomics employs dozens of OMICs technologies to explore the functions of DNA, RNA and protein regulators in gene regulation processes. Despite each of these technologies being powerful tools on their own, like the parable of blind men and an elephant, any one single technology has a limited ability to depict the complex regulatory system. Integrative OMICS approaches have emerged and become an important area in biology and medicine. It provides a precise and effective way to study gene regulations.

Results

This article reviews current popular OMICs technologies, OMICs data integration strategies, and bioinformatics tools used for multi‐dimensional data integration. We highlight the advantages of these methods, particularly in elucidating molecular basis of biological regulatory mechanisms.

Conclusions

To better understand the complexity of biological processes, we need powerful bioinformatics tools to integrate these OMICs data. Integrating multi‐dimensional OMICs data will generate novel insights into system‐level gene regulations and serves as a foundation for further hypothesis‐driven research.
The Generalized Problematic Internet Use Scale 2: Validation and test of the model to Facebook use
Authors: Assunção Raquel S. , Matos Paula Mena
Published: November 2016

The main goals of the present study were to test the psychometric properties of a Portuguese version of the GPIUS2 (Generalized Problematic Internet Use Scale 2, Caplan, 2010), and to test whether the cognitive‐behavioral model proposed by Caplan (2010) replicated in the context of Facebook use. We used a sample of 761 Portuguese adolescents (53.7% boys, 46.3% girls, mean age = 15.8). Our results showed that the data presented an adequate fit to the original model using confirmatory factor analysis. The scale presented also good internal consistency and adequate construct validity. The cognitive‐behavioral model was also applicable to the Facebook context, presenting good fit. Consistently with previous findings we found that preference for online social interaction and the use of Facebook to mood regulation purposes, predicted positively and significantly the deficient self‐regulation in Facebook use, which in turn was a significant predictor of the negative outcomes associated with this use.
Predicting school adjustment from multiple perspectives on parental behaviors
Authors: Ratelle Catherine F. , Duchesne Stéphane , Guay Frédéric
Published: November 2016

Past research supported the importance of parental autonomy support, involvement, and structure for student outcomes. The goal of this study was to test the contribution of these behaviors from mothers and fathers in predicting adolescents' adjustment in school using a multi‐informant approach. A sample of 522 adolescents (233 boys, 389 girls), their mothers (n = 535), and fathers (n = 296) participated in the study. Results revealed that parents' self‐evaluations explained additional variance in children's school adjustment, over and beyond the contribution of children's evaluation of their parents. Maternal reports on their positive behaviors (autonomy support, involvement, and structure) predicted their child's academic and emotional adjustment while their reported control predicted lower levels of these. Fathers' self‐reported positive behaviors predicted academic adjustment while their control predicted lower academic and personal‐emotional adjustment. These findings support the importance of multiple assessments of parental behaviors for improving the prediction of adjustment in school.
Thinner temporal and parietal cortex is related to incident clinical progression to dementia in patients with subjective cognitive decline
Authors: Verfaillie Sander C.J. , Tijms Betty , Versteeg Adriaan , Benedictus Marije R. , Bouwman Femke H. , Scheltens Philip , Barkhof Frederik , Vrenken Hugo , van der Flier Wiesje M.
Published: November 2016

Introduction

We aimed to investigate if thinner cortex of the Alzheimer's disease (AD)‐signature region was related to clinical progression in patients with subjective cognitive decline (SCD).

Methods

We included 302 SCD patients with clinical follow‐up (≥1 year) and three‐dimensional T1 magnetic resonance imaging. We estimated AD‐signature cortical thickness, consisting of nine frontal, parietal, and temporal gyri and hippocampal volume. We used Cox proportional hazard models (hazard ratios and 95% confidence intervals) to evaluate cortical thickness in relation to clinical progression to mild cognitive impairment (MCI) or dementia.

Results

After a follow‐up of the mean (standard deviation) 3 (2) years, 49 patients (16%) showed clinical progression to MCI (n = 32), AD (n = 9), or non‐AD dementia (n = 8). Hippocampal volumes, thinner cortex of the AD‐signature (hazard ratio [95% confidence interval], 5 [2–17]) and various AD‐signature subcomponents were associated with increased risk of clinical progression. Stratified analyses showed that thinner AD‐signature cortex was specifically predictive for clinical progression to dementia but not to MCI.

Discussion

In SCD patients, thinner regional cortex is associated with clinical progression to dementia.
Cutting through the Online Review Jungle — Investigating Selective eWOM Processing
Authors: Gottschalk Sabrina A. , Mafael Alexander
Published: November 2016

Consumers frequently rely on online reviews, a prominent form of electronic word-of-mouth (eWOM), before making a purchase decision. However, consumers are usually confronted with hundreds of reviews for a single product or service, as well as rich information cues on online review websites (review texts, helpfulness ratings, author information, etc.). In turn, consumers face more information cues on online review websites than they can or want to process, and are likely to proceed selectively. This paper investigates selective processing of such eWOM information cues. Results of Study 1, an exploratory study using verbal protocols, confirm that consumers display selective eWOM processing patterns and are able to articulate them. Study 2 develops and applies a measurement instrument to capture these patterns. A subsequent cluster analysis on members of a large-scale online panel (N = 2,295) indicates five prominent eWOM processing types, termed “The Efficients”, “The Meticulous”, “The Quality-Evaluators”, “The Cautious Critics”, and “The Swift Pessimists”. Insights of this research can help firms to better understand consumers’ eWOM processing and improve the user-friendliness of online review websites.
Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample
Authors: Brenowitz Willa D. , Hubbard Rebecca A. , Keene C. Dirk , Hawes Stephen E. , Longstreth W.T. , Woltjer Randy L. , Kukull Walter A.
Published: November 2016

Introduction

Whether co‐occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co‐occurring Lewy body disease (LBD) or vascular brain injury (VBI).

Methods

Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center.

Results

Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP.

Discussion

The impact of co‐occurring pathologies on progression may depend on severity of ADNP.
Diffuse interstitial fibrosis assessed by cardiac magnetic resonance is associated with dispersion of ventricular repolarization in patients with hypertrophic cardiomyopathy
Authors: Hurtado‐de‐Mendoza David , Corona‐Villalobos Celia P. , Pozios Iraklis , Gonzales Jorge , Soleimanifard Yalda , Sivalokanathan Sanjay , Montoya‐Cerrillo Diego , Vakrou Styliani , Kamel Ihab , Mormontoy‐Laurel Wilfredo , Dolores‐Cerna Ketty , Suarez Jacsel , Perez‐Melo Sergio , Bluemke David A. , Abraham Theodore P. , Zimmerman Stefan L. , Abraham M. Roselle
Published: November 2016

Background

Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy, disarray, fibrosis, and increased risk for ventricular arrhythmias. Increased QT dispersion has been reported in patients with HCM, but the underlying mechanisms have not been completely elucidated. In this study, we examined the relationship between diffuse interstitial fibrosis, replacement fibrosis, QTc dispersion and ventricular arrhythmias in patients with HCM. We hypothesized that fibrosis would slow impulse propagation and increase dispersion of ventricular repolarization, resulting in increased QTc dispersion on surface electrocardiogram (ECG) and ventricular arrhythmias.

Methods

ECG and cardiac magnetic resonance (CMR) image analyses were performed retrospectively in 112 patients with a clinical diagnosis of HCM. Replacement fibrosis was assessed by measuring late gadolinium (Gd) enhancement (LGE), using a semi‐automated threshold technique. Diffuse interstitial fibrosis was assessed by measuring T1 relaxation times after Gd administration, using the Look–Locker sequence. QTc dispersion was measured digitally in the septal/anterior (V1–V4), inferior (II, III, and aVF), and lateral (I, aVL, V5, and V6) lead groups on surface ECG.

Results

All patients had evidence of asymmetric septal hypertrophy. LGE was evident in 70 (63%) patients; the median T1 relaxation time was 411±38 ms. An inverse correlation was observed between T1 relaxation time and QTc dispersion in leads V1–V4 (p<0.001). Patients with HCM who developed sustained ventricular tachycardia had slightly higher probability of increased QTc dispersion in leads V1–V4 (odds ratio, 1.011 [1.004–1.0178, p=0.003). We found no correlation between presence and percentage of LGE and QTc dispersion.

Conclusion

Diffuse interstitial fibrosis is associated with increased dispersion of ventricular repolarization in leads, reflecting electrical activity in the hypertrophied septum. Interstitial fibrosis combined with ion channel/gap junction remodeling in the septum could lead to inhomogeneity of ventricular refractoriness, resulting in increased QTc dispersion in leads V1–V4.
Postural Sway, Balance Confidence, and Fear of Falling in Women With Knee Osteoarthritis in Comparison to Matched Controls
Authors: Taglietti Marcelo , Dela Bela Laís Faganello , Dias Josilainne Marcelino , Pelegrinelli Alexandre Roberto Marcondes , Nogueira Jéssyca Fernandes , Batista Júnior João Pedro , Carvalho Rodrigo Gustavo da Silva , McVeigh Joseph Gerard , Facci Ligia Maria , Moura Felipe Arruda , Cardoso Jefferson Rosa
Published: November 2016

Background

Osteoarthritis (OA) is a chronic degenerative disease that commonly affects the knee joints. Individuals older than 65 years of age with knee OA have a greater risk of falls. However, there has been limited examination of the parameters of postural sway (increased time, speed, and postural sway area [center of pressure{CoP}]), and OA of the knee.

Objectives

The primary objective of this study was to determine whether the CoP variables discriminate between patients with knee OA and matched healthy volunteers, and to correlate the CoP variables with the Activities‐Specific Balance Confidence Scale (ABC) and Falls Self‐Efficacy Scale (FES). The secondary objective was to compare the CoP of older women with OA with a control group in bipedal support condition with eyes opened and closed.

Design

Cross‐sectional study.

Setting

University Biomechanics Laboratory.

Participants

A total of 22 participants were divided into the following 2 groups of 11 participants each: an OA group (mean = 68 years, standard deviation = 7.4 years) and a control group (mean = 66 years, standard deviation = 4.4 years).

Methods

Static postural balance was measured by a portable force platform. Data were collected in both visual conditions (eyes open and closed), in random order. Three attempts of 30 seconds were allowed for each participant on the force platform, with a 1‐minute interval between attempts.

Main Outcome Measure

Variables were the CoP total displacement of sway (TDS, in centimeters), anteroposterior amplitude displacement (APAD, in centimeters), medial‐lateral amplitude displacement (MLAD, in centimeters), total mean velocity (TMV, in centimeters per second), and dispersion of the center of pressure (AREA, in centimeters squared).

Results

The postural sway analysis found statistically significant differences in the eyes open condition for the TDS (P = .020), APAD (P = .042), TMV (P = .010), and AREA (P = .045). In the discriminant analysis, none of the CoP variables were able to classify the groups (P = .15). The correlation analysis showed that only the AREA with eyes closed was associated with the ABC Scale (rho = −0.42).

Conclusions

Women with knee OA had greater postural sway when compared with a control group for the eyes open condition. CoP variables could not discriminate between the groups. The AREA was negatively correlated with the ABC Scale, when the eyes were closed.

Level of Evidence

III
Clinically Significant Envenomation From Postmortem Copperhead (Agkistrodon contortrix)
Authors: Emswiler Michael P. , Griffith F. Phillip , Cumpston Kirk L.
Published: November 2016

Over 14,000 copperhead ( Agkistrodon contortrix) bites were reported to United States poison centers between 1983 and 2008, and 1809 cases were reported to poison centers in 2014. The copperhead is primarily found in the southeastern United States and belongs to the pit viper subfamily Crotalinae, which also includes the water moccasin ( Agkistrodon piscivorus) and rattlesnakes ( Crotalus and Sistrurus genera). Postmortem rattlesnakes have been reported to cause clinically significant envenomation; we report a case of a postmortem copperhead causing clinically significant envenomation after inadvertent puncture with the deceased copperhead fang. The copperhead was transected twice, leaving the snake in 3 separate pieces. While handling the snake head, an inadvertent puncture occurred on the right index finger followed by pain and swelling in the affected extremity necessitating antivenom administration. Care should be taken when handling deceased pit vipers due to the continued risk of envenomation.
A Significantly Hotter Mantle Beneath Iceland
Authors: Cook Terri
Published: November 2016

Estimates of crystallization temperatures from four eruptions in northern Iceland offer improved constraints on the mantle's temperature beneath this anomalous divergent plate boundary.
Science Is Bipartisan Issue, White House Science Adviser Says
Authors: Showstack Randy
Published: November 2016

Holdren said that investing in climate change science and policy measures is good for the economy, national security, and the environment.
Discovery of cofactor-specific, bactericidal
Mycobacterium tuberculosis
InhA inhibitors using DNA-encoded library technology
Authors: Soutter Holly H. , Centrella Paolo , Clark Matthew A. , Cuozzo John W. , Dumelin Christoph E. , Guie Marie-Aude , Habeshian Sevan , Keefe Anthony D. , Kennedy Kaitlyn M. , Sigel Eric A. , Troast Dawn M. , Zhang Ying , Ferguson Andrew D. , Davies Gareth , Stead Eleanor R. , Breed Jason , Madhavapeddi Prashanti , Read Jon A.
Published: November 2016

Significance

The increasing prevalence of multidrug-resistant strains of tuberculosis has created an urgent need for novel therapies to treat tuberculosis infections. Here we have demonstrated the successful utilization of the DNA-encoded X-Chem technology for the discovery inhibitors of
Mycobacterium tuberculosis
enoyl–acyl-carrier protein (ACP) reductase, InhA, a validated target for the treatment of tuberculosis. The identified inhibitors are cofactor specific and have activity in multiple cellular assays. Crystal structures of representative compounds from five chemical series revealed that the compounds bind adjacent to the NADH cofactor and adopt a variety of conformations, including two previously unreported binding modes. The compounds identified may serve as useful leads in the development of new antibacterial drugs with efficacy against multidrug-resistant tuberculosis.
On the (un)predictability of a large intragenic fitness landscape
Authors: Bank Claudia , Matuszewski Sebastian , Hietpas Ryan T. , Jensen Jeffrey D.
Published: November 2016

Significance

The study of fitness landscapes is fundamentally concerned with understanding the relative roles of stochastic and deterministic processes in adaptive evolution. Here, the authors present a uniquely large and complete multiallelic intragenic fitness landscape of 640 systematically engineered mutations in the heat-shock protein Hsp90 in yeast. Using a combination of traditional and recently proposed theoretical approaches, they study the accessibility of the global fitness peak and the potential for predictability of the fitness landscape topography. They report local ruggedness of the landscape and the existence of epistatic hotspot mutations, which together make extrapolation and hence predictability inherently difficult if mutation-specific information is not considered.
Root nodule symbiosis in
Lotus japonicus
drives the establishment of distinctive rhizosphere, root, and nodule bacterial communities
Authors: Zgadzaj Rafal , Garrido-Oter Ruben , Jensen Dorthe Bodker , Koprivova Anna , Schulze-Lefert Paul , Radutoiu Simona
Published: November 2016

Significance

Legumes are known as pioneer plants colonizing marginal soils, and as enhancers of the nutritional status in cultivated soils. This beneficial activity has been explained by their capacity to engage in symbiotic relationship with nitrogen-fixing rhizobia. We performed a community profiling analysis of
Lotus japonicus
wild type and mutants to investigate the role of the nodulation pathway on the structure of the root-associated bacterial microbiota. We found that several bacterial orders were almost entirely depleted from the mutant roots, and that an intact symbiosis is needed for the establishment of taxonomically diverse and distinctive bacterial communities in the root and rhizosphere. Our findings imply that a symbiosis-linked bacterial community, rather than dinitrogen-fixing rhizobia alone, contributes to legume growth and ecological performance.
Epstein–Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation
Authors: Liang Jun , Zhou Hufeng , Gerdt Catherine , Tan Min , Colson Tyler , Kaye Kenneth M. , Kieff Elliott , Zhao Bo
Published: November 2016

Significance

EBV infection causes African Burkitt's lymphoma; Hodgkin's disease; lymphomas in immune suppressed people, including HIV infected people; nasopharyngeal carcinoma; and ∼10% of gastric carcinomas. We recently found EBV super-enhancer (ESE) to be critical for lymphoblastoid cell (LCL) growth and survival. We now identified an ESE constituent, enhancer RNA (eRNA), that is important for ESE function. These eRNAs were activated by viral transactivator, EBV nuclear antigen 2 (EBNA2). MYC oncogene ESE eRNAs were able to enhance ESE activation of MYC expression and are essential for LCL growth. Targeting ESE eRNAs may lead to new therapeutics for EBV-associated malignancies.
Effect of Fe-rich particles and solutes on the creep behaviour of 8xxx alloys
Authors: Pan L. , Mirza F. A. , Liu K. , Chen X.-G.
Published: November 2016

The creep behavior of 8xxx aluminum conductor alloys with different quantities of Fe-rich particles and solutes was investigated. Creep resistance was significantly improved with large amounts of Fe-rich particles and solutes. At 100 °C, a high Fe solute content (0.023 wt.%) had a stronger effect on creep resistance than FeAl3 particles. However, as the temperature increased to 150 and 200 °C, the effect of a high amount of FeAl3 particles (2.5 vol.%) was stronger. The threshold stress increased with increasing FeAl3 particle and Fe solute contents, with the effect of each factor being independent, but it decreased with increasing temperature. The true stress exponents were calculated to be 3.1, 3.8, and 4.5 at 100, 150 and 200 °C, respectively.

GRAPHICAL ABSTRACT
The effects of high resistance–few repetitions and low resistance–high repetitions resistance training on climbing performance
Authors: Hermans Espen , Andersen Vidar , Saeterbakken Atle Hole
Published: November 2016

The aim of the study was to compare the effects of different strength training intensities on climbing performance, climbing‐specific tests and a general strength test. Thirty lower grade and intermediate‐level climbers participated in a 10‐week training programme. The participants were randomized into three groups: high resistance–few repetitions training groups (HR‐FR), low resistance–high repetitions training groups (LR‐HR) and a control group (CON) which continued climbing/training as usual. Post‐testing results demonstrated statistical tendencies for climbing performance improvements in the HR‐FR and LR‐HR (p = 0.088–0.090, effect size = 0.55–0.73), but no differences were observed between the groups (p = 0.950). For the climbing‐specific tests, no differences were observed between the groups (p = 0.507–1.000), but the HR‐FR and LR‐HR improved their time in both Dead‐hang (p = 0.004–0.026) and Bent‐arm hang (p < 0.001–0.002). The HR‐FR and LR‐HR improved their 12RM strength in pull‐down (p ≤ 0.001), but not the CON group (p = 0.250). No differences were observed in the CON group in any of the tests (p = 0.190–0.596) with the exception of improvement in Bent‐arm Hang (p = 0.018). The training groups reduced their climbing sessions during the intervention compared to the CON group (p = 0.057–0.074). In conclusion, HR‐FR and LR‐HR training programmes demonstrated an 11% and 12% non‐significant improvement in climbing performance despite a 50% reduction in climbing sessions, but improved the results in strength and climbing‐specific tests. None of the training intensities was superior compared to the others.
The effects of a three‐year integrated Olympic education programme on adolescents’ prosocial behaviours
Authors: Sukys Saulius , Majauskiene Daiva , Dumciene Audrone
Published: November 2016

The concept of Olympic education and its use of moral education to shape the development of personality have received insufficient empirical support. The aim of this study was to examine the effects of an integrated Olympic education programme on the development of prosocial behaviour in adolescents. A natural experimental research design was applied in this study. The pre‐test sample included 411 adolescents (aged 13–14) who were randomly selected from schools that had begun to apply an integrated Olympic education programme, along with 430 adolescents from schools without an Olympic education programme. The post‐test sample included 381 students from schools implementing the Olympic education programme and 402 students from schools without an Olympic education programme. The revised prosocial tendencies measure was administered to the participants at pre‐ and post‐test time points to assess changes in prosocial behaviour and specifically on six types of prosocial behaviour: public, anonymous, dire, emotional, compliant, and altruistic. The analyses showed significant improvements in prosocial behaviour in adolescents from schools that had implemented an integrated Olympic education programme. Changes in prosocial behaviour following the implementation of an integrated Olympic education programme were observed for the compliant, altruistic, and dire types of prosocial behaviour. In conclusion, these findings suggest that an integrated Olympic education programme effectively encourages prosocial behaviour in adolescents. This study expands our understanding of the efficiency of implementing an Olympic education programme in schools. We suggest that future research should investigate the behavioural changes in students of different ages from perspective of both teachers and students.
Sensory organisation and reactive balance control of amateur rugby players: A cross‐sectional study
Authors: Chow Gary C. C. , Chung Joanne W. Y. , Ma Ada W. W. , Macfarlane Duncan J. , Fong Shirley S. M.
Published: November 2016

Purpose: This study compared the sensory organisation and reactive balance control of amateur rugby players and a control group. Methods: Forty‐one amateur rugby players (22 males: 19 females; mean height ± SD = 168.8 ± 8.8 cm; mean weight ± SD = 63.9 ± 12.5 kg) and 31 control participants (22 males: 9 females; mean height ± SD = 171.5 ± 10.3 cm; mean weight ± SD = 63.8 ± 10.3 kg) completed the study. Their sensory organisation and standing balance performance were evaluated using a sensory organisation test (SOT), and their reactive balance performance was quantified using a motor control test (MCT). The SOT equilibrium scores (ES) and sensory ratios and the MCT motor response latencies were the major outcome measures. Results: The results revealed that compared to the controls, amateur rugby players had lower SOT ESs under different sensory environments (P < .001, = 0.142–0.254) and prolonged reactive motor response times in the MCT (P < .001, d = 0.890). The vestibular and visual ratios were also lower in the rugby group (P = .005, = 0.107 and 0.108, respectively). No significant difference was found in the somatosensory ratio (P = .853, < 0.001) between the two groups. Conclusions: Amateur rugby players demonstrated inferior standing balance performance compared to their non‐trained counterparts. They relied less heavily on vestibular and visual inputs to maintain standing balance under different sensory environments. In addition, they reacted more slowly to postural disturbance, reflecting their suboptimal reactive balance ability in standing.
Markets, Transportation Infrastructure, and Food Prices in Nepal
Authors: Shively Gerald , Thapa Ganesh
Published: November 2016

We study transportation infrastructure and food markets in Nepal over the period 2002 to 2010, combining monthly price data from thirty‐seven local and regional markets, and seven Indian border markets. We use a series of autoregressive models to study price determination, spatial and temporal price transmission, and price variance. We account for district‐level agricultural production, correcting for bi‐directional causality between output and prices using ground station rainfall data. In addition, to test hypotheses regarding the importance of transportation infrastructure we incorporate information on road and bridge density and fuel costs. For both rice and wheat, we find strong evidence of local price intertemporal carryover and very weak evidence of price transmission from regional, central, and border markets to local markets, suggesting very low degrees of market integration. Fuel costs are positively correlated with food prices, and road and bridge density are negatively correlated with prices. We find evidence of asymmetric effects: positive price shocks are correlated with higher subsequent price volatility compared with negative price shocks of similar magnitude. Roads and bridges are important for moderating price levels and price volatility in Nepal's rice and wheat markets, which explains roughly half of the spatial and temporal variation in price mark‐ups between regional and local markets.
Predict drug permeability to blood–brain-barrier from clinical phenotypes: drug side effects and drug indications
Authors: Gao Zhen , Chen Yang , Cai Xiaoshu , Xu Rong
Published: November 2016

Motivation

Blood–Brain-Barrier (BBB) is a rigorous permeability barrier for maintaining homeostasis of Central Nervous System (CNS). Determination of compound’s permeability to BBB is prerequisite in CNS drug discovery. Existing computational methods usually predict drug BBB permeability from chemical structure and they generally apply to small compounds passing BBB through passive diffusion. As abundant information on drug side effects and indications has been recorded over time through extensive clinical usage, we aim to explore BBB permeability prediction from a new angle and introduce a novel approach to predict BBB permeability from drug clinical phenotypes (drug side effects and drug indications). This method can apply to both small compounds and macro-molecules penetrating BBB through various mechanisms besides passive diffusion.

Results

We composed a training dataset of 213 drugs with known brain and blood steady-state concentrations ratio and extracted their side effects and indications as features. Next, we trained SVM models with polynomial kernel and obtained accuracy of 76.0%, AUC 0.739, and F1 score (macro weighted) 0.760 with Monte Carlo cross validation. The independent test accuracy was 68.3%, AUC 0.692, F1 score 0.676. When both chemical features and clinical phenotypes were available, combining the two types of features achieved significantly better performance than chemical feature based approach (accuracy 85.5% versus 72.9%, AUC 0.854 versus 0.733, F1 score 0.854 versus 0.725; P < e−90). We also conducted de novo prediction and identified 110 drugs in SIDER database having the potential to penetrate BBB, which could serve as start point for CNS drug repositioning research.

Availability and Implementation

https://github.com/bioinformatics-gao/CASE-BBB-prediction-Data

Supplementary information

Supplementary data are available at Bioinformatics online.
Hum-mPLoc 3.0: prediction enhancement of human protein subcellular localization through modeling the hidden correlations of gene ontology and functional domain features
Authors: Zhou Hang , Yang Yang , Shen Hong-Bin
Published: November 2016

Motivation

Protein subcellular localization prediction has been an important research topic in computational biology over the last decade. Various automatic methods have been proposed to predict locations for large scale protein datasets, where statistical machine learning algorithms are widely used for model construction. A key step in these predictors is encoding the amino acid sequences into feature vectors. Many studies have shown that features extracted from biological domains, such as gene ontology and functional domains, can be very useful for improving the prediction accuracy. However, domain knowledge usually results in redundant features and high-dimensional feature spaces, which may degenerate the performance of machine learning models.

Results

In this paper, we propose a new amino acid sequence-based human protein subcellular location prediction approach Hum-mPLoc 3.0, which covers 12 human subcellular localizations. The sequences are represented by multi-view complementary features, i.e. context vocabulary annotation-based gene ontology (GO) terms, peptide-based functional domains, and residue-based statistical features. To systematically reflect the structural hierarchy of the domain knowledge bases, we propose a novel feature representation protocol denoted as HCM (Hidden Correlation Modeling), which will create more compact and discriminative feature vectors by modeling the hidden correlations between annotation terms. Experimental results on four benchmark datasets show that HCM improves prediction accuracy by 5–11% and F1 by 8–19% compared with conventional GO-based methods. A large-scale application of Hum-mPLoc 3.0 on the whole human proteome reveals proteins co-localization preferences in the cell.

Availability and Implementation

www.csbio.sjtu.edu.cn/bioinf/Hum-mPLoc3/

Supplementary information

Supplementary data are available at Bioinformatics online.
Context-sensitive network-based disease genetics prediction and its implications in drug discovery
Authors: Chen Yang , Xu Rong
Published: November 2016

Motivation

Disease phenotype networks play an important role in computational approaches to identifying new disease-gene associations. Current disease phenotype networks often model disease relationships based on pairwise similarities, therefore ignore the specific context on how two diseases are connected. In this study, we propose a new strategy to model disease associations using context-sensitive networks (CSNs). We developed a CSN-based phenome-driven approach for disease genetics prediction, and investigated the translational potential of the predicted genes in drug discovery.

Results

We constructed CSNs by directly connecting diseases with associated phenotypes. Here, we constructed two CSNs using different data sources; the two networks contain 26 790 and 13 822 nodes respectively. We integrated the CSNs with a genetic functional relationship network and predicted disease genes using a network-based ranking algorithm. For comparison, we built Similarity-Based disease Networks (SBN) using the same disease phenotype data. In a de novo cross validation for 3324 diseases, the CSN-based approach significantly increased the average rank from top 12.6 to top 8.8% for all tested genes comparing with the SBN-based approach (p<e−22). The area under the receiver operating characteristic curve for the CSN approach was also significantly higher than the SBN approach (0.91 versus 0.87, p<e−3). In addition, we predicted genes for Parkinson’s disease using CSNs, and demonstrated that the top-ranked genes are highly relevant to PD pathologenesis. We pin-pointed a top-ranked drug target gene for PD, and found its association with neurodegeneration supported by literature. In summary, CSNs lead to significantly improve the disease genetics prediction comparing with SBNs and provide leads for potential drug targets.

Availability and Implementation

nlp.case.edu/public/data/
caspo: a toolbox for automated reasoning on the response of logical signaling networks families
Authors: Videla Santiago , Saez-Rodriguez Julio , Guziolowski Carito , Siegel Anne
Published: November 2016

We introduce the caspo toolbox, a python package implementing a workflow for reasoning on logical networks families. Our software allows researchers to (i) learn a family of logical networks derived from a given topology and explaining the experimental response to various perturbations; (ii) classify all logical networks in a given family by their input-output behaviors; (iii) predict the response of the system to every possible perturbation based on the ensemble of predictions; (iv) design new experimental perturbations to discriminate among a family of logical networks; and (v) control a family of logical networks by finding all interventions strategies forcing a set of targets into a desired steady state.

Availability and Implementation

caspo is open-source software distributed under the GPLv3 license. Source code is publicly hosted at http://github.com/bioasp/caspo.
Green listed—a CRISPR screen tool
Authors: Panda Sudeepta Kumar , Boddul Sanjay V , Jiménez-Andrade Guillermina Yanek , Jiang Long , Kasza Zsolt , Fernandez-Ricaud Luciano , Wermeling Fredrik
Published: November 2016

Motivation

Genome editing using versions of the bacterial CRISPR/Cas9 system can be used to probe the function of selected genes in any organism. Green Listed is a web-based tool that rapidly designs custom CRISPR screens targeting sets of genes defined by the user. It could thus be used to design screens targeting for example all genes differentially expressed during a specific stimuli or all genes related to a specific pathway or function, as well as to generate targeted secondary screens following a large-scale screen.

Availability and Implementation

The software, including a demo function as well as explanatory texts and videos, is available through greenlisted.cmm.ki.se.