bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression
Authors: Leone Marina , Musa Gentian , Engel Felix Benedikt
Published: March 2018

Aims

After birth mammalian cardiomyocytes initiate a last cell cycle which results in binucleation due to cytokinesis failure. Despite its importance for cardiac regenerative therapies, this process is poorly understood. Here, we aimed at a better understanding of the difference between cardiomyocyte proliferation and binucleation and providing a new tool to distinguish these two processes.

Methods and results

Monitoring of cell division by time-lapse imaging revealed that rat cardiomyocyte binucleation stems from a failure to properly ingress the cleavage furrow. Astral microtubule required for actomyosin ring anchorage and thus furrow ingression were not symmetrically distributed at the periphery of the equatorial region during anaphase in binucleating cardiomyocytes. Consequently, RhoA, the master regulator of actomyosin ring formation and constriction, non-muscle myosin IIB, a central component of the actomyosin ring, as well as IQGAP3 were abnormally localized during cytokinesis. In agreement with improper furrow ingression, binucleation in vitro and in vivo was associated with a failure of RhoA and IQGAP3 to localize to the stembody of the midbody.

Conclusion

Taken together, these results indicate that naturally occurring cytokinesis failure in primary cardiomyocytes is due to an aberrant mitotic microtubule apparatus resulting in inefficient anchorage of the actomyosin ring to the plasma cell membrane. Thus, cardiomyocyte binucleation and division can be discriminated by the analysis of RhoA as well as IQGAP3 localization.
Three-dimensional structure of the Upper Scorpius association with the Gaia first data release
Authors: Galli Phillip A B , Joncour Isabelle , Moraux Estelle
Published: March 2018

Using new proper motion data from recently published catalogues, we revisit the membership of previously identified members of the Upper Scorpius association. We confirmed 750 of them as cluster members based on the convergent point method, compute their kinematic parallaxes, and combined them with Gaia parallaxes to investigate the 3D structure and geometry of the association using a robust covariance method. We find a mean distance of 146 ± 3 ± 6 pc and show that the morphology of the association defined by the brightest (and most massive) stars yields a prolate ellipsoid with dimensions of 74 × 38 × 32 pc3, while the faintest cluster members define a more elongated structure with dimensions of 98 × 24 × 18 pc3. We suggest that the different properties of both populations are an imprint of the star formation history in this region.
Why Public Comments Matter: The Case of the National Institutes of Health Policy on Single Institutional Review Board Review of Multicenter Studies
Authors: Ervin Ann-Margret , Taylor Holly A. , Ehrhardt Stephan , Meinert Curtis L.
Published: March 2018

Purpose

In 2014, the National Institutes of Health (NIH) requested public comments on a draft policy requiring NIH-funded, U.S.-based investigators to use a single institutional review board (sIRB) for ethical review of multicenter studies. The authors conducted a directed content analysis and qualitative summary of the comments and discuss how they shaped the final policy.

Method

Two reviewers independently assessed support for the policy from a review of comments on the draft policy in 2016. A reviewer conducted an open text review to identify prespecified and additional comment themes. A second researcher reviewed 20% of comments; discrepancies were resolved through discussion.

Results

The NIH received 167 comments: 65% (108/167) supportive of the policy, 23% (38/167) not supportive, and 12% (21/167) not indicating support. Clarifications or changes to the policy were suggested in 102/167 comments (61%). Criteria for selecting sIRBs were addressed in 32/102 comments (31%). Also addressed were institutional review board (IRB) responsibilities (39/102; 38%), cost (27/102; 26%), the role of local IRBs (14/102; 14%), and allowable policy exceptions (19/102; 19%). The NIH further clarified or provided guidance for selection criteria, IRB responsibilities, and cost in the final policy (June 2016). Local IRB reviews and exemptions guidance were unchanged.

Conclusions

In this case study, public comments were effective in shaping policy as the NIH modified provisions or planned supplemental guidance in response to comments. Yet critical knowledge gaps remain, and empirical data are necessary. The NIH is considering mechanisms to support the establishment of best practices for sIRB implementation.
Vaginal pH: a simple assessment highly correlated with vaginal morphology and symptoms in postmenopausal women
Authors: Tucker Kelly M. , Godha Keshav , Mirkin Sebastian , Archer David F.
Published: March 2018

Objective:

The aim of the study was to determine the utility of vaginal pH as a marker of menopause and vulvar and vaginal atrophy (VVA) before and after local estrogen treatment.

Methods:

Vaginal pH was determined using standard pH paper strips in two clinical trials involving postmenopausal women with signs and symptoms of VVA evaluated before and after intervention with vaginal estradiol in softgel capsules. The utility of vaginal pH was evaluated as a screening method for VVA due to menopause and correlations were analyzed between vaginal pH and VVA symptoms, physical changes, and maturation of the vaginal epithelium.

Results:

Changes in vaginal pH were significantly correlated with changes in superficial and parabasal cell counts; vaginal epithelial changes of color, integrity, thickness, and secretion; and the VVA symptoms of vaginal dryness and dyspareunia (vaginal pain with intercourse).

Conclusions:

Vaginal pH consistently correlated with parabasal and superficial cells and the visual vaginal epithelial changes and symptoms of dryness and dyspareunia, and is thus a simple outpatient procedure that reflects the hormonal milieu and its effects on the vaginal epithelium.
Association between waist-to-height ratio and anxiety in middle-aged women: a secondary analysis of a cross-sectional multicenter Latin American study
Authors: Arroyo Karen J. , Ramos-Torres Gabriela , Mezones-Holguin Edward , Blümel Juan E. , Barón Germán , Bencosme Ascanio , Benítez Zully , Bravo Luz M. , Calle Andrés , Flores Daniel , Espinoza María T. , Gómez Gustavo , Hernández-Bueno José A. , Martino Mabel , Lima Selva , Monterrosa Alvaro , Mostajo Desiree , Ojeda Eliana , Onatra William , Sánchez Hugo , Tserotas Konstantinos , Vallejo María S. , Witis Silvina , Zúñiga María C. , Chedraui Peter
Published: March 2018

Objective:

The aim of the study was to evaluate the association between waist-to-height ratio (WHtR) and anxiety in middle-aged women.

Methods:

We carried out a secondary analysis of data from a multicenter study of women between 40 and 59 years old from 11 Latin America countries. Anxiety was assessed using the Goldberg Anxiety and Depression Scale. WHtR was calculated according to World Health Organization standards and categorized in tertiles: upper, middle, and lower using 0.45 and 0.6 as cutoff values. Prevalence ratios (PRs) and 95% CIs were calculated by generalized linear models of Poisson family with robust standard errors, both crude and adjusted models based on statistical and epidemiological criteria.

Results:

Data of a total of 5,580 women were analyzed. Mean age was 49.7 ± 5.5 years, and 57.9% were postmenopausal. The 61.3% of women had anxiety and mean WHtR was 0.54 ± 0.1. In the crude model, compared with women in lower tertile, those in the middle (PR: 1.07; 95% CI, 1.01-1.13) and upper (PR: 1.23 95% CI, 1.07-1.29) WHtR tertile were significantly more likely to have anxiety. In the adjusted models, only women in upper tertile were, however, more likely of displaying anxiety than those in lower tertile (PR: 1.13; 95% CI, 1.08-1.18).

Conclusions:

In this series, WHtR was associated with anxiety in middle-aged women. It is advisable to further study this anthropometric measure in order for it to be incorporated in the routine clinical practice and evaluation of middle-aged women.
Climacteric-related symptoms in menopause transition and beyond: a prospective 19-year follow-up study on previously hysterectomized women
Authors: Katainen Riina , Engblom Janne R. , Polo-Kantola Päivi
Published: March 2018

Objective:

Only a few extended follow-up studies have investigated the natural progress of climacteric-related symptoms. The results have been conflicting. Thus, our aim was to evaluate, through a 19-year longitudinal study, whether these symptoms decrease or disappear as time elapses after menopause.

Methods:

Our study was a prospective follow-up survey of 65 hysterectomized peri or postmenopausal women. The women were interviewed at the baseline, and at 6 and 19 years thereafter. Changes in various climacteric-related symptoms were evaluated by repeated-measures analysis of variance with time as the independent variable. The analyses were adjusted for baseline age, body mass index, employment, and use of hormone therapy. Climacteric-related symptoms were evaluated with the Women's Health Questionnaire, of which we included seven symptom domains (vasomotor, sleep, depressive, anxiety/fears, cognitive, sexual, and somatic).

Results:

Vasomotor symptoms decreased remarkably during the follow-up period. In addition, a statistically significant decrease was found in sleep problems and cognitive difficulties. However, the decrease was minor, and thus probably clinically insignificant.

Conclusions:

The only symptom with notable decrease was vasomotor symptoms. The etiology of other symptoms, commonly connected to menopause transition, is probably multifactorial and not substantially dependent on the climacteric.
Characteristics and Health Outcomes of Post-9/11 Caregivers of US Service Members and Veterans Following Traumatic Brain Injury
Authors: Brickell Tracey A. , French Louis M. , Lippa Sara M. , Lange Rael T.
Published: March 2018

Objectives:

To (a) characterize a sample of post-9/11 caregivers providing help to service members and veterans (SMV) following traumatic brain injury (TBI), (b) examine the level of support provided, and (c) determine caregiver health and well-being outcomes.

Setting:

Military treatment facility.

Participants:

Caregivers (N = 278) of SMVs who sustained a mild, moderate, severe, or penetrating TBI (96.0% female; 86.0% spouse/partner; age: M = 38.7 years, SD = 10.4). Participants were divided into 3 groups on the basis of the level of support provided (low, medium, high).

Design:

Prospective observational.

Main Measures:

Caregiver Appraisal Scale, SF-36v2 Health Survey, Mayo-Portland Adaptability Inventory-4, Caregiver Questionnaire.

Results:

The majority of caregivers were helping an SMV with mild TBI and comorbid posttraumatic stress disorder/depression, who was injured in a blast-related incident during combat. Caregivers helped predominantly with activities of daily living and/or instrumental activities of daily living and spent more than 40 hours per week providing care. High-support caregivers were more likely to be caring for an SMV with comorbid posttraumatic stress disorder, report poor physical and mental health outcomes, and have a negative impact on employment and finances.

Conclusions:

A better understanding of protective factors is required to ensure that burden of care does not exceed the caregiver's health and financial capacity, or undermine the care, well-being, and recovery of the SMV.
Persistent Increased Enteric Glial Expression of S100β is Associated With Low-grade Inflammation in Patients With Diverticular Disease
Authors: Cossais François , Leuschner Sebastian , Barrenschee Martina , Lange Christina , Ebsen Michael , Vogel Ilka , Böttner Martina , Wedel Thilo
Published: March 2018

Background:

Diverticular disease (DD) is a common gastrointestinal inflammatory disorder associated with an enteric neuropathy. Although enteric glial cells (EGCs) are essential regulators of intestinal inflammation and motility functions, their contribution to the pathophysiology of DD remains unclear. Therefore, we analyzed the expression of specific EGC markers in patients with DD.

Materials and Methods:

Expression of the glial markers S100β, GFAP, Sox10, and Connexin 43 was analyzed by real-time quantitative PCR in colonic specimens of patients with DD and in that of controls. Protein expression levels of S100β, GFAP, and Connexin 43 were further analyzed using immunohistochemistry in the submucosal and myenteric plexus of patients with DD and in that of controls. Expression of the inflammatory cytokines tumor necrosis factor-α and interleukin-6 was quantified using qPCR, and infiltration of CD3+ lymphocytes was determined using immunohistochemistry.

Results:

Expression of S100β was increased in the submucosal and myenteric plexus of patients with DD compared with that in controls, whereas expression of other glial factors remained unchanged. This increased expression of S100β was correlated to CD3+ lymphocytic infiltrates in patients with DD, whereas no correlation was observed in controls.

Conclusions:

DD is associated with limited but significant alterations of the enteric glial network. The increased expression of S100β is associated with a persistent low-grade inflammation reported in patients with DD, further emphasizing the role of EGCs in intestinal inflammation.
Prospective Follow-up Study of the Recurrence of Pancreatic Cancer Diagnosed at an Early Stage
Authors: Ikemoto Juri , Hanada Keiji , Minami Tomoyuki , Okazaki Akihito , Abe Tomoyuki , Amano Hironobu , Yonehara Shuji
Published: March 2018

Objectives

Most patients with pancreatic cancer (PC) demonstrate recurrences in the form of metastatic disease. We prospectively evaluated recurrence in PC cases diagnosed at an early stage.

Methods

Thirty cases of PC stage 0 or IA were prospectively followed for at least 1 year after initial surgery. We performed blood tests and contrast-enhanced computed tomography (CT) every 3 to 6 months. Endoscopic ultrasonography (EUS) was performed if CT revealed abnormal findings in the remnant pancreas (RP).

Results

The median follow-up period was 53.9 months. Pancreatic cancer recurred in the RP (n = 8) and liver (n = 1). Computed tomography revealed mass lesions in 5 cases, a cystic lesion in 2 cases, and pancreatic duct dilatation in 1 case. Endoscopic ultrasonography detected mass lesions in 3 cases without a detectable mass on CT. The sensitivity of EUS-guided fine-needle aspiration and pancreatic juice cytology was 75%. Five of 8 cases underwent total resection of the RP, with pathologic findings revealing stage IA in 1 case, stage II in 1 case, and stage III in 3 cases.

Conclusions

Careful long-term follow-up including EUS should be performed in resected PC cases diagnosed at an early stage to check recurrence in the RP.
Barriers and Facilitators to a Good Bowel Preparation for Colonoscopy in Children
Authors: Hart Lara , Nael Humaira , Longmire Natasha M. , Zachos Mary
Published: March 2018

Background:

A well‐visualized colon during colonoscopy has a direct impact on interpretation of findings and need for repeat procedure. Studies have been conducted in the adult population to assess factors contributing to improved bowel preparation. The primary aim of this study was to determine barriers and facilitators to good preparation in children.

Methods:

A qualitative descriptive approach was utilized. Children age 2 to 18 years old, and their parents were recruited from the McMaster University Gastroenterology clinic from May 2015 to January 2016. Semistructured interviews were conducted assessing the understanding of the preparation protocol, and the compliance and tolerability of the preparation. A thematic analysis was conducted.

Results:

Eleven families participated (7 children and 14 parents). Fifty percent of the children were under 11 years of age, and 73% were undergoing bowel preparation for the first time. Participants identified 26 subthemes, which were categorized into 4 broad themes. Barriers included confusion regarding mixing of the preparation and allowable diet during the preparation day, as well as lack of clarity on expected stool end goals. Facilitators included ease of access of the gastroenterology team, small volume of liquid mixed with the preparation, few adverse effects, and the provision of an understandable handout. Parental motivation to achieve a good outcome was also a facilitator.

Conclusions:

This is the first qualitative study focusing on children undergoing a home bowel preparation for a colonoscopy. Being able to identify barriers and facilitators will allow gastroenterologists to improve the quality of bowel preparation and overall experience for the pediatric population.
Comparison of Transjugular Liver Biopsy and Percutaneous Liver Biopsy With Tract Embolization in Pediatric Patients
Authors: Tulin‐Silver Sheryl , Obi Chrystal , Kothary Nishita , Lungren Matthew P.
Published: March 2018

Purpose:

The aim of the study was to compare safety and efficacy of transjugular liver biopsy (TJLB) and percutaneous liver biopsy (PLB) with tract embolization in pediatric patients with liver disease.

Materials and Methods:

TJLB and PLB between December 2009 and October 2015 were retrospectively reviewed. Primary endpoints were adequate sampling and complication rate. Patient age, weight, coagulation factors, ascites, blood transfusions, adequacy of biopsy sample, number of biopsy samples, and complications were compared.

Results:

There were 39 TJLB (average age 10.6 years) and 120 PLB (average age 7.1 years) (P value <0.05). Average weight was 40.2 kg for TJLB and 26.8 kg for PLB (P value <0.05). Average platelets were 155 for TJLB and 252 for PLB (P value <0.05). Average international normalized ratio was 1.7 for TJLB and 1.3 for PLB (P value <0.05). Mean postbiopsy hematocrit decrease was 0.8 and 0.9, for TJLB and PLB, respectively. Mean postbiopsy hemoglobin decrease was 0.3 in both groups. Number of core biopsy samples was 4.5 and 4.3, for TJLB and PLB, respectively. There was 1 biopsy yielding insufficient sample in each group. TJLB had 1 (2.6%) complication of supraventricular tachycardia. PLB had 4 (3.3%) complications, with 1 hemoperitoneum, 1 hypotension, 1 patient with decreased hemoglobin, and 1 patient with bilious drainage from the biopsy site.

Conclusions:

TJLB and PLB with gelatin sponge pledget tract embolization are both safe and effective for the diagnosis of hepatic disease in pediatric patients. To avoid radiation, PLB may be considered as first‐line approach in the pediatric population, even in the setting of coagulopathy.
Somatic Mutations and Intratumoral Heterogeneity of MYH11 Gene in Gastric and Colorectal Cancers
Authors: Jo Yun Sol , Kim Min Sung , Yoo Nam Jin , Lee Sug Hyung
Published: March 2018

MYH11 functions as a contractile protein, converting chemical energy into mechanical energy through adenosine triphosphate hydrolysis. In cancers, an oncogenic fusion CBFB/MYH11 and frameshift mutations have been reported. Truncating mutants of MYH11 exhibited increased ATPase and motor activity, suggesting their roles in energy balance and movement of cancer cells. MYH11 gene has a mononucleotide repeat (C8) in the coding sequences that could be a mutational target in the cancers exhibiting microsatellite instability (MSI). We analyzed the C8 repeat in 79 gastric cancers (GCs) and 124 colorectal cancers (CRCs) including 113 high MSI (MSI-H) and 90 microsatellite stable/low MSI cases. We detected MYH11 frameshift mutations in 4 (11.8%) GCs and 17 (21.5%) CRCs with MSI-H (21/113, 18.6%), but not in microsatellite stable/low MSI cancers (0/90) (P<0.001). We also analyzed intratumoral heterogeneity (ITH) of the MYH11 frameshift mutations and found that 10 of 16 CRCs (62.5%) harbored the regional ITH. Our results show that MYH11 gene harbors somatic frameshift mutations mostly associated with mutational ITH, which together may be features of MSI-H GCs and CRCs. Practically, the data suggest that multiregional analysis is needed for a better evaluation of mutation status in MSI-H tumors to overcome ITH.
Presentation and Investigation of Pediatric Bone and Joint Infections in the Pediatric Emergency Department
Authors: Akinkugbe Olugbenga , Stewart Charles , McKenna Caoimhe
Published: March 2018

Objective

The objective of this study was to evaluate the presenting features of bone and joint infections with a view to identify distinguishing trends that will be useful for pediatric emergency departments.

Methods

We performed a retrospective review of patient records over a 12-year period in the pediatric emergency department of a large regional pediatric teaching center serving a diverse population.

Results

There were 88 cases of osteoarticular infections during the study period. Pain, fever, and impaired function were commonly reported, but overall, there was inconsistency in the presenting features. Inflammatory makers were sensitive tools, particularly in combination. When C-reactive protein, total white cell count, and erythrocyte sedimentation rate were all abnormal, 98% of bone and joint infections were identified.

Causative organisms were identified in only 38% of cases, mostly from cultures of synovial fluid and bone. Streptococcal organisms were significantly more likely to be isolated in children under 5 years than in children over 5 years (P = <0.014). Staphylococcal organisms were significantly more likely to be isolated in children over 5 years than in children under 5 years (P = <0.001). Identification of virulent organisms such as Panton-Valentine leukocidin Staphylococcus aureus and methicillin-resistant S. aureus in our study should prompt review of diagnostic techniques and antibiotic choices.

Conclusions

Overall, children under 5 years were significantly more likely to be diagnosed with septic arthritis than osteomyelitis (P = 0. 006). Children over 12 years were significantly more likely to be diagnosed with osteomyelitis than septic arthritis (P = 0. 019). These trends are useful to consider at presentation and in cases of diagnostic uncertainty.
Poststroke Depression
Authors: Arwert Henk J. , Meesters Jorit J.L. , Boiten Jelis , Balk Ferdi , Wolterbeek Ron , Vliet Vlieland Thea P.M.
Published: March 2018

Objective

The aim of the study was to ascertain the prevalence of depressive mood and its determinants in the chronic phase after stroke.

Design

Five hundred seventy-six consecutive patients were invited to participate 2 to 5 yrs after hospitalization for a first-ever stroke. Stroke characteristics at hospitalization were collected retrospectively from medical records. Patients and their caregivers completed questionnaires on depression (Hospital Anxiety and Depression Scale [HADS]), sociodemographic characteristics, healthcare usage, daily activities, quality of life, and caregiver strain. Patients with HADS depression scores of less than 8 were compared with patients with HADS depression scores of 8 or higher by means of univariate logistic regression analyses, adjusted for age, sex, and Barthel Index at discharge.

Results

Two hundred seven patients (36%) returned the questionnaires. After a mean follow-up of 36.3 mos, 67 patients (34%) had a HADS depression score of 8 or higher. Male sex and being born abroad were statistically significantly associated with a high HADS depression score, adjusted for age, sex, and stroke severity. Depressed patients had higher anxiety levels, a more avoidant coping style, less daily activities, and a lower quality of life; their caregivers experienced a higher burden.

Conclusions

In the chronic phase after stroke, a considerable proportion of patients has depressive symptoms. This seems to be related to sex, country of origin, anxiety, coping style, daily activities, quality of life, and caregivers' strain. Future research should focus on causal relationships and opportunities for treatment.
Arterial Lactate Concentration at the End of Liver Transplantation Is an Early Predictor of Primary Graft Dysfunction
Authors: Golse Nicolas , Guglielmo Nicola , El Metni Albert , Frosio Fabio , Cosse Cyril , Naili Salima , Ichaï Philippe , Ciacio Oriana , Pittau Gabriella , Allard Marc-Antoine , Castaing Denis , S. A. Cunha Antonio , Cherqui Daniel , Adam René , Vibert Eric
Published: March 2018

Background:

Although many prognostic factors of primary graft dysfunction after liver transplantation (LT) are available, it remains difficult to predict failure in a given recipient.

Objective:

We aimed to determine whether the intraoperative assay of arterial lactate concentration at the end of LT (LCEOT) might constitute a reliable biological test to predict early outcomes [primary nonfunction (PNF), early graft dysfunction (EAD)].

Methods:

We reviewed data from a prospective database in a single center concerning patients transplanted between January 2015 and December 2016 (n = 296).

Results:

There was no statistical imbalance between the training (year 2015) and validation groups (year 2016) for epidemiological and perioperative feature. Ten patients (3.4%) presented with PNF, and EAD occurred in 62 patients (20.9%); 9 patients died before postoperative day (POD) 90. LCEOT ≥5 mmol/L was the best cut-off point to predict PNF (Se=83.3%, SP=74.3%, positive likelihood ratio (LR+)=3.65, negative likelihood ratio (LR−)=0.25, diagnostic odds ratio (DOR)=14.44) and was predictive of PNF (P = 0.02), EAD (P = 0.05), and death ≤ POD90 (P = 0.06). Added to the validated BAR-score, LCEOT improved its predictive value regarding POD 90 survival with a better AUC (0.87) than BAR score (0.74). The predictive value of LCEOT was confirmed in the validation cohort.

Conclusion:

As a reflection of both hypoperfusion and tissue damage, the assay of arterial LCEOT ≥5 mmol/L appears to be a strong predictor of early graft outcomes and may be used as an endpoint in studies assessing the impact of perioperative management. Its accessibility and low cost could impose it as a reliable parameter to anticipate postoperative management and help clinicians for decision-making in the first PODs.
Spectral analysis of localized rotating waves in parabolic systems
Authors: Beyn Wolf-Jürgen , Otten Denny
Published: March 2018

In this paper, we study the spectra and Fredholm properties of Ornstein–Uhlenbeck operators

where

is the profile of a rotating wave satisfying

as

, the map

is smooth and the matrix

has eigenvalues with positive real parts and commutes with the limit matrix

. The matrix

is assumed to be skew-symmetric with eigenvalues (λ
1
,…,λ

d

)=(±i
σ
1
,…,±i
σ

k

,0,…,0). The spectra of these linearized operators are crucial for the nonlinear stability of rotating waves in reaction–diffusion systems. We prove under appropriate conditions that every

satisfying the dispersion relation

belongs to the essential spectrum

in
L

p

. For values Re λ to the right of the spectral bound for

, we show that the operator

is Fredholm of index 0, solve the identification problem for the adjoint operator

and formulate the Fredholm alternative. Moreover, we show that the set

belongs to the point spectrum

in
L

p

. We determine the associated eigenfunctions and show that they decay exponentially in space. As an application, we analyse spinning soliton solutions which occur in the Ginzburg–Landau equation and compute their numerical spectra as well as associated eigenfunctions. Our results form the basis for investigating the nonlinear stability of rotating waves in higher space dimensions and truncations to bounded domains. This article is part of the themed issue ‘Stability of nonlinear waves and patterns and related topics’.
Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer
Authors: Berndt Nikolaus , Egners Antje , Mastrobuoni Guido , Vvedenskaya Olga , Fragoulis Athanassios , Dugourd Aurélien , Bulik Sascha , Pietzke Matthias , Bielow Chris , Gassel Rob van , Damink Steven Olde , Erdem Merve , Saez-Rodriguez Julio , Holzhütter Hermann-Georg , Kempa Stefan , Cramer Thorsten
Published: March 2018

Metabolic alterations can serve as targets for diagnosis and therapy of cancer. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation. Here, we applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterize metabolic reprogramming in murine liver cancer. We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to scale maximal enzyme capacities. Model simulations predicted tumor - specific alterations of various components of the CCM, a selected number of which were subsequently verified byin vitroandin vivoexperiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumor cell killing. Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer.
Individual Variation in Brain Network Topology Predicts Emotional Intelligence
Authors: George Ling , Ivy Lee , Synthia Guimond , Olivia Lutz , Neeraj Tandon , Dost Öngür , Shaun Eack , Kathryn Lewandowski , Matcheri Keshavan , Roscoe Brady
Published: March 2018

Background

Social cognitive ability is a significant determinant of functional outcome and deficits in social cognition are a disabling symptom of psychotic disorders. The neurobiological underpinnings of social cognition are not well understood, hampering our ability to ameliorate these deficits.

Objective

Using ‘resting-state’ fMRI (functional magnetic resonance imaging) and a trans-diagnostic, data-driven analytic strategy, we sought to identify the brain network basis of emotional intelligence, a key domain of social cognition.

Methods

Study participants included 60 participants with a diagnosis of schizophrenia or schizoaffective disorder and 46 healthy comparison participants. All participants underwent a resting-state fMRI scan. Emotional Intelligence was measured using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). A connectome-wide analysis of brain connectivity examined how each individual brain voxel’s connectivity correlated with emotional intelligence using multivariate distance matrix regression (MDMR).

Results

We identified a region in the left superior parietal lobule (SPL) where individual network topology predicted emotional intelligence. Specifically, the association of this region with the Default Mode Network predicted higher emotional intelligence and association with the Dorsal Attention Network predicted lower emotional intelligence. This correlation was observed in both schizophrenia and healthy comparison participants.

Conclusion

Previous studies have demonstrated individual variance in brain network topology but the cognitive or behavioral relevance of these differences was undetermined. We observe that the left SPL, a region of high individual variance at the cytoarchitectonic level, also demonstrates individual variance in its association with large scale brain networks and that network topology predicts emotional intelligence.
miR-21-5p and miR-30a-5p are identical in human and bovine, have similar isomiR distribution, and cannot be used to identify xenomiR uptake from cow milk
Authors: Fromm Bastian , Tosar Juan Pablo , Lu Yin , Halushka Marc K. , Witwer Kenneth W.
Published: March 2018

microRNAs (miRNAs) are often highly conserved across species, but species-specific sequences are known. In addition, miRNA “isomiRs” arise from the same precursor molecule but differ in post-processing length and modification, usually at the 3’ end. A recently published feeding study reported the intriguing result that two bovine milk-specific miRNAs were taken up into human circulation after ingestion of bovine milk. Unfortunately, this interpretation is based on annotation errors in a public microRNA database. Reanalysis using databses including the MirGeneDB database reveals that the miRNAs in question, miR-21-5p and miR-30a-5p, arise from 100% identical 5’ precursor sequences in human and bovine, and the putative bovine-specific isomiRs appear to be depleted, not enriched, in bovine milk. Thus, enrichment of these isomiRs in human blood is inconsistent with uptake of xenomiRs and likely betrays endogenous miRNA regulation in response to diet or technical artifact.
Imputing missing distances in molecular phylogenetics
Authors: Xia Xuhua
Published: March 2018

Missing data are frequently encountered in molecular phylogenetics and need to be imputed. For a distance matrix with missing distances, the least-squares approach is often used for imputing the missing values. Here I develop a method, similar to the expectation-maximization algorithm, to impute multiple missing distance in a distance matrix. I show that, for inferring the best tree and missing distances, the minimum evolution criterion is not as desirable as the least-squares criterion. I also discuss the problem involving cases where the missing values cannot be uniquely determined, e.g., when a missing distance involve two sister taxa. The new method has the advantage over the existing one in that it does not assume a molecular clock. I have implemented the function in DAMBE software which is freely available at available at http://dambe.bio.uottawa.ca
Ultra-parallel ChIP-seq by barcoding of intact nuclei
Authors: Arrigoni L. , Al-Hasani H. , Ramírez F. , Panzeri I. , Ryan D.P , Santacruz D. , Kress N. , Pospisilik A. , Böenisch U. , Manke T.
Published: March 2018

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is an invaluable tool for mapping chromatin-associated proteins. However, sample preparation is still a largely individual and labor-intensive process that hinders assay throughput and comparability. Here, we present a novel method for ultra-parallelized high-throughput ChIP-seq that addresses the aforementioned problems. The method, called RELACS (Restriction Enzyme-based Labeling of Chromatin in Situ), employs barcoding of chromatin within intact nuclei extracted from different sources (e.g. tissues, treatments, time points). Barcoded nuclei are pooled and processed within the same ChIP, for maximal comparability and significant workload reduction. The choice of user-friendly, straightforward, enzymatic steps for chromatin fragmentation and barcoding makes RELACS particularly suitable for implementation large-scale clinical studies and scarce samples. RELACS can generate ChIP-seq libraries from hundreds of samples within three days and with less than 1000 cells per sample.
Measurement error and variant-calling in deep Illumina sequencing of HIV
Authors: Howison Mark , Coetzer Mia , Kantor Rami
Published: March 2018

Motivation

Next-generation deep sequencing of viral genomes, particularly on the Illumina platform, is increasingly applied in HIV research. Yet, there is no standard protocol or method used by the research community to account for measurement errors that arise during sample preparation and sequencing. Correctly calling high and low frequency variants while controlling for erroneous variant calls is an important precursor to downstream interpretation, such as studying the emergence of HIV drug-resistance mutations, which in turn has clinical applications and can improve patient care.

Results

We developed a new variant-calling pipeline, hivmmer, for Illumina sequences from HIV viral genomes. First, we validated hivmmer by comparing it to other variant-calling pipelines on real HIV plasmid data sets, which have known sequences. We found that hivmmer achieves a lower rate of erroneous variant calls, and that all methods agree on the frequency of correctly called variants. Next, we compared the methods on an HIV plasmid data set that was sequenced using an amplicon-tagging protocol called Primer ID, which is designed to reduce errors and amplification bias during library preparation. We show that the Primer ID consensus does indeed have fewer erroneous variant calls compared to the variant-calling pipelines, and that hivmmer more closely approaches this low error rate compared to the other pipelines. Surprisingly, the frequency estimates from the Primer ID consensus do not differ significantly from those of the variant-calling pipelines. Finally, we built a predictive model for classifying errors in the hivmmer alignment, and show that it achieves high accuracy for identifying erroneous variant calls.

Availability

hivmmer is freely available for non-commercial use from https://github.com/mhowison/hivmmer.

Contact

mhowison@brown.edu
Dual BRD4 and AURKA Inhibition is Synergistic against MYCN-amplified and nonamplified Neuroblastoma
Authors: Felgenhauer Joshua , Tomino Laura , Selich-Anderson Julia , Bopp Emily , Shah Nilay
Published: March 2018

A majority of cases of high-risk neuroblastoma, an embryonal childhood cancer, are driven by MYC or MYCN-driven oncogenic signaling. While considered to be directly “undruggable” therapeutically, MYC and MYCN can be repressed transcriptionally by inhibition of Bromodomain-containing protein 4 (BRD4) or destabilized posttranslationally by inhibition of Aurora Kinase A (AURKA). Preclinical and early-phase clinical studies of BRD4 and AURKA inhibitors, however, show limited efficacy against neuroblastoma when used alone. We report our studies on the concomitant use of the BRD4 inhibitor IBET-151 and AURKA inhibitor alisertib. We show that, in vitro, the drugs act synergistically to inhibit viability in three models of high-risk neuroblastoma. We demonstrate that this synergy is driven, in part, by the ability of IBET-151 to mitigate reflexive upregulation of AURKA, MYC, and MYCN in response to AURKA inhibition. We then demonstrate that IBET-151 and alisertib are effective in prolonging survival in three xenograft neuroblastoma models in vivo, and this efficacy is augmented by the addition of the antitubule chemotherapeutic vincristine. These data suggest that epigenetic and posttranslational inhibition of MYC/MYCN-driven pathways may have significant clinical efficacy against neuroblastoma.

Abbreviations

AURKA, aurora kinase A; BRD4, Bromodomain-containing protein 4; CI, combination index; Fa, fraction affected; LOH, loss of heterozygosity; 11q, long arm of chromosome 11

Funding sources

This work was supported by the Families for a Cure foundation (grant number 20064014) and CancerFree Kids (grant number 82178416).
Modelling Large, Dynamic, and Heterogeneous Populations Using DNA Libraries
Authors: Andrade Helena , Thomas Alvin K. , Lin Weilin , Reddavide Francesco V. , Zhang Yixin
Published: March 2018

The study of any population of large size and high diversity is limited by the lack of data and associated insights. For a pool of individuals, each associated with a unique characteristic feature, as the pool size grows, the possible interactions increase exponentially, quickly beyond the scope of computation, not to mention experimental manipulation and analysis. Herein, we report a facile RT-PCR-based method, to correlate the amplification curves with various DNA libraries of defined diversity, and perform operations with groups of quaternary numbers as input and diversity as output. An attractive feature of this approach is the possibility of realizing parallel computation with an eventually unlimited number of variables. We demonstrate that DNA libraries can be used to model heterogeneous populations, exhibiting functions such as self-protection, subjected to biased expansion, and to evolve into complex structures. Moreover, the method can be applied to drug discovery using DNA-encoded chemical library (DECL) technology, to optimize selection conditions for identifying potent and specific bio-molecular interactions.
Lean implementation in small- and medium-sized enterprises
Authors: Sahoo Saumyaranjan , Yadav Sudhir
Published: March 2018

Purpose

The purpose of this paper is to examine the extent to which lean management practices are adopted by small- and medium-sized manufacturing organizations in India and their impact on firm’s operational performance (OP). Also, the paper makes an attempt to identify the barriers and challenges faced by Indian SMEs that are striving to succeed with improvement efforts based on lean manufacturing.

Design/methodology/approach

In this paper, acceptability and implementation of lean manufacturing in Indian Manufacturing SMEs were analyzed using three constructs, namely, process improvement (PI), flow management (FM) and waste minimization (WM). The responding firms were categorized into “lean-Beginners,” “In-transition lean” and “lean” group based on their phases of lean implementation. Using a survey questionnaire, data were collected from 121 manufacturing SMEs in India. Lean tools and barriers, identified from the literature review, were also included in the survey. The reliability and validity of the practice and performance measures were evaluated. Correlation analysis was employed to investigate the effects of three constructs on OP.

Findings

The results indicate that all the three lean constructs are significantly related to OP. In the context of Indian manufacturing SMEs, “PI” and “WM” practices have shown a higher level of significance on OP, compared to “FM” practices. “5S -workplace organization” was found to be the most practiced lean tool. “Attitude of workmen” was highlighted as the main obstacle in successfully implementing lean. The findings suggest overall positive effects as a result of applying lean tools and philosophy in Indian SMEs.

Research limitations/implications

The research results may lack qualitative justification because of the chosen research approach. Therefore, the researchers are encouraged to explore the inter-relationship among various lean tools/practices and performance criteria by conducting a qualitative study in the form of a case study or action research.

Practical implications

This paper is a beneficial source of information that highlights the contribution of lean implementation in enhancing manufacturing productivity. The major tools and techniques used by Indian SMEs have been highlighted and discussed; it could be a genuine source of motivation to lean practitioner and entrepreneurs of SMEs to go in for lean implementation. The findings are also expected to benefit the lean practitioners and entrepreneurs of SMEs to focus on vital issues to facilitate successful lean implementation in an organization.

Originality/value

The paper demonstrates that practical implication of lean implementation can bring real breakthroughs in productivity to small- and medium-scale manufacturing firms.
A fuzzy fault tree analysis based risk assessment approach for enterprise resource planning projects
Authors: Moeinedini Mina , Raissi Sadigh , Khalili-Damghani Kaveh
Published: March 2018

Purpose

Enterprise resource planning (ERP) is assumed as a commonly used solution in order to provide an integrated view of core business processes, including product planning, manufacturing cost, delivery, marketing, sales, inventory management, shipping and payment. Selection and implementation of a suitable ERP solution are not assumed a trivial project because of the challenging nature of it, high costs, long-duration of installation and customization, as well as lack of successful benchmarking experiences. During the ERP projects, several risk factors threat the successful implementation of the project. These risk factors usually refer to different phases of the ERP projects including purchasing, pilot implementation, teaching, install, synchronizing, and movement from old systems toward new ones, initiation and utilization. These risk factors have dominant effects on each other. The purpose of this paper is to explore the hybrid reliability-based method is proposed to assess the risk factors of ERP solutions.

Design/methodology/approach

In this regard, the most important risk factors of ERP solutions are first determined. Then, the interactive relations of these factors are recognized using a graph based method, called interpretive structural modeling. The resultant network of relations between these factors initiates a new viewpoint toward the cause and effect relations among risk factors. Afterwards, a fuzzy fault tree analysis is proposed to calculate Failure Fuzzy Possibility (FFP) for the basic events of the fault tree leading to a quantitative evaluation of risk factors.

Findings

The whole proposed method is applied in a well-known Iranian foodservice distributor as a case study. The most impressive risk factors are identified, classified and prioritized. Moreover, the cause and effect diagram between the risk factors are identified. So, the ERP leader can plan a low-risk project and increase the chance of success.

Originality/value

According to the authors’ best knowledge, such approach was not reported before in the literature of ERP risk assessments.
Investigating the role of social media in polio prevention in India: a Delphi-DEMATEL approach
Authors: Kumar Anil , Kaviani Mohamad Amin , Bottani Eleonora , Dash Manoj Kumar , Zavadskas Edmundas Kazimieras
Published: March 2018

Purpose

This study aims to evaluate the role of social media (SM) tools in polio prevention in an Indian context by using a hybrid Delphi-decision-making trial and evaluation laboratory (DEMATEL) approach.

Design/methodology/approach

A preliminary list of suitable evaluation criteria was derived from an extensive literature review. Ten experts were then contacted to collect data and finalize the most prominent criteria by using the Delphi method. To establish cause-effect relationships among the criteria, further data were collected from 21 experts. The DEMATEL method was applied to process and interpret the data collected.

Findings

The analysis grouped criteria into two sets, i.e. cause and effect. The results show that awareness of social cause and government utilization of resources fall into the cause group; these elements are critical as both directly affect the remaining criteria. These outcomes can help government and businesses to utilize SM for public health surveillance, e.g. to promote schemes/initiatives through sites concerning polio or related health issues.

Practical implications

The findings of this research are useful for governments and individual companies to conceive their marketing initiatives akin to polio prevention issues by using SM.

Originality/value

Despite the emergence of SM, there has been little discussion in existing literature on their role in polio prevention; however, measuring such role could be useful in practice to help decision-makers in exploiting the potential of SM in the health-care context. To fill this gap, this study aims to measure the role of SM in polio prevention in the Indian context and to create a cause-effect evaluation model. Using an integrated Delphi-DEMATEL framework for decision-making in the health-care context is another novelty of this study.