bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cdh2 stabilizes FGFR1 and contributes to primed-state pluripotency in mouse epiblast stem cells
Authors: Takehara Toshiyuki , Teramura Takeshi , Onodera Yuta , Frampton John , Fukuda Kanji 
Published: September 2015

AbstractThe cell adhesion molecule Cadherin 2 (Cdh2) plays important roles in somatic cell adhesion, proliferation and migration. Cdh2 is also highly expressed in mouse epiblast stem cells (mEpiSCs), but its function in these cells is unknown. To understand the function of Cdh2 in mEpiSCs, we compared the expression of pluripotency-related genes in mEpiSCs and mouse embryonic stem cells (mESCs) after either Cdh2 knockdown or Cdh2 over-expression. Introduction of specific siRNA against Cdh2 led to attenuation of pluripotency-related genes. Pluripotent gene expression was not recovered by over-expression of Cdh1 following Cdh2 knockdown. Western blot analysis and co-immunoprecipitation assays revealed that Cdh2 stabilizes FGFR1 in mEpiSCs. Furthermore, stable transfection of mESCs with Cdh2 cDNA followed by FGF2 supplementation accelerated cell differentiation. Thus, Cdh2 contributes to the establishment and maintenance of FGF signaling-dependent self-renewal in mEpiSCs through stabilization of FGFR1.
Endoplasmic reticulum protein 29 (ERp29) confers radioresistance through the DNA repair gene, O6-methylguanine DNA-methyltransferase, in breast cancer cells
Authors: Chen Shaohua , Zhang Yu , Zhang Daohai 
Published: September 2015

AbstractResistance of cancer cells to radiotherapy is a major clinical problem in cancer treatment. Therefore, understanding the molecular basis of cellular resistance to radiotherapy and identification of novel targets are essential for improving treatment efficacy for cancer patients. Our previous studies have demonstrated a significant role of ERp29 in breast cancer cell survival against doxorubicin-induced genotoxic stress. We here reported that ERp29 expression in the triple negative MDA-MB-231 breast cancer cells significantly increased cell survival against ionizing radiation. Methylation PCR array analysis identified that ERp29 expression increased promoter hypomethylation of the DNA repair gene, O6-methylguanine DNA-methyltransferase (MGMT), by downregulating DNA methyltransferase 1. Knockdown of MGMT in the ERp29-transfected cancer cells increased radiosensitivity, leading to a decreased post-irradiation survival. In addition, radiation treatment in the MGMT-knockdown cells elevated phosphorylation of γ-H2AX and cleavage of caspase 3, indicating that depletion of MGMT facilitates DNA double strands breaks and increases cell apoptosis. Hence, our studies prove a novel function of ERp29\MGMT in cancer cell survival against radiation. Targeting ERp29\MGMT axis may be useful for providing better treatment efficacy in combination with radiotherapy in breast cancer.
Characterization of DNA variants in the human kinome in breast cancer
Authors: Agarwal Divyansh , Qi Yuan , Jiang Tingting , Liu Xiuping , Shi Weiwei , Wali Vikram B. , Turk Benjamin , Ross Jeffrey S , Fraser Symmans W , Pusztai Lajos , Hatzis Christos 
Published: September 2015

AbstractKinases play a key role in cancer biology and serve as potential clinically useful targets for designing cancer therapies. We examined nucleic acid variations in the human kinome and several known cancer-related genes in breast cancer. DNA was extracted from fine needle biopsies of 73 primary breast cancers and 19 metastatic lesions. Targeted sequencing of 518 kinases and 68 additional cancer related genes was performed using the SOLiD sequencing platform. We detected 1561 unique, non-synonymous variants in kinase genes in the 92 cases and 74 unique variants in 43 kinases that were predicted to have major functional impact on the protein. Three kinase groups—CMGC, STE and TKL—showed greater mutational load in metastatic compared to primary cancer samples, however, after correction for multiple testing the difference was significant only for the TKL group (P = 0.04). We also observed that a higher proportion of histologic grade 1 and 2 cases had high functional impact variants in the SCYL2 gene compared with grade 3 cases. Our findings indicate that individual breast cancers harbor a substantial number of potentially functionally important nucleotide variations in kinase genes, most of which are present in unique combinations and include both somatic and germline functional variants.
Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway
Authors: Brum Andrea M. , van de Peppel Jeroen , van der Leije Cindy S. , Schreuders-Koedam Marijke , Eijken Marco , van der Eerden Bram C. J. , van Leeuwen Johannes P. T. M. 
Published: September 2015

Significance
Osteoporosis, a disease characterized by increased bone fragility and fracture risk, affects over 20% of the ever-growing elderly population. It is important to further our knowledge of bone cell biology so we can develop new bone anabolic treatments. By combining genomic and bioinformatic tools against the backdrop of osteogenic differentiating human mesenchymal stromal cells, we have identified a previously unidentified bone anabolic compound that induces osteoblast differentiation in a subset of the hMSC population through cytoskeletal changes and increased bone morphogenetic protein 2 activity. Through this novel approach we identified an important mechanism of lineage allocation and demonstrated the significance of cytoskeletal organization in osteogenic differentiation, providing us with a novel mechanism for bone formation to target for new osteoporosis treatments.
Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins
Authors: Gautam Avneesh Kumar , Panse Yogesh , Ghosh Payel , Reza Malik Johid , Mullick Jayati , Sahu Arvind 
Published: September 2015

SignificanceThe complement system discriminates self from nonself targets solely owing to the presence of complement regulators on the host cells, which primarily belong to the regulators of complement activation (RCA) protein family. These regulators control complement activation on the host cell surface by two mechanisms termed “cofactor activity” (CFA) and “decay-accelerating activity.” Here, we have identified the critical structural determinants of an RCA protein responsible for imparting the CFA and show that these determinants bridge MG2 (macroglobulin-2) and CUB (complement C1r-C1s, Uegf, Bmp1) domains of C3b and interact with factor I. As a proof of principle, we show that incorporation of putative membrane cofactor protein (CD46) regions responsible for the bridging and factor I interaction in decay acceleration factor (CD55) results in gain of function. We, thus, define the molecular events that govern CFA.
Discriminating direct and indirect connectivities in biological networks
Authors: Kang Taek , Moore Richard , Li Yi , Sontag Eduardo , Bleris Leonidas 
Published: September 2015

Significance
We used a combination of computational and theoretical approaches coupled to synthetic biology experimentation in mammalian cells to study direct and indirect connectivities in biological networks. After subjecting benchmark circuits to a range of perturbations, we recovered the edge weights using nonparametric single-cell data resampling coupled with modular response analysis. We discovered that inferred weights of specific network edges undergo divergent shifts under differential perturbations, and that the particular behavior is topology dependent. Incorporating this insight in the analysis of high-throughput experiments may provide a sought-after solution to a longstanding reverse engineering problem.
SPARC triggers a cell-autonomous program of synapse elimination
Authors: López-Murcia Francisco J. , Terni Beatrice , Llobet Artur 
Published: September 2015

Significance
Neuronal circuits require eliminating the excess of synaptic connectivity to acquire complete functionality. Here we show that secreted protein acidic and rich in cysteine (SPARC), a molecule secreted exclusively by glia, is a trigger for synapse elimination. Acting through a region located in its C-terminal domain, SPARC activates synapse disassembly and formation of retracted axon terminals in cholinergic neurons in vitro. The onset of this cell-autonomous program in the tails of living tadpoles drives a loss of motor innervation, causing transient paralysis. We propose that along with their well-established role in ending the process of synapse elimination by engulfing retracted terminals, glia can also act as a trigger through the release of specific molecules, such as SPARC.
Structural and evolutionary relationships of “AT-less” type I polyketide synthase ketosynthases
Authors: Lohman Jeremy R. , Ma Ming , Osipiuk Jerzy , Nocek Boguslaw , Kim Youngchang , Chang Changsoo , Cuff Marianne , Mack Jamey , Bigelow Lance , Li Hui , Endres Michael , Babnigg Gyorgy , Joachimiak Andrzej , Phillips George N. , Shen Ben 
Published: September 2015

Significance
There are many differences in the sequences of ketosynthase (KS) domains from the well-studied type I polyketide synthases (PKSs) and the more recently discovered acyltransferase (AT)-less type I PKSs. The AT-less type I PKSs generate polyketides with a high degree of structural diversity, which stems from their evolution by horizontal gene transfer. In comparison, canonical type I PKSs evolve by gene duplication. The seven structures of AT-less type I PKS KSs reveal the molecular details surrounding the evolution of substrate specificity and structural diversity, and their overall differences with canonical type I PKS KSs. Understanding the mechanism of substrate specificity will allow reprogramming of the KS active sites to generate polyketide analogues by PKS and polyketide biosynthetic pathway engineering.
Reveal Digital: an open access model empowering libraries to become publishers
Authors: GLAHN Peggy 
Published: September 2015

Key points
Digitizing cultural heritage, humanities, content is currently being undertaken with institutional or government support but there are opportunities for greater library collaboration.
Using a crowdfunding model to support the creation of digitized collections empowers librarians but also challenges them to think like investors and publishers.
The described model creates an open access collection for the benefit of all scholars and also provides additional benefits for the participating libraries.
The BMJ online: lessons from a 20‐year digital presence
Authors: PAYNE David 
Published: September 2015

Key points
The current BMJ is a far cry from the 1995 ‘brochureware’ site.
Journals need to be flexible in their delivery mechanisms to meet user needs.
Online publishing provides an opportunity to extend the target readership.
Responding to user demands to be balanced against proactive development.
Not everything works, but it is better to be innovating than overly cautious.
How to do (or not to do) … translation of national health accounts data to evidence for policy making in a low resourced setting
Authors: Price Jennifer A , Guinness Lorna , Irava Wayne , Khan Idrish , Asante Augustine , Wiseman Virginia 
Published: September 2015

Abstract
For more than a decade, the Organization for Economic Co-operation and Development (OECD), the World Health Organization (WHO) and the World Bank have promoted the international standardization of National Health Accounts (NHA) for reporting global statistics on public, private and donor health expenditure and improve the quality of evidence-based decision-making at country level. A 2010–2012 World Bank review of NHA activity in 50 countries found structural and technical constraints (rather than cost) were key impediments to institutionalizing NHA in many low- and middle-income countries (LMICs). Pilot projects focused resources on data production, neglecting longer-term capacity building for analysing the data, developing ownership among local stakeholders and establishing routine production, utilization and dissemination of NHA data. Hence, genuine institutionalization of NHA in most LMICs has been slow to materialize. International manuals focus on the production of NHA data and do not include practical, incremental and low-cost strategies to guide countries in translating the data into evidence for policy-making. The main aim of this article is to recommend strategies for bridging this divide between production and utilization of NHA data in low-resource settings. The article begins by discussing the origins and purpose of NHA, including factors currently undermining their uptake. The focus then turns to the development and application of strategies to assist LMICs in ‘unlocking’ the hidden value of their NHA. The article draws on the example of Fiji, a country currently attempting to integrate their NHA data into policy formulation, despite minimal resources, training and familiarity with economic analysis of health systems. Simple, low cost recommendations such as embedding health finance indicators in planning documents, a user-friendly NHA guide for evaluating local health priorities, and sharing NHA data for collaborative research have helped translate NHA from raw data to evidence for policymaking.
Bivalved Versus Circumferential Cast Immobilization for Displaced Forearm Fractures: A Randomized Clinical Trial to Assess Efficacy and Safety
Authors: Bae Donald S. , Valim Clarissa , Connell Patricia , Brustowicz Katherine A. , Waters Peter M. 
Published: September 2015

Background:
The purpose of this study was to determine the effects of bivalved versus circumferential cast immobilization on maintenance of reduction and associated complications after closed reduction (CR) of radius and/or ulna fractures in children.

Methods:
Two hundred two children with displaced radius and/or ulna fractures were randomized to either circumferential (n=101) or bivalved (n=101) long-arm casts after CR. The mean age was 10±3 years. There were no significant differences between groups in terms of age, sex, or initial fracture displacement or angulation. Clinical and radiographic evaluations were performed at 1, 2, 4, and 6 weeks postreduction. Radiographic loss of reduction (LOR), need for remanipulation or surgery, and associated complications of compartment syndrome, cast saw injury, and neurovascular compromise were recorded.

Results:
Overall, the median angulation of the radius and ulna fractures improved from 20 and 18 degrees to 3 and 2 degrees after CR, respectively. The median cast index after reduction was 0.78 in the bivalved group and 0.80 in the circumferential group. The median angulation of the radius and ulna was 8 and 1 degrees at 4 weeks, with no significant difference between groups. By the fourth week of follow-up, 70 patients (34%)—35 bivalved and 35 circumferential—had radiographic LOR. Forty-seven patients (23%)—23 bivalved and 24 circumferential—underwent remanipulation or surgical reduction and fixation. There were no significant differences between groups with respect to LOR rate or need for surgical treatment. One bivalved patient sustained a cast saw injury, and 3 bivalved patients had transient neurological abnormalities. No patients developed compartment syndrome.

Conclusions:
Cast immobilization is effective in the majority of patients after CR of displaced forearm fractures. There were no significant differences in maintenance of reduction, need for surgery, or complications between bivalved or circumferential long-arm casts.

Level of Evidence:
Level I—therapeutic.
Spontaneous Fatal Intraoperative Rupture of Great Vessel During Growing Rod Lengthening: Do Children With Ehlers-Danlos Syndrome Require the Availability of Vascular Expertise? A Case Report and Review of the Literature
Authors: Working Zachary M. , Hsiao Mark , Sanders John C. , Bratton Susan L. , D’Astous Jacques L. 
Published: September 2015

Background:
Ehlers-Danlos syndrome (EDS) is a family of inherited connective tissue diseases. Kyphoscoliotic EDS (kEDS) is associated with severe and early spinal deformity. Very little has been reported regarding the orthopaedic surgical care of kEDS likely due to its rare incidence. A more common subtype is the vascular-type EDS (vEDS, previously labeled type IV), which is associated with reports of vascular complications in the literature.

Methods:
The case report of a single, fatal complication of spontaneous rupture of the superior vena cava, after extubation, subsequent to revision minimal growing rod lengthening in a child with kEDS. We additionally review prior reported cases of kEDS for pediatric spine surgery and the sentinel event of spontaneous vascular rupture in all EDS patients.

Results:
The anterior thoracoabdominal approach in children with kEDS has been associated with severe intravascular complications, with no deaths reported to date. Posterior spinal procedures were associated with frequent overall complications, but no events of perioperative or spontaneous vascular injury were identified before our case.
Reports of spontaneous vessel rupture (n=39) appear more frequently in vEDS, but have been documented in patients with EDS type I (classic EDS or cEDS) and kEDS disease. The 30-day mortality in these patients was 59%. The majority of the deaths occurred on the day of the vascular event. Surviving patients overwhelmingly received intraoperative consultation and treatment from either general or vascular surgeons at their respective institutions for assistance.

Conclusions:
Providers should consider their proximity to available emergent consultation before operating on patients with EDS of any subtype.

Level of Evidence:
Level V—expert opinion.
Successful Pavlik Harness Treatment for Developmental Dysplasia of the Hip and Normal X-Ray at the Age of 2 Years: Is a Longer Follow-up Necessary?
Authors: Allington Nanni J. 
Published: September 2015

Background:
Management of developmental dysplasia of the hip (DDH) with a Pavlik harness is a well-known treatment.
Follow-up until skeletal maturity is recommended as long-term studies mention late sequelae.The purpose of this study was to determine whether such a follow-up is necessary in patients treated successfully under a strict protocol.

Methods:
A retrospective review of a consecutive series of normal infants treated for DDH between January 1995 and July 2004 was undertaken.
Only normal infants with frankly pathologic hips treated successfully with a Pavlik harness were included, and with a normal anteroposterior (AP) pelvis x-ray at the age of 2 years.
All infants with any type of neurological disease, syndrome, other form of treatment for DDH, and failure of the Pavlik harness were excluded.
At the last follow-up, a clinical examination and a standing AP pelvis x-ray were performed.

Results:
A total of 109 hips in 83 children were available for review. The mean follow-up was of 10 years and 2 months. All 109 hips had a normal clinical examination and a normal AP pelvis x-ray: a mean center-edge angle (CEA) of 29.5 degrees, SD±4.1 degrees, a mean acetabular index (AI) of 1457±3.74 degrees, a mean Sharp’s angle of 41.92±3.42 degrees, a Seringe-Severin score of IA, a normal teardrop figure, no signs of avascular necrosis, and Moses circles <2.

Conclusion:
This study strongly suggests that in a selected group of patients treated for DDH with a Pavlik harness, under a strict protocol, and a normal x-ray at 2 years of age, a long-term follow-up is not necessary.

Level of Evidence:
Level III—therapeutic.
Candidate Loci are Revealed by an Initial Genome-wide Association Study of Juvenile Osteochondritis Dissecans
Authors: Yellin Joseph L. , Trocle Ashley , Grant Struan F.A. , Hakonarson Hakon , Shea Kevin G. , Ganley Theodore J. 
Published: September 2015

Background:
Osteochondritis dissecans (OCD) is a condition that oftentimes causes significant knee pain in pediatric patient populations. If left untreated, OCD significantly increases the risk of developing degenerative osteoarthritis along with its associated consequences and costs. Although a genetic component has been suggested to play a role in this disorder, few studies have been carried out in order to determine the underlying genetic etiology of this relatively common complex trait. The goal of our study was to perform an initial genome-wide association study (GWAS) to uncover candidate loci associated with the pathogenesis of OCD.

Methods:
Blood samples were acquired from 2 cohorts, aged 0 to 18 years old, consisting of 209 OCD cases and 1855 population-matched controls. Agencourt Genfind DNA isolation technology was used to isolate high-quality DNA from each sample. Genotype data was then generated utilizing the Illumina Infinium BeadChip array to examine single-nucleotide polymorphisms (SNPs).

Results:
In an initial GWAS analysis of our cohort, where a SNP was excluded if the Hardy-Weinberg Equilibrium test P<0.0001, the minor allele frequency<5%, and the genotyping call rate<90%, we obtained our first results for OCD. Although there was no SNP strictly reaching the threshold for genome-wide significance at this early stage, multiple SNPs (35) at several loci revealed evidence of suggestive association with OCD (P<5.0×10−5).

Conclusions:
The results from our preliminary study are encouraging. Herein we not only discuss the relevance and applicability of GWAS in studying a genetic basis for OCD, but have also identified top signals that may suggest loci involved in coordinated expression as well as a transcription factor involved in development that may be highly relevant to this trait.

Clinical Relevance:
If genetic predispositions for OCD are detected early enough in life, attempts at activity modification, counseling, and orthopaedic monitoring may successfully reduce progression of this condition, which may lead to progressive osteoarthritis in the third to fourth decade in at-risk patients.