bluuebunny/crossref_metadata_2025_split huggingface dataset:
Netter: re-ranking gene network inference predictions using structural network properties
Authors: Ruyssinck Joeri , Demeester Piet , Dhaene Tom , Saeys Yvan 
Published: February 2016

Abstract
Background
Many algorithms have been developed to infer the topology of gene regulatory networks from gene expression data. These methods typically produce a ranking of links between genes with associated confidence scores, after which a certain threshold is chosen to produce the inferred topology. However, the structural properties of the predicted network do not resemble those typical for a gene regulatory network, as most algorithms only take into account connections found in the data and do not include known graph properties in their inference process. This lowers the prediction accuracy of these methods, limiting their usability in practice.

Results
We propose a post-processing algorithm which is applicable to any confidence ranking of regulatory interactions obtained from a network inference method which can use, inter alia, graphlets and several graph-invariant properties to re-rank the links into a more accurate prediction. To demonstrate the potential of our approach, we re-rank predictions of six different state-of-the-art algorithms using three simple network properties as optimization criteria and show that Netter can improve the predictions made on both artificially generated data as well as the DREAM4 and DREAM5 benchmarks. Additionally, the DREAM5 E.coli. community prediction inferred from real expression data is further improved. Furthermore, Netter compares favorably to other post-processing algorithms and is not restricted to correlation-like predictions. Lastly, we demonstrate that the performance increase is robust for a wide range of parameter settings. Netter is available at http://bioinformatics.intec.ugent.be.

Conclusions
Network inference from high-throughput data is a long-standing challenge. In this work, we present Netter, which can further refine network predictions based on a set of user-defined graph properties. Netter is a flexible system which can be applied in unison with any method producing a ranking from omics data. It can be tailored to specific prior knowledge by expert users but can also be applied in general uses cases. Concluding, we believe that Netter is an interesting second step in the network inference process to further increase the quality of prediction.
Analysing multiple types of molecular profiles simultaneously: connecting the needles in the haystack
Authors: X. Menezes Renée , Mohammadi Leila , J. Goeman Jelle , M. Boer Judith 
Published: February 2016

Abstract
Background
It has been shown that a random-effects framework can be used to test the association between a gene’s expression level and the number of DNA copies of a set of genes. This gene-set modelling framework was later applied to find associations between mRNA expression and microRNA expression, by defining the gene sets using target prediction information.

Methods and results
Here, we extend the model introduced by Menezes et al. 2009 to consider the effect of not just copy number, but also of other molecular profiles such as methylation changes and loss-of-heterozigosity (LOH), on gene expression levels. We will consider again sets of measurements, to improve robustness of results and increase the power to find associations. Our approach can be used genome-wide to find associations and yields a test to help separate true associations from noise.
We apply our method to colon and to breast cancer samples, for which genome-wide copy number, methylation and gene expression profiles are available. Our findings include interesting gene expression-regulating mechanisms, which may involve only one of copy number or methylation, or both for the same samples. We even are able to find effects due to different molecular mechanisms in different samples.

Conclusions
Our method can equally well be applied to cases where other types of molecular (high-dimensional) data are collected, such as LOH, SNP genotype and microRNA expression data. Computationally efficient, it represents a flexible and powerful tool to study associations between high-dimensional datasets. The method is freely available via the SIM BioConductor package.
ksRepo: a generalized platform for computational drug repositioning
Authors: Brown Adam S. , Kong Sek Won , Kohane Isaac S. , Patel Chirag J. 
Published: February 2016

AbstractBackgroundRepositioning approved drug and small molecules in novel therapeutic areas is of key interest to the pharmaceutical industry. A number of promising computational techniques have been developed to aid in repositioning, however, the majority of available methodologies require highly specific data inputs that preclude the use of many datasets and databases. There is a clear unmet need for a generalized methodology that enables the integration of multiple types of both gene expression data and database schema.ResultsksRepo eliminates the need for a single microarray platform as input and allows for the use of a variety of drug and chemical exposure databases. We tested ksRepo’s performance on a set of five prostate cancer datasets using the Comparative Toxicogenomics Database (CTD) as our database of gene-compound interactions. ksRepo successfully predicted significance for five frontline prostate cancer therapies, representing a significant enrichment from over 7000 CTD compounds, and achieved specificity similar to other repositioning methods.ConclusionsWe present ksRepo, which enables investigators to use any data inputs for computational drug repositioning. ksRepo is implemented in a series of four functions in the R statistical environment under a BSD3 license. Source code is freely available athttp://github.com/adam-sam-brown/ksRepo. A vignette is provided to aid users in performing ksRepo analysis.
LowMACA: exploiting protein family analysis for the identification of rare driver mutations in cancer
Authors: Melloni Giorgio E. M. , de Pretis Stefano , Riva Laura , Pelizzola Mattia , Céol Arnaud , Costanza Jole , Müller Heiko , Zammataro Luca 
Published: February 2016

AbstractBackgroundThe increasing availability of resequencing data has led to a better understanding of the most important genes in cancer development. Nevertheless, the mutational landscape of many tumor types is heterogeneous and encompasses a long tail of potential driver genes that are systematically excluded by currently available methods due to the low frequency of their mutations. We developed LowMACA (Low frequency Mutations Analysis via Consensus Alignment), a method that combines the mutations of various proteins sharing the same functional domains to identify conserved residues that harbor clustered mutations in multiple sequence alignments. LowMACA is designed to visualize and statistically assess potential driver genes through the identification of their mutational hotspots.ResultsWe analyzed the Ras superfamily exploiting the known driver mutations of the trioK-N-HRAS,identifying new putative driver mutations and genes belonging to less known members of the Rho, Rab and Rheb subfamilies. Furthermore, we applied the same concept to a list of known and candidate driver genes, and observed that low confidence genes show similar patterns of mutation compared to high confidence genes of the same protein family.ConclusionsLowMACA is a software for the identification of gain-of-function mutations in putative oncogenic families, increasing the amount of information on functional domains and their possible role in cancer. In this context LowMACA emphasizes the role of genes mutated at low frequency otherwise undetectable by classical single gene analysis.LowMACA is an R package available athttp://www.bioconductor.org/packages/release/bioc/html/LowMACA.html. It is also available as a GUI standalone downloadable at:https://cgsb.genomics.iit.it/wiki/projects/LowMACA
Candidate gene analysis in a case of congenital absence of the endometrium
Authors: Simavli Serap , Abreu Ana Paula , Kwaan Mary R. , Dluhy Robert G. , Yanushpolsky Elena H. , Feltmate Colleen , Cerda Sandra R. , Carroll Rona S. , Kaiser Ursula B. , Kuohung Wendy 
Published: February 2016

Abstract
Background
Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea.

Case presentation
A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus.

Conclusions
Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case.
A matter of time: study of circadian clocks and their role in inflammation
Authors: Carter Stuart J , Durrington Hannah J , Gibbs Julie E , Blaikley John , Loudon Andrew S , Ray David W , Sabroe Ian 
Published: February 2016

Abstract
Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance.
First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction
Authors: Gertz Morie A. , Landau Heather , Comenzo Raymond L. , Seldin David , Weiss Brendan , Zonder Jeffrey , Merlini Giampaolo , Schönland Stefan , Walling Jackie , Kinney Gene G. , Koller Martin , Schenk Dale B. , Guthrie Spencer D. , Liedtke Michaela 
Published: February 2016

Purpose Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). Patients and Methods Patients who had completed at least one previous anti–plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. Results Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. Conclusion Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.
PTHrP Nuclear Localization and Carboxyl Terminus Sequences Modulate Dental and Mandibular Development in Part via the Action of p27
Authors: Sun Wen , Wu Jun , Huang Linying , Liu Hong , Wang Rong , Karaplis Andrew , Goltzman David , Miao Dengshun 
Published: February 2016

Abstract
To determine whether the action of the PTHrP nuclear localization sequence and C terminus is mediated through p27 in modulating dental and mandibular development, compound mutant mice, which are homozygous for both p27 deletion and the PTHrP1–84 knock-in mutation (p27−/−PthrpKI/KI), were generated. Their teeth and mandibular phenotypes were compared with those of p27−/−, PthrpKUK\ and wild-type mice. At 2 weeks of age, the mandibular mineral density, alveolar bone volume, osteoblast numbers, and dental volume, dentin sialoprotein-immunopo-sitive areas in the first molar were increased significantly in p27−/− mice and decreased dramatically in both PthrpKI/KI and p27−/− PthrpKI/KI mice compared with wild-type mice; however, these parameters were partly rescued in p27−/− PthrpKI/KI mice compared with PthrpKI/KI mice. These data demonstrate that the deletion of p27 in PthrpKI/KI mice can partially rescue defects in dental and mandibular development. Furthermore, we found that deletion of p27 in PthrpKI/KI mice partially corrected the dental and mandibular phenotype by modulating cell cyclin-regulating molecules and antioxidant enzymes. This study therefore indicates that the p27 pathway may function downstream in the action of PTHrP nuclear localization sequence to regulate dental and mandibular development. (Endocrinology 157: 1372–1384, 2016)
Emulsified Isoflurane Protects Against Transient Focal Cerebral Ischemia Injury in Rats via the PI3K/Akt Signaling Pathway
Authors: Zhang Hongfei , Xiong Xiaoxing , Liu Jin , Gu Lijuan , Li Fengxian , Wan Yi , Xu Shiyuan 
Published: February 2016

BACKGROUND:
Phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathway activation may promote neuronal survival via neuroprotection during inflammation after cerebral ischemia. In this study, we investigated whether IV pretreatment with emulsified isoflurane (EI) could decrease ischemic brain injury related to the PI3K/Akt pathway.

METHODS:
Male Sprague-Dawley rats received different doses of IV EI (1, 2, 4, or 8 mL/kg/h) or Intralipid® (8 mL/kg/h) for 30 minutes (n = 6–12 per group), followed by middle cerebral artery occlusion (MCAO) for 100 minutes to induce transient focal ischemia. The neurologic score and infarct volume were measured 48 hours after MCAO. Immunostaining, Western blot analysis, and an enzyme-linked immunosorbent assay were used to assess EI effects on the cell inflammatory response, high-mobility group box-1 release, and phosphorylated Akt (expression. LY294002, a PI3K inhibitor, was also infused into the ventricular space before EI to determine the effect of EI.

RESULTS:
Four milliliters per kilogram per hour of EI reduced the infarct size (21.08 ± 11.24 vs 37.09 ± 10.46, P = 0.006), improved neurologic scores after MCAO (1.13 ± 0.48 vs 1.95 ± 0.65, P = 0.015), significantly reinforced neuronal survival (982.7 ± 364.4 vs 439.8 ± 278.4, P = 0.036), and inhibited CD68+ macrophage/macroglial infiltration in the ischemic core (188.2 ± 49.1 vs 282 ± 49.4, P = 0.018) compared with the vehicle group. In the EI pretreatment group, the serum high-mobility group box-1 concentration (3.62 ± 0.72 vs 5.73 ± 0.65, P < 0.001) was decreased, and the cerebral phosphorylated Akt level (50.33 ± 4.73 vs 37.5 ± 3.11, P = 0.007) was increased at 48 hours, which was inhibited by LY294002 compared with the vehicle group (5.31 ± 0.72 vs 5.73 ± 0.65, P = 0.216; 43.00 ± 4.84 vs 37.5 ± 3.11, P = 0.091).

CONCLUSIONS:
These findings suggest that EI pretreatment protects against ischemic brain injury via the inhibition of cerebral inflammation and is associated with the PI3K-Akt pathway in rats with MCAO. This drug may be a novel therapeutic agent for patients after stroke.
Data Extraction And Management In Networks Of Observational Health Care Databases
For Scientific Research: A Comparison Among EU-ADR, OMOP, Mini-Sentinel And MATRICE
Strategies
Authors: Gini Rosa , Schuemie Martijn , Brown Jeffrey , Ryan Patrick , Vacchi Edoardo , Coppola Massimo , Cazzola Walter , Coloma Preciosa , Berni Roberto , Diallo Gayo , Oliveira José Luis , Avillach Paul , Trifirò Gianluca , Rijnbeek Peter , Bellentani Mariadonata , Van Der Lei Johan , Klazinga Niek , Sturkenboom Miriam 
Published: February 2016

Introduction: We see increased use of existing observational data in order to
achieve fast and transparent production of empirical evidence in health care research.
Multiple databases are often used to increase power, to assess rare exposures or
outcomes, or to study diverse populations. For privacy and sociological reasons,
original data on individual subjects can’t be shared, requiring a distributed network
approach where data processing is performed prior to data sharing.Case Descriptions and
Variation Among Sites: We created a conceptual framework distinguishing three steps in
local data processing: (1) data reorganization into a data structure common across the
network; (2) derivation of study variables not present in original data; and (3)
application of study design to transform longitudinal data into aggregated data sets for
statistical analysis. We applied this framework to four case studies to identify
similarities and differences in the United States and Europe: Exploring and
Understanding Adverse Drug Reactions by Integrative Mining of Clinical Records and
Biomedical Knowledge(EU-ADR),Observational Medical Outcomes Partnership(OMOP), the Food
and Drug Administration’s (FDA’s) Mini-Sentinel, and the Italian network—the Integration
of Content Management Information on the Territory of Patients with Complex Diseases or
with Chronic Conditions (MATRICE).Findings: National networks (OMOP, Mini-Sentinel,
MATRICE) all adopted shared procedures for local data reorganization. The multinational
EU-ADR network needed locally defined procedures to reorganize its heterogeneous data
into a common structure. Derivation of new data elements was centrally defined in all
networks but the procedure was not shared in EU-ADR. Application of study design was a
common and shared procedure in all the case studies. Computer procedures were embodied
in different programming languages, including SAS, R, SQL, Java, and
C++.Conclusion: Using our conceptual framework we found several areas that would benefit
from research to identify optimal standards for production of empirical knowledge from
existing databases.
Workforce: Goals for Research and Innovation
Authors: McLaughlin Colleen , Sedlezky Lori , Belcher Harolyn , Marquand Abby , Hewitt Amy 
Published: February 2016

Abstract
Across the United States, there is growing demand for a competent and stable workforce able to effectively support the health and community lives of individuals with intellectual and developmental disabilities (IDD) throughout the lifespan. This article describes national goals for research and innovation to advance the IDD workforce. The research goals outlined address important workforce topics that include increasing capacity and sustainability, competency development and quality support, the use of technology, family support, and the vital role of direct support professionals in helping people with IDD to become fully included and valued members of their communities.
Gendered Geographies of Memory: Place, Violence, and Exigency at the Birmingham Civil Rights Institute
Authors: Poirot Kristan 
Published: February 2016

Abstract
Although scholars recognize the importance of recovery projects that aim to recenter women’s roles in black freedom struggles, when it comes to these memory practices, the “woman problem” of civil rights memory is more acknowledged than understood. This essay argues that memories of civil rights movements are mapped spatially and rhetorically to depict correlations among Jim Crow contexts and acts of black resistance. The relationship among these spatial and rhetorical configurations is termed the “rhetorical geography of memory.” Through an account of the rhetorical geography of memory of the Birmingham Civil Rights Institute, this essay posits that place, violence, and masculinity animate a relationship between exigency and response, producing a gendered landscape of memory that limits at the outset the conditions and possibilities for women’s emergence.