bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction
Authors: Crowe Brandon L. , Larue Ross C. , Yuan Chunhua , Hess Sonja , Kvaratskhelia Mamuka , Foster Mark P. 
Published: February 2016

Significance
Bromodomain and extraterminal domain (BET) proteins recruit a variety of cellular factors to epigenetic marks on chromatin to modulate essential cellular processes, including DNA repair and transcription. To facilitate their recruitment to chromosomal DNA made accessible by epigenetically modified chromatin dynamics, conserved sequences in γ-retroviral integrases bind to the highly conserved extraterminal (ET) domains of BET proteins. The solution structure of the complex between the Brd4 ET domain and a conserved sequence from murine leukemia virus integrase reveals the basis for γ-retroviral integration pattern, with implications for retrovirus-based gene therapy. Moreover, the studies suggest how BET proteins might interact with cognate binding partners involved in a diverse array of cellular phenomena including transcriptional activation, cancer, viral latency, and viral integration.
Ultrasensitive microchip based on smart microgel for real-time online detection of trace threat analytes
Authors: Lin Shuo , Wang Wei , Ju Xiao-Jie , Xie Rui , Liu Zhuang , Yu Hai-Rong , Zhang Chuan , Chu Liang-Yin 
Published: February 2016

Significance
Real-time detection of trace threat analytes is critical for global sustainability. The key challenge is how to efficiently convert and amplify the analyte signal into simple readouts. Here we report an ultrasensitive microfluidic platform incorporated with stimuli-responsive smart microgel for real-time detection of trace threat analytes. The microgel swells in response to specific analyte, thus converting trace analyte concentration into significantly amplified signal of flow rate change for highly sensitive, fast, and selective detection, which can be monitored on cell phone for timely warning and terminating of pollution. This work provides a generalizable platform for incorporating myriad microgels to achieve ever-better performance for real-time detection of various trace threat molecules, and may expand the scope of applications of detection techniques.
Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex
Authors: Large Adam M. , Vogler Nathan W. , Mielo Samantha , Oswald Anne-Marie M. 
Published: February 2016

Significance
Understanding the interplay between excitation and inhibition in feedforward and recurrent circuits is essential for elucidating the mechanisms of cortical function. However, disentangling the relative contributions of feedforward or recurrent inhibition to cortical responses has been difficult. This study capitalizes on the unique laminar architecture of the piriform cortex to investigate feedforward and recurrent circuits in isolation. We find that feedforward inhibition and excitation are balanced, whereas recurrent inhibition dominates intracortical excitation. Furthermore, we find that feedforward and recurrent circuits differentially recruit the three classes of cortical excitatory neurons, functionally segregating their roles in the cortical representation of olfactory information. This study provides insight to circuit mechanisms that regulate subthreshold and suprathreshold processing of afferent input to the cortex.
Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses
Authors: Li Yize , Banerjee Shuvojit , Wang Yuyan , Goldstein Stephen A. , Dong Beihua , Gaughan Christina , Silverman Robert H. , Weiss Susan R. 
Published: February 2016

Significance
RNase L, an antiviral enzyme activated during infection, degrades viral and cellular RNAs, inhibits protein synthesis, and restricts the replication and spread of diverse viruses. RNase L activation depends on 2′,5′-oligoadenylates synthesized by different oligoadenylate synthetases (OASs), i.e., OAS1, OAS2, and OAS3. OASs are induced by interferon and are activated by viral dsRNA. It has been unclear which of these OAS proteins is necessary and/or sufficient to activate RNase L during viral infections. We show that OAS3, but not OAS1 or OAS2, is required to activate RNase L and to restrict the replication of four different human viruses. These findings suggest that OAS3 may provide a target for antiviral therapies and that OAS1 and OAS2 may have alternative roles.
Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes
Authors: Kowal Joanna , Arras Guillaume , Colombo Marina , Jouve Mabel , Morath Jakob Paul , Primdal-Bengtson Bjarke , Dingli Florent , Loew Damarys , Tkach Mercedes , Théry Clotilde 
Published: February 2016

Significance
The last decade has seen a rapid expansion of interest in extracellular vesicles (EVs), proposed to mediate cell–cell communication in patho/physiological conditions. Although heterogeneity of EVs has become obvious, as highlighted recently by the International Society for Extracellular Vesicles, the field is lacking specific tools to distinguish EVs of different intracellular origins, and thus probably different functions. Here, thanks to a comprehensive comparison of different types of EVs isolated from a single cell type, we define proteins generically present in EVs, small EV-specific and -excluded ones, and a few specific of endosome-derived exosomes or nonexosomal small EVs. This work will allow proper evaluation of the molecular mechanisms of biogenesis and secretion and the respective functions of subtypes of EVs.
Inbreeding drives maize centromere evolution
Authors: Schneider Kevin L. , Xie Zidian , Wolfgruber Thomas K. , Presting Gernot G. 
Published: February 2016

SignificanceThe diversity of centromere-specific DNA repeats in different species (centromere paradox) and the seemingly parallel rapid evolution of the cenH3 histone protein have previously been interpreted to be related to evolutionary pressures acting on both molecules based on their interaction (centromere drive hypothesis). Here we describe the detailed mechanism and chronology of centromere repeat replacement, and identify inbreeding as a major driver of centromeric DNA replacement that ultimately gives rise to new tandem centromere repeats at genetically indistinguishable loci. These insights explain both the frequently observed disturbance of established centromeres in crop plants following their domestication and the rapid appearance of novel centromere repeat sequences in genetically isolated individuals in nature during speciation.
Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease
Authors: Schafer Nicholas P. , Truong Ha H. , Otzen Daniel E. , Lindorff-Larsen Kresten , Wolynes Peter G. 
Published: February 2016

Significance
Membrane proteins perform diverse functions in the cell while being embedded in lipid bilayers, but the presence of the anisotropic, nonpolar membrane environment has slowed progress in understanding how these proteins fold and function. Herein, we study GlpG, an intramembrane protease, using computationally efficient models to fill in structural details that are currently invisible to experimental techniques and inaccessible to atomistic simulations. We find that GlpG’s modular functional architecture leaves an imprint throughout its folding and functional landscape, leading to multiple possible folding pathways and the population of near-native states with functional significance. We propose a mechanism by which destabilizing mutations can accelerate folding in detergent micelles, a previously puzzling experimental observation.
The evolution of collectivity in nuclei and the proton–neutron interaction
Authors: Casten R F , Cakirli R B 
Published: February 2016

Abstract
We survey the evolution of nuclear structure with N and Z, focusing on collective behavior and its relation to the underlying single particle configurations, and their interactions. We exploit a number of complementary observables, from multiple perspectives, and interpret the observed behavior in terms of simple models. The paper includes a discussion of key observables, how to evaluate theories, and some of the dangers of statistical tests. We conclude with a discussion of schemes to predict the properties of unknown nuclei, founded on the importance of valence proton–neutron interactions, and correlate empirical values for these interactions with the onset of collectivity and deformation.
Harnessing next-generation informatics for personalizing medicine: a report
from AMIA’s 2014 Health Policy Invitational Meeting
Authors: Wiley Laura K , Tarczy-Hornoch Peter , Denny Joshua C , Freimuth Robert R , Overby Casey L , Shah Nigam , Martin Ross D , Sarkar Indra Neil 
Published: February 2016

Abstract
The American Medical Informatics Association convened the 2014 Health Policy Invitational Meeting to develop recommendations for updates to current policies and to establish an informatics research agenda for personalizing medicine. In particular, the meeting focused on discussing informatics challenges related to personalizing care through the integration of genomic or other high-volume biomolecular data with data from clinical systems to make health care more efficient and effective. This report summarizes the findings ( n  = 6) and recommendations ( n  = 15) from the policy meeting, which were clustered into 3 broad areas: (1) policies governing data access for research and personalization of care; (2) policy and research needs for evolving data interpretation and knowledge representation; and (3) policy and research needs to ensure data integrity and preservation. The meeting outcome underscored the need to address a number of important policy and technical considerations in order to realize the potential of personalized or precision medicine in actual clinical contexts.
Modeling information flows in clinical decision support: key insights for enhancing system effectiveness
Authors: Medlock Stephanie , Wyatt Jeremy C , Patel Vimla L , Shortliffe Edward H , Abu-Hanna Ameen 
Published: February 2016

Abstract
A fundamental challenge in the field of clinical decision support is to determine what characteristics of systems make them effective in supporting particular types of clinical decisions. However, we lack such a theory of decision support itself and a model to describe clinical decisions and the systems to support them. This article outlines such a framework. We present a two-stream model of information flow within clinical decision-support systems (CDSSs): reasoning about the patient (the clinical stream), and reasoning about the user (the cognitive-behavioral stream). We propose that CDSS “effectiveness” be measured not only in terms of a system’s impact on clinical care, but also in terms of how (and by whom) the system is used, its effect on work processes, and whether it facilitates appropriate decisions by clinicians and patients. Future research into which factors improve the effectiveness of decision support should not regard CDSSs as a single entity, but should instead differentiate systems based on their attributes, users, and the decision being supported.
Extracting information from the text of electronic medical records to improve case detection: a systematic review
Authors: Ford Elizabeth , Carroll John A , Smith Helen E , Scott Donia , Cassell Jackie A 
Published: February 2016

Abstract
Background Electronic medical records (EMRs) are revolutionizing health-related research. One key issue for study quality is the accurate identification of patients with the condition of interest. Information in EMRs can be entered as structured codes or unstructured free text. The majority of research studies have used only coded parts of EMRs for case-detection, which may bias findings, miss cases, and reduce study quality. This review examines whether incorporating information from text into case-detection algorithms can improve research quality.
Methods A systematic search returned 9659 papers, 67 of which reported on the extraction of information from free text of EMRs with the stated purpose of detecting cases of a named clinical condition. Methods for extracting information from text and the technical accuracy of case-detection algorithms were reviewed.
Results Studies mainly used US hospital-based EMRs, and extracted information from text for 41 conditions using keyword searches, rule-based algorithms, and machine learning methods. There was no clear difference in case-detection algorithm accuracy between rule-based and machine learning methods of extraction. Inclusion of information from text resulted in a significant improvement in algorithm sensitivity and area under the receiver operating characteristic in comparison to codes alone (median sensitivity 78% (codes + text) vs 62% (codes), P  = .03; median area under the receiver operating characteristic 95% (codes + text) vs 88% (codes), P  = .025).
Conclusions Text in EMRs is accessible, especially with open source information extraction algorithms, and significantly improves case detection when combined with codes. More harmonization of reporting within EMR studies is needed, particularly standardized reporting of algorithm accuracy metrics like positive predictive value (precision) and sensitivity (recall).
Data interchange using i2b2
Authors: Klann Jeffrey G , Abend Aaron , Raghavan Vijay A , Mandl Kenneth D , Murphy Shawn N 
Published: February 2016

Abstract
Objective Reinventing data extraction from electronic health records (EHRs) to meet new analytical needs is slow and expensive. However, each new data research network that wishes to support its own analytics tends to develop its own data model. Joining these different networks without new data extraction, transform, and load (ETL) processes can reduce the time and expense needed to participate. The Informatics for Integrating Biology and the Bedside (i2b2) project supports data network interoperability through an ontology-driven approach. We use i2b2 as a hub, to rapidly reconfigure data to meet new analytical requirements without new ETL programming.
Materials and Methods Our 12-site National Patient-Centered Clinical Research Network (PCORnet) Clinical Data Research Network (CDRN) uses i2b2 to query data. We developed a process to generate a PCORnet Common Data Model (CDM) physical database directly from existing i2b2 systems, thereby supporting PCORnet analytic queries without new ETL programming. This involved: a formalized process for representing i2b2 information models (the specification of data types and formats); an information model that represents CDM Version 1.0; and a program that generates CDM tables, driven by this information model. This approach is generalizable to any logical information model.
Results Eight PCORnet CDRN sites have implemented this approach and generated a CDM database without a new ETL process from the EHR. This enables federated querying within the CDRN and compatibility with the national PCORnet Distributed Research Network.
Discussion We have established a way to adapt i2b2 to new information models without requiring changes to the underlying data. Eight Scalable Collaborative Infrastructure for a Learning Health System sites vetted this methodology, resulting in a network that, at present, supports research on 10 million patients’ data.
Conclusion New analytical requirements can be quickly and cost-effectively supported by i2b2 without creating new data extraction processes from the EHR.
Properties of galaxies around AGNs with the most massive supermassive black holes revealed by clustering analysis
Authors: Shirasaki Yuji , Komiya Yutaka , Ohishi Masatoshi , Mizumoto Yoshihiko 
Published: February 2016

Abstract
We present results of the clustering analysis between active galactic nuclei (AGNs) and galaxies at redshift 0.1–1.0, which was performed to investigate the properties of galaxies associated with the AGNs and reveal the nature of the fueling mechanism of supermassive black holes (SMBHs). We used 8059 AGNs/quasi-stellar objects (QSOs) for which virial masses of individual SMBHs were measured, and divided them into four mass groups.Cross-correlation analysis was performed to reconfirm our previous result that cross-correlation length increases with SMBH mass MBH; we obtained consistent results. A linear bias of AGN for each mass group was measured as 1.47 for MBH = 107.5–108.2 M⊙ and 3.08 for MBH = 109–1010 M⊙. The averaged color and luminosity distributions of galaxies around the AGNs/QSOs were also derived for each mass group. The galaxy color Dopt-IR was estimated from a spectral energy distribution (SED) constructed from a catalog derived by merging the Sloan Digital Sky Survey (SDSS) and the UKIRT Infrared Deep Sky Survey (UKIDSS) catalogs. The distributions of color and luminosity were derived by a subtraction method, which does not require redshift information of galaxies. The main results of this work are as follows. (1) A linear bias increases by a factor of two from the lower-mass group to the highest-mass group. (2) The environment around AGNs with the most massive SMBHs (MBH &gt; 109 M⊙) is dominated by red sequence galaxies. (3) Marginal indication of decline in luminosity function at dimmer side of MIR &gt; −19.5 is found for galaxies around AGNs with MBH = 108.2–109 M⊙ and nearest redshift group (z = 0.1–0.3). These results indicate that AGNs with the most massive SMBHs reside in haloes where a large fraction of galaxies have been transited to the red sequence. The accretion of hot halo gas as well as recycled gas from evolving stars can be one of the plausible mechanisms to fuel the SMBHs above ∼ 109 M⊙.
Return of Voice for Ventilated Tracheostomy Patients in ICU: A Randomized Controlled Trial of Early-Targeted Intervention*
Authors: Freeman-Sanderson Amy L. , Togher Leanne , Elkins Mark R. , Phipps Paul R. 
Published: February 2016

Objectives:
A cuffed tracheostomy tube facilitates prolonged mechanical ventilation and weaning but usually leads to prolonged voicelessness, which can be one of the most negative experiences of hospitalization. No randomized trials have examined the effects of targeted early communication intervention for the restoration of voice in ventilated tracheostomy patients in the ICU.

Design:
A prospective randomized clinical trial.

Setting:
The trial was conducted in the ICU of an urban tertiary level hospital.

Patients:
Thirty adult participants enrolled, with 15 randomly allocated to the intervention and control groups.

Interventions:
The early intervention group received early cuff deflation and insertion of an in-line speaking valve during mechanical ventilation. The control group received standard cuff deflation and a speaking valve during self-ventilation. A speech-language pathologist provided all treatments.

Measurements and Main Results:
The primary outcome measure was time from tracheostomy insertion to phonation. Early intervention significantly hastened return to phonation (median difference = 11 d; hazard ratio = 3.66; 95% CI, 1.54–8.68) with no significant effect on duration of tracheostomy cannulation (hazard ratio = 1.40; 95% CI, 0.65–3.03), duration of mechanical ventilation in days from tracheostomy insertion (hazard ratio = 1.19; 95% CI, 0.58–2.51), length of stay in ICU (hazard ratio = 1.16; 95% CI, 0.54–2.52), or time to return to oral intake (hazard ratio = 2.35; 95% CI, 0.79–6.98). Adverse events were low and equal in both groups. There was no significant change in measures of quality of life.

Conclusions:
Focused early intervention for communication during mechanical ventilation allows the restoration of phonation significantly sooner than standard treatment, with no increase in complications in a small patient cohort. Although these results are favorable, further research is needed to determine whether the effects on any of the secondary outcomes are statistically significant and clinically important.
Bacterial Bioburden Decrease in Orthokeratology Lens Storage Cases After Forewarning: Assessment by the DNA Dot Hybridization Assay
Authors: Fang Po-Chiung , Lo Jung , Chang Tsung C. , Chien Chun-Chih , Hsiao Chang-Chun , Tseng Shin-Ling , Lai Yu-Hsuan , Kuo Ming-Tse 
Published: February 2016

Background:
The aim of this study was to measure the changes in the bacterial bioburden in orthokeratology (OK) lens storage cases using the DNA dot hybridization assay (DHA) after forewarning patients about their bacterial contamination severity.

Methods:
Thirty-one OK lens wearers were prospectively enrolled in this study. Dot hybridization assay was used for serial measurements of bacterial bioburden in OK storage cases after lenses had been soaked for approximately 6 hr. After the first assessment, the lens wearers were informed of the extent of case contamination and the possible risk of microbial keratitis (MK), and best practices for lens care and lens case hygiene were reviewed and reinforced. A second assessment by the same DHA method was performed after approximately 6 months.

Results:
Two universal bacterial probes confirmed a significant decrease in bacterial bioburden at the second assessment (P<0.01 and P<0.001). Genus-specific probes showed significant reductions in Acinetobacter and Klebsiella (P=0.02 and P=0.01), but not in Pseudomonas (P=0.42).

Conclusions:
Making OK lens wearers aware of the bacterial bioburden in their lens cases resulted in improved quality of case care and reduced bioburden. Our results suggest that a strategy of bioburden assessment with forewarning could be a useful method to decrease the incidence of OK-related MK.
Biomarkers p16, Human Papillomavirus and p53 Predict Recurrence and Survival in Early Stage Squamous Cell Carcinoma of the Vulva
Authors: Hay Casey M. , Lachance Jason A. , Lucas F.L. , Smith Kahsi A. , Jones Michael A. 
Published: February 2016

Objective
Vulvar squamous cell carcinoma (VSCC) develops through 2 distinct molecular pathways, one involving high-risk human papillomavirus (HPV) infection and the other through early p53 suppressor gene mutation. We sought to evaluate the influence of p53 mutation, HPV status, and p16 expression on local recurrence and disease-specific mortality in early stage VSCC.

Materials and Methods
We performed a retrospective chart review of all patients with stage I VSCC at the Maine Medical Center from 1998 to 2007 (n = 92). Tumor size, depth of invasion, lymphatic/vascular space invasion, and growth pattern were recorded. Paraffin-embedded tissue blocks were stained by immunohistochemistry for p16 and p53; high-risk HPV was detected by polymerase chain reaction assay. Margin distance was determined by a gynecologic pathologist. Survival analyses were conducted to examine predictors of VSCC recurrence and disease-specific mortality.

Results
Age, depth of invasion, lymphatic/vascular space invasion, growth pattern, and margin status were not significant predictors of recurrence or disease-specific mortality. Tumor size of greater than 4.0 cm indicated a 4-fold increase in disease-specific mortality but did not significantly increase recurrence. p16-Positive patients were less likely to recur and had no VSCC-related deaths. Human papillomavirus–positive patients were less likely to recur and had no VSCC-related deaths. p53-positive patients were 3 times more likely to recur and nearly 7 times more likely to die from vulvar cancer.

Conclusions
Our findings suggest that HPV and the surrogate biomarker p16 indicate a less aggressive type of vulvar cancer. p53 positivity was associated with poor prognosis and significantly increased both recurrence and disease-specific mortality.