bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addressing Beacon re-identification attacks: quantification and mitigation of privacy risks
Authors: Raisaro Jean Louis , Tramèr Florian , Ji Zhanglong , Bu Diyue , Zhao Yongan , Carey Knox , Lloyd David , Sofia Heidi , Baker Dixie , Flicek Paul , Shringarpure Suyash , Bustamante Carlos , Wang Shuang , Jiang Xiaoqian , Ohno-Machado Lucila , Tang Haixu , Wang XiaoFeng , Hubaux Jean-Pierre 
Published: December 2016

Abstract
The Global Alliance for Genomics and Health (GA4GH) created the Beacon Project as a means of testing the willingness of data holders to share genetic data in the simplest technical context—a query for the presence of a specified nucleotide at a given position within a chromosome. Each participating site (or “beacon”) is responsible for assuring that genomic data are exposed through the Beacon service only with the permission of the individual to whom the data pertains and in accordance with the GA4GH policy and standards.
While recognizing the inference risks associated with large-scale data aggregation, and the fact that some beacons contain sensitive phenotypic associations that increase privacy risk, the GA4GH adjudged the risk of re-identification based on the binary yes/no allele-presence query responses as acceptable. However, recent work demonstrated that, given a beacon with specific characteristics (including relatively small sample size and an adversary who possesses an individual’s whole genome sequence), the individual’s membership in a beacon can be inferred through repeated queries for variants present in the individual’s genome.
In this paper, we propose three practical strategies for reducing re-identification risks in beacons. The first two strategies manipulate the beacon such that the presence of rare alleles is obscured; the third strategy budgets the number of accesses per user for each individual genome. Using a beacon containing data from the 1000 Genomes Project, we demonstrate that the proposed strategies can effectively reduce re-identification risk in beacon-like datasets.
Lessons from characterization and treatment of the autoinflammatory syndromes
Authors: Aksentijevich Ivona , McDermott Michael F. 
Published: December 2016

Purpose of review
The list of genes associated with systemic inflammatory diseases has been steadily growing because of the explosion of new genomic technologies. Significant advances in the past year have deepened our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: haploinsufficiency of A20, otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis.

Recent findings
The scope of autoinflammation has been broadened to include defects in deubiquitination and cellular redox homeostasis. At the clinical level, we discuss the biological rationale for treatment with cytokine inhibitors and colchicine in respective conditions and the use of interleukin-1 antagonism for diagnostic and therapeutic purposes in the management of undifferentiated autoinflammatory disorders.

Summary
Gene discoveries coupled with studies of molecular function provide knowledge into the biology of inflammatory responses and form the basis for genomically informed therapies. Diseases of dysregulated ubiquitination constitute a novel category of human inflammatory disorders.
Predictors of Positive Margins at Time of Loop Electrosurgical Excision Procedure
Authors: Liss Jill , Alston Meredith , Krull Mona B. , Mazzoni Sara E. 
Published: December 2016

ObjectiveThe aim of the study was to identify factors associated with the presence of high-grade squamous intraepithelial lesion (HSIL) at surgical margins of loop electrosurgical excision procedure (LEEP) pathology specimens.Materials and MethodsAll women evaluated for lower genital tract disease at a single academic institution were prospectively entered into a database. The database was queried for all women who had a LEEP performed for indications within contemporary American Society of Colposcopy and Cervical Pathology guidelines between April 1, 2013, and April 30, 2015. Factors extracted from the database included demographics, contraception, weight, tobacco use, provider volume, resident participation, history of cervical procedure, and pathology features including preceding Pap test category. A positive margin was defined as HSIL on either the endocervical or ectocervical margin of the LEEP specimen or in endocervical curettage specimen after LEEP. We performed univariable statistics to identify factors associated with positive margins and then logistic regression modeling on significant factors for the outcome of positive margins.ResultsTwo hundred sixty-nine women were identified. Seventy five (27.8%) of these women had positive margins. Only tobacco use, gravity, parity, and preceding Pap category were significant on univariable analysis. After multivariable analysis, smokers remained more likely to have positive margins (odds ratio = 2.01; CI = 1.12–3.6;p< .01) as did those with preceding HSIL Pap tests (odds ratio = 1.96; CI = 1.13–3.41;p< .01).ConclusionsIn our population, of all the factors assessed, only tobacco use and preceding high-grade Pap tests were associated with positive margins at time of LEEP. This information may be helpful in preprocedural planning to optimize treatment.
The Accuracy of Large Loop Excision of the Transformation Zone Specimen Dimensions in Determining Volume: A Multicentric Prospective Observational Study
Authors: Carcopino Xavier , Mancini Julien , Prendiville Walter , Gondry Jean , Chevreau Julien , Lamblin Gery , Atallah Anthony , Lavoue Vincent , Caradec Claire , Baldauf Jean-Jacques , Bryand Angélique , Henno Sébastien , Agostini Aubert , Douvier Serge , Jarniat Adelaide , Riethmuller Didier , Mendel Anne , Brun Jean-Luc , Rakotomahenina Hajanarina , Preaubert Lise 
Published: December 2016

Objective
The aim of the study was to determine which mathematical formula of specimen dimensions is the most accurate method of determining volume of the excised specimen at loop excision of the transformation zone.

Materials and Methods
A multicenter prospective observational study was conducted. A total of 258 patients who had a loop excision of the transformation zone performed as treatment of cervical intraepithelial neoplasia 2–3 were included. The dimensions and the volume of the specimen were measured at the time of the procedure, before formaldehyde fixation. The volume was measured by immersing the specimen in a graduated cylinder using Archimedes fluid displacement technique. The measured volume was compared with the calculated volume using different volume formulas, that is, a cone, a cylinder, a parallelepiped, and a hemiellipsoid. The main outcome measure was the relationship between calculated volume (using the dimensions of thickness, length, and circumference) and the measured volume of the specimen.

Results
The mean (SD) thickness, length, and circumference of specimens were 8.8 mm (3.8), 12.7 mm (5.9), and 45.7 mm (16.8), respectively. The mean (SD) measured volume was 2.53 (1.49) mL. Using the formula for the volume of a cone, a cylinder, a parallelepiped and a hemiellipsoid, estimated volumes were 1.03 mL (1.22), 3.10 mL (3.65), 6.20 mL (7.31), and 2.07 mL (2.44), respectively. The highest intraclass correlation coefficient between measured and calculated volume was observed when using the formula for the volume of a hemiellipsoid specimen (0.47, 95% CI = 0.36–0.56).

Conclusions
The hemiellipsoid formula is the most accurate determinant of the excised volume. Other formulas do not allow for an accurate estimation of the excised volume.
Public Health Benefit of Peer-Referral Strategies for Detecting Undiagnosed HIV Infection Among High-Risk Heterosexuals in New York City
Authors: Gwadz Marya , Cleland Charles M. , Perlman David C. , Hagan Holly , Jenness Samuel M. , Leonard Noelle R. , Ritchie Amanda S. , Kutnick Alexandra 
Published: December 2016

Abstract:
Identifying undiagnosed HIV infection is necessary for the elimination of HIV transmission in the United States. The present study evaluated the efficacy of 3 community-based approaches for uncovering undiagnosed HIV among heterosexuals at high-risk (HHR), who are mainly African American/Black and Hispanic. Heterosexuals comprise 24% of newly reported HIV infections in the United States, but experience complex multilevel barriers to HIV testing. We recruited African American/Black and Hispanic HHR in a discrete urban area with both elevated HIV prevalence and poverty rates. Approaches tested were (1) respondent-driven sampling (RDS) and confidential HIV testing in 2 sessions (n = 3116); (2) RDS and anonymous HIV testing in one session (n = 498); and (3) venue-based sampling (VBS) and HIV testing in a single session (n = 403). The main outcome was newly diagnosed HIV infection. RDS with anonymous testing and one session reached HHR with less HIV testing experience and more risk factors than the other approaches. Furthermore, RDS with anonymous (4.0%) and confidential (1.0%) testing yielded significantly higher rates of newly diagnosed HIV than VBS (0.3%). Thus peer-referral approaches were more efficacious than VBS for uncovering HHR with undiagnosed HIV, particularly a single-session/anonymous strategy, and have a vital role to play in efforts to eliminate HIV transmission.
Frailty and Circulating Markers of Inflammation in HIV+ and HIV− Men in the Multicenter AIDS Cohort Study
Authors: Margolick Joseph B. , Bream Jay H. , Martínez-Maza Otoniel , Lopez Joe , Li Xiuhong , Phair John P. , Koletar Susan L. , Jacobson Lisa P. 
Published: December 2016

Background:Frailty is associated with immune activation and inflammation in the elderly general population, but whether this is true in the younger HIV-infected (HIV+) population is not known.Methods:We analyzed 24 serologic biomarkers of monocyte, T-cell, or B-cell activation in HIV− (n = 207) and HIV+ (n = 714; 75% virologically suppressed) men who have sex with men in the Multicenter AIDS Cohort Study (MACS) and were classified as frail or nonfrail according to expression or nonexpression of the frailty phenotype at 2 consecutive study visits.Results:After correction for multiple comparisons and adjustment for age, race, study site, and education, frailty in HIV+ men was significantly (P< 0.002) associated with higher levels of sCD14, sIL2Rα, sTNF-R2, IL-6, and TNF-α; the association with higher levels of C-reactive protein (CRP) approached significance (P= 0.003). After further adjustment for body mass index (BMI), smoking, and comorbidities, only the association with C-reactive protein was significant atP< 0.002, with levels approximately 50% higher in frail compared with nonfrail men. These conclusions were not altered by restricting the analysis to HIV+ men who were virologically suppressed. Among HIV− men, none of these markers differed significantly by frailty.Conclusions:These data suggest that frailty in virologically suppressed HIV+ men was associated with immune activation beyond that due to treated HIV infection. The inflammatory markers associated with frailty were primarily products of activated monocytes/macrophages. Much, but not all, activation was accounted for by harmful behaviors and comorbidities. However, C-reactive protein, which is regulated by IL-6, was elevated in HIV+ frail men independent of these factors.
Prescription of Postexposure Prophylaxis for HIV-1 in the Emergency Room: Correct Transmission Risk Assessment Remains Challenging
Authors: Marzel Alex , Heinrich Henriette , Schilliger Lukas , Fehr Jan S. , Günthard Huldrych F. , Kouyos Roger , Rampini Silvana K. 
Published: December 2016

Background:
Limited data are available about the accuracy of postexposure prophylaxis (PEP) prescription in the emergency rooms. Here, we evaluated PEP prescription decision making with respect to the risk of sexual HIV transmission and the exposed person's fear vis-à-vis HIV.

Methods:
Using a risk assessment algorithm, we retrospectively evaluated the adequacy of PEP prescription for all persons presenting at the emergency room of the University Hospital Zurich after consensual sex from 2007 to 2013. We used logistic regression to identify factors that correlate with risk-concordant and risk-discordant decisions.

Results:
We documented 975 persons with a total of 1051 visits for PEP: 83% were men, 71% were Swiss, and 37% were men who have sex with men. In 74% of visits, the decisions were concordant with the risk evaluation algorithm (22% discordant, 4% unknown). In 61% (644/1051) PEP was prescribed; however, in 12% (76/644) the prescriptions were without indication of HIV transmission risk and were attributed to the exposed person's request. Importantly, in 10% (101/1051) of all visits, there were potential risks but PEP was not prescribed, either because of physician's decision or exposed person's refusal. The presence of the source partner strongly correlated with appropriately withholding PEP (adjusted odds ratio for giving PEP 0.05; 95% confidence interval: 0.03 to 0.08).

Conclusions:
We found that 22% of PEP decisions were risk discordant because of exposed person's request, incorrect estimation of the sexual transmission risk by the physician, or exposed person's refusal to accept PEP. Emergency physicians may benefit from specialized risk assessment training and patients from education in HIV transmission risk awareness.
Optimal blood pressure target in stroke prevention
Authors: Yannoutsos Alexandra , Dreyfuss Tubiana Céline , Safar Michel E. , Blacher Jacques 
Published: December 2016

Purpose of review
A generalized single blood pressure (BP) goal may appear not suitable to achieve an optimal stroke prevention at the individual level. The aim of the present review is to consider the clinical relevance of individualized BP goal according to patient's age, comorbidities and established cerebrovascular disease.

Recent findings
Observational and interventional data support heterogeneity in target organ prevention in that lower BP values than recommended by hypertension guidelines are associated with further stroke risk reduction. However, more ambitious BP treatment targets appear not broadly applicable to ageing hypertensive individuals or patients with established cerebrovascular disease.

Summary
Strict BP control in early diagnosed hypertensive individuals, without established arterial disease, should be a priority in primary stroke prevention. In ageing hypertensive individuals, difficult to control SBP can be considered as a marker of increased systemic arterial disease in the brain, the heart and the kidneys. A delayed aggressive intervention to reduce BP in these high-risk patients may be associated with a J-shaped relationship between BP level and adverse events. Moreover, patients suffering from stroke frequently presented with a high burden of small cerebral vessel lesions that are associated with an increased risk of cognitive decline progression, particularly with stringent BP levels.
Glyceraldehyde-3-Phosphate Dehydrogenase and Seven in Absentia Homolog -1 Interactions in Mammalian Cells Visualized Using Proximity Ligation Assay
Authors: Singh Harkewal , Melm Christopher 
Published: December 2016

AbstractProteins seldom function in isolation and thus protein-protein interactions are critical in understanding the molecular basis of diseases and health (1,2). There are several well established techniques that are used to investigate protein-protein interactions(3). Most of the methods require some form of genetic modification of the target protein and thus always adds extra steps. However, Proximity Ligation Assay(4-6) (PLA)akaDuolink® is one such method that requires no genetic modification of the target protein and probes protein-protein interactions in fixed live cells and tissues. Briefly, PLA requires the use of primary antibodies specific to the proteins of interest. Once the sample (fixed cells or tissues) is incubated with species specific primary antibodies, secondary antibodies that are conjugated with oligonucleotides (also known as PLUS and MINUS probes respectively) and connecter oligonucleotides are added. This complex is ligated if the two PLUS and MINUS probes are within 40nm of each other. The resulting nucleic acid is amplified using rolling circle amplification and then probed with appropriate fluorescent probes. If the two proteins are interacting, one could visualize the interaction as a single red foci (for example Far Red Detection) using fluorescent microscopy. Here, we used PLA to probe protein-protein interactions between Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and seven in absentia homolog -1 (Siah-1) – an E3 ubiquitin ligase. We first use PLA to show that GAPDH and Siah-1 proteins exist endogenously in the cytosol of multiple mammalian cell lines. Our data suggest the use of DU145 and T98G cell lines to show translocation of the GAPDH-Siah- 1 complex. Next, we used common nitrosylation agents(7,8) (S-nitrosoglutathione-GSNO and S-Nitroso-N-acetyl-DL-pencillamine–SNAP) in different concentrations and observed that GAPDH and Siah-1 interact presumably due to the nitrosylation of the former, which is consistent with previous studies(9,10). Interestingly, no interactions were observed between the two proteins in the absence of GSNO or SNAP indicating that nitrosylation might be critical for GAPDH-Siah1 interactions. Our results suggest that GAPDH-Siah-1 interactions originate in the cytosol and migrate to the nucleus under the conditions tested. We quantify the PLA signal using Duolink® Image Tool and observe a clear enhancement of GAPDH-Siah-1 PLA signal upon treating the cells with GSNO or SNAP. Next, we used R-(-)-Deprenyl (deprenyl), a known inhibitor of GAPDH4, and show that it abrogates GAPDH-Siah-1 PLA complex under the conditions tested. Finally, our data suggest that PLA can detect and quantify the GAPDH-Siah1 complex; a well-known protein-protein interaction implicated in neurodegeneration(9-11) and thus could be a method of choice for similar applications.
The effect of known mutator alleles in a cluster of clinicalSaccharomyces cerevisiaestrains
Authors: Skelly Daniel A. , Magwene Paul M. , Meeks Brianna , Murphy Helen A. 
Published: December 2016

AbstractNatural selection has the potential to act on all phenotypes, including genomic mutation rate. Classic evolutionary theory predicts that in asexual populations, mutator alleles, which cause high mutation rates, can fix due to linkage with beneficial mutations. This phenomenon has been demonstrated experimentally and may explain the frequency of mutators found in bacterial pathogens. In contrast, in sexual populations, recombination decouples mutator alleles from beneficial mutations, preventing mutator fixation. In the facultatively sexual yeastSaccharomyces cerevisiae, segregating alleles ofMLH1andPMS1have been shown to be incompatible, causing a high mutation rate when combined. These alleles had never been found together naturally, but were recently discovered in a cluster of clinical isolates. Here we report that the incompatible mutator allele combination only marginally elevates mutation rate in these clinical strains. Genomic and phylogenetic analyses provide no evidence of a historically elevated mutation rate. We conclude that the effect of the mutator alleles is dampened by background genetic modifiers. Thus, the relationship between mutation rate and microbial pathogenicity may be more complex than once thought. Our findings provide rare observational evidence that supports evolutionary theory suggesting that sexual organisms are unlikely to harbor alleles that increase their genomic mutation rate.
MetaSRA: normalized sample-specific metadata for the Sequence Read Archive
Authors: Bernstein Matthew N. , Doan AnHai , Dewey Colin N. 
Published: December 2016

AbstractMotivationThe NCBI’s Sequence Read Archive (SRA) promises great biological insight if one could analyze the data in the aggregate; however, the data remain largely underutilized, in part, due to the poor structure of the metadata associated with each sample. The rules governing submissions to the SRA do not dictate a standardized set of terms that should be used to describe the biological samples from which the sequencing data are derived. As a result, the metadata include many synonyms, spelling variants, and references to outside sources of information. Furthermore, manual annotation of the data remains intractable due to the large number of samples in the archive. For these reasons, it has been difficult to perform large-scale analyses that study the relationships between biomolecular processes and phenotype across diverse diseases, tissues, and cell types present in the SRA.ResultsWe present MetaSRA, a database of normalized SRA sample-specific metadata following a schema inspired by the metadata organization of the ENCODE project. This schema involves mapping samples to terms in biomedical ontologies, labeling each sample with a sample-type category, and extracting real-valued properties. We automated these tasks via a novel computational pipeline.AvailabilityThe MetaSRA database is available athttp://deweylab.biostat.wisc.edu/metasra. Software implementing our computational pipeline is available athttps://github.com/deweylab/metasra-pipeline.Contactcdewey@biostat.wisc.edu
Temporal anticipation based on memory
Authors: Cravo André M. , Rohenkohl Gustavo , Santos Karin Moreira , Nobre Anna C. 
Published: December 2016

AbstractThe fundamental role that our long-term memories play in guiding perception is increasingly recognised, but the functional and neural mechanisms are just beginning to be explored. Though experimental approaches are being developed to investigate the influence of long-term memories on perception, these remain mostly static and neglect their temporal and dynamic nature. Here we show we show that our long-term memories can guide attention proactively and dynamically based on learned temporal associations. Across two experiments we found that detection and discrimination of targets appearing within previously learned contexts are enhanced when the timing of target appearance matches the learned temporal contingency. Neural markers of temporal preparation revealed that the learned temporal associations trigger specific temporal predictions. Our findings emphasize the ecological role that memories play in predicting and preparing perception of anticipated events, calling for revision of the usual conceptualisation of contextual associative memory as a reflective and retroactive function.