bluuebunny/crossref_metadata_2025 huggingface dataset:
PREVALENCE OF VITREOMACULAR ADHESION IN PATIENTS WITHOUT MACULOPATHY OLDER THAN 40 YEARS
Authors: Rodman Julie A. , Shechtman Diana , Sutton Brad M. , Pizzimenti Joseph J. , Bittner Ava K. ,   VAST Study Group
Published: August 2017

Purpose:

To determine the prevalence and factors influencing vitreomacular adhesion (VMA) or vitreomacular traction (VMT) in subjects without maculopathy older than age 40 years.

Methods:

In a prospective cross-sectional study, 1,950 eyes in 1,090 participants aged 40 to 89 years representing various ethnic groups from 14 centers in the United States underwent a comprehensive eye examination, including spectral domain optical coherence tomography. A team of independent, masked readers classified the presence or absence of VMA/VMT on spectral domain optical coherence tomography based on the International Vitreomacular Traction Study Group rubric.

Results:

Across all eyes, the prevalence of VMA or VMT was 39% or 1%, respectively. For every 1-year increase in age, there was a statistically significant 7% decreased odds of having VMA or VMT (95% confidence interval [CI]: 0.89–0.96;P< 0.001), whereas African Americans had 55% significantly reduced odds of having VMA or VMT when than whites (95% CI: 0.23–0.90;P= 0.025). Vitreomacular adhesion >1,500μm was significantly more likely than VMA <1,500μm in younger adults (95% CI: 0.70–0.86;P< 0.001), hyperopes versus emmetropes (95% CI: 1.49–35.9;P= 0.01), primary eye care versus tertiary practices (95% CI: 0.03–0.92;P= 0.04), and patients without hyperlipidemia (95% CI: 0.04–0.83;P= 0.03).

Conclusion:

Vitreomacular adhesion is highly prevalent among middle-aged adults. Diagnostic screening with spectral domain optical coherence tomography may help to accurately detect VMA or VMT, prompting routine monitoring and timely therapeutic intervention.
A Smartphone Application for Customized Frequency Table Selection in Cochlear Implants
Authors: Jethanamest Daniel , Azadpour Mahan , Zeman Annette M. , Sagi Elad , Svirsky Mario A.
Published: August 2017

Hypothesis:

A novel smartphone-based software application can facilitate self-selection of frequency allocation tables (FAT) in postlingually deaf cochlear implant (CI) users.

Background:

CIs use FATs to represent the tonotopic organization of a normal cochlea. Current CI fitting methods typically use a standard FAT for all patients regardless of individual differences in cochlear size and electrode location. In postlingually deaf patients, different amounts of mismatch can result between the frequency-place function they experienced when they had normal hearing and the frequency-place function that results from the standard FAT. For some CI users, an alternative FAT may enhance sound quality or speech perception. Currently, no widely available tools exist to aid real-time selection of different FATs. This study aims to develop a new smartphone tool for this purpose and to evaluate speech perception and sound quality measures in a pilot study of CI subjects using this application.

Methods:

A smartphone application for a widely available mobile platform (iOS) was developed to serve as a preprocessor of auditory input to a clinical CI speech processor and enable interactive real-time selection of FATs. The application's output was validated by measuring electrodograms for various inputs. A pilot study was conducted in six CI subjects. Speech perception was evaluated using word recognition tests.

Results:

All subjects successfully used the portable application with their clinical speech processors to experience different FATs while listening to running speech. The users were all able to select one table that they judged provided the best sound quality. All subjects chose a FAT different from the standard FAT in their everyday clinical processor. Using the smartphone application, the mean consonant–nucleus–consonant score with the default FAT selection was 28.5% (SD 16.8) and 29.5% (SD 16.4) when using a self-selected FAT.

Conclusion:

A portable smartphone application enables CI users to self-select frequency allocation tables in real time. Even though the self-selected FATs that were deemed to have better sound quality were only tested acutely (i.e., without long-term experience with them), speech perception scores were not inferior to those obtained with the clinical FATs. This software application may be a valuable tool for improving future methods of CI fitting.
Physiological Mechanisms in Combined Electric–Acoustic Stimulation
Authors: Sato Mika , Baumhoff Peter , Tillein Jochen , Kral Andrej
Published: August 2017

Objective:

Electrical stimulation is normally performed on ears that have no hearing function, i.e., lack functional hair cells. The properties of electrically-evoked responses in these cochleae were investigated in several previous studies. Recent clinical developments have introduced cochlear implantation (CI) in residually-hearing ears to improve speech understanding in noise. The present study documents the known physiological differences between electrical stimulation of hair cells and of spiral ganglion cells, respectively, and reviews the mechanisms of combined electric and acoustic stimulation in the hearing ears.

Data Sources:

Literature review from 1971 to 2016.

Conclusions:

Compared with pure electrical stimulation the combined electroacoustic stimulation provides additional low-frequency information and expands the dynamic range of the input. Physiological studies document a weaker synchronization of the evoked activity in electrically stimulated hearing ears compared with deaf ears that reduces the hypersynchronization of electrically-evoked activity. The findings suggest the possibility of balancing the information provided by acoustic and electric input using stimulus intensity. Absence of distorting acoustic–electric interactions allows exploiting these clinical benefits of electroacoustic stimulation.
Isolated Second Implant Adaptation Period in Sequential Cochlear Implantation in Adults
Authors: Smilsky Kari , Dixon Peter R. , Smith Leah , Shipp David , Ng Amy , Millman Tara , Stewart Suzanne , Nedzelski Julian M. , Lin Vincent Y. , Chen Joseph M.
Published: August 2017

Objective:

To determine if depriving the use of the first cochlear implant (CI1) impacts adaptation to a sequential implant (CI2).

Study Design:

Prospective cohort.

Setting:

Academic center.

Patients:

Sixteen unilateral cochlear implant recipients undergoing contralateral implantation (sequential bilateral) were matched according to age, etiology, duration of deafness, device age, and delay between implants.

Intervention:

During a 4-week adaptation period after CI2 activation, patients underwent deprivation of CI1 or were permitted continued use of it.

Main Outcome Measures:

Speech perception scores and subjective quality of life outcomes before CI2 and at 1, 3, 6, and 12-months following activation.

Results:

Maximal CI2 speech perception scores in quiet were achieved by 1-month postactivation for the “deprivation” group (71.3% for hearing in noise test [HINT], p = 0.767 for change beyond 1-mo) compared with 6-months for the “continued use” group (67.9% for HINT, p = 0.064 for change beyond 6-mo). The “deprivation” group experienced a temporary drop in CI1 scores (67.9% for HINT in quiet at 1-mo versus 78.4% pre-CI2, p = 0.009) recovering to 77.3% by 3-months; unchanged from baseline levels (p = 1.0). A binaural advantage over the better hearing ear was present for HINT sentences with noise (72.4% versus 58.8% for “deprivation”, p = 0.001; 71.5% versus 52.7% for “continued use,” p = 0.01). Missing data precluded a meaningful analysis of subjective quality of life outcome scales.

Conclusion:

Bilateral cochlear implantation improves speech perception compared with one implant. A period of deprivation from CI1 shortens time to maximum speech perception by CI2 without long-term consequences on the performance of CI1.
The Impact of Comorbidities in the Aging Population on Cochlear Implant Outcomes
Authors: Wilkerson Brent Jerome , Porps Sandra F. , Babu Seilesh C.
Published: August 2017

Objectives:

Cochlear implants have been used for many years for bilateral profound hearing loss. General longevity has continued to increase and, therefore, the age at which cochlear implants are placed has concomitantly increased. Our purpose is to determine whether outcomes and complications are significantly different in the elderly.

Study Design:

Retrospective, clinical review.

Setting:

Tertiary referral center, primarily ambulatory setting.

Patients:

One hundred and one patients with moderate-to-profound hearing loss who ranged in age from 18 to 89 years. Subjects were divided into younger (<69, n = 51) and older (>70, n = 50) groups for analysis.

Intervention:

All patients received either a unilateral or bilateral multichannel cochlear implant. The change in hearing in noise testing and AZBio testing between pre and postimplantation was evaluated in each group.

Main Outcome Measures:

Primary outcome measures include preimplant and postimplant hearing in noise test (HINT) and/or AZBio speech perception testing. Preimplant HINT/AZBio was compared with postimplant HINT/AZBio for each patient and between the two groups. In addition, we reviewed the comorbidities between the two groups as well as complication rates between less than 70 and more than 70 group.

Results:

Both the younger and the older group demonstrated a significant improvement in postimplant HINT and/or AZBio scores. No statistically significant difference was noted in precochlear implant HINT/AZBio testing (p = 0.65/p = 0.48) between the two groups or the postimplant HINT/AZBio testing (p = 0.19/p = 0.22) between the two groups. Although, more than 70 yo group had significantly more comorbidities, the complication rates between the groups were insignificant. There was no shown association of specific comorbidities to complications between the two groups.

Conclusions:

Both older and younger patients can receive a significant improvement in speech perception with cochlear implantation. Older patients tend to have more comorbidities compared with the younger patients, however, the complication rates are not higher in this population.
Long-term Quality of Life Following Vestibular Schwannoma Excision Via the Translabyrinthine Approach
Authors: Broomfield Stephen J. , Mandavia Ashish K. , Nicholson Jack S. , Mahmoud Osama , King Andrew T. , Rutherford Scott A. , Ramsden Richard T.
Published: August 2017

Objective:

To assess postoperative quality of life (QOL) and other patient-reported outcomes following surgery for vestibular schwannoma.

Study Design:

Cross-sectional retrospective case review using postal questionnaires.

Setting:

Tertiary referral center.

Patients:

Five hundred consecutive patients undergoing surgery for vestibular schwannoma.

Intervention(s):

Patients undergoing surgery via the translabyrinthine approach (excluding neurofibromatosis type 2) under the senior author, with a minimum of 5 years follow-up, were included.

Main Outcome Measure(s):

QOL was assessed using the Short Form 36 (SF-36) questionnaire and a disease-specific survey to assess patients’ subjective outcomes.

Results:

The SF-36 scores in this group were significantly lower than the general UK population, though 24% of respondents reported a subjective improvement in overall QOL. Tumors larger than 4 cm were related to a reduced SF-36 total mental component score (p = 0.037). Increased age at time of surgery correlated with a reduced physical component of QOL (correlation coefficient = −0.26) and an improved mental component (correlation coefficient = 0.26). Subjective reports of postoperative symptoms and return to work, driving and social activities were similar to other published studies. 35% of patients reported vivid dreams or nightmares following surgery; the first reported incidence of this phenomenon in a large group of vestibular schwannoma patients.

Conclusions:

Generic measures of QOL in patients following translabyrinthine surgery for vestibular schwannoma do not always match subjective reports, reflecting the complexity of QOL assessment and the range of outcomes in this group. Increased time since surgery appears to be associated with an improvement in mental health.
Perceptions of Support Groups Among Older Breast Cancer Survivors
Authors: Green Emily K. , Wodajo Amelework , Yang Yajuan , Sleven Miriam , Pieters Huibrie C.
Published: August 2017

Background:

Cancer survivors transitioning from active treatment to posttreatment may lack critical support and information about their posttreatment care. Support groups have the potential to address this gap.

Objective:

The aim of this study was to describe how breast cancer survivors 65 years and older perceived professionally led, in-person support groups.

Methods:

Individual interviews with 54 women were analyzed using grounded theory informed by constructivism.

Results:

Strong negative assumptions about cancer support groups were described. Tension existed between two opposing categories: participants' preconceptions of support groups and characterizations of their members and the women's perceptions of their own informational and emotional needs. Participants also described what sources of support they used in lieu of professionally led support groups.

Conclusions:

Despite awareness and availability, most participants did not use support groups as a resource during their primary or post–cancer treatment.

Implications for Practice:

Structural changes can benefit existing models of support groups including how and when support needs and services are discussed with survivors and a shift toward the inclusion of practical information.
Dimensions of Posttraumatic Growth in Patients With Cancer
Authors: Heidarzadeh Mehdi , Rassouli Maryam , Brant Jeannine M. , Mohammadi-Shahbolaghi Farahnaz , Alavi-Majd Hamid
Published: August 2017

Background:

Posttraumatic growth (PTG) refers to positive outcomes after exposure to stressful events. Previous studies suggest cross-cultural differences in the nature and amount of PTG.

Objective:

The aim of this study was to explore different dimensions of PTG in Iranian patients with cancer.

Methods:

A mixed method study with convergent parallel design was applied to clarify and determine dimensions of PTG. Using the Posttraumatic Growth Inventory (PTGI), confirmatory factor analysis was used to quantitatively identify dimensions of PTG in 402 patients with cancer. Simultaneously, phenomenological methodology (in-depth interview with 12 patients) was used to describe and interpret the lived experiences of cancer patients in the qualitative part of the study.

Results:

Five dimensions of PTGI were confirmed from the original PTGI. Qualitatively, new dimensions of PTG emerged including “inner peace and other positive personal attributes,” “finding meaning of life,” “being a role model,” and “performing health promoting behaviors.”

Conclusion:

Results of the study indicated that PTG is a 5-dimensional concept with a broad range of subthemes for Iranian cancer patients and that the PTGI did not reflect all growth dimensions in Iranian cancer patients.

Implications for Practice:

Awareness of PTG dimensions can enable nurses to guide their use as coping strategies and provide context for positive changes in patients to promote quality care.
The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation
Authors: Kelly Ronan J. , Zaidi Ali H. , Smith Matthew A. , Omstead Ashten N. , Kosovec Juliann E. , Matsui Daisuke , Martin Samantha A. , DiCarlo Christina , Werts E. Day , Silverman Jan F. , Wang David H. , Jobe Blair A.
Published: August 2017

Objective:

The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials.

Summary Background Data:

Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients.

Methods:

To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation.

Results:

The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure.

Conclusions:

Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.
The genetic architecture of osteoarthritis: insights from UK Biobank
Authors: Zengini Eleni , Hatzikotoulas Konstantinos , Tachmazidou Ioanna , Steinberg Julia , Hartwig Fernando P. , Southam Lorraine , Hackinger Sophie , Boer Cindy G. , Styrkarsdottir Unnur , Suveges Daniel , Killian Britt , Gilly Arthur , Ingvarsson Thorvaldur , Jonsson Helgi , Babis George C. , McCaskie Andrew , Uitterlinden Andre G. , van Meurs Joyce B. J. , Thorsteinsdottir Unnur , Stefansson Kari , Smith George Davey , Wilkinson Mark J. , Zeggini Eleftheria
Published: August 2017

Osteoarthritis is a common complex disease with huge public health burden. Here we perform a genome-wide association study for osteoarthritis using data across 16.5 million variants from the UK Biobank resource. Following replication and meta-analysis in up to 30,727 cases and 297,191 controls, we report 9 new osteoarthritis loci, in all of which the most likely causal variant is non-coding. For three loci, we detect association with biologically-relevant radiographic endophenotypes, and in five signals we identify genes that are differentially expressed in degraded compared to intact articular cartilage from osteoarthritis patients. We establish causal effects for higher body mass index, but not for triglyceride levels or type 2 diabetes liability, on osteoarthritis.
Multiscale Model Within-host and Between-host for Viral Infectious Diseases
Authors: Almocera Alexis Erich S. , Nguyen Van Kinh , Hernandez-Vargas Esteban A.
Published: August 2017

Multiscale models possess the potential to uncover new insights into infectious diseases. Here, a rigorous stability analysis of a multiscale model within-host and between-host is presented. The within-host model describes virus replication and the respective immune response while disease transmission is represented by a simple susceptible-infected (SI) model.

The bridge of within-to between-host is by considering transmission as a function of the viral load of the within-host level. Consequently, stability and bifurcation analyses were developed coupling the two basic reproduction numbersandfor the within- and the between-host subsystems, respectively. Local stability results for each subsystem, such as a unique stable equilibrium point, recapitulate classical approaches to infection and epidemic control.

Using a Lyapunov function, global stability of the between-host system was obtained. A main result was the derivation of theas a general increasing function of. Numerical analyses reveal that a Michaelis-Menten form based on the virus is more likely to recapitulate the behavior between the scales than a form directly proportional to the virus. Our work contributes basic understandings of the two models and casts light on the potential effects of the coupling function on linking the two scales.
Patterns of thaumarchaeal gene expression in culture and diverse marine environments
Authors: Carini Paul , Dupont Christopher L. , Santoro Alyson E.
Published: August 2017

Thaumarchaea are ubiquitous in marine habitats where they participate in carbon and nitrogen cycling. Although metatranscriptomes suggest thaumarchaea are active microbes in marine waters, we understand little about how thaumarchaeal gene expression patterns relate to substrate utilization and activity. Here, we report the global transcriptional response of the marine ammonia-oxidizing thaumarchaeon ‘CandidatusNitrosopelagicus brevis’ str. CN25 to ammonia limitation using RNA-Seq. We further describe the genome and transcriptome ofCa. N. brevis str. U25, a new strain capable of urea utilization. Ammonia limitation in CN25 resulted in reduced expression of transcripts coding for ammonia oxidation proteins, and increased expression of a gene coding an Hsp20-like chaperone. Despite significantly different transcript abundances across treatments, two ammonia monooxygenase subunits (amoAB), a nitrite reductase (nirK), and both ammonium transporter genes were always among the most abundant transcripts, regardless of growth state.Ca. N. brevis str. U25 cells expressed a urea transporter 139-fold more than the urease catalytic subunitureC. Gene co-expression networks derived from culture transcriptomes and ten thaumarchaea-enriched metatranscriptomes revealed a high degree of correlated gene expression across disparate environmental conditions and identified a module of genes, includingamoABCandnirK, that we hypothesize to represent the core ammonia oxidation machinery.

Originality-Significance Statement

Discovering gene function in fastidious or uncultivated lineages remains one of the biggest challenges in environmental microbiology. Here, we use an approach that combines controlled laboratory experiments within situtranscript abundance data from the environment to identify genes that share similar transcription patterns in marine ammonia-oxidizing thaumarchaea. These findings demonstrate how transcriptomes from microbial cultures can be used together with complex environmental samples to identify suites of co-expressed genes that are otherwise enigmatic and provide new insights into the mechanism of ammonia oxidation. Our results add to the growing body of literature showing that relatively small changes in transcript abundance are linked to large changes in growth in organisms with reduced genomes, suggesting they have limited capacity for metabolic regulation or that they rely on mechanisms other than transcriptional regulation to deal with a fluctuating environment.
Chlorinated electron acceptor availability selects for specificDehalococcoidespopulations in dechlorinating enrichment cultures and in groundwater
Authors: Pérez-de-Mora A. , Lacourt A. , McMaster M.L. , Liang X. , Dworatzek S.M. , Edwards E.A.
Published: August 2017

IndividualDehalococcoides mccartyi (Dhc)strains differ primarily from one another by the number and identity of the reductive dehalogenase homologous catalytic subunit A (rdhA) genes contained within their respective genomes. While thousands ofrdhAgenes have been sequenced, the activity of the corresponding proteins have been identified in only a handful of cases. Most effort has focused on identifying the enzymes that dechlorinate substrates including trichloroethene (TCE), cis-dichloroethene (cDCE) and vinyl chloride (VC) relevant to groundwater remediation. The associatedrdhAgenes, namelytceA, bvcA,andvcrA, along with theD. mccartyi16S rRNA gene are often used to track growth and dechlorinating activity in DNA extracted from field samples. In this study, we augmented the typical suite of three characterizedrdhAgenes to include an additional 12 uncharacterizedrdhAsequences identified in the metagenome in the mixedDhc-containing culture KB-1 to track population shifts within the culture and at two bioaugmented field sites. Quantitative PCR assays were developed for the 15 selectedD. mccartyi rdhAgenes and evaluated using 11 different sub-cultures of KB-1, each enriched on different chlorinated ethenes and ethanes. The proportion ofrdhAgene copies relative toDhc16S gene copies indicated the presence of multiple distinctDhcpopulations in each culture. The specific electron acceptor amended to each culture had a major influence on the distribution ofD. mccartyipopulations and their associatedrdhAgenes. We also surveyed the abundance ofrdhAgenes in samples obtained from two bioaugmented field sites. Growth of the dominantD. mccartyipopulation in the KB-1 inoculum was detected in the UK site samples. At both field sites, the measurement of relativerdhAabundances revaled significantD. mccartyipopulation shifts over time as dechlorination progressed from TCE through cDCE to VC and ethene, indicating that the selective pressure of the most abundant chlorinated electron acceptor that was observed in lab cultures was also occurring in the populations in the field. Understanding driving forces behindD. mccartyipopulation selection and activity is improving predictability of remediation performance at chlorinated solvent contaminated sites.
Immunologic Effect of Polysaccharides Extracted fromSipunculus nudus(SNP) on Hepatoma HepG2-bearing Mice
Authors: Su Jie , Jiang Linlin , Wu Jingna , Liu Zhiyu , Wu Yuping
Published: August 2017

Since many studies have clarified the biological activity of polysaccharides, we investigated the effect of SNP which was the water-soluble polysaccharides extracted fromSipunculus nuduson Hepatoma HepG2-bearing Mice to verify the potential of SNP as an effective clinical agent for liver cancer therapy. SNP were administered at the doses of 50,100, and 200 mg/kg to HepG2-bearing mice to determine their antitumor effects. SNP had an inhibitory effect on the growth of HepG2 cells and enhanced the immunological effect on HepG2 tumor-bearing mice. SNP increased the expression of IL-2, IFN-γ, and TNF-α cytokines in serum, suggesting that SNP can strengthen the antitumor immune response. In addition, SNP increased ATF4, DDIT3, and IkBα expression and decreased CYR61, HSP90, and VEGF expression, all of which are proteins involved in antitumor activity and cell death/survival. our results suggested that SNP may be a novel antitumor agent.

Summary statement

SNP(polysaccharides extracted fromSipunculus nudus) mediates anti-tumor activity through influencing immunoregulation, and SNP can be explored as a promising candidate for future anticancer drug.
The role of a single non-coding nucleotide in the evolution of an epidemic African clade ofSalmonella
Authors: Hammarlöf Disa L. , Kröger Carsten , Owen Siân V. , Canals Rocío , Lora Lizeth Lacharme , Wenner Nicolas , Wells Timothy J. , Henderson Ian R. , Wigley Paul , Hokamp Karsten , Feasey Nicholas A. , Gordon Melita A. , Hinton Jay C. D.
Published: August 2017

Introductory Paragraph

Salmonella entericaserovar Typhimurium ST313 is a relatively newly emerged sequence type that is causing a devastating epidemic of bloodstream infections across sub-Saharan Africa. Analysis of hundreds ofSalmonellagenomes has revealed that ST313 is closely-related to the ST19 group ofS. Typhimurium that cause gastroenteritis across the world. The core genomes of ST313 and ST19 vary by just 1000 single-nucleotide polymorphisms (SNPs). We hypothesised that the phenotypic differences that distinguish AfricanSalmonellafrom ST19 are caused by certain SNPs that directly modulate the transcription of virulence genes.

Here we identified 3,597 transcriptional start sites (TSS) of the ST313 strain D23580, and searched for a gene expression signature linked to pathogenesis ofSalmonella. We identified a SNP in the promoter of thepgtEgene that caused high expression of the PgtE virulence factor in AfricanS.Typhimurium, increased the degradation of the factor B component of human complement, contributed to serum resistance and modulated virulence in the chicken infection model. The PgtE protease is known to mediate systemic infection in animal models. We propose that high levels of expression PgtE of by AfricanS. Typhimurium ST313 promotes bacterial survival and bacterial dissemination during human infection.

Our finding of a functional role for an extra-genic SNP shows that approaches used to deduce the evolution of virulence in bacterial pathogens should include a focus on non-coding regions of the genome.
A Next Generation Clustering Tool Enables Identification of Functional Cancer Subtypes with Associated Biological Phenotypes
Authors: Nyamundanda Gift , Eason Katherine , Sadanandam Anguraj
Published: August 2017

One of the major challenges faced in defining clinically applicable and homogeneous molecular tumor subtypes is assigning biological and/or clinical interpretations to etiological (intrinsic) subtypes. The conventional approach involves at least three steps: Firstly, identify subtypes using unsupervised clustering of patient tumours with molecular (etiological) profiles; secondly associate the subtypes with clinical or phenotypic information (covariates) to infer some biological meaning to the redefined subtypes; and thirdly, identify clinically relevant biomarkers associated with the subtypes. Here, we report the implementation of a tool, phenotype mapping (phenMap), which combines these three steps to definefunctional subtypeswith associated phenotypic information and molecular signatures.phenMapmodels meta (unobserved) variables as a function of covariates to expose any underlying clustering structure within the data and discover associations between subtypes and phenotypes. We demonstrate how this tool can more avidly identify functional subtypes that are an improvement over already existing etiological subtypes by analysing published breast cancer gene expression data.
Performance-optimized partitioning of clonotypes from high-throughput immunoglobulin repertoire sequencing data
Authors: Nouri Nima , Kleinstein Steven H.
Published: August 2017

Motivation

During adaptive immune responses, activated B cells expand and undergo somatic hypermutation of their immunoglobulin (Ig) receptor, forming a clone of diversified cells that can be related back to a common ancestor. Identification of B cell clonotypes from high-throughput Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) data relies on computational analysis. Recently, we proposed an automate method to partition sequences into clonal groups based on single-linkage clustering of the Ig receptor junction region with length-normalized hamming distance metric. This method could identify clonally-related sequences with high confidence on several benchmark experimental and simulated data sets. However, this approach was computationally expensive, and unable to provide estimates of accuracy for new data. Here, a new method is presented that address this computational bottleneck and also provides a study-specific estimation of performance, including sensitivity and specificity. The method uses a finite mixture modeling fitting procedure for learning the parameters of two univariate curves which fit the bimodal distributions of the distance vector between pairs of sequences. These distribution are used to estimate the performance of different threshold choices for partitioning sequences into clonotypes. These performance estimates are validated using simulated and experimental datasets. With this method, clonotypes can be identified from AIRR-seq data with sensitivity and specificity profiles that are user-defined based on the overall goals of the study.

Availability

Source code is freely available at the Immcantation Portal:www.immcantation.comunder the CC BY-SA 4.0 license.

Contact

steven.kleinstein@yale.edu
Increased anxiety and decreased sociability in adulthood following paternal deprivation involve oxytocin in the mPFC
Authors: He Zhixiong , Wang Limin , Luo luo , Jia Rui , Yuan Wei , Hou Wenjuan , Yang Jinfeng , Yang Yang , Tai Fadao
Published: August 2017

Early adverse experiences often have devastating consequences on adult emotional and social behavior. However, whether paternal deprivation (PD) during the pre-weaning period affects brain and behavioral development remains unexplored in socially mandarin vole (Microtus mandarinus). We found that PD increased anxiety-like behavior and attenuated social preference in adult males and females; decreased prelimbic cortex OT-immunoreactive fibers and paraventricular nucleus OT positive neurons; reduced levels of medial prefrontal cortex (mPFC) OT receptor protein in females and OT receptor and V1a receptor protein in males. Intra-prelimbic cortical OT injections reversed anxiety-like behavior and social preferences affected by PD, whereas injections of OT and OT receptor antagonist blocked this reversal. These findings demonstrate that PD leads to increased anxiety-like behavior and attenuated social preferences with involvement of the mPFC OT system. The prelimbic cortex OT system may be an important target for the treatment of disorders related to early adverse experiences.
Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits and implications for the future
Authors: Zhang Yan , Qi Guanghao , Park Ju-Hyun , Chatterjee Nilanjan
Published: August 2017

Summary-level statistics from genome-wide association studies are now widely used to estimate heritability and co-heritability of traits using the popular linkage-disequilibrium-score (LD-score) regression method. We develop a likelihood-based approach for analyzing summary-level statistics and external LD information to estimate common variants effect-size distributions, characterized by proportion of underlying susceptibility SNPs and a flexible normal-mixture model for their effects. Analysis of summary-level results across 32 GWAS reveals that while all traits are highly polygenic, there is wide diversity in the degrees of polygenicity. The effect-size distributions for susceptibility SNPs could be adequately modeled by a single normal distribution for traits related to mental health and ability and by a mixture of two normal distributions for all other traits. Among quantitative traits, we predict the sample sizes needed to identify SNPs which explain 80% of GWAS heritability to be between 300K-500K for some of the early growth traits, between 1-2 million for some anthropometric and cholesterol traits and multiple millions for body mass index and some others. The corresponding predictions for disease traits are between 200K-400K for inflammatory bowel diseases, close to one million for a variety of adult onset chronic diseases and between 1-2 million for psychiatric diseases.
Spatial and temporal control of norovirus protease activity is determined by polyprotein processing and intermolecular interactions within the viral replication complex
Authors: Emmott Edward , de Rougemont Alexis , Haas Jürgen , Goodfellow Ian
Published: August 2017

Norovirus infections are a major cause of acute viral gastroenteritis and a significant burden to human health globally. A vital process for norovirus replication is the processing of the nonstructural polyprotein, by an internal protease, into the necessary viral components required to form the viral replication complex. This cleavage occurs at different rates resulting in the accumulation of stable precursor forms. In this report, we characterized how precursor forms of the norovirus protease accumulate during infection. Using stable forms of the protease precursors we demonstrated that these are all proteolytically activein vitro, but that when expressed in cells, activity is determined by both substrate and protease localization. Whilst all precursors could cleave a replication complex-associated substrate, only a subset of precursors lacking NS4 were capable of efficiently cleaving a cytoplasmic substrate. For the first time, the full range of protein-protein interactions between murine and human norovirus proteins were mapped by LUMIER assay, with conserved interactions between replication complex members, modifying the localization of a subset of precursors. Finally, we demonstrate that re-targeting of a poorly cleaved artificial cytoplasmic substrate to the replication complex is sufficient to permit efficient cleavage in the context of norovirus infection. This offers a model for how norovirus can regulate the timing of substrate cleavage throughout the replication cycle. The norovirus protease represents a key target in the search for effective antiviral treatments for norovirus infection. An improved understanding of protease function and regulation, as well as identification of interactions between the other non-structural proteins, offers new avenues for antiviral drug design.
Ubiquitin-related genes are differentially expressed in isogenic lines contrasting for pericarp cell size and grain weight in hexaploid wheat
Authors: Brinton Jemima , Simmonds James , Uauy Cristobal
Published: August 2017

Background

There is an urgent need to increase global crop production. Identifying and combining genes controlling indidviual yield components, such as grain weight, holds the potential to enhance crop yields. Transcriptomics is a powerful tool to gain insights into the complex gene regulatory networks that underlie such traits, but relies on the availability of a high-quality reference sequence and accurate gene models. Previously, we identified a grain weight QTL on wheat chromosome 5A (5A QTL) which acts during early grain development to increase grain length through cell expansion in the pericarp. In this study, we performed RNA-sequencing on near isogenic lines (NILs) segregating for the 5A QTL and used the latest gene models to identify differentially expressed (DE) genes and pathways that potentially influence pericarp cell size and grain weight in wheat.

Results

We sampled grains at four and eight days post anthesis and found genes associated with metabolism, biosynthesis, proteoloysis and defence response to be upregulated during this stage of grain development in both NILs. We identified a specific set of 112 transcripts DE between 5A NILs at either time point, including seven potential candidates for the causal gene underlying the 5A QTL. The 112 DE transcripts had functional annotations including non-coding RNA, transpon-associated, cell-cycle control, and ubiquitin-related processes. Many of the wheat genes identified belong to families that have been previously associated with seed/grain development in other species. However, few of these wheat genes are the direct orthologs and none have been previously characterised in wheat. Notably, we identified DE transcripts at almost all steps of the pathway associated with ubiquitin-mediated protein degradation. In the promoters of a subset of DE transcripts we identified enrichment of binding sites associated with C2H2, MYB/SANT, YABBY, AT HOOK and Trihelix transcription factor families.

Conclusions

In this study, we identified DE transcripts with a diverse range of predicted biological functions, reflecting the complex nature of the pathways that control early grain development. Further functional characterisation of these candidates and how they interact could provide new insights into the control of grain size in cereals, ultimately improving crop yield.
Family-based association analysis identifies variance-controlling loci without confounding by genotype-environment correlations
Authors: Conley Dalton , Johnson Rebecca , Domingue Ben , Dawes Christopher , Boardman Jason , Siegal Mark
Published: August 2017

The propensity of a trait to vary within a population may have evolutionary, ecological, or clinical significance. In the present study we deploy sibling models to offer a novel and unbiased way to ascertain loci associated with the extent to which phenotypes vary (variance-controlling quantitative trait loci, or vQTLs). Previous methods for vQTL-mapping either exclude genetically related individuals or treat genetic relatedness among individuals as a complicating factor addressed by adjusting estimates for non-independence in phenotypes. The present method uses genetic relatedness as a tool to obtain unbiased estimates of variance effects rather than as a nuisance. The family-based approach, which utilizes random variation between siblings in minor allele counts at a locus, also allows controls for parental genotype, mean effects, and non-linear (dominance) effects that may spuriously appear to generate variation.

Simulations show that the approach performs equally well as two existing methods (squared Z-score and DGLM) in controlling type I error rates when there is no unobserved confounding, and performs significantly better than these methods in the presence of confounding. Using height and BMI as empirical applications, we investigate SNPs that alter within-family variation in height and BMI, as well as pathways that appear to be enriched. One significant SNP for BMI variability, in the MAST4 gene, replicated. Pathway analysis revealed one gene set, encoding members of several signaling pathways related to gap junction function, which appears significantly enriched for associations with within-family height variation in both datasets (while not enriched in analysis of mean levels). We recommend approximating laboratory random assignment of genotype using family data and more careful attention to the possible conflation of mean and variance effects.
Utility of rapid whole-exome sequencing in the diagnosis of Niemann–Pick disease type C presenting with fetal hydrops and acute liver failure
Authors: Rohanizadegan Mersedeh , Abdo Sara M. , O'Donnell-Luria Anne , Mihalek Ivana , Chen Peggy , Sanders Marilyn , Leeman Kristen , Cho Megan , Hung Christina , Bodamer Olaf
Published: August 2017

Rapid whole-exome sequencing (rWES) is used in critically ill newborn infants to inform about diagnosis, clinical management, and prognosis. Here we report a male newborn infant with hydrops, pancytopenia, and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure-related morbidity and mortality, and lack of diagnosis, we used rWES in the proband and both parents with a turnaround time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant inNPC1, suggestive of a diagnosis of Niemann–Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near-normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care, where he died after 4 wk. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.
Persisting in defaunated landscapes: Reduced plant population connectivity after seed dispersal collapse
Authors: Pérez‐Méndez Néstor , Jordano Pedro , Valido Alfredo
Published: August 2017

Defaunation of large‐bodied frugivores could be causing severe losses of crucial ecosystem functions such as seed dispersal. The immediate ecological consequences may include alteration or even collapse of seed‐mediated gene flow affecting plant population connectivity, with impacts on the regional scale distribution of genetic variation. Yet, these far‐reaching consequences of defaunation remain understudied.

Here, we tested whether human‐induced defaunation of the Canarian frugivorous lizards (Gallotia, Lacertidae) altered within‐island population connectivity and the amount and large‐scale distribution of genetic variation of Neochamaelea pulverulenta (Rutaceae), which relies exclusively on these lizards for seed dispersal. Our study system defines a lizard downsizing gradient with three contrasted ecological scenarios (islands) with relatively optimal (Gran Canaria; large‐sized lizards), suboptimal (Tenerife; medium) and collapsed seed dispersal processes (La Gomera; small). We extensively sampled individual plant genotypes from 80 populations spanning the full geographical range of the plant to examine their genetic diversity, population‐genetic network topologies, and the patterns of isolation both by distance (IBD) and resistance (IBR) across these three ecological scenarios.

Plant genetic diversity appeared unaffected by defaunation‐mediated downsizing of frugivorous lizards. However, we found a reduced overall plant population connectivity together with an increased isolation by distance within the most defaunated islands (La Gomera and, to a lesser extent, Tenerife) when compared with the scenario preserving the functionality of lizard‐mediated seed dispersal (Gran Canaria). The results, with a significant effect of lizard downsizing, were robust when controlling for biotic/abiotic differences among the three islands by means of isolation by resistance models (IBR).

Synthesis. Our results provide valuable insights into the far‐reaching consequences of the deterioration of mutualisms on plant population dynamics over very large spatial scales. Conservation of large‐bodied frugivores is, thus, essential because their irreplaceable mutualistic dispersal services maintain an extensive movement of seeds across the landscape, crucial for maintaining the genetic cohesiveness of metapopulations and the adaptive potential of plant species across their entire geographical range.
Environmental Hazards and Mortgage Credit Risk: Evidence from Texas Pipeline Incidents
Authors: Xu Minhong , Xu Yilan
Published: August 2017

This study examines the effects of pipeline hazards on credit risk using evidence from the 2005–2011 home mortgage loans in Texas. Difference‐in‐difference analyses show a permanently lower origination rate by 1.9% in the pipeline‐present areas compared to the pipeline‐free areas, which was further enlarged by 1.8% whenever pipeline incidents happened. Evidence suggests that the permanent difference in credit access reflects lenders’ concerns about collateral value and borrowers’ repayment ability. The elevated post‐incident risk perceptions indicate lenders’ aversion to environmental liabilities. Lenders’ risk management strategies differed by borrowers’ income and evolved with the tightening of the securitization market.