bluuebunny/crossref_metadata_2025 huggingface dataset:
The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy
Authors: Constantine Ginger D. , Simon James A. , Pickar James H. , Archer David F. , Kushner Harvey , Bernick Brian , Gasper Gina , Graham Shelli , Mirkin Sebastian
Published: December 2016

Objective:

To evaluate the safety and efficacy of TX-004HR vaginal estradiol soft-gel capsules for moderate-to-severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy.

Methods:

In this randomized, double-blind, placebo-controlled, phase 3 study, postmenopausal women with a self-identified most bothersome symptom of dyspareunia received 4, 10, or 25 μg TX-004HR or placebo for 12 weeks. Four co-primary efficacy endpoints were change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia. Secondary endpoints included severity of vaginal dryness and vulvar and/or vaginal itching or irritation. Endometrial histology and adverse events (AEs) were included in the safety endpoints.

Results:

In all, 764 women were randomized (modified intent-to-treat population, n = 747; mean age 59 y). Compared with placebo, all three doses of TX-004HR significantly improved the four co-primary endpoints (P < 0.0001 for all, except dyspareunia with 4 μg, P = 0.0149). Changes in cytology, pH, and dyspareunia were also significant at weeks 2, 6, and 8. Vaginal dryness and vaginal itching/irritation improved. Sex hormone binding globulin concentrations did not change with treatment. TX-004HR was well-tolerated, with no clinically meaningful differences in treatment-emergent AEs versus placebo, and no treatment-related serious AEs or deaths.

Conclusions:

TX-004HR (4, 10, and 25 μg) was safe, well-tolerated, and effective for treating moderate-to-severe dyspareunia within 2 weeks with minimal systemic estrogen exposure. This novel product may be a potential new treatment option for women experiencing postmenopausal vulvar and vaginal atrophy.
Minimally Invasive Fundoplication is Safe and Effective in Patients with Severe Esophageal Hypomotility
Authors: Goldberg Michael B. , Abbas Abbas El-Sayed , Smith Michael S. , Parkman Henry P. , Schey Ron , Dempsey Daniel T.
Published: December 2016

Objective

Fundoplication is used to treat refractory gastroesophageal reflux disease (GERD). A subset of patients has coexisting esophageal dysmotility, including aperistalsis or hypoperistalsis. These patients may be at increased risk of dysphagia after fundoplication. To evaluate the outcomes of minimally invasive fundoplication (MIF) in patients with GERD and esophageal hypomotility.

Methods

Retrospective review of all patients who underwent MIF and had severe esophageal hypomotility from January 2003 to June 2013. Patients underwent both pH testing and high-resolution esophageal manometry before surgery, in addition to symptom assessment before and after surgery. Severe esophageal hypomotility was defined as mean distal amplitude of contraction of less than 30 mm Hg and liquid bolus clearance of less than 50%.

Results

Thirty-four patients with GERD and esophageal hypomotility were included. By manometry, 38% had scleroderma-like esophagus and the other 62% had ineffective peristalsis. Ten patients (29%) had systemic scleroderma. Fundoplications performed (34 laparoscopically and 4 robotically) included Toupet (30), Dor (2), and Nissen (2). All patients tolerated oral feeding at a median of 1 day. One patient required surgical revision at 4 months postoperatively. Mean follow-up was 36 weeks, at which time 41% were asymptomatic and 56% had reduced symptoms. Persistent dysphagia was noted in four patients (11.7%) and was successfully treated with endoscopic dilation.

Conclusions

Minimally invasive fundoplication is both safe and effective in treating patients with severe GERD and concomitant esophageal hypomotility. Those with postoperative dysphagia are successfully managed by endoscopic treatments.
Regional Cerebral Abnormalities Measured by Frequency-Domain Near-Infrared Spectroscopy in Pediatric Patients During Extracorporeal Membrane Oxygenation
Authors: Tian Fenghua , Jenks Christopher , Potter Donald , Miles Darryl , Raman Lakshmi
Published: December 2016

Extracorporeal membrane oxygenation (ECMO) is a form of advanced cardiorespiratory support provided to critically ill patients with severe respiratory or cardiovascular failure. While children undergoing ECMO therapy have significant risk for neurological morbidity, currently there is a lack of reliable bedside tool to detect the neurologic events for patients on ECMO. This study assessed the feasibility of frequency-domain near-infrared spectroscopy (NIRS) for detection of intracranial complications during ECMO therapy. The frequency-domain NIRS device measured the absorption coefficient (µ
a) and reduced scattering coefficient (µ
s′) at six cranial positions from seven pediatric patients (0–16 years) during ECMO support and five healthy controls (2–14 years). Regional abnormalities in both absorption and scattering were identified among ECMO patients. A main finding in this study is that the abnormalities in scattering appear to be associated with lower-than-normal µ
s′ values in regional areas of the brain. Because light scattering originates from the intracellular structures (such as nuclei and mitochondria), a reduction in scattering primarily reflects loss or decreased density of the brain matter. The results from this study indicate a potential to use the frequency-domain NIRS as a safe and complementary technology for detection of intracranial complications during ECMO therapy.
Bioengineered Renal Cell Therapy Device for Clinical Translation
Authors: Pino Christopher J. , Westover Angela J. , Buffington Deborah A. , Humes H. David
Published: December 2016

The bioartificial renal epithelial cell system (BRECS) is a cell-based device to treat acute kidney injury through renal cell therapy from an extracorporeal circuit. To enable widespread implementation of cell therapy, the BRECS was designed to be cryopreserved as a complete device, cryostored, cryoshipped to an end-use site, thawed as a complete device, and employed in a therapeutic extracorporeal hemofiltration circuit. This strategy overcomes storage and distribution issues that have been previous barriers to cell therapy. Previous BRECS housings produced by computer numerical control (CNC) machining, a slow process taking hours to produce one bioreactor, was also prohibitively expensive (>$600/CNC-BRECS); major obstacles to mass production. The goal of this study was to produce a BRECS to be mass produced by injection-molded BRECS (IM-BRECS), decreasing cost (<$20/unit), and improving manufacturing speed (hundreds of units/h), while maintaining the same cell therapy function as the previous CNC-BRECS, first evaluated through prototypes produced by stereolithography BRECS (SLA-BRECS). The finalized IM-BRECS design had a significantly lower fill volume (10 ml), mass (49 g), and footprint (8.5 cm × 8.5 cm × 1.5 cm), and was demonstrated to outperform the previous BRECS designs with respect to heat transfer, significantly improving control of cooling during cryopreservation and reducing thaw times during warming. During in vitro culture, IM-BRECS performed similarly to previous CNC-BRECS with respect to cell metabolic activity (lactate production, oxygen consumption, and glutathione metabolism) and amount of cells supported.
Impact of Medicare’s Nonpayment Program on Hospital-acquired Conditions
Authors: Thirukumaran Caroline P. , Glance Laurent G. , Temkin-Greener Helena , Rosenthal Meredith B. , Li Yue
Published: December 2016

Background:

Medicare’s Nonpayment Program of 2008 (hereafter called Program) withholds hospital reimbursement for costs related to hospital-acquired conditions (HACs). Little is known whether a hospital’s Medicare patient load [quantified by the hospital’s Medicare utilization ratio (MUR), which is the proportion of inpatient days financed by Medicare] influences its response to the Program.

Objective:

To determine whether the Program was associated with changes in HAC incidence, and whether this association varies across hospitals with differential Medicare patient load.

Research Design:

Quasi-experimental study using difference-in-differences estimation. Incidence of HACs before and after Program implementation was compared across hospital MUR quartiles.

Subjects:

A total of 867,584 elderly Medicare stays for acute myocardial infarction, congestive heart failure, pneumonia, and stroke that were discharged from 159 New York State hospitals from 2005 to 2012.

Measures:

For descriptive analysis, hospital-level mean HAC rates by month, MUR quartile, and Program phase are reported. For multivariate analysis, primary outcome is incidence of the any-or-none indicator for occurrence of at least 1 of 6 HACs. Secondary outcomes are the incidence of each HAC.

Results:

The Program was associated with decline in incidence of (i) any-or-none indicator among MUR quartile 2 hospitals (conditional odds ratio=0.57; 95% confidence interval, 0.38–0.87), and (ii) catheter-associated urinary tract infections among MUR quartile 3 hospitals (conditional odds ratio=0.30; 95% confidence interval, 0.12–0.75) as compared with MUR quartile 1 hospitals. Significant declines in certain HACs were noted in the stratified analysis.

Conclusions:

The Program was associated with decline in incidence of selected HACs, and this decline was variably greater among hospitals with higher MUR.
Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease
Authors: Liao Fan , Yoon Hyejin , Kim Jungsu
Published: December 2016

Purpose of review

APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease.

Recent findings

ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis.

Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.
Fear of Recurrence as a Predictor of Care Needs for Long-Term Breast Cancer Survivors
Authors: Fang Su-Ying , Fetzer Susan Jane , Lee Kuo-Ting , Kuo Yao-Lung
Published: December 2016

Background:

The improved survival rate for breast cancer has increased the number of women living with the diagnosis for more than 5 years. Limited studies have focused on the care needs for long-term healthy survivors of breast cancer.

Objective:

The aims of this study were to understand the care needs of long-term breast cancer survivors and identify related factors that influence these needs.

Methods:

A convenience sampling with a correlational study design was used. Women at least 20 years old, who were given a diagnosis of breast cancer at least 5 years, were recruited from 2 hospital clinics in southern Taiwan. A self-administered questionnaire measuring cancer survivors’ unmet needs was administered after obtaining informed consent. Binary logistic regression was used to examine variables associated with unmet care needs.

Results:

Of the 192 women participating, the highest unmet needs related to existential survivorship. The most frequently endorsed unmet need was for an ongoing case manager. Fear of recurrence was associated with 3 aspects including existential survivorship, comprehensive cancer, and quality-of-life unmet needs (odds ratio, 1.14–1.21).

Conclusions:

Even 5 years after the diagnosis and completion of therapy, women continue to report unmet needs. Evaluating women’s fear of recurrence to identify high-risk women with unmet needs is critical to providing quality care.

Implication for Practice:

Developing appropriate survivorship care programs combined with managing concerns regarding recurrence by a nursing case manager is needed.
Communication About Maternal Breast Cancer With Children
Authors: Huang Xiaoyan , O’Connor Margaret , Hu Yan , Gao Hongyun , Lee Susan
Published: December 2016

Background:

Communication with children is a major concern for mothers with breast cancer. Chinese people have specific understanding of cancer and death, which may affect their way of communication.

Objective:

The aim of this study is to explore how Chinese mothers with breast cancer communicate about their illness with their children.

Methods:

An interpretive description study was conducted. Forty mothers with nonterminal breast cancer in mainland China were interviewed individually. The data were analyzed using 3 steps of coding: free coding, descriptive coding, and interpretive coding.

Results:

Four themes were identified: breaking the news, explaining to children, disclosing versus concealing, and information needs. Most Chinese mothers disclosed their diagnosis of breast cancer to their children mainly because it was impossible to conceal the truth. They explained illness in a factual manner; however, they tended to allow children to observe their physical changes and overhear conversations between adults. This was because they did not know how to communicate appropriately with their children, and they preferred to allow children to understand the event in a natural way.

Conclusions:

The communication about maternal breast cancer between mothers and children was influenced by traditional culture. Quantitative studies with large sample sizes should be conducted to compare the opinions of mothers of different characteristics and to investigate the factors predicting communication.

Implications for Practice:

Resources should be developed to help mothers with breast cancer communicate appropriately with their children about their illness. Healthcare professionals, especially nurses, need education to provide consultation services to these mothers and children.
A Sleep Hygiene and Relaxation Intervention for Children With Acute Lymphoblastic Leukemia
Authors: Zupanec Sue , Jones Heather , McRae Lyndsey , Papaconstantinou Efrosini , Weston Julie , Stremler Robyn
Published: December 2016

Background:

Sleep disturbance and fatigue are common and distressing pediatric cancer-related outcomes. Sleep hygiene education and relaxation techniques are recommended to improve sleep in healthy children and adult cancer survivors. No studies have tested these interventions to improve sleep and fatigue for children with acute lymphoblastic leukemia (ALL) in the home setting.

Objectives:

The aim of this study is to establish the feasibility and acceptability of a sleep hygiene and relaxation intervention to improve sleep and fatigue for children receiving maintenance chemotherapy for ALL. The child's fatigue and sleep data were collected to inform sample size calculations for a future trial.

Methods:

In this pilot randomized controlled trial, 20 children were allocated randomly to the sleep intervention or control group. The sleep intervention group received a 60-minute educational session to discuss sleep and fatigue in children with cancer and strategies to improve sleep, including use of 2 storybooks to teach deep breathing and progressive muscle relaxation. Objective sleep data were collected using actigraphy and fatigue was measured using the Childhood Cancer Fatigue Scale.

Results:

The intervention was acceptable to families, and feasibility of the intervention and data collection was clearly established. Although not statistically significant, increases in mean nighttime sleep and decreases in mean wake time after sleep onset in the sleep intervention group represented clinically important improvements.

Conclusions:

This pilot study demonstrated the feasibility and acceptability of a sleep hygiene and relaxation intervention for children undergoing maintenance chemotherapy for ALL.

Implications for practice:

Given the clinically important improvements in sleep observed, replication in a larger, adequately powered randomized controlled trial is merited.
Stability and Change in Personality Disorder Symptoms in 1-Year Follow-up of Depressed Adolescent Outpatients
Authors: Strandholm Thea , Kiviruusu Olli , Karlsson Linnea , Pankakoski Maiju , Pelkonen Mirjami , Marttunen Mauri
Published: December 2016

We investigated stability and change in personality disorder (PD) symptoms and whether depression severity, comorbid clinical psychiatric disorders, and social support predict changes in personality pathology among adolescent outpatients. The 1-year outcome of PD symptoms among consecutive adolescent psychiatric outpatients with depressive disorders (N = 189) was investigated with symptom count of depression, comorbid psychiatric disorders, and perceived social support as predictors. An overall decrease in PD symptoms in most PD categories was observed. Decreases in depression severity and in number of comorbid diagnoses correlated positively with decreases in PD symptoms of most PD categories. Social support from close friends predicted a decrease in schizotypal and narcissistic, whereas support from family predicted a decrease in paranoid symptoms. Our results suggest that among depressed adolescent outpatients, PD symptoms are relatively unstable, changes co-occuring with changes/improvement in overall psychopathology. Social support seems a possibly effective point for intervention efforts regarding positive outcome of PD symptoms.
Feasibility and Acceptability of Health Communication Interventions Within a Combination Intervention Strategy for Improving Linkage and Retention in HIV Care in Mozambique
Authors: Sutton Roberta , Lahuerta Maria , Abacassamo Fatima , Ahoua Laurence , Tomo Maria , Lamb Matthew R. , Elul Batya
Published: December 2016

Background:

Challenges to ensuring timely linkage to and retention in HIV care are well documented. Combination intervention strategies can be effective in improving the HIV care continuum. Data on feasibility and acceptability of intervention types within intervention packages are limited.

Methods:

The Engage4Health study assessed the effectiveness of a combination intervention strategy to increase linkage and retention among adults newly diagnosed with HIV in Mozambique. The study included 2 health communication interventions—modified delivery of pre-antiretroviral therapy (pre-ART) counseling sessions and SMS reminders—and 3 structural interventions—point-of-care CD4 testing after diagnosis, accelerated ART initiation, and noncash financial incentives. We used a process evaluation framework to assess dose delivered—extent each intervention was delivered as planned—and dose received—participant acceptability—of health communication versus structural interventions in the effectiveness study to understand associated benefits and challenges. Data sources included study records, participant interviews, and clinical data.

Results:

For dose delivered of health communication interventions, 98% of eligible clients received pre-ART counseling and 90% of participants received at least one SMS reminder. For structural interventions, 74% of clients received CD4 testing and 53% of eligible participants initiated ART within 1 month. Challenges for structural interventions included facility-level barriers, staffing limitations, and machine malfunctions. For dose received, participants reported pre-ART counseling and CD4 testing as the most useful interventions for linkage and financial incentives as the least useful for linkage and retention.

Discussion:

Findings demonstrate that health communication interventions can be feasibly and acceptably integrated with structural interventions to create combination intervention strategies.
A Pooled Analysis of Robotic Versus Laparoscopic Surgery for Colon Cancer
Authors: Duan Bo-Shi , Zhao Guo-Hua , Yang Helen , Wang Yue
Published: December 2016

Objective:

An increasing number of studies have been reported since the “Da Vinci” Robotic System was used in gastrointestinal disease. Thus, we conducted this meta-analysis to evaluate the safety and efficacy of robotic colectomy (RC) compared with laparoscopic colectomy (LC) in the treatment of colon cancer.

Method:

A systematic search of Medline, Embase databases, and the Cochrane Library was performed to identify studies that compared RC and LC and were published up to February 2015. The methodological quality of the selected studies was assessed. Depending on statistical heterogeneity, the fixed or the random-effect model was used for the meta-analysis. Outcomes of interest included the operating time, blood loss, the length of hospital stay, conversion rates to open, postoperative complications, and related outcomes were evaluated.

Results:

Fourteen studies were included in the meta-analysis. These studies involved a total of 125,989 patients: 4924 of them underwent RC and 121,055 underwent LC. The meta-analysis showed that the RC group had a longer operating time (P<0.01), lower blood loss (P<0.01), lower intraoperative conversion to open rate (P<0.01), shorter hospital stay (P<0.01), lower postoperative complication rate (P<0.01), and significantly faster bowel function recovery (P<0.01). There were no differences in the number of lymph nodes harvested (P>0.05).

Conclusions:

Our data suggest that RC may be a safe, feasible, and minimally invasive alternative to its LC counterpart when performed by experienced surgeons in selected patients. However, the long-term outcomes between the 2 techniques need to be further examined.
Invasions and extinctions through the looking glass of evolutionary ecology
Authors: Colautti Robert I. , Alexander Jake M. , Dlugosch Katrina M. , Keller Stephen R. , Sultan Sonia E.
Published: December 2016

Invasive and endangered species reflect opposite ends of a spectrum of ecological success, yet they experience many similar eco-evolutionary challenges including demographic bottlenecks, hybridization and novel environments. Despite these similarities, important differences exist. Demographic bottlenecks are more transient in invasive species, which (i) maintains ecologically relevant genetic variation, (ii) reduces mutation load, and (iii) increases the efficiency of natural selection relative to genetic drift. Endangered species are less likely to benefit from admixture, which offsets mutation load but also reduces fitness when populations are locally adapted. Invading species generally experience more benign environments with fewer natural enemies, which increases fitness directly and also indirectly by masking inbreeding depression. Adaptive phenotypic plasticity can maintain fitness in novel environments but is more likely to evolve in invasive species encountering variable habitats and to be compromised by demographic factors in endangered species. Placed in an eco-evolutionary context, these differences affect the breadth of the ecological niche, which arises as an emergent property of antagonistic selection and genetic constraints. Comparative studies of invasions and extinctions that apply an eco-evolutionary perspective could provide new insights into the environmental and genetic basis of ecological success in novel environments and improve efforts to preserve global biodiversity.

This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences’.
Phenological shifts of native and invasive species under climate change: insights from the
Boechera–Lythrum
model
Authors: Colautti Robert I. , Ågren Jon , Anderson Jill T.
Published: December 2016

Warmer and drier climates have shifted phenologies of many species. However, the magnitude and direction of phenological shifts vary widely among taxa, and it is often unclear when shifts are adaptive or how they affect long-term viability. Here, we model evolution of flowering phenology based on our long-term research of two species exhibiting opposite shifts in floral phenology:
Lythrum salicaria
, which is invasive in North America, and the sparse Rocky Mountain native
Boechera stricta
. Genetic constraints are similar in both species, but differences in the timing of environmental conditions that favour growth lead to opposite phenological shifts under climate change. As temperatures increase, selection is predicted to favour earlier flowering in native
B. stricta
while reducing population viability, even if populations adapt rapidly to changing environmental conditions. By contrast, warming is predicted to favour delayed flowering in both native and introduced
L. salicaria
populations while increasing long-term viability. Relaxed selection from natural enemies in invasive
L. salicaria
is predicted to have little effect on flowering time but a large effect on reproductive fitness. Our approach highlights the importance of understanding ecological and genetic constraints to predict the ecological consequences of evolutionary responses to climate change on contemporary timescales.

This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences’.
Adaptation to fragmentation: evolutionary dynamics driven by human influences
Authors: Cheptou Pierre-Olivier , Hargreaves Anna L. , Bonte Dries , Jacquemyn Hans
Published: December 2016

Fragmentation—the process by which habitats are transformed into smaller patches isolated from each other—has been identified as a major threat for biodiversity. Fragmentation has well-established demographic and population genetic consequences, eroding genetic diversity and hindering gene flow among patches. However, fragmentation should also select on life history, both predictably through increased isolation, demographic stochasticity and edge effects, and more idiosyncratically via altered biotic interactions. While species have adapted to natural fragmentation, adaptation to anthropogenic fragmentation has received little attention. In this review, we address how and whether organisms might adapt to anthropogenic fragmentation. Drawing on selected case studies and evolutionary ecology models, we show that anthropogenic fragmentation can generate selection on traits at both the patch and landscape scale, and affect the adaptive potential of populations. We suggest that dispersal traits are likely to experience especially strong selection, as dispersal both enables migration among patches and increases the risk of landing in the inhospitable matrix surrounding them. We highlight that suites of associated traits are likely to evolve together. Importantly, we show that adaptation will not necessarily rescue populations from the negative effects of fragmentation, and may even exacerbate them, endangering the entire metapopulation.

This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences’.
Adaptive capabilities and fitness consequences associated with pollution exposure in fish
Authors: Hamilton Patrick B. , Rolshausen Gregor , Uren Webster Tamsyn M. , Tyler Charles R.
Published: December 2016

Many fish populations are exposed to harmful levels of chemical pollution and selection pressures associated with these exposures have led to the evolution of tolerance. Our understanding of the physiological basis for these adaptations is limited, but they are likely to include processes involved with the absorption, distribution, metabolism and/or excretion of the target chemical. Other potential adaptive mechanisms include enhancements in antioxidant responses, an increased capacity for DNA and/or tissue repair and alterations to the life cycle of fish that enable earlier reproduction. Analysis of single-nucleotide polymorphism frequencies has shown that tolerance to hydrocarbon pollutants in both marine and estuarine fish species involves alteration in the expression of the xenobiotic metabolism enzyme CYP1A. In this review, we present novel data showing also that variants of the CYP1A gene have been under selection in guppies living in Trinidadian rivers heavily polluted with crude oil. Potential costs associated with these adaptations could reduce fitness in unpolluted water conditions. Integrating knowledge of local adaptation to pollution is an important future consideration in conservation practices such as for successful restocking, and improving connectivity within river systems.

This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences’.
The Aquarius/EMB-4 helicase licenses co-transcriptional gene silencing
Authors: Akay Alper , Domenico Tomas Di , Suen Kin M. , Nabih Amena , Parada Guillermo E. , Larance Mark , Medhi Ragini , Berkyurek Ahmet C. , Zhang Xinlian , Wedeles Christopher J. , Ma Ping , Lamond Angus I. , Hemberg Martin , Claycomb Julie M. , Miska Eric A.
Published: December 2016

Small RNAs (sRNAs) play an ancient role in genome defence against transposable elements. In animals, plants and fungi small RNAs guide Argonaute proteins to nascent RNA transcripts to induce co-transcriptional gene silencing. In animals the link between small RNA pathways and the transcriptional machinery remains unclear. Here we show that theCaenorhabditis elegansgermline Argonaute HRDE-1 physically interacts with the conserved RNA helicase Aquarius/EMB-4. We demonstrate that the Aquarius/EMB-4 helicase activity is required to initiate small RNA-induced co-transcriptional gene silencing. HRDE-1 and Aquarius/EMB-4 are required to silence the transcription of overlapping sets of transposable elements. Surprisingly, removal of introns from a small RNA pathway target abolishes the requirement for Aquarius/EMB-4, but not HRDE-1, for gene silencing. We conclude that the Aquarius/EMB-4 helicase activity allows HRDE-1/sRNA complexes to efficiently engage nascent RNA transcripts - in competition with the general RNA processing machinery. We postulate that Aquarius/EMB-4 facilitates the surveillance of the nascent transcriptome to detect and silence transposable elements through small RNA pathways.
How Cancer Genomics Drives Cancer Biology: Does Synthetic Lethality Explain Mutually Exclusive Oncogenic Mutations?
Authors: Varmus Harold , Unni Arun M. , Lockwood William W.
Published: December 2016

Large-scale analyses of cancer genomes are revealing patterns of mutations that suggest biologically significant ideas about many aspects of cancer, including carcinogenesis, classification, and preventive and therapeutic strategies. Among those patterns is “mutual exclusivity”, a phenomenon observed when two or more mutations that are commonly observed in samples of a type of cancer are not found combined in individual tumors. We have been studying a striking example of mutual exclusivity: the absence of co-existing mutations in theKRASandEGFRproto-oncogenes in human lung adenocarcinomas, despite the high individual frequencies of such mutations in this common type of cancer. Multiple lines of evidence suggest that toxic effects of the joint expression ofKRASandEGFRmutant oncogenes, rather than loss of any selective advantages conferred by a second oncogene that operates through the same signaling pathway, are responsible for the observed mutational pattern. We discuss the potential for understanding the physiological basis of such toxicity, for exploiting it therapeutically, and for extending the studies to other examples of mutual exclusivity.
Bacterial genome reduction as a result of short read sequence assembly
Authors: Williamson Charles H.D. , Sanchez Andrew , Vazquez Adam , Gutman Joshua , Sahl Jason W.
Published: December 2016

High-throughput comparative genomics has changed our view of bacterial evolution and relatedness. Many genomic comparisons, especially those regarding the accessory genome that is variably conserved across strains in a species, are performed using assembled genomes. For completed genomes, an assumption is made that the entire genome was incorporated into the genome assembly, while for draft assemblies, often constructed from short sequence reads, an assumption is made that genome assembly is an approximation of the entire genome. To understand the potential effects of short read assemblies on the estimation of the complete genome, we downloaded all completed bacterial genomes from GenBank, simulated short reads, assembled the simulated short reads and compared the resulting assembly to the completed assembly. Although most simulated assemblies demonstrated little reduction, others were reduced by as much as 25%, which was correlated with the repeat structure of the genome. A comparative analysis of lost coding region sequences demonstrated that up to 48 CDSs or up to ~112,000 bases of coding region sequence, were missing from some draft assemblies compared to their finished counterparts. Although this effect was observed to some extent in 32% of genomes, only minimal effects were observed on pan-genome statistics when using simulated draft genome assemblies. The benefits and limitations of using draft genome assemblies should be fully realized before interpreting data from assembly-based comparative analyses.
Monolayer-Crystal Streptavidin Support Films Provide an Internal Standard of cryo-EM Image Quality
Authors: Han Bong-Gyoon , Watson Zoe , Cate Jamie H. D. , Glaeser Robert M.
Published: December 2016

Analysis of images of biotinylatedEscherichia coli70S ribosome particles, bound to streptavidin affinity grids, demonstrates that the image-quality of particles can be predicted by the image-quality of the monolayer crystalline support film. The quality of the Thon rings is also a good predictor of the image-quality of particles, but only when images of the streptavidin crystals extend to relatively high resolution. When the estimated resolution of streptavidin was 5 Å or worse, for example, the ribosomal density map obtained from 22,697 particles went to only 9.5 Å, while the resolution of the map reached 4.0 Å for the same number of particles, when the estimated resolution of streptavidin crystal was 4 Å or better. It thus is easy to tell which images in a data set ought to be retained for further work, based on the highest resolution seen for Bragg peaks in the computed Fourier transforms of the streptavidin component. The refined density map obtained from 57,826 particles obtained in this way extended to 3.6 Å, a marked improvement over the value of 3.9 Å obtained previously from a subset of 52,433 particles obtained from the same initial data set of 101,213 particles after 3-D classification. These results are consistent with the hypothesis that interaction with the air-water interface can damage particles when the sample becomes too thin. Streptavidin monolayer crystals appear to provide a good indication of when that is the case.
Similar evolutionary trajectories for retrotransposon accumulation in mammals
Authors: Buckley Reuben M , Kortschak R Daniel , Raison Joy M , Adelson David L
Published: December 2016

The factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their non-autonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analysed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalise retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organisation, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.
Colonization and transmission of the gut microbiota of the burying beetle,Nicrophorus vespolloides, through development
Authors: Wang Yin , Rozen Daniel E.
Published: December 2016

Carrion beetles in the genusNicrophorusrear their offspring on decomposing carcasses where larvae are exposed to a diverse microbiome of decomposer bacteria. Parents coat the carcass with antimicrobial secretions prior to egg hatch (defined as Pre-Hatch care) and also feed regurgitated food, and potentially bacteria, to larvae throughout development (defined as Full care). Here we partition the roles of pre- and post-hatch parental care in the transmission and persistence of culturable symbiotic bacteria to larvae. Using three treatment groups (Full-Care, Pre-Hatch care only, and No Care), we found that larvae receiving Full-Care are predominantly colonized by bacteria resident in the maternal gut, while larvae receiving No Care are colonized exclusively with bacteria from the carcass. More importantly, larvae receiving only Pre-Hatch care were also predominantly colonized by maternal bacteria; this result indicates that parental treatment of the carcass, including application of bacteria to the carcass surface, is sufficient to ensure symbiont transfer even in the absence of direct larval feeding. Later in development, we found striking evidence that pupae undergo a aposymbiotic stage, after which they are recolonized at eclosion with bacteria shed in the moulted larval cuticle and on the wall of the pupal chamber. Our results clarify the importance of pre-hatch parental care for symbiont transmission inNicrophorus vespilloides, and suggest that these bacteria successfully outcompete decomposer bacteria during larval and pupal gut colonization.

Importance

Here we examine the origin and persistence of the culturable gut microbiota of larvae in the burying beetleNicrophorus vespilloides.This insect is particularly interesting for this study because larvae are reared on decomposing vertebrate carcasses where they are exposed to high-densities of carrion-decomposing microbes. Larvae also receive extensive parental care in the form of carcass preservation and direct larval feeding. We find that parents transmit their gut bacteria to larvae both directly, through regurgitation, and indirectly via their effects on the carcass. In addition, we find that larvae become aposymbiotic during pupation, but are recolonized from bacteria shed onto the insect cuticle before adult eclosion. Our results highlight the diverse interactions between insect behavior and development on microbiota composition. They further indicate that strong competitive interactions mediate the bacterial composition ofNicrophoruslarvae, suggesting that the bacterial communities of these insects may be highly coevolved with their host species.
Adaptive evolution by spontaneous domain fusion and protein relocalisation
Authors: Farr Andrew D , Rainey Paul B
Published: December 2016

Knowledge of adaptive processes encompasses understanding of the emergence of new genes. Computational analyses of genomes suggest that new genes can arise by domain swapping, however, empirical evidence has been lacking. Here we describe a set of nine independent deletion mutations that arose during the course of selection experiments with the bacteriumPseudomonas fluorescensin which the membrane-spanning domain of a fatty acid desaturase became translationally fused to a cytosolic di-guanylate cyclase (DGC) generating an adaptive phenotype. Detailed genetic analysis of one chimeric fusion protein showed that the DGC domain had become membrane-localised resulting in a new biological function. The relative ease by which this new gene arose along with its profound functional and regulatory effects provides a glimpse of mutational events and their consequences that are likely to play a significant role in the evolution of new genes.
Specific expression and function of the Six3optixin serially homologous organs
Authors: Khatib Amer Al , Siomava Natalia , Posnien Nico , Casares Fernando
Published: December 2016

Organ size and pattern results from the integration of two positional information systems. One global, encoded by the Hox genes, links organ type with position along the main body axis. Within specific organs, local information is conveyed by signaling molecules that regulate organ growth and pattern. The mesothoracic (T2) wing and the metathoracic (T3) haltere ofDrosophilarepresent a paradigmatic example of this coordination. The Hox geneUltrabithorax (Ubx), expressed in the developing T3, selects haltere identity by, among other processes, modulating the production and signaling efficiency of Dpp, a BMP2-like molecule that acts as a major regulator of size and pattern. Still, the mechanisms of the Hox-signal integration even in this well-studied system, are incomplete. Here we have investigated this issue by studying the expression and function of the Six3 transcription factoroptixduring the development of theDrosophilawing and haltere development. We find that in both organs Dpp defines the expression domain ofoptixthrough repression, and that the specific position of this domain in wing and haltere seems to reflect the differential signaling profile among these organs. We show thatoptixexpression in wing and haltere primordia is conserved beyondDrosophilain other higher diptera. Despite the similar expression pattern,optixplays different roles in wing and haltere. In the wing,optixis required for the growth of the most anterior/proximal region (the “marginal cell”) and for the correct formation of sensory structures along the proximal anterior wing margin. In contrast, in the haltereoptixis necessary for the suppression of sensory bristles without any noticeable effect on organ growth. Therefore,optixshows an organ-specific function. Beyond dipterans,optixexpression in the anterior wing has been shown also in butterflies. We propose that the ancestral role ofoptixmight have been structural in the anterior wing. Once expressed in the wing,optixexpression had been re-deployed for wing spot formation in other parts of the wing of Heliconius butterflies.
Discovery of an autoimmunity-associated IL2RA enhancer by unbiased targeting of transcriptional activation
Authors: Simeonov Dimitre R. , Gowen Benjamin G. , Boontanrart Mandy , Roth Theodore , Lee Youjin , Chan Alice , Nguyen Michelle L. , Gate Rachel E. , Subramaniam Meena , Woo Jonathan M. , Mitros Therese , Ray Graham J. , Bray Nicolas L. , Curie Gemma L. , Naddaf Nicki , Boyer Eric , Van Gool Frederic , Schumann Kathrin , Daly Mark J. , Fahr Kyle K. , Ye Chun , Bluestone Jeffrey A. , Anderson Mark S. , Corn Jacob E. , Marson Alexander
Published: December 2016

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell type-specific transcriptional programs and responses to specific extracellular cues 1-3. In order to understand the mechanisms by which non-coding genetic variation contributes to disease, systematic mapping of functional enhancers and their biological contexts is required. Here, we develop an unbiased discovery platform that can identify enhancers for a target gene without prior knowledge of their native functional context. We used tiled CRISPR activation (CRISPRa) to synthetically recruit transcription factors to sites across large genomic regions (>100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA (interleukin-2 receptor alpha; CD25). We identified several CRISPRa responsive elements (CaREs) with stimulation-dependent enhancer activity, including an IL2RA enhancer that harbors an autoimmunity risk variant. Using engineered mouse models and genome editing of human primary T cells, we found that sequence perturbation of the disease-associated IL2RA enhancer does not block IL2RA expression, but rather delays the timing of gene activation in response to specific extracellular signals. This work develops an approach to rapidly identify functional enhancers within non-coding regions, decodes a key human autoimmunity association, and suggests a general mechanism by which genetic variation can cause immune dysfunction.
An improved circuit for modulator based on nanostructured memristor
Authors: Wang Shao-Fu , Xu D.Z.
Published: December 2016

Purpose

This paper aims to propose the modeling of nanostructured memristor, and the circuit of amplitude modulator was designed and analyzed with memristor. The simulation results show that the nanostructured memristor can be utilized to implement the desired amplitude modulated signal.

Design/methodology/approach

The modeling of nanostructured memristor is proposed in this paper, and the circuit of amplitude modulator was designed and analyzed with memristor, amplifiers and BPF device. For measuring the modulated signal, the emulator circuit of memristor is designed. The simulation results show that the nanostructured memristor can be utilized to implement the desired amplitude modulated signal.

Findings

The innovations of this work are as follows: the AM modulator circuit using memristor has been proposed, analyzed and simulated. The emulator of memristor is given.

Originality/value

The innovations of this work are as follows: the AM modulator circuit using memristor has been proposed, analyzed and simulated. The emulator of memristor is given, and the results of this work demonstrate that the nonlinearity of the memristor can be used to generate the desired amplitude modulation free of harmonic sidebands, because of distortion of the modulating signal.