bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjustment of Intrastromal Corneal Ring Segments After Unsuccessful Implantation in Keratoconic Eyes
Authors: Monteiro Tiago , Mendes José Ferreira , Faria-Correia Fernando , Franqueira Nuno , Madrid-Costa David , Alfonso José F.
Published: November 2017

Purpose:

To evaluate visual, refractive, and corneal topography outcomes in eyes with keratoconus that have undergone exchange/adjustment surgery with a new intrastromal corneal ring segment (ICRS) combination after unsuccessful visual and/or refractive outcomes after primary ICRS surgery.

Methods:

A retrospective nonrandomized case series was conducted including consecutive eyes of patients with keratoconus that underwent ICRS adjustment after an unsuccessful visual outcome. Patients were divided into 2 groups: group 1 was made up of patients with Intacs ICRSs that were exchanged for the Ferrara ICRS type, and group 2 consisted of patients who maintained the same ICRS type after undergoing ICRS adjustment surgery (change of the arc length or thickness). Uncorrected distance visual acuity, best-corrected distance visual acuity (CDVA), keratometry, asphericity, higher-order aberrations, and corneal regularity indexes (ISV and IHD) (Pentacam HR; OCULUS) were assessed preoperatively and 12 months after each procedure.

Results:

Twenty-six eyes from 26 patients were included, 8 eyes in group 1 and 18 eyes in group 2. The eyes in both groups improved their CDVA values after ICRS exchange, in group 1 from 0.27 ± 0.11 preoperatively to 0.54 ± 0.17 postoperatively (P = 0.001), and in group 2 from 0.34 ± 0.22 to 0.61 ± 0.15 (P < 0.0001). In both groups, there was also a significant improvement in the refractive cylinder, topographic cylinder, and coma after ICRS adjustment (P < 0.05).

Conclusions:

ICRS implantation has been shown to be a reversible and adjustable surgical procedure for keratoconus treatment. Good outcomes can be obtained after ICRSs are exchanged.
Systematic approach to musculoskeletal benign tumors
Authors: Umer Masood , Hasan Obada H.A. , Khan Dawar , Uddin Nasir , Noordin Shahryar
Published: November 2017

The radiologic workup of musculoskeletal tumors can be both cost-efficient and extremely helpful to the referring clinician if one proceeds in a thoughtful and logical manner. It should be remembered that plain films remain the most reliable imaging method for assessment of both biological activity and probable histologic diagnosis of an osseous lesion. Further investigations are of help to determine the extent of lesion and to help in staging. In order to do this, we have found it useful to include an assessment of 10 determinants in the description of a tumor. If these determinants are accurately described, the correct diagnosis or at least a limited differential diagnosis usually becomes obvious.
Norovirus and Rotavirus Disease Severity in Children: Systematic Review and Meta-analysis
Authors: Riera-Montes Margarita , O’Ryan Miguel , Verstraeten Thomas
Published: November 2017

Background:

Rotaviruses (RVs) and noroviruses (NoVs) are the most common causes of severe acute gastroenteritis in children. It is generally accepted that RVs cause severe acute gastroenteritis in a higher proportion of cases compared with NoVs. To our knowledge, there are no systematic reviews and meta-analyses comparing the severity of NoV and RV disease.

Methods:

We searched MEDLINE for studies reporting data for NoV and RV medically attended disease severity in children. We included studies where all children had been tested for both NoV (reverse transcription polymerase chain reaction) and RV (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction) and that reported disease severity using the Vesikari or modified Vesikari score, or provided clinical information on severity. We generated pooled estimates of the mean with 95% confidence intervals using random effects meta-analysis.

Results:

We identified 266 publications, of which 31 were retained for qualitative analysis and 26 for quantitative analysis. Fourteen studies provided data on severity score for the meta-analysis. The pooled mean severity scores (95% confidence interval) among outpatients were 10 (8–12) and 11 (8–14) for NoV and RV, respectively. Among inpatients, they were 11 (9–13) for NoV and 12 (10–14) for RV. The difference was statistically significant among inpatients, but relatively small (1 point in a 20-point scale). About 20% more children with RV required rehydration when compared with children with NoV.

Conclusions:

NoV causes moderate to severe disease similar to RV in young children. This information should be useful for future evaluations of an eventual introduction of NoV vaccines in national immunization programs.
Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain
Authors: Bobinski Franciane , Teixeira Juliana Maia , Sluka Kathleen Anne , Santos Adair Roberto Soares
Published: November 2017

Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4−/− mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4−/− mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and β-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and β-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain.
Gender dysphoria in youth: a review of recent literature
Authors: Cartaya Julia , Lopez Ximena
Published: November 2017

Purpose of review

Transgender individuals including pubertal young people require hormonal therapy, in conjunction with mental health support. These youths are a unique population, with specific and individual desires and needs as they move through the physical and mental transition to the gender with which they identify.

Recent findings

The number of transgender youth presenting for treatment is increasing rapidly. They continue to have a high prevalence of mental health disorders, though not when supported in their sex identities by family in younger age. Older children are more susceptible to peer support or lack thereof. Treatment with gonadotropin-releasing hormone agonists remains a mainstay of early therapy, but is associated with high costs and decrease in bone mineral density; androgenic progestogens could be used as a lower cost alternative. Fertility preservation is discussed with the majority of transgender youth, but use of such services is low.

Transgender youth are an increasingly identified population in need of medical and mental health treatment, as well as social support throughout life.
Potential mechanisms underlying the effect of bariatric surgery on eating behaviour
Authors: Zakeri Roxanna , Batterham Rachel L.
Published: November 2017

Purpose of review

Reduced energy intake, resulting from favourable changes in eating behaviour, is the predominant driver of weight loss following bariatric surgery. Here we review the most recent studies examining the impact of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, the two most common bariatric procedures, upon eating behaviour and the suggested underlying biological mechanisms.

Recent findings

Following RYGB or sleeve gastrectomy, most people report subjective changes in appetite, taste and food preference, with decreased high-fat preference most commonly reported. Objective postsurgery changes in taste and olfactory acuity occur. A new phenomenon, ‘meal-size aversion’, may contribute to reduced postoperative energy intake. Recent studies provide evidence for peptide YY3–36, glucagon-like peptide-1, ghrelin, neurotensin and oleoylethanolamide as mediators of postoperative eating behaviour changes. Factors modulating these changes include sex, type 2 diabetes status, genetics and bariatric procedure. New studies implicate central dopaminergic and opioid receptor signalling as key neural mediators driving altered eating behaviour. Brain neuroimaging studies show that obesity-associated changes in food-cue responses, brain connectivity and structural abnormalities are normalized following bariatric surgery.

Understanding the biological mechanisms mediating the eating behaviour changes engendered by bariatric surgery may lead to the development of novel therapeutic strategies for people with obesity.
Update on endocrine aspects of childhood obesity
Authors: Baskaran Charumathi , Kandemir Nurgun
Published: November 2017

Purpose of review

Although childhood obesity has leveled off in the last decade, ‘severe obesity’ continues to be on the rise. Various genetic, environmental and hormonal factors contribute to obesity. This article reviews the most current understanding of obesity's multifactorial origin and recent recommendations for its management in childhood and adolescence.

Recent findings

Epigenetics plays a key role in transmitting obesity risk to offspring. Single-nucleotide polymorphisms at genetic loci for adipokines and their receptors are associated with obesity. Gut microbiota is an important regulator of weight status, and Bifidobacterium species improves metabolic status. The incidence of comorbidities including prediabetes and type 2 diabetes has increased. Novel biomarkers such as alpha-hydroxybutyrate and branched-chain amino acids correlate with insulin sensitivity and predict glycemic control in adolescents. Lifestyle modifications and pharmacotherapy can produce small BMI changes. Bariatric surgery induces substantial weight loss and remission of comorbidities.

Alterations in genetics, epigenetics and microbiota influence childhood obesity. Lifestyle modification remains the mainstay of management and pharmacotherapy with Food and Drug Administration approved medications is recommended only for patients resistant to lifestyle changes and for comorbidities. Bariatric surgery produces sustained weight loss and cardiovascular benefits and is an effective option for adolescents with severe obesity.
Abscessing Infection by Streptococcus mitis Mimicking Metastatic Lesions in a 5-Year-Old Girl With Nephroblastoma: A Case Report
Authors: Imhof Lara , Schrading Simone , Braunschweig Till , Steinau Gerhard , Spillner Jan Wilhelm , Puzik Alexander , Lassay Lisa , Kontny Udo
Published: November 2017

Streptococcus mitis is a common pathogen causing infections in oncological patients. However, cases of abscesses caused by Streptococcus mitis in oncological patients have not been reported so far. We report on 5-year-old child with nephroblastoma and pulmonary and hepatic metastases at diagnosis who went into complete remission undergoing chemotherapy and nephrectomy, and who developed new round lesions in liver and lungs under continuous chemotherapy suggestive of new metastases. Biopsy of the lesions revealed abscesses with detection of Streptococcus mitis. The child was successfully treated with antibiotics, finished chemotherapy per protocol and has been in complete remission for 14 months. Infectious lesions involving organs of typical metastatic dissemination can easily be misdiagnosed as metastases, especially in the absence of symptoms. Histologic proof of lesions suspicious of metastases is mandatory if it leads to a change of prognosis and therapy. Streptococcus mitis can be a causative organism of pulmonary and hepatic abscesses in oncological patients.
Screening for Trichomonas vaginalis in a Large High-Risk Population: Prevalence Among Men and Women Determined by Nucleic Acid Amplification Testing
Authors: Schwebke Jane , Merriweather Anthony , Massingale Sharon , Scisney Mary , Hill Craig , Getman Damon
Published: November 2017

Men and women attending family planning and sexually transmitted disease clinics for sexually transmitted infection screening in 2012 to 2013 were tested for Trichomonas vaginalis (TV) using a sensitive nucleic acid amplification test. T. vaginalis prevalence in urogenital samples was 11.3% in 77,740 women and 6.1% in 12,604 men, and increased with age in both sexes.
End-Tidal Carbon Dioxide Use for Tracheal Intubation: Analysis From the National Emergency Airway Registry for Children (NEAR4KIDS) Registry
Authors: Langhan Melissa L. , Emerson Beth L. , Nett Sholeen , Pinto Matthew , Harwayne-Gidansky Ilana , Rehder Kyle J. , Krawiec Conrad , Meyer Keith , Giuliano John S. , Owen Erin B. , Tarquinio Keiko M. , Sanders Ron C. , Shepherd Michael , Bysani Gokul Kris , Shenoi Asha N. , Napolitano Natalie , Gangadharan Sandeep , Parsons Simon J. , Simon Dennis W. , Nadkarni Vinay M. , Nishisaki Akira
Published: November 2017

Objective:

Waveform capnography use has been incorporated into guidelines for the confirmation of tracheal intubation. We aim to describe the trend in waveform capnography use in emergency departments and PICUs and assess the association between waveform capnography use and adverse tracheal intubation–associated events.

Design:

A multicenter retrospective cohort study.

Setting:

Thirty-four hospitals (34 ICUs and nine emergency departments) in the National Emergency Airway Registry for Children quality improvement initiative.

Patients:

Primary tracheal intubation in children younger than 18 years.

Interventions:

None.

Measurements and Main Results:

Patient, provider, and practice data for tracheal intubation procedure including a type of end-tidal carbon dioxide measurement, as well as the procedural safety outcomes, were prospectively collected. The use of waveform capnography versus colorimetry was evaluated in association with esophageal intubation with delayed recognition, cardiac arrest, and oxygen desaturation less than 80%. During January 2011 and December 2015, 9,639 tracheal intubations were reported. Waveform capnography use increased over time (39% in 2010 to 53% in 2015; p < 0.001), whereas colorimetry use decreased (< 0.001). There was significant variability in waveform capnography use across institutions (median 49%; interquartile range, 25–85%; p < 0.001). Capnography was used more often in emergency departments as compared with ICUs (66% vs. 49%; p < 0.001). The rate of esophageal intubation with delayed recognition was similar with waveform capnography versus colorimetry (0.39% vs. 0.46%; p = 0.62). The rate of cardiac arrest was also similar (p = 0.49). Oxygen desaturation occurred less frequently when capnography was used (17% vs. 19%; p = 0.03); however, this was not significant after adjusting for patient and provider characteristics.

Conclusions:

Significant variations existed in capnography use across institutions, with the use increasing over time in both emergency departments and ICUs. The use of capnography during intubation was not associated with esophageal intubation with delayed recognition or the occurrence of cardiac arrest.
Extravascular Migratory Metastasis (Pericytic Mimicry) in Sarcomatoid Squamous Cell Carcinoma of the Vulva: A Report of 2 Cases
Authors: Koay M.H. Eleanor , Stewart Colin J.R.
Published: November 2017

Extravascular migratory metastasis (EVMM), also known as pericytic mimicry or angiotropism, is a mechanism of angiocentric tumor spread that has been investigated mainly in cutaneous malignant melanoma where it has been associated with an increased risk of metastasis. In EVMM, the tumor cells spread along the external (ablumenal) aspect of vessels without breaching the endothelium, a process that is therefore distinct from the more widely recognized intraluminal invasion. Although EVMM has also been reported in a limited range of other tumor types, to our knowledge it has not been described in squamous cell carcinoma (SCC). Herein we report EVMM in 2 cases of sarcomatoid SCC of the vulva. The tumors arose in patients aged 78 and 61 yr both of whom had previous histories of histologically conventional vulval SCCs occurring in a background of lichen sclerosus and differentiated-type vulval intraepithelial neoplasia. Both tumors recurred leading to fatal metastasis in 1 patient and a requirement for pelvic exenteration in the second. Intravascular tumor involvement was not identified in either case. These cases support the view that sarcomatoid SCCs of the vulva are clinically aggressive neoplasms, and EVMM may contribute toward the risk of local and distant spread in these tumors.
Ovarian Sex Cord-stromal Tumors With Melanin Pigment: Report of a Previously Undescribed Phenomenon
Authors: Taylor Jennifer , McCluggage W. Glenn
Published: November 2017

We report 2 ovarian sex cord-stromal tumors, a luteinized adult granulosa cell tumor and a cellular fibroma, with melanin pigment. These occurred in 44 and 61-yr-old patients, respectively. As far as we are aware, melanin pigment has not been described previously in an ovarian sex cord-stromal tumor, although it has been reported in a testicular Sertoli cell tumor. We review ovarian neoplasms containing melanin pigment.
HIV and Age Do Not Synergistically Affect Age-Related T-Cell Markers
Authors: Farhadian Shelli , Jalbert Emilie , Deng Yanhong , Goetz Matthew B. , Park Lesley S. , Justice Amy C. , Dubrow Robert , Emu Brinda
Published: November 2017

Introduction:

Despite major progress in controlling HIV disease through antiretroviral therapy, changes in immune phenotype and function persist in individuals with chronic HIV, raising questions about accelerated aging of the immune system.

Methods:

We conducted a cross-sectional study (2005–2007) of HIV-infected (n = 111) and uninfected (n = 114) men from the Veterans Aging Cohort Study. All HIV-infected subjects were on antiretroviral therapy with VL <400 copies/mL for at least 3 years. T-cell markers were examined using flow cytometry. We evaluated the impact of HIV serostatus and age on T-cell phenotypes (expressed as percentages of the total CD4+ and CD8+ T-cell population) using multivariate linear regression, adjusted for smoking, alcohol, and race/ethnicity. We tested for interactions between HIV and age by including interaction terms.

Results:

Among both HIV-infected and uninfected subjects, increasing age was associated with a decreased proportion of naive CD4+ T cells (P = 0.014) and CD8+ T cells (P < 0.0001). Both HIV infection and increasing age were associated with higher proportions of effector memory CD4+ T cells (P < 0.0001 for HIV; P = 0.04 for age) and CD8+ T cells (P = 0.0001 for HIV; P = 0.0004 for age). HIV infection, but not age, was associated with a higher proportion of activated CD8+ T cells (P < 0.0001). For all T-cell subsets tested, there were no significant interactions between HIV infection and age.

Conclusions:

Age and HIV status independently altered the immune system, but we found no conclusive evidence that HIV infection and advancing age synergistically result in accelerated changes in age-associated T-cell markers among virally suppressed individuals.
Can Urodynamic Parameters Predict Sling Revision for Voiding Dysfunction in Women Undergoing Synthetic Midurethral Sling Placement?
Authors: Linder Brian J. , Trabuco Emanuel C. , Gebhart John B. , Klingele Christopher J. , Occhino John A. , Elliott Daniel S. , Lightner Deborah J.
Published: November 2017

Objective

The objective of the study was to evaluate the utility of urodynamic studies performed before primary midurethral sling placement for stress urinary incontinence in predicting the need for subsequent sling release for voiding dysfunction.

Methods

The health records of women managed with primary synthetic midurethral sling placement at Mayo Clinic (Rochester, MN) from January 1, 2002, to December 31, 2012, were reviewed. The primary outcome was surgical sling release for postoperative voiding dysfunction (ie, prolonged retention, elevated postvoid residual volumes with new voiding symptoms, or de novo onset or worsening of overactive bladder symptoms). Logistic regression models were used to evaluate associations between potential clinical risk factors and the primary outcome.

Results

Overall, 1629 women underwent primary synthetic midurethral sling placement during the study time frame, including 1081 patients (66%) who underwent a preoperative multichannel urodynamic evaluation. A sling release for voiding dysfunction was performed for 51 patients (3.1%) at a median of 1.9 months postoperatively (interquartile range, 1.3–9.3 months). Patients undergoing sling release were significantly more likely to have had retropubic sling placement (P = 0.003) and concomitant prolapse surgery (P = 0.005). On univariate analysis, no urodynamic parameters were associated with the risk of sling release; evaluated parameters included peak flow rate (P = 0.20), postvoid residual volume (P = 0.37), voiding without detrusor contraction (P = 0.96), and detrusor pressure at maximal flow (P = 0.23).

Conclusions

Sling release for voiding dysfunction was rare in our cohort. No urodynamic parameters were associated with the risk of sling release.
Origin of life in a digital microcosm
Authors: C G Nitash , LaBar Thomas , Hintze Arend , Adami Christoph
Published: November 2017

While all organisms on Earth share a common descent, there is no consensus on whether the origin of the ancestral self-replicator was a one-off event or whether it only represented the final survivor of multiple origins. Here, we use the digital evolution system Avida to study the origin of self-replicating computer programs. By using a computational system, we avoid many of the uncertainties inherent in any biochemical system of self-replicators (while running the risk of ignoring a fundamental aspect of biochemistry). We generated the exhaustive set of minimal-genome self-replicators and analysed the network structure of this fitness landscape. We further examined the evolvability of these self-replicators and found that the evolvability of a self-replicator is dependent on its genomic architecture. We also studied the differential ability of replicators to take over the population when competed against each other, akin to a primordial-soup model of biogenesis, and found that the probability of a self-replicator outcompeting the others is not uniform. Instead, progenitor (most-recent common ancestor) genotypes are clustered in a small region of the replicator space. Our results demonstrate how computational systems can be used as test systems for hypotheses concerning the origin of life.

This article is part of the themed issue ‘Reconceptualizing the origins of life’.
The role of public goods in planetary evolution
Authors: McInerney James O. , Erwin Douglas H.
Published: November 2017

Biological public goods are broadly shared within an ecosystem and readily available. They appear to be widespread and may have played important roles in the history of life on Earth. Of particular importance to events in the early history of life are the roles of public goods in the merging of genomes, protein domains and even cells. We suggest that public goods facilitated the origin of the eukaryotic cell, a classic major evolutionary transition. The recognition of genomic public goods challenges advocates of a direct graph view of phylogeny, and those who deny that any useful phylogenetic signal persists in modern genomes. Ecological spillovers generate public goods that provide new ecological opportunities.

This article is part of the themed issue ‘Reconceptualizing the origins of life’.
Novel large-scale chromosomal transfer in Bacteroides fragilis contributes to its pan-genome and rapid environmental adaptation
Authors: Husain Fasahath , Tang Kevin , Veeranagouda Yaligara , Boente Renata , Patrick Sheila , Blakely Garry , Wexler Hannah M.
Published: November 2017

Bacteroides fragilis, an important component of the human gastrointestinal microbiota, can cause lethal extra-intestinal infection upon escape from the gastrointestinal tract. We demonstrated transfer and recombination of large chromosomal segments from B. fragilis HMW615, a multidrug resistant clinical isolate, to B. fragilis 638R. In one example, the transfer of a segment of ~435 Kb/356 genes replaced ~413 Kb/326 genes of the B. fragilis 638R chromosome. In addition to transfer of antibiotic resistance genes, these transfers (1) replaced complete divergent polysaccharide biosynthesis loci; (2) replaced DNA inversion-controlled intergenic shufflons (that control expression of genes encoding starch utilization system outer membrane proteins) with more complex, divergent shufflons; and (3) introduced additional intergenic shufflons encoding divergent Type 1 restriction/modification systems. Conjugative transposon-like genes within a transferred segment and within a putative integrative conjugative element (ICE5) ~45 kb downstream from the transferred segment both encode proteins that may be involved in the observed transfer. These data indicate that chromosomal transfer is a driver of antigenic diversity and nutrient adaptation in Bacteroides that (1) contributes to the dissemination of the extensive B. fragilis pan-genome, (2) allows rapid adaptation to a changing environment and (3) can confer pathogenic characteristics to host symbionts.
Bayesian estimation of MSM population size in Côte d’Ivoire
Authors: Datta Abhirup , Lin Wenyi , Rao Amrita , Diouf Daouda , Kouame Abo , Edwards Jessie K , Bao Le , Louis Thomas A , Baral Stefan
Published: November 2017

Côte d’Ivoire has one of the largest HIV epidemics in West Africa with around half million people living with HIV. Key populations like gay men and other men who have sex with men (MSM) are often disproportionately burdened with HIV due to specific acquisition and transmission risks. Quantifying the MSM population sizes at subnational level is critical to improving the HIV prevention interventions. While survey-based direct estimates of MSM numbers are available at a few urban centers in Cˆote d’Ivoire, no data on MSM population size exists at other areas without any community infrastructure to facilitate sufficient access to the MSM community. We use this limited data in a Bayesian regression setup to produce first empirically calculated estimates of the numbers of MSM in all areas of Cˆote d’Ivoire prioritized in the HIV response. Our hierarchical model imputes missing covariates using geospatial information and allows for proper uncertainty quantification leading to meaningful confidence bounds for the predicted MSM population size estimates. The intended impact of this process is to increase uptake and use of high quality, comprehensive epidemiologic and interventional data in program planning. These estimates will help design future surveys and support the planning of the scale and content of HIV prevention and treatment programs for MSM in Cˆote d’Ivoire.
Mitochondrial Genomes Of The Regionally Extinct Nittany Lion (Puma Concolor From Pennsylvania)
Authors: Evanitsky Maya N. , George Richard J. , Johnson Stephen , Dowell Stephanie , Perry George H.
Published: November 2017

Mountain lions (Puma concolor) were once endemic across the United States. The Northeastern population of mountain lions has been largely nonexistent since the early 1800s and was officially declared extinct in 2011. This regionally extinct mountain lion is Pennsylvania State University’s official mascot, where it is referred to as the ‘Nittany Lion’. Our goal in this study was to use recent methodological advances in ancient DNA and massively parallel sequencing to reconstruct complete mitochondrial DNA (mtDNA) genomes of multiple Nittany Lions by sampling from preserved skins. This effort is part of a broader Nittany Lion Genome project intended to involve undergraduates in ancient DNA and bioinformatics research and to engage the broader Penn State community in discussions about conservation biology and extinction. Complete mtDNA genome sequences were obtained from five individuals. When compared to previously published sequences, Nittany Lions are not more similar to each other than to individuals from the Western U.S. and Florida. Supporting previous findings, North American mountain lions overall were more closely related to each other than to those from South America and had lower genetic diversity. This result emphasizes the importance of continued conservation in the Western U.S. and Florida to prevent further regional extinctions.
Towards sustainable bioplastic production in resource limited environments using the photoferroautotrophic and photoelectroautotrophic bacteriumRhodopseudomonas palustrisTIE-1
Authors: Ranaivoarisoa Tahina Onina , Rengasamy Karthikeyan , Guzman Michael S. , Singh Rajesh , Bose Arpita
Published: November 2017

Bioplastics are an attractive alternative to petroleum-derived plastics because of the harmful environmental effects of conventional plastics and the impending fossil fuel crisis. Polyhydroxybutyrate (PHB) is a well-known bioplastic that is produced by several microbes using organic carbon sources. Autotrophic (using carbon dioxide or CO2) PHB production is reported for only a few organisms. Sustainable PHB bioproduction using other autotrophic microbes needs to be explored.Rhodopseudomonas palustris, a metabolically versatile purple non-sulfur bacterium (PNSB) is known to produce PHBs under photoheterotrophic conditions.Rhodopseudomonas palustrisstrain TIE-1 demonstrates extended metabolic versatility by using electron sources such as ferrous iron and poised electrodes for photoautotrophy. Here we report the ability of TIE-1 to produce PHB under photoferroautotrophic (light - energy source, ferrous iron - electron source and CO2- carbon source) and photoelectroautotrophic (light - energy source, poised electrodes - electron source and CO2- carbon source) growth conditions. PHB accumulation was observed both under nitrogen (N2) fixing and non-N2fixing conditions. For comparison, we determined PHB production under chemoheterotrophic, photoheterotrophic and photoautotrophic conditions using hydrogen as the electron donor. Photoferroautotrophic and photoelectroautotrophic PHB production was on par with that observed from organic carbon substrates such as butyrate. PHB production increased during N2fixation under photoheterotrophic conditions but not during photoautotrophic growth. Electron microscopy confirmed that TIE-1 cells accumulate PHBs internally under the conditions that showed highest production. However, gene expression analysis suggests that PHB cycle genes are not differentially regulated despite observable changes in biopolymer production.
The Distribution of Bacterial Doubling Times in the Wild
Authors: Gibson Beth , Wilson Daniel , Feil Edward , Eyre-Walker Adam
Published: November 2017

Generation time varies widely across organisms and is an important factor in the life cycle, life history and evolution of organisms. Although the doubling time (DT), has been estimated for many bacteria in the lab, it is nearly impossible to directly measure it in the natural environment. However, an estimate can be obtained by measuring the rate at which bacteria accumulate mutations per year in the wild and the rate at which they mutate per generation in the lab. If we assume the mutation rate per generation is the same in the wild and in the lab, and that all mutations in the wild are neutral, an assumption that we show is not very important, then an estimate of the DT can be obtained by dividing the latter by the former. We estimate the DT for four species of bacteria for which we have both an accumulation and a mutation rate estimate. We also infer the distribution of DTs across all bacteria from the distribution of the accumulation and mutation rates. Both analyses suggest that DTs for bacteria in the wild are substantially greater than those in the lab, that they vary by orders of magnitude between different species of bacteria and that a substantial fraction of bacteria double very slowly in the wild.
Evolutionary dynamics and molecular features of intra-tumor heterogeneity
Authors: Raynaud Franck , Mina Marco , Ciriello Giovanni
Published: November 2017

The systematic assessment of intra-tumor heterogeneity is still limited and often unfeasible. In silico investigations of large tumor cohorts can be used to decipher how multiple clones emerge and organize into complex architectures. Here, we addressed this challenge by integrating mathematical modeling of cancer evolution with algorithmic inference of clonal phylogenies in 2,600 human tumors from 15 tumor types. Through numerical simulations, we could discriminate between observable and hidden intra-tumor heterogeneity, the latter characterized by clones that are missed by DNA sequencing of human samples. To overcome this limitation in human tumors, we show that population frequencies of detectable clones can be used to estimate the extent of hidden heterogeneity. Overall, simulated and human clonal architectures were highly concordant and showed that high numbers of clones invariably emerge through branching lineages. Interestingly, high numbers of alterations were not necessarily associated with high intra-tumor heterogeneity. Indeed, tumors with alterations in proliferation-associated genes exhibited high numbers of clonal mutations, but few clones. Instead, mutations of chromatin remodeling genes characterized tumors with high numbers of subclonal alterations and multiple clones. Our results identify evolutionary and genetic determinants of tumor clonal architectures to guide functional investigations of intra-tumor heterogeneity.
Arteria: An automation system for a sequencing core facility
Authors: Dahlberg Johan , Hermansson Johan , Sturlaugsson Steinar , Larsson Pontus
Published: November 2017

Arteria is an automation system aimed at sequencing core facilities. It is built on existing open source technologies, with a modular design allowing for a community-driven effort to create plug-and-play micro-services. Herein we describe the Arteria system and elaborate on the underlying conceptual framework. The Arteria system breaks down into three conceptual levels; orchestration, process and execution. At the orchestration level it utilizes an event-based model of automation. It models processes, e.g. the steps involved in processing sequencing data, as workflows and executes these in a micro-service based environment. This creates a system which is both flexible and scalable. The Arteria Project code is available as open source software at http://www.github.com/arteria-project.
Variation in competitive ability with mating system, ploidy and range expansion in fourCapsellaspecies
Authors: Yang Xuyue , Lascoux Martin , Glémin Sylvain
Published: November 2017

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://dx.doi.org/10.24072/pci.evolbiol.100054)

Self-fertilization is often associated with ecological traits corresponding to the ruderal strategy in Grime’s Competitive-Stress-tolerant-Ruderal (CSR) classification of ecological strategies. Consequently, selfers are expected to be less competitive than outcrossers, either because of a colonization/competition trade-off or because of the deleterious genetic effects of selfing. Range expansion could reduce further competitive ability while polyploidy could mitigate the effects of selfing. Although suggested by meta-analyses, these predictions have not been directly tested yet. We compared the competitive ability of fourCapsellaspecies differing by their mating system and ploidy level. For vegetative traits we found no difference in competitive ability neither among species nor among populations. For flower production, we found that the two diploid selfing species (C. rubellaandC. orientalis) were more sensitive to competition than the diploid outcrosser (C. grandiflora), and that the tetraploid selfer (C. bursa-pastoris) was intermediate. WithinC. bursa-pastoris, we also found that sensitivity to competition increased in parallel to range expansion. These results highlight the possible roles of ecological context and ploidy in the evolutionary trajectories of selfing species.
Isolation of a natural DNA virus ofDrosophila melanogaster, and characterisation of host resistance and immune responses
Authors: Palmer William H. , Medd Nathan , Beard Philippa M. , Obbard Darren J.
Published: November 2017

Drosophila melanogasterhas played a key role in our understanding of invertebrate immunity. However, both functional and evolutionary studies of host-virus interaction inDrosophilahave been limited by a dearth of native virus isolates. In particular, despite a long history of virus research, DNA viruses ofD. melanogasterhave only recently been described, and none have been available for experimental study. Here we report the isolation and comprehensive characterisation of Kallithea virus, a large double-stranded DNA virus, and the first DNA virus to have been reported from wild populations ofD. melanogaster. We find that Kallithea virus infection is costly for adult flies, reaching high titres in both sexes and disproportionately reducing survival in males and movement and late fecundity in females. Using theDrosophilaGenetic Reference Panel, we quantify host genetic variance for virus-induced mortality and viral titre and identify candidate host genes that may underlie this variation, includingCdc42-interacting protein 4. Using full transcriptome sequencing of infected males and females, we examine the transcriptional response of flies to Kallithea virus infection, and describe differential regulation of virus-responsive genes. This work establishes Kallithea virus as a new tractable model to study the natural interaction betweenD. melanogasterand DNA viruses, and we hope it will serve as a basis for future studies of immune responses to DNA viruses in insects.

Author Summary

The fruit flyDrosophila melanogasteris a useful model species to study host-virus interaction and innate immunity. However, few natural viruses ofDrosophilahave been available for experiments, and no natural DNA viruses ofDrosophila melanogasterhave been available at all. Although infecting flies with viruses from other insects has been useful to uncover general immune mechanisms, viruses that naturally infect wild flies could help us to learn more about the coevolutionary process, and more about the genes that underlie the host-virus interaction. Here we present an isolate of a DNA virus (named Kallithea Virus) that naturally infects the model speciesDrosophila melanogasterin the wild. We describe the basic biology of infection by this virus, finding that both male and females flies die from infection, but females are more tolerant of infection than males, while laying lay fewer eggs than uninfected females. We quantify genetic variation for virus resistance in the flies, and we use RNA sequencing to see which genes are expressed in male and female flies in response to infection. These results will form the basis for further research to understand how insects defend themselves against infection by DNA viruses, and how DNA viruses can overcome antiviral defence.
Widespread ancient whole genome duplications in Malpighiales coincide with Eocene global climatic upheaval
Authors: Cai Liming , Xi Zhenxiang , Amorim André M. , Sugumaran M. , Rest Joshua S. , Liu Liang , Davis Charles C.
Published: November 2017

Ancient whole genome duplications (WGDs) are important in eukaryotic genome evolution, and are especially prominent in plants. Recent genomic studies from large vascular plant clades, including ferns, gymnosperms, and angiosperms suggest that WGDs may represent a crucial mode of speciation. Moreover, numerous WGDs have been dated to events coinciding with major episodes of global and climatic upheaval, including the mass extinction at the KT boundary (~65 Ma) and during more recent intervals of global aridification in the Miocene (~10-5 Ma). These findings have led to the hypothesis that polyploidization may buffer lineages against the negative consequences of such disruptions. Here, we explore WGDs in the large, and diverse flowering plant clade Malpighiales using a combination of transcriptomes and complete genomes from 42 species. We conservatively identify 22 ancient WGDs, widely distributed across Malpighiales subclades. Our results provide strong support for the hypothesis that WGD is an important mode of speciation in plants. Importantly, we also identify that these events are clustered around the Eocene-Paleocene Transition (~54 Ma), during which time the planet was warmer and wetter than any period in the Cenozoic. These results establish that the Eocene Climate Optimum represents another, previously unrecognized, period of prolific WGDs in plants, and lends support to the hypothesis that polyploidization promotes adaptation and enhances plant survival during major episodes of global change. Malpighiales, in particular, may have been particularly influenced by these events given their predominance in the tropics where Eocene warming likely had profound impacts owing to the relatively tight thermal tolerances of tropical organisms.

Significance Statement

Whole genome duplications (WGDs) are hypothesized to generate adaptive variations during episodes of climate change and global upheaval. Using large-scale phylogenomic assessments, we identify an impressive 22 ancient WGDs in the large, tropical flowering plant clade Malpighiales. This supports growing evidence that ancient WGDs are far more common than has been thought. Additionally, we identify that WGDs are clustered during a narrow window of time, ~54 Ma, when the climate was warmer and more humid than during any period in the last ~65 Ma. This lends support to the hypothesis that WGDs are associated with surviving climatic upheavals, especially for tropical organisms like Malpighiales, which have tight thermal tolerances.
SAFE-clustering: Single-cell Aggregated (From Ensemble) Clustering for Single-cell RNA-seq Data
Authors: Yang Yuchen , Huh Ruth , Culpepper Houston W. , Lin Yuan , Love Michael I. , Li Yun
Published: November 2017

Motivation

Accurately clustering cell types from a mass of heterogeneous cells is a crucial first step for the analysis of single-cell RNA-seq (scRNA-Seq) data. Although several methods have been recently developed, they utilize different characteristics of data and yield varying results in terms of both the number of clusters and actual cluster assignments.

Results

Here, we present SAFE-clustering, Single-cell Aggregated (From Ensemble) clustering, a flexible, accurate and robust method for clustering scRNA-Seq data. SAFE-clustering takes as input, results from multiple clustering methods, to build one consensus solution. SAFE-clustering currently embeds four state-of-the-art methods, SC3, CIDR, Seurat and t-SNE + k-means; and ensembles solutions from these four methods using three hypergraph-based partitioning algorithms. Extensive assessment across 12 datasets with the number of clusters ranging from 3 to 14, and the number of single cells ranging from 49 to 32,695 showcases the advantages of SAFE-clustering in terms of both cluster number (18.9 - 50.0% reduction in absolute deviation to the truth) and cluster assignment (on average 28.9% improvement, and up to 34.5% over the best of the four methods, measured by adjusted rand index). Moreover, SAFE-clustering is computationally efficient to accommodate large datasets, taking <10 minutes to process 28,733 cells.

Availability and implementation

SAFE-clustering, including source codes and tutorial, is free available on the web at http://yunliweb.its.unc.edu/safe/.

Contact

yunli@med.unc.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
Authors: Cazet Aurélie S. , Hui Mun N. , Elsworth Benjamin L. , Wu Sunny Z. , Roden Daniel , Chan Chia-Ling , Skhinas Joanna N. , Collot Raphaël , Yang Jessica , Harvey Kate , Johan M. Zahied , Cooper Caroline , Nair Radhika , Herrmann David , McFarland Andrea , Deng Nian-Tao , Ruiz-Borrego Manuel , Rojo Federico , Trigo José M. , Bezares Susana , Caballero Rosalía , Lim Elgene , Timpson Paul , O’Toole Sandra , Watkins D. Neil , Cox Thomas R. , Samuel Michael , Martín Miguel , Swarbrick Alexander
Published: November 2017

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC.

SIGNIFICANCE

Compared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.