bluuebunny/crossref_metadata_2025 huggingface dataset:
FA01.05: EARLY RESULTS OF ROBOT ASSISTED ESOPHAGECTOMY COMPARED WITH CONVENTIONAL THORACOSCOPIC APPROACH FOR ESOPHAGEAL CANCER: A RANDOMIZED CLINICAL TRIAL
Authors: Li Bin , Li Zhigang
Published: September 2018

Background

Minimally invasive esophagectomy (MIE) has become increasingly adopted as a standard surgical approach for esophageal cancer because of less tissue damage and a more rapid recovery. Recent developments in robotic technology have made robot-assisted minimally esophagectomy as another surgical option for MIE. The aim of the study was to compare early results between robot-assisted thoraco-laparoscopic esophagectomy (RATLE) and conventional thoraco-laparoscopic esophagectomy(CTLE) for the treatment of esophageal squamous cell carcinoma (ESCC).

Methods

We designed a randomized controlled parallel-group trial study. Patients aged 18–75 years with histologically proven surgically resectable (cT1b-3, N0–2, M0) ESCC of the intrathoracic esophagus were randomly assigned to receive either RATLE or CTLE. All patients received McKeown esophagectomy. Clinical characteristics and perioperative outcomes between the two groups were compared.

Results

Seventy patients were randomly assigned to RATLE group(n = 36) and CTLE group(n = 34). The two groups were comparable in preoperative clinical characteristics. Patients who underwent RATLE had shorter total operation time than the CTLE group (217.3 ± ± 44.5 vs. 261.5 ± 62.1 minutes, P = 0.001), particularly in thoracoscopic time (74.0 ± 23.6 vs. 104.1 ± 34.2 minutes, P < 0.001). The incidence of recurrent laryngeal palsy is higher in RATLE group(25%) than CTLE group(11.8%), but it was not statistically significant (P = 0.155). Intraoperative blood loss, length of hospital stay and the incidence of postoperative complications were not statistically different between the two groups. Four (11.1%) patients have anastomotic leakage in the RATLE group, compared to 4 (11.8%) patients in the CTLE group (P = 0.772). The RATLE and CTLE groups did not differ significantly with regard to the total number of harvested lymph nodes (18.8 ± 7.0 vs. 20.1 ± 8.3, P = 0.468), the numbers of lymph nodes dissected from recurrent laryngeal nerve chains(4.7 ± 3.1 vs. 4.9 ± 3.4, P = 0.779) and the abdomen(5.9 ± 3.5 vs. 5.1 ± 3.1, P = 0.354).

Conclusion

There is technical superiority with shorter operation time and similar short-term surgical results for RATLE compared with CTLE. Though the incidence of postoperative recurrent laryngeal palsy is slightly higher for RATLE, it doesn’t affect postoperative recovery. Long-term survival data should be followed in the future to compare the oncological outcome between the two groups.

Disclosure

All authors have declared no conflicts of interest.
FA02.01: PREVALENCE AND RISK FACTORS FOR ESOPHAGEAL CANCER FOLLOWING ACHALASIA TREATMENT: NATIONAL POPULATION-BASED CASE-CONTROL STUDY
Authors: Markar Sheraz , Wiggins Tom , Mackenzie Hugh , Faiz Omar , Zaninotto Giovanni , Hanna George
Published: September 2018

Background

Achalasia is associated with an increased risk of esophageal cancer, however the specific population at greatest risk remains unknown. The objectives of the present study were from a large national population based cohort study to: (i) Identify the prevalence of esophageal cancer in treated achalasia patients. (ii) Consider patient and treatment related risk factors, associated with an increased prevalence of esophageal cancer.

Methods

Patients with esophageal achalasia diagnosed and receiving a treatment between 2002 and 2012 were identified from the Hospital Episode Statistics database. The primary outcome measure was esophageal cancer. All patients with a diagnosis of esophageal cancer within one year of achalasia primary treatment were excluded to avoid inclusion of pseudoachalasia patients. Patient and treatment factors were compared between patients who developed esophageal cancer and those that did not using univariate and multivariate analyses.

Results

Over the 11-year study period 7487 patients receiving an interventional treatment for esophageal achalasia were included and 101 patients (1.3%) developed esophageal cancer. The median time to cancer development was 3 years (range 1 to 11 years) from primary achalasia treatment. Patients who developed esophageal cancer were older with a greater proportion of patients aged > 60 (71.3% vs. 45.4%; P < 0.001), and more commonly were primarily treated with pneumatic dilation (82.2% vs. 60.3%; P < 0.001). In the esophageal cancer group there was also an increase in the number of patients requiring re-interventions (47.5% vs. 38.0%; P = 0.041) and the average total number of re-interventions per patient over the study period (1.2 vs. 0.8; P = 0.026). Subset analyses for surgical myotomy and pneumatic dilation primary treatment groups showed similar associations between re-intervention and increased risk of cancer. Multivariate analysis confirmed associations between increased patient age (> 80 years, HR = 18.71; 95%CI 4.30–81.44) and pneumatic dilation (HR = 2.27; 95%CI 1.03–5.03), and risk of esophageal cancer.

Conclusion

This national achalasia population based case-control study identified increasing patient age, pneumatic dilation and re-intervention as potential risk factors associated with the development of esophageal cancer. Patients with these risk factors should receive more intensive endoscopic surveillance to ensure esophageal cancer is appropriately diagnosed at an early stage.

Disclosure

All authors have declared no conflicts of interest.
FA03.01: LONG-TERM OUTCOMES OF PATIENTS WITH RECURRENT SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS UNDERGOING SALVAGE ENDOSCOPIC RESECTION
Authors: Ego Mai , Abe Seiichiro , Nakatani Yukihiro , Nonaka Satoru , Suzuki Haruhisa , Yoshinaga Shigetaka , Oda Ichiro , Kato Ken , Honma Yoshitaka , Ito Yoshinori , Itami Jyun , Daiko Hiroyuki , Boku Narikazu
Published: September 2018

Background

introduction:

Definitive chemoradiotherapy (dCRT) is a treatment option for esophageal squamous cell carcinoma (ESCC). Salvage endoscopic resection (ER) has a potential of cure for patients with local recurrence or residual tumor after dCRT, which is less invasive compared with salvage esophagectomy. Aim:

To evaluate the long-term outcomes of patients with recurrence ESCC undergoing salvage ER and to identify risk factors associated with disease recurrence after salvage ER.

Methods

Retrospective analysis of 42 patients with ESCC treated with salvage ER for either local failure or recurrent disease after dCRT between January 2000 and December 2017. Salvage ER was indicated for clinically diagnosed T1N0M0 post dCRT in our hospital. Cox hazard model analysis was used to identify risk factors for recurrence after post-salvage ER.

Results

A total of 42 patients (35 males, 5 females), mean age 65 years (39–85), TNM stage before dCRT (I, II, III) 22/13/6, complete response (35 [85%]) were evaluated. The median time to salvage ER from the initiation of dCRT was 18.3months (2–130). ESD, EMR-C, and SB were performed for 4, 26, 11 patients. En-bloc resection rates were 100% (4/4), 61% (16/26) and 18% (2/11) for ESD, EMR-C, SB, respectively. There were no severe adverse event. Histological findings in the ER specimen was as follows; depth of invasion: T1a/T1b = 27/14(65/35%), lymphovascular invasion +/− = 7/34 (17/83%), vertical margin: 0/1/X = 34/4/3, and horizontal margin: 0/1/X = 25/5/11. A total of 19 patients (46%) developed recurrence after salvage ER. Recurrence sites were local/lymph node/local + lymph node/lymph nodes + distant metastasis in 9/8/2. For recurrent disease after ER, esophagectomy, lymphadenectomy and chemotherapy and best supportive care were performed for 8, 2, 4, 4 and 2, respectively, resulting in 6 death from ESCC. Three-year recurrence free survival rate, overall survival rate, and disease specific survival rate were 53.9%, 84.2%, and 88.4%, respectively. Multivariate analysis revealed that lymphovascular invasion was independent predictor of disease recurrence after salvage ER (HR = 2.96, 95%C. I 1.05–8.38, P = 0.04).

Conclusion

Salvage ER is clinically safe and effective in patients with local recurrence of ESCC after dCRT.

Careful follow-up might be recommended for the patients with lymphovascular invasion.

Disclosure

All authors have declared no conflicts of interest.
FA03.02: IS SURGERY STILL NECESSARY IN RESECTABLE OESOPHAGEAL CANCER? META-ANALYSES OF DEFINITIVE CHEMORADIOTHERAPY VERSUS TRIMODALITY THERAPY
Authors: Voeten Daan , Den Bakker Chantal , Van Der Peet Donald
Published: September 2018

Background

Standard therapy for resectable oesophageal carcinoma is trimodality therapy (TMT) consisting of neoadjuvant chemoradiotherapy and oesophagectomy. Evidence of survival advantage of TMT over organ preserving definitive chemoradiotherapy (dCRT) is inconclusive. The aim of this study is to compare survival between TMT and dCRT.

Methods

A systematic review and meta-analyses were conducted. Randomised controlled trials and observational studies on primary resectable, curatively treated, oesophageal carcinoma patients above 18 years were included. Three online databases were searched for studies comparing TMT with dCRT. Primary outcomes were two-, three- and five-year overall survival rates. Risk of bias was assessed using the Cochrane risk of bias tools for RCTs and cohort studies.

Results

Thirty-two studies described in 35 articles were included in this systematic review, thirty-three were included in the meta-analyses. Two-, three- and five-year overall survival was significantly lower in dCRT compared to TMT, with relative risks (RR) of 0.69 (95%CI, 0.57–0.83), 0.76 (95%CI, 0.63–0.92), and 0.57 (95%CI, 0.47–0.71) respectively. However, when only analysing studies with equal patient groups at baseline no differences for two-, three- and five-year overall survival were found with RRs of 0.83 (95%CI, 0.62–1.10), 0.81 (95%CI 0.57–1.14), 0.63 (95%CI, 0.36–1.12). The forest plot for three-year overall survival is presented in figure 1. Figure 1. 3 year overall survival rates

Conclusion

Despite limitations of the available evidence these meta-analyses suggest there is no survival advantage for TMT over dCRT, assuming comparable groups at baseline. Selection of surgical candidates in oesophageal carcinoma should be part of personalised and tailored care.

Disclosure

All authors have declared no conflicts of interest.
FA03.06: THE COST BENEFIT OF A WATCH AND WAIT POLICY FOR COMPLETE CLINICAL RESPONDERS FOLLOWING NEO-ADJUVANT THERAPY IN ESOPHAGEAL CANCER
Authors: Abdelatif Asila , Walsh Thomas , Coomara Arielle
Published: September 2018

Background

Survival for esophageal cancer remains poor despite neo-adjuvant chemo-radiotherapy (nCRT) and surgical resection. The median survival for nCRT plus surgery in the CROSS trial was 48 months with a pathological complete response (pCR) rate of 29%. All pCR patients will have been clinical complete responders (cCR) and while surveillance and salvage surgery (S + SS) for cCR in rectal cancer is well investigated, it is unclear whether the outcomes are similar in esophageal cancer. As morbidity and mortality following esophagectomy is high, avoidance of surgery for predicted pCR would represent a clear advantage. Our unit offers a supported choice for cCR patients to opt for surgery or for surveillance. There is currently no literature on the cost benefit of a watch and wait policy for esophageal cancer patients with a complete clinical response.

Methods

We identified all cCR patients from a prospectively collected database of esophageal cancer patients offered curative treatment with nCRT from 1999 to 2017. We costed the S + SS group for whom accurate costing data was available and we matched these, according to time of follow up, to a control group of cCR who underwent surgery. Cost (from the National DRG cost manual) was calculated based on cost of surgery, ICU stay, admission length, and follow up radiological and endoscopic procedures. The data was analysed using a two-tailed, equal variance t-test.

Results

Of 237 patients who received nCRT, 86 had a cCR. Of these, 15 patients in the S + SS fulfilled the selection criteria with a mean follow up of 10.2 compared with 10.4 months in the control group (P = 0.925). The mean number of days in hospital was 19.2 vs. 43.2 days consecutively during the follow up period. The mean estimated cost to the HSE was €91,480 for S + SS compared with €301,280 for the controlled surgery group (P = 0.01).

Conclusion

This study identified a significant cost benefit for surveillance over surgery. Further studies are required to accurately identify those who cannot benefit from surgery and to assess quality of life years gained and cost per year of life are needed.

Disclosure

All authors have declared no conflicts of interest.
Unusual Presentation of Severe Endobronchial Obstruction Caused by Cryptococcus gattii in a Child
Authors: Huynh Julie , Saddi Vishal , Cooper Peter , Cheng Alan T , Meyer Weiland , Chen Sharon , Isaacs David
Published: September 2018

Disease caused by Cryptococcus gattii typically manifests as meningoencephalitis or pulmonary nodules. Endobronchial lesions are rare, and most cases are caused by Cryptococcus neoformans. We describe here a case of endobronchial disease in a child caused by C gattii. The disease spectrum in this patient was notable for the discovery of anti–granulocyte macrophage colony-stimulating factor autoantibodies.
The PCR Simulator: an on-line application for teaching Design of Experiments and the polymerase chain reaction
Authors: Fellermann Harold , Shirt-Ediss Ben , Koryza Jerzy W. , Linsley Matthew , Lendrem Dennis W. , Howard Thomas P.
Published: September 2018

Our PCR Simulator is a web-based application designed to introduce concepts of multi-factorial experimental design and support teaching of the polymerase chain reaction. Learners select experimental settings and receive results of their simulated reactions quickly, allowing rapid iteration between data generation and analysis. This enables the student to perform complex iterative experimental design strategies within a short teaching session. Here we provide a short overview of the user interface and underpinning model, and describe our experience using this tool in a teaching environment.
Multiple modulation synthesis with high spatial resolution for noninvasive deep neurostimulation
Authors: Xiao Qiaoqin , Lai Xiaozheng , Chen Hao
Published: September 2018

Noninvasive neurostimulation plays a pivotal role in direct control of neural circuit and modulating neuronal function. However, it is difficult to balance both spatial focality and depth of penetration in stimulating deep neurons. Here, we designed time-division, frequency & polarity modulation synthesis (TMFPMS) for stimulating deep neurons noninvasively with low-frequency envelope. We demonstrated its spatial resolution: mm-level via computational simulation including finite element analysis and Hodgkin-Huxley action potential model. Taken together, the results of this study indicate that TMFPMS neurostimulation with high spatial resolution is steerable and may replace traditional implanted electrode.
Can pharmacological enhancement of the placebo effect be a novel therapy for working memory impairments?
Authors: Zhao Weihua , Becker Benjamin , Yao Shuxia , Ma Xiaole , Kou Juan , Kendrick Keith M
Published: September 2018

Working memory is considered as a core aspect of cognitive function and its impairment in a wide range of mental disorders has resulted in it being considered as an important transdiagnostic feature. To date pharmacological and behavioural strategies for augmenting working memory have achieved only moderate success. Here we have taken a different approach by combining expectancy effects with intranasal oxytocin as an adjunct given previous evidence that it may enhance placebo effects. In a randomised controlled clinical trial we demonstrate that while working memory performance is not influenced by expectancy per se when it is given in conjunction with oxytocin performance in terms of accuracy can be significantly enhanced following positive expectancy induction (placebo effect) and impaired following negative expectancy induction (nocebo effect). Thus combining expectancy effects with intranasal oxytocin may represent a radical new approach for improving working memory function in mental disorders.
Oxytocin amplifies sex differences in human mate choice
Authors: Xu Lei , Becker Benjamin , Luo Ruixue , Zheng Xiaoxiao , Zhao Weihua , Zhang Qiong , Kendrick Keith M.
Published: September 2018

Infidelity is the major cause of breakups and individuals with a history of infidelity are more likely to repeat it, but may also present a greater opportunity for short-term sexual relationships. Here in a pre-registered, double-blind study involving 160 subjects we report that while both sexes valued faithful individuals most for long-term relationships, both single men and those in a relationship were more interested in having short-term relationships with previously unfaithful individuals than women. Oxytocin administration resulted in men rating the faces of unfaithful women as more attractive but in women rating those of unfaithful men as less attractive and also finding them less memorable. Oxytocin also increased men’s interest in having short-term relationships with previously unfaithful women whereas it increased women’s interest in having long-term relationships with faithful men. Thus, oxytocin release during courtship may first act to amplify sex-dependent priorities in attraction and mate choice before subsequently promoting romantic bonds.
Evaluating the evidence for biotypes of depression: attempted replication of Drysdale et.al. 2017
Authors: Dinga Richard , Schmaal Lianne , Penninx Brenda , Tol Marie Jose van , Veltman Dick J. , Velzen Laura van , Wee Nic van der , Marquand Andre
Published: September 2018

Background

Psychiatric disorders are highly heterogeneous, defined based on symptoms with little connection to potential underlying biological mechanisms. A possible approach to dissect biological heterogeneity is to look for biologically meaningful subtypes. A recent study Drysdale et al. (2017) showed promising results along this line by simultaneously using resting state fMRI and clinical data and identified four distinct subtypes of depression with different clinical profiles and abnormal resting state fMRI connectivity. These subtypes were predictive of treatment response to transcranial magnetic stimulation therapy.

Objective

Here, we attempted to replicate the procedure followed in the Drysdale et al. study and their findings in an independent dataset of a clinically more heterogeneous sample of 187 participants with depression and anxiety. We aimed to answer the following questions: 1) Using the same procedure, can we find a statistically significant and reliable relationship between brain connectivity and clinical symptoms? 2) Is the observed relationship similar to the one found in the original study? 3) Can we identify distinct and reliable subtypes? 4) Do they have similar clinical profiles as the subtypes identified in the original study?

Methods

We followed the original procedure as closely as possible, including a canonical correlation analysis to find a low dimensional representation of clinically relevant resting state fMRI features, followed by hierarchical clustering to identify subtypes. We extended the original procedure using additional statistical tests, to test the statistical significance of the relationship between resting state fMRI and clinical data, and the existence of distinct subtypes. Furthermore, we examined the stability of the whole procedure using resampling.

Results and Conclusion

We were not able to replicate the findings of the original study. Relationships between brain connectivity and clinical symptoms were not statistically significant and we also did not find clearly distinct subtypes of depression. We argue, that based on our rigorous approach and in-depth review of the original results, that the evidence for the existence of the distinct resting state connectivity based subtypes of depression is weak and should be interpreted with caution.
Telomere length, individual quality and fitness in female European starlings (Sturnus vulgaris) during breeding
Authors: Criscuolo F. , Fowler M.F. , Fuhrer V.A. , Zahn S. , Williams T.D.
Published: September 2018

Telomeres, short guanine-rich repeats that cap linear chromosomes, are involved in cell senescence and organismal ageing. Our present understanding of telomere function oscillates between a marker of individual quality, which should be positively correlated with reproduction, to a marker of costs of reproduction (e.g. due to DNA damage). To test these ‘quality’ and ‘cost’ hypotheses, we tested the output of very simple predictions in a free-living population of European starlings Sturnus vulgaris where reproductive success of adult females was followed over 2 breeding seasons (with 2 broods per breeding). If telomere length indicate individual quality, low quality females (LQ, no fledgling) should have lower telomere lengths than high quality females (which produced fledglings in 1st and 2nd broods). Additionally, physiological determinants of adult individual quality (established in a previous study) and provisioning rate should be positively associated with adult telomere lengths. Finally, telomere length should predict future reproductive success. Adult telomere length was lower in LQ females but only during the chick-rearing period. Females producing larger clutches at fledging in the 1st brood of the 1st year also had longer telomeres. Provisioning rate was positively related to telomere length, as were plasma markers of oxidative damage, non-esterified fatty acids and triglycerides. Despite these associations, we found weak support for telomeres as indicators of individual quality. Telomere length failed in predicting future reproduction success and there was a lack of consistency in within-individual telomere length over the breeding season. In starlings, we suggest that telomere length may indicate current breeding capacities and energy status of female adults, rather than future fecundity/survival.
Expansion history and environmental suitability shape effective population size in a plant invasion
Authors: Braasch Joseph E , Barker Brittany S , Dlugosch Katrina M
Published: September 2018

The margins of an expanding range are predicted to be challenging environments for adaptation. Marginal populations should often experience low effective population sizes (Ne) where genetic drift is high due to demographic expansion and/or census population size is low due to unfavorable environmental conditions. Nevertheless, invasive species demonstrate increasing evidence of rapid evolution and potential adaptation to novel environments encountered during colonization, calling into question whether significant reductions in Ne are realized during range expansions in nature. Here we report one of the first empirical tests of the joint effects of expansion dynamics and environment on effective population size variation during invasive range expansion. We estimate contemporary values of Ne using rates of linkage disequilibrium among genome-wide markers within introduced populations of the highly invasive plant Centaurea solstitialis (yellow starthistle) in North America (California, USA), as well as in native European populations. As predicted, we find that Ne within the invasion is positively correlated with both expansion history (time since founding) and habitat quality (abiotic climate). History and environment had independent additive effects with similar effect sizes, supporting an important role of both factors in this invasion. These results support theoretical expectations for the population genetics of range expansion, though whether these processes can ultimately arrest the spread of an invasive species remains an open question.
Transite: A computational motif-based analysis platform that identifies RNA-binding proteins modulating changes in gene expression
Authors: Krismer Konstantin , Varmeh Shohreh , Bird Molly A. , Gattinger Anna , Kong Yi Wen , Handly Erika D. , Bernwinkler Thomas , Anderson Daniel A. , Heinzel Andreas , Joughin Brian A. , Cannell Ian G. , Yaffe Michael B.
Published: September 2018

RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. In response to various stimuli, alterations in RBP function contribute to global changes in gene expression, but identifying which specific RBPs are responsible for the observed changes in gene expression patterns remains an unmet need. Here, we presentTransitea multi-pronged computational approach that systematically infers RBPs influencing gene expression changes through alterations in RNA stability and degradation. As a proof of principle, we applied Transite to public RNA expression data from human patients with non-small cell lung cancer whose tumors were sampled at diagnosis, or after recurrence following treatment with platinum-based chemotherapy. Transite implicated known RBP regulators of the DNA damage response and identified hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a generalizable framework for the identification of RBPs responsible for gene expression changes that drive cell-state transitions and adds additional value to the vast wealth of publicly-available gene expression data.
DNA copy number imbalances in primary cutaneous lymphomas (PCL)
Authors: Gug Georgiana , Huang Qingyao , Chiticariu Elena , Solovan Caius , Baudis Michael
Published: September 2018

Cutaneous lymphomas (CL) represent a clinically defined group of extranodal non-Hodgkin lymphomas harboring heterogeneous and incompletely delineated molecular aberrations. Over the past decades, molecular studies have identified several chromosomal aberrations, but the interpretation of individual genomic studies can be challenging.

We conducted a meta-analysis to delineate genomic alterations for different types of PCL. Searches of PubMed and ISI Web of Knowledge for the years 1996 to 2016 identified 32 publications reporting the investigation of PCL for genome-wide copy number alterations, by means of comparative genomic hybridization techniques and whole genome and exome sequencing. For 449 samples from 22 publications, copy number variation data was accessible for sample based meta-analysis. Summary profiles for genomic imbalances, generated from case-specific data, identified complex genomic imbalances, which could discriminate between different subtypes of CL and promise a more accurate classification. The collected data presented in this study are publicly available through the “Progenetix” online repository.
Tree reconciliation combined with subsampling improves large scale inference of orthologous group hierarchies
Authors: Heller Davide , Szklarczyk Damian , Mering Christian von
Published: September 2018

Background

An orthologous group (OG) comprises a set of orthologous and paralogous genes that share a last common ancestor (LCA). OGs are defined with respect to a chosen taxonomic level, which delimits the position of the LCA in time to a specified speciation event. A hierarchy of OGs expands on this notion, connecting more general OGs, distant in time, to more recent, fine-grained OGs, thereby spanning multiple levels of the tree of life. Large scale inference of OG hierarchies with independently computed taxonomic levels can suffer from inconsistencies between successive levels, such as the position in time of a duplication event. This can be due to confounding genetic signal or algorithmic limitations. Importantly, inconsistencies limit the potential use of OGs for functional annotation and third-party applications.

Results

Here we present a new methodology to ensure hierarchical consistency of OGs across taxonomic levels. To resolve an inconsistency, we subsample the protein space of the OG members and perform gene tree-species tree reconciliation for each sampling. Differently from previous approaches, by subsampling the protein space, we avoid the notoriously diffcult task of accurately building and reconciling very large phylogenies. We implement the method into a high-throughput pipeline and apply it to the eggNOG database. We use independent protein domain definitions to validate its performance.

Conclusion

The presented consistency pipeline shows that, contrary to previous limitations, tree reconciliation can be a useful instrument for the construction of OG hierarchies. The key lies in the combination of sampling smaller trees and aggregating their reconciliations for robustness. Results show comparable or greater performance to previous pipelines. The code is available on Github at: https://github.com/meringlab/og_consistency_pipeline
Accelerating the Calculation of Protein-Ligand Binding Free Energy and Residence Times using Dynamically Optimized Collective Variables
Authors: Brotzakis Z. Faidon , Limongelli Vittorio , Parrinello Michele
Published: September 2018

Elucidation of the ligand/protein binding interaction is of paramount relevance in pharmacology to increase the success rate of drug design. To this end a number of computational methods have been proposed, however all of them suffer from limitations since the ligand binding/unbinding transitions to the molecular target involve many slow degrees of freedom that hamper a full characterization of the binding process. Being able to express this transition in simple and general slow degrees of freedom, would give a distinctive advantage, since it would require minimal knowledge of the system under study, while in turn it would elucidate its physics and accelerate the convergence speed of enhanced sampling methods relying on collective variables. In this study we pursuit this goal by combining for the first time Variation Approach to Conformational dynamics with Funnel-Metadynamics. In so doing, we predict for the benzamidine/trypsin system the ligand binding mode, and we accurately compute the absolute protein-ligand binding free energy and unbinding rate at unprecedented low computational cost. Finally, our simulation protocol reveals the energetics and structural details of the ligand binding mechanism and shows that water and binding pocket solvation/desolvation are the dominant slow degrees of freedom.
Deuteros: software for rapid analysis and visualization of data from differential hydrogen deuterium exchange-mass spectrometry
Authors: Lau Andy M. C. , Ahdash Zainab , Martens Chloe , Politis Argyris
Published: September 2018

Hydrogen deuterium exchange-mass spectrometry (HDX-MS) has emerged as a powerful technique for interrogating the conformational dynamics of proteins and their complexes. Currently, analysis of HDX-MS data remains a laborious procedure, mainly due to the lack of streamlined software to process the large datasets. We present Deuteros which is a standalone software designed to be coupled with Waters DynamX HDX data analysis software, allowing the rapid analysis and visualization of data from differential HDX-MS.

Availability

Deuteros is open-source and can be downloaded from https://github.com/andymlau/Deuteros, under the Apache 2.0 license.

Implementation

written in MATLAB and supported on both Windows and MacOS. Requires the MATLAB runtime library.

Contact

argyris.politis@kcl.ac.uk
Genomic prediction of cognitive traits in childhood and adolescence
Authors: Allegrini A.G. , Selzam S. , Rimfeld K. , von Stumm S. , Pingault J.B. , Plomin R.
Published: September 2018

Recent advances in genomics are producing powerful DNA predictors of complex traits, especially cognitive abilities. Here, we leveraged summary statistics from the most recent genome-wide association studies of intelligence and educational attainment to build prediction models of general cognitive ability and educational achievement. To this end, we compared the performances of multi-trait genomic and polygenic scoring methods. In a representative UK sample of 7,026 children at age 12 and 16, we show that we can now predict up to 11 percent of the variance in intelligence and 16 percent in educational achievement. We also show that predictive power increases from age 12 to age 16 and that genomic predictions do not differ for girls and boys. Multivariate genomic methods were effective in boosting predictive power and, even though prediction accuracy varied across polygenic scores approaches, results were similar using different multivariate and polygenic score methods. Polygenic scores for educational attainment and intelligence are the most powerful predictors in the behavioural sciences and exceed predictions that can be made from parental phenotypes such as educational attainment and occupational status.
The Resistome: updating a standardized resource for analyzing resistance phenotypes
Authors: Winkler J.D.
Published: September 2018

Advances in genome engineering have enabled routine engineering and interrogation of microbial resistance on a scale previously impossible, but developing an integrated understanding of resistance from these data remains challenging. As part of our continued efforts to address this challenge, we present a significant update of our previously released Resistome database of standardized genotype-resistance phenotype relationships, along with a new web interface to enable facile searches of genomic, transcriptomic, and phenotypic data within the database. Revisiting our previous analysis of resistance, we again find distinct mutational biases associated with random selection versus genome-scale libraries, along with pervasive pleiotropy among resistant mutants. Attempts to predict mutant phenotypes using machine learning identified the lack of comprehensive phenotype screening and small size of the Resistome corpus as challenges for effective model training. Overall, the Resistome represents a unique platform for understanding the interconnections between both current and future resistant mutants, and is available for use at https://resistome-web-interface.herokuapp.com.
Neural System and Receptor Diversity in the ctenophoreBeroe abyssicola
Authors: Norekian Tigran P. , Moroz Leonid L.
Published: September 2018

Although, neuro-sensory systems might evolve independently in ctenophores, very little is known about their neural organization. Most of the ctenophores are pelagic and deep-water species and cannot be bred in the laboratory. Thus, it is not surprising that neuroanatomical data are available for only one genus within the group -Pleurobrachia.Here, using immunohistochemistry and scanning electron microscopy, we describe the organization of two distinct neural subsystems (subepithelial and mesogleal) and the structure of different receptor types in the comb jellyBeroe abyssicola -the voracious predator from North Pacific. A complex subepithelial neural network ofBeroe,with five receptor types, covers the entire body surface and expands deeply into the pharynx. Three types of mesogleal neurons are comparable to the cydippidPleurobrachia. The predatory lifestyle ofBeroeis supported by the extensive development of ciliated and muscular structures including the presence of giant muscles and feeding macrocilia. The obtained neuroanatomy atlas provides unique examples of lineage-specific innovations within these enigmatic marine animals, and remarkable complexity of sensory and effector systems in this clade of basal Metazoa.

Graphical Abstract

Although, neuro-sensory systems might evolve independently in ctenophores, very little is known about their neuroanatomy. Here, using immunohistochemistry and scanning electron microscopy, we describe the organization of two neural systems and five different receptor types in the comb jellyBeroe abyssicola -the voracious predator from North Pacific. The predatory lifestyle ofBeroeis supported by the extensive development of ciliated, muscular, and nervous systems including the presence of giant muscles and exceptional feeding macrocilia. The obtained neuroanatomy atlas provides unique examples of lineage-specific innovations within this enigmatic group of marine animals.
Transient spectral events in resting state MEG predict individual time-frequency task responses
Authors: Becker R , Vidaurre D , Quinn AJ , Abeysuriya R , Parker Jones O , Jbabdi S , Woolrich MW
Published: September 2018

Even in response to apparently simple tasks such as hand moving, human brain activity shows remarkable inter-subject variability. Presumably, this variability reflects genuine behavioural or functional variability. Recently, spatial variability of resting-state features in fMRI - specifically connectivity - has been shown to explain (spatial) task-response variability. Such a link, however, is still missing for M/EEG data and its spectrally rich structure. At the same time, it has recently been shown that task responses in M/EEG can be well represented using transient spectral events bursting at fast time scales. Here, we show that individual differences in the spatio-spectral structure of M/EEG task responses, can, to a reasonable degree, be predicted from individual differences in transient spectral events identified at rest. In a MEG dataset of diverse task conditions (including motor responses, working memory and language comprehension tasks) and resting-state sessions for each subject (n = 89), we used Hidden-Markov-Modelling to identify transient spectral events as a feature set to learn the mapping of space-time-frequency content from rest to task. Resulting trial-averaged, subject-specific task-response predictions were then compared with the actual task responses in left-out subjects. All task conditions were predicted significantly above chance. Furthermore, we observed a systematic relationship between genetic similarity (e.g. unrelated subjects vs. twins) and predictability. These findings support the idea that subject-specific transient spectral events in resting-state neural activity are linked to, and predictive of, subject-specific trial-averaged task responses in a wide range of experimental conditions.
Metabolic modeling ofStreptococcus mutansreveals complex nutrient requirements of an oral pathogen
Authors: Jijakli Kenan , Jensen Paul A.
Published: September 2018

Streptococcus mutansis a Gram positive bacterium that thrives under acidic conditions and is a primary cause of tooth decay (dental caries). To better understand the metabolism ofS. mutanson a systematic level, we manually constructed a genome-scale metabolic model of theS. mutanstype strain UA159. The model, called iSMU, contains 656 reactions involving 514 metabolites and the products of 488 genes.

We interrogatedS. mutans’ nutrient requirements using model simulations and nutrient removal experiments in defined media. The iSMU model matched experimental results in greater than 90% of the conditions tested. We also simulated effects of single gene deletions. The model’s predictions agreed with 78.1% and 84.4% of the gene essentiality predictions from two experimental datasets. Our manually curated model is more accurate thanS. mutansmodels generated from automated reconstruction pipelines. We believe the iSMU model is an important resource for understanding how metabolism enables the cariogenicity ofS. mutans.
Chromatin compaction states, nuclear shape fluctuations and auxeticity: A biophysical interpretation of the epigenetic landscape of stem cells
Authors: Tripathi Kamal , Menon Gautam I.
Published: September 2018

When embryonic stem cells differentiate, the mechanical properties of their nuclei evolve en route to their terminal state. Measurements of the deformability of cell nuclei in the transitional state that intervenes between the embryonic stem cell state and the differentiation primed state of mouse stem cells, indicate that such nuclei are auxetic i.e. have a negative Poisson’s ratio. We show, using a theoretical model, how this unusual mechanical behaviour results from the coupling between chromatin compaction states and nuclear shape. Our biophysical approach, which treats chromatin as an active polymer system whose mechanics is modulated by nucleosome binding and unbinding, reproduces experimental results while providing new predictions. We discuss ways of testing these predictions. Our model suggests a biophysical interpretation of the epigenetic landscape of stem cells.
Collective search with finite perception: transient dynamics and search efficiency
Authors: Gosztolai Adam , Carrillo Jose A. , Barahona Mauricio
Published: September 2018

Motile organisms often use finite spatial perception of their surroundings to navigate and search their habitats. Yet standard models of search are usually based on purely local sensory information. To model how a finite perceptual horizon affects ecological search, we propose a framework for optimal navigation that combines concepts from random walks and optimal control theory. We show that, while local strategies are optimal on asymptotically long and short search times, finite perception yields faster convergence and increased search efficiency over transient time scales relevant in biological systems. The benefit of the finite horizon can be maintained by the searchers tuning their response sensitivity to the length scale of the stimulant in the environment, and is enhanced when the agents interact as a result of increased consensus within subpopulations. Our framework sheds light on the role of spatial perception and transients in search movement and collective sensing of the environment.
Age-related differences in functional asymmetry during memory retrieval revisited: no evidence for contralateral over-activation or compensation
Authors: Roe James M. , Vidal-Piñeiro Didac , Sneve Markus H. , Kompus Kristiina , Greve Douglas N. , Walhovd Kristine B. , Fjell Anders M. , Westerhausen René
Published: September 2018

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-differences in asymmetry across the entire cerebral cortex, using fMRI data from 89 young and 76 older adults during successful retrieval, and surface-based methods that allowed direct homotopic comparison of activity between hemispheres. An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment, but primarily reflected either less deactivation in contralateral regions reliably signalling retrieval failure in the young, or lower recruitment of the dominant hemisphere—suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry neither predicted current memory performance, nor the extent of memory change across the preceding ∼8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.
Mitotic Regulators and the SHP2-MAPK Pathway Promote Insulin Receptor Endocytosis and Feedback Regulation of Insulin Signaling
Authors: Choi Eunhee , Kikuchi Sotaro , Gao Haishan , Brodzik Karolina , Nassour Ibrahim , Yopp Adam , Singal Amit G. , Zhu Hao , Yu Hongtao
Published: September 2018

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellularly regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.
Trans-ethnic genome-wide association study of kidney function provides novel insight into effector genes and causal effects on kidney-specific disease aetiologies
Authors: Morris Andrew P , Le Thu H , Wu Haojia , Akbarov Artur , van der Most Peter J , Hemani Gibran , Smith George Davey , Mahajan Anubha , Gaulton Kyle J , Nadkarni Girish N , Valladares-Salgado Adan , Wacher-Rodarte Niels , Mychaleckyj Josyf C , Dueker Nicole D , Guo Xiuqing , Hai Yang , Haessler Jeffrey , Kamatani Yoichiro , Stilp Adrienne M , Zhu Gu , Cook James P , Arnlov Johan , Blanton Susan H , de Borst Martin H , Bottinger Erwin P , Buchanan Thomas A , Charchar Fadi J , Damman Jeffrey , Eales James , Gharavi Ali G , Giedraitis Vilmantas , Heath Andrew C , Ipp Eli , Kiryluk Krzysztof , Kubo Michiaki , Larsson Anders , Lindgren Cecilia M , Lu Yingchang , Madden Pamela AF , Mattix-Kramer Holly J , Montgomery Grant W , Papanicolaou George J , Raffel Leslie J , Sacco Ralph L , Sanchez Elena , Sundstrom Johan , Taylor Kent D , Xiang Anny H , Lind Lars , Ingelsson Erik , Martin Nicholas G , Whitfield John B , Cai Jianwen , Laurie Cathy C , Okada Yukinori , Matsuda Koichi , Kooperberg Charles , Chen Yii-Der Ida , Rundek Tanja , Rich Stephen S , Loos Ruth JF , Parra Esteban J , Cruz Miguel , Rotter Jerome I , Snieder Harold , Tomaszewski Maciej , Humphreys Benjamin D , Franceschini Nora ,   on behalf of the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium
Published: September 2018

Chronic kidney disease (CKD) affects ∼10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.