bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of the peroxin Pex34p suppresses impaired acetate utilization in yeast lacking the mitochondrial aspartate/glutamate carrier Agc1p
Authors: Chalermwat Chalongchai , Thosapornvichai Thitipa , Wongkittichote Parith , Phillips John D , Cox James E , Jensen Amornrat N , Wattanasirichaigoon Duangrurdee , Jensen Laran T
Published: November 2019

PEX34, encoding a peroxisomal protein implicated in regulating peroxisome numbers, was identified as a high copy suppressor, capable of bypassing impaired acetate utilization of agc1∆ yeast. However, improved growth of agc1∆ yeast on acetate is not mediated through peroxisome proliferation. Instead, stress to the endoplasmic reticulum and mitochondria from PEX34 overexpression appears to contribute to enhanced acetate utilization of agc1∆ yeast. The citrate/2-oxoglutarate carrier Yhm2p is required for PEX34 stimulated growth of agc1∆ yeast on acetate medium, suggesting that the suppressor effect is mediated through increased activity of a redox shuttle involving mitochondrial citrate export. Metabolomic analysis also revealed redirection of acetyl-coenzyme A (CoA) from synthetic reactions for amino acids in PEX34 overexpressing yeast. We propose a model in which increased formation of products from the glyoxylate shunt, together with enhanced utilization of acetyl-CoA, promotes the activity of an alternative mitochondrial redox shuttle, partially substituting for loss of yeast AGC1.
Simulation of induced seismic ground motions using coupled geomechanical and seismic wave propagation models
Authors: Paap Bob , Kraaijpoel Dirk , Wassing Brecht , van Wees Jan-Diederik
Published: November 2019

Numerical simulations of seismic wave propagation usually rely on a simple source model consisting of an idealized point location and a moment tensor. In general, this is a valid approximation when the source dimensions are small relative to the distance of points at which the seismic wave motions are to be evaluated. Otherwise, a more realistic spatio-temporal source representation is required to accurately calculate ground motions at the position of monitoring stations. Here, we present a generic approach to couple geomechanical simulations to seismic wave propagation models using the concept of the equivalent force field. This approach allows the simulation of seismic wave propagation resulting from the spatio-temporal dependent earthquake nucleation and rupture processes. Within the geomechanical package two separate geomechanics codes are used to simulate both the slow loading stage leading to earthquake nucleation as well as the successive dynamic rupture stage. We demonstrate the approach to a case of induced seismicity, where fault reactivation occurs due to production from a natural gas reservoir.
The 2-Component BKP Grassmannian and Simple Singularities of Type D
Authors: Cheng Jipeng , Milanov Todor
Published: November 2019

It was proved in 2010 that the principal Kac–Wakimoto hierarchy of type $D$ is a reduction of the 2-component BKP hierarchy. On the other hand, it is known that the total descendant potential of a singularity of type $D$ is a tau-function of the principal Kac–Wakimoto hierarchy. We find explicitly the point in the Grassmannian of the 2-component BKP hierarchy (in the sense of Shiota) that corresponds to the total descendant potential. We also prove that the space of tau-functions of Gaussian type is parametrized by the base of the miniversal unfolding of the simple singularity of type $D$.
Evolutionary Reinforcement Learning for Adaptively Detecting Database Intrusions
Authors: Choi Seul-Gi , Cho Sung-Bae
Published: November 2019

Relational database management system (RDBMS) is the most popular database system. It is important to maintain data security from information leakage and data corruption. RDBMS can be attacked by an outsider or an insider. It is difficult to detect an insider attack because its patterns are constantly changing and evolving. In this paper, we propose an adaptive database intrusion detection system that can be resistant to potential insider misuse using evolutionary reinforcement learning, which combines reinforcement learning and evolutionary learning. The model consists of two neural networks, an evaluation network and an action network. The action network detects the intrusion, and the evaluation network provides feedback to the detection of the action network. Evolutionary learning is effective for dynamic patterns and atypical patterns, and reinforcement learning enables online learning. Experimental results show that the performance for detecting abnormal queries improves as the proposed model learns the intrusion adaptively using Transaction Processing performance Council-E scenario-based virtual query data. The proposed method achieves the highest performance at 94.86%, and we demonstrate the usefulness of the proposed method by performing 5-fold cross-validation.
Stricturing CMV enteritis in an adult liver transplant recipient
Authors: Helmick Ryan A , Agbim Uchenna A
Published: November 2019

Cytomegalovirus (CMV) is a common posttransplant infection, most commonly seen in settings of excessive immunosuppression. Before the advent of CMV specific antiviral therapies, the standard treatment approaches for CMV disease were immunosuppression reductions to let the transplant recipient mount an immunologic response against CMV. Additionally, CMV is rarely identified as causing stricturing enteritis and has not previously been reported as causing stricturing enteritis in an adult transplant recipient. All identified reports of stricturing CMV enteritis have been reported in either pediatric patient populations or those with severe immunosuppression from human immunodeficiency virus and acquired immune deficiency syndrome. Our report presents the unusual case of an adult liver transplant recipient many years after transplant and on minimal immunosuppression with mycophenolate alone who developed stricturing CMV enteritis.
The information content of Cosmic Infrared Background anisotropies
Authors: Reischke Robert , Desjacques Vincent , Zaroubi Saleem
Published: November 2019

We use analytic computations to predict the power spectrum as well as the bispectrum of Cosmic Infrared Background (CIB) anisotropies. Our approach is based on the halo model and takes into account the mean luminosity-mass relation. The model is used to forecast the possibility to simultaneously constrain cosmological, CIB and halo occupation distribution (HOD) parameters in the presence of foregrounds. For the analysis we use wavelengths in eight frequency channels between 200 and 900 GHz with survey specifications given by Planck and LiteBird. We explore the sensitivity to the model parameters up to multipoles of ℓ = 1000 using auto- and cross-correlations between the different frequency bands. With this setting, cosmological, HOD and CIB parameters can be constrained to a few percent. Galactic dust is modeled by a power law and the shot noise contribution as a frequency dependent amplitude which are marginalized over. We find that dust residuals in the CIB maps only marginally influence constraints on standard cosmological parameters. Furthermore, the bispectrum yields tighter constraints (by a factor four in 1σ errors) on almost all model parameters while the degeneracy directions are very similar to the ones of the power spectrum. The increase in sensitivity is most pronounced for the sum of the neutrino masses. Due to the similarity of degeneracies a combination of both analysis is not needed for most parameters. This, however, might be due to the simplified bias description generally adopted in such halo model approaches.
H i column density statistics of the cold neutral medium from absorption studies
Authors: Vishwakarma Pavan Kumar , Dutta Prasun
Published: November 2019

Physical properties of the tiny scale structures in the cold neutral medium (CNM) of galaxies is a long-standing puzzle. Only a few lines of sights in our Galaxy have been studies with mixed results on the scale-invariant properties of such structures. Moreover, since these studies measure the variation of neutral hydrogen optical depth, they do not directly constrain the density structures. In this letter, we investigate the possibility of measuring the properties of density and spin temperature structures of the H i from absorption studies of H i . Our calculations show that irrespective of the thermal properties of the clouds, the scale structure of the H i column density can be estimated, whereas, H i absorption studies alone cannot shed much light on either the amplitude of the density fluctuations and their temperature structures. Detailed methodology and calculations with some fiducial examples are presented.
Young stars as tracers of a barred-spiral Milky Way
Authors: Pettitt Alex R , Ragan Sarah E , Smith Martin C
Published: November 2019

Identifying the structure of our Galaxy has always been fraught with difficulties, and while modern surveys continue to make progress building a map of the Milky Way, there is still much to understand. The arm and bar features are important drivers in shaping the interstellar medium, but their exact nature and influence still require attention. We present results of smoothed particle hydrodynamic simulations of gas in the Milky Way including star formation, stellar feedback, and ISM cooling, when exposed to different arm and bar features, with the aim of better understanding how well newly formed stars trace out the underlying structure of the Galaxy. The bar is given a faster pattern speed than the arms, resulting in a complex, time-dependent morphology and star formation. Inter-arm branches and spurs are easily influenced by the bar, especially in the two-armed spiral models where there is a wide region of resonance overlap in the disc. As the bar over-takes the spiral arms it induces small boosts in star formation and enhances spiral features, which occur at regularly spaced beat-like intervals. The locations of star formation events are similar to those seen in observational data, and do not show a perfect 1:1 correspondence with the underlying spiral potential, though arm tangencies are generally well traced by young stars. Stellar velocity fields from the newly formed stars are compared to data from Gaia DR2, showing that the spiral and bar features can reproduce many of the non-axisymmetric features seen in the data. A simple analytical model is used to show many of these feature are a natural response of gas to rigidly rotating spiral and bar potentials.
The mRNA repressor TRIM71 cooperates with Nonsense-Mediated Decay factors to destabilize the mRNA of CDKN1A/p21
Authors: Torres-Fernández Lucia A , Jux Bettina , Bille Maximilian , Port Yasmine , Schneider Karin , Geyer Matthias , Mayer Günter , Kolanus Waldemar
Published: November 2019

Nonsense-mediated decay (NMD) plays a fundamental role in the degradation of premature termination codon (PTC)-containing transcripts, but also regulates the expression of functional transcripts lacking PTCs, although such ‘non-canonical’ functions remain ill-defined and require the identification of factors targeting specific mRNAs to the NMD machinery. Our work identifies the stem cell-specific mRNA repressor protein TRIM71 as one of these factors. TRIM71 plays an essential role in embryonic development and is linked to carcinogenesis. For instance, TRIM71 has been correlated with advanced stages and poor prognosis in hepatocellular carcinoma. Our data shows that TRIM71 represses the mRNA of the cell cycle inhibitor and tumor suppressor CDKN1A/p21 and promotes the proliferation of HepG2 tumor cells. CDKN1A specific recognition involves the direct interaction of TRIM71 NHL domain with a structural RNA stem-loop motif within the CDKN1A 3′UTR. Importantly, CDKN1A repression occurs independently of miRNA-mediated silencing. Instead, the NMD factors SMG1, UPF1 and SMG7 assist TRIM71-mediated degradation of CDKN1A mRNA, among other targets. Our data sheds light on TRIM71-mediated target recognition and repression mechanisms and uncovers a role for this stem cell-specific factor and oncogene in non-canonical NMD, revealing the existence of a novel mRNA surveillance mechanism which we have termed the TRIM71/NMD axis.
Prognostic values of left ventricular mass index in chronic kidney disease patients
Authors: Tripepi Giovanni , D’Arrigo Graziella , Mallamaci Francesca , London Gerard , Tangri Navdeep , Hsu Jesse Yenchih , Feldman Harold I , Zoccali Carmine
Published: November 2019

Background

Left ventricular hypertrophy is causally implicated in the high risk of death and heart failure (HF) in chronic kidney disease (CKD) patients. Whether the left ventricular mass index (LVMI) adds meaningful predictive power for mortality and de novo HF to simple risk models has not been tested in the CKD population.

Methods

We investigated this problem in 1352 CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC). LVMI was measured by echocardiography and the risks for death and HF were estimated by the Study of Heart and Renal Protection (SHARP) score, a well-validated risk score in CKD patients.

Results

During a median follow-up of 7.7 years, 326 patients died and 208 had de novo HF. The LVMI and the SHARP score and a cross-validated model for HF (CRIC model) were all significantly (P < 0.001) related to the risk of death and HF. LVMI showed a discriminatory power for death (Harrell’s C index 66%) inferior to that of the SHARP score (71%) and the same was true for the risk of HF both in the test (LVMI 72%, CRIC model 79%) and in the validation cohort (LVMI 71%, CRIC model 74%). LVMI increased very little the discriminatory (2–3%) and the risk reclassification power (3.0–4.8%) by the SHARP score and the CRIC model for HF for the same outcomes.

Conclusions

In CKD, measurement of LVMI solely for the stratification of risk of death and perhaps for the risk of HF does not provide evident prognostic values in this condition.
Increasing incidence and prevalence of ANCA-associated vasculitis in Northern Norway
Authors: Nilsen Aksel Thuv , Karlsen Christine , Bakland Gunnstein , Watts Richard , Luqmani Raashid , Koldingsnes Wenche
Published: November 2019

Objective

ANCA-associated vasculitides (AAV) have increased in prevalence since the 1980s. We aimed to investigate the incidence and prevalence of AAV during a 15-year period from 1999 to 2013 in Northern Norway, looking for variations during this period.

Methods

Patient records were retrieved from The Northern Norwegian Vasculitis Registry; in addition we searched all regional hospital databases. Patients diagnosed with AAV from 1999 through to 2013 were included. For prevalence data, patients residing in the area, but with AAV diagnosis prior to 1999, were also included. The diagnosis of AAV was based on the European Medicines Agency algorithm.

Results

We identified 140 cases; 88 were classified as granulomatosis with polyangiitis (GPA), 37 as microscopic polyangiitis (MPA) and 15 as eosinophilic granulomatosis with polyangiitis (EGPA). Adult (age ≥15 years) annual incidence rates per million were as follows: for GPA 15.6 (95% CI: 12.5, 19.2), MPA 6.5 (95% CI: 4.6, 9.0), EGPA 2.7 (95% CI: 1.5, 4.5) and overall AAV 24.7 (95% CI: 20.8, 29.2). Incidences of MPA and overall AAV showed an increasing trend (P < 0.05). Adult point prevalence rates per million in 2013 were 261 (95% CI: 213, 316) for GPA, 58.2 (95% CI: 36.9, 87.3) for MPA, 32.9 (95% CI: 17.5, 56.3) for EGPA and 351 (95% CI: 296, 416) for overall AAV.

Conclusion

The incidence rate of GPA and the prevalence rates of GPA and EGPA are currently the highest reported. MPA increased significantly from a prior low incidence. The overall AAV annual incidence and prevalence are still increasing.
Geospatial analysis of dengue emergence in rural areas in the Southern Province of Sri Lanka
Authors: Mutucumarana Charmaine P , Bodinayake Champica K , Nagahawatte Ajith , Devasiri Vasantha , Kurukulasooriya Ruvini , Anuradha Thamali , De Silva Aruna Dharshan , Janko Mark M , Østbye Truls , Gubler Duane J , Woods Christopher W , Reller Megan E , Tillekeratne L Gayani , Lantos Paul M
Published: November 2019

Background

Dengue is a major cause of acute febrile illness in Sri Lanka. Dengue has historically been considered an urban disease. In 2012–2013, we documented that acute dengue was surprisingly associated with self-reported rural residence in the Southern Province of Sri Lanka.

Methods

Patients admitted with an acute febrile illness were enrolled from June 2012–May 2013 in a cross-sectional surveillance study at the largest tertiary care hospital in the Southern Province. Acute dengue was diagnosed by serology and virology testing. Site visits were performed to collect residential geographical coordinates. Spatial variation in odds of acute dengue was modeled using a spatial generalized additive model predicted onto a grid of coordinate pairs covering the Southern Province.

Results

Of 800 patients, 333 (41.6%) had laboratory-confirmed acute dengue. Dengue was spatially heterogeneous (local probability of acute dengue 0.26 to 0.42). There were higher than average odds of acute dengue in the rural northeast of the Southern Province and lower than average odds in the urbanized southwest of the Southern Province, including the city Galle.

Conclusions

Our study further affirms the emergence of dengue in rural southern Sri Lanka and highlights both the need for real-time geospatial analyses to optimize public health activities as well as the importance of strengthening dengue surveillance in non-urban areas.
Histiocytoid Melanoma
Authors: Harvey Nathan T. , Grewal Jagbir , Ardakani Nima Mesbah , Robinson Cleo , Leecy Tamazin N. , Forrest Cindy , Texler Michael , Kattampallil Joseph , Lam Minh , Wallace Corrine , Lum Dennis , Wood Benjamin A.
Published: November 2019

While most melanomas display well-characterised and readily recognised architectural and cytomorphological features, unusual variants can create diagnostic difficulties. Variants which mimic benign or reactive processes are particularly problematic. We report 5 cases of melanoma characterised by a subtle microscopic appearance reminiscent of a benign dermal histiocytic infiltrate, which we refer to as “histiocytoid melanoma.” These lesions are characterised clinically by ill-defined areas of cutaneous pigmentation, which in several cases reached large proportions. Microscopically, there is a subtle interstitial pattern of infiltration by predominantly single cells with a histiocytoid morphology, often resembling melanophages. Immunohistochemical confirmation was typically required, with the cells showing positive labelling for Sox-10 as well as Melan-A. In several examples, the proliferation extended to clinically uninvolved surgical margins, necessitating multiple excisions, and many of our patients have experienced locoregional recurrence. However, none have developed distant metastases or died of melanoma. While uncommon, this subtle variant is important to recognise in order to ensure adequate histological clearance is obtained.
Integration of Clinical and Molecular Features into Prediction Models for Outcomes in Endometrial Cancer
Authors: MILLER MARINA D. , DEVOR ERIC J.
Published: November 2019

Endometrial cancer recurrence carries a poor prognosis. The rising incidence of endometrial cancer calls for improvements in treatment of advanced and recurrent diseases. Efforts have been made to molecularly characterize endometrial cancer with the goal of improving therapies. The study presented here describes the utilization of molecular features of endometrial cancer tumors that are likely to recur, along with clinical characteristics utilized together to predict recurrence. This work further studies recurrent endometrial cancers to group them into “clusters” based on the tumor’s molecular makeups with the ultimate aim to focus therapy on the molecular pathways potentially leading to recurrence.
Ankle-Brachial Index in Addition to Stress Testing in Patients Who Presented With Chest Pain and 1-Year Major Cardiovascular Events
Authors: Lotfi Amir , Shakoor Muhammad , Ahmed Mashrafi , Daoulah Amin , Navaravong Leenhapong , Hiser William , Knee Alexander
Published: November 2019

Background:

Chest pain is a common presentation to the emergency department, and the best approach for risk stratification with long-term outcomes is limited. Our goal was to assess the utility of ankle-brachial index (ABI) in addition to stress testing among patients (males >40 and females >50 years old) who presented with chest pain, undetectable biomarkers, and unchanged electrocardiogram.

Methods:

A total of 348 consecutive patients were enrolled in a prospective cohort study and completed an ABI and cardiovascular stress test.

Results:

Patients with an abnormal ABI were twice as likely to have an abnormal stress test (odds ratio = 2.03; 95% confidence interval [CI], 1.11–3.70). At 1 year, the incidence of adjusted major cardiovascular events (MCE) was lowest (8.2%) among those with a normal ABI and normal stress test. When compared with this low-risk group, the adjusted risk of 1-year MCE was 8.4% higher (95% CI, −1.0% to 17.8%; P = 0.080) in the normal ABI with abnormal stress test group; 5.3% higher (95% CI, −4.5% to 15.1%; P = 0.291) in the abnormal ABI with normal stress test group; and finally, 12.1% higher (95% CI, −2.5% to 26.6%; P = 0.105) in the abnormal ABI with abnormal stress test group.

Conclusions:

Although additional research needs to be conducted, either an abnormal stress test or abnormal ABI suggested an increase of MCE at 1 year with abnormal stress test and ABI demonstrating the highest risk. The addition of ABI to patients undergoing stress testing may enhance risk stratification in patients who present with chest pain.
Smartwatch for the Detection of Atrial Fibrillation
Authors: Tajrishi Farbod Zahedi , Chitsazan Mandana , Chitsazan Mitra , Shojaei Fahimehalsadat , Gunnam Vamsikrishna , Chi Gerald
Published: November 2019

Atrial fibrillation (AF) is the most common arrhythmia and poses a substantial economic burden due to associated thromboembolic complications. Screening for AF may theoretically be effective, but there is no consensus regarding the optimal screening method because the available tools are either invasive or not cost-effective. Recently, smartwatch industry has received a surge of interest for this purpose by introducing technologies such as photoplethysmography, artificial intelligence, and actual electrodes taking an electrocardiogram to measure and analyze heart rate and rhythm with relatively acceptable accuracy. Combined with other features such as ease of use and connectivity, smartwatches can potentially be used for large-scale AF screening and might eventually replace the current gold standards. In this review, we discuss the feasibility of this approach and summarize the current evidence on AF detection with smartwatches.
In vivo measurement of cytoplasmic organelle water fraction using diffusion-weighted imaging
Authors: Ling Chenhan , Shi Feina , Zhang Jianmin , Jiang Biao , Dong Fei , Zeng Qiang
Published: November 2019

Recently, we have proposed a theoretical modified tri-exponential model for multi-b-value diffusion-weighted imaging (DWI) to measure the cytoplasmic organelle water fraction (COWF). This study aims to investigate whether COWF maps are effective in evaluating the malignant degree of gliomas and distinguishing primary central nervous system lymphomas (PCNSL) from gliomas.

We performed this retrospective study based on our prospectively collected data. All patients underwent preoperative multi-b-value DWI. Parametric maps were derived from multi-b-value DWI maps using the modified tri-exponential model. Receiver operating characteristic analyses were used to assess the diagnostic accuracy of the parameter maps. Pearson correlation coefficients were calculated to investigate the correlations between the parameters and the Ki-67 proliferation index.

A total of 66 patients were enrolled, including 16 low-grade gliomas (LGG), 45 high-grade gliomas (HGG), and 5 PCNSL. The mean COWF values were significantly different among LGG (3.1 ± 1.4%), HGG (6.9 ± 2.8%), and PCNSL (14.0 ± 2.2%) (P < .001). The areas under the curves of the mean COWF value in distinguishing HGG from LGG and distinguishing PCNSL from gliomas were 0.899 and 0.980, respectively. The mean COWF value had a moderate correlation with the Ki-67 proliferation index (r = 0.647).

The COWF map is useful in malignant grading of gliomas, and may be helpful in distinguishing PCNSL from gliomas.
Academic-Practice Partnerships
Authors: Beal Judy A. , Zimmermann Deborah
Published: November 2019

The American Organization of Nurse Leaders and the American Association of Colleges of Nursing have been working together since 2010 to address how academic-practice partnerships can most effectively advance the profession by preparing a well-educated workforce. This article describes the work to date and future strategic priorities.
SNPector: SNP inspection tool for diagnosing gene pathogenicity and drug response in a naked sequence
Authors: Habib Peter T. , Alsamman Alsamman M. , Shereif Ghada A. , Hamwieh Aladdin
Published: November 2019

Due to the ability to diagnose diseases early and evaluate the effectiveness of medicinal drugs, single nucleotide polymorphism (SNP) identification receives significant interest. Detection and diagnosis of genetic variation through skill-less computational tools would help researchers reducing the severity of such health complications and improving the well-tailored therapies using discovered and previously known information. We introduce SNPector, which is a standalone SNP inspection software could be used to diagnose gene pathogenicity and drug reaction in naked genomic sequences. It identifies and extracts gene-related SNPs, and reports their genomic position, associated phenotype disorder, associated diseases, linkage disequilibrium, in addition to various drug reaction information. SNPector detects and verifies the existence of an SNP in a given DNA sequence based on different clinically relevant SNP databases such as NCBI Clinvar database, Awesome database, and PharmGKB and generates highly informative visualizations of the recovered information.
VelA and LaeA are key regulators of theEpichloë festucaetranscriptomic response during symbiosis with perennial ryegrass
Authors: Rahnama M. , Maclean P. , Fleetwood D.J. , Johnson R.D.
Published: November 2019

VelA (or VeA) is a key global regulator in fungal secondary metabolism and development which we previously showed is required during the symbiotic interaction ofEpichloë festucaewith perennial ryegrass. In this study, comparative transcriptomics analyses of ΔvelAmutant compared to wild typeE. festucae, under three different conditions (in culture, infected seedlings and infected mature plants) were performed to investigate the impact VelA on theE. festucaetranscriptome. These comparative transcriptomics studies showed that VelA regulates the expression of genes encoding proteins involved in membrane transport, fungal cell wall biosynthesis, host cell wall degradation and secondary metabolism, along with a number of small secreted proteins and a large number of proteins with no predictable functions. In addition, these results were compared with previous transcriptomics experiments studying the impact of LaeA, another key global regulator of secondary metabolism and development that we have shown is important for theE. festucae- perennial ryegrass interaction. The results showed that although VelA and LaeA regulate a sub-set ofE. festucaegenes in a similar manner, they also regulated many other genes independently of each other suggesting specialised roles.
Patient-specific functional genomics and disease modeling suggest a role for LRP2 in hypoplastic left heart syndrome
Authors: Theis Jeanne L. , Vogler Georg , Missinato Maria A. , Li Xing , Martinez-Fernandez Almudena , Nielsen Tanja , Walls Stanley M. , Kervadec Anais , Zeng Xin-Xin I , Kezos James N. , Birker Katja , Evans Jared M. , O’Byrne Megan M. , Fogarty Zachary C. , Terzic André , Grossfeld Paul , Ocorr Karen , Nelson Timothy J. , Olson Timothy M. , Colas Alexandre R. , Bodmer Rolf
Published: November 2019

Congenital heart diseases (CHD), such as hypoplastic left heart syndrome (HLHS), are considered to have complex genetic underpinnings that are poorly understood. Here, an integrated multi-disciplinary approach was applied to identify novel genes and underlying mechanisms associated with HLHS. A family-based strategy was employed that coupled whole genome sequencing (WGS) with RNA sequencing of patient-derived induced pluripotent stem cells (iPSCs) from a sporadic HLHS proband-parent trio to identify, prioritize and functionally evaluate candidate genes in model systems. Consistent with the hypoplastic phenotype, the proband’s iPSCs had reduced proliferation capacity. Filtering WGS for rare de novo, recessive, and loss-of-function variants revealed 10 candidate genes with recessive variants and altered expression compared to the parents’ iPSCs. siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiac progenitors and in thein vivo Drosophilaheart model revealed that LDL receptor related proteinLRP2and apolipoproteinAPOBare required for robust hiPSC-derived cardiomyocyte proliferation and normal hear structure and function, possibly involving an oligogenic mechanism via growth-promoting WNT and SHH signaling.LRP2was further validated as a CHD gene in a zebrafish heart model and rare variant burden testing in an HLHS cohort. Collectively, this cross-functional genetic approach to complex congenital heart disease revealed LRP2 dysfunction as a likely novel genetic driver of HLHS, and hereby established a scalable approach to decipher the oligogenic underpinnings of maladaptive left heart development.

One sentence summary

Whole genome sequencing and a multi-model system candidate gene validation - human iPSC-derived cardiomyocytes andDrosophilaand zebrafish hearts - identified lipoproteinLRP2as a new potential driver in congenital heart disease and suggests a deficit in proliferation as a hallmark of hypoplastic left heart syndrome.
Mutation severity spectrum of rare alleles in the human genome is predictive of disease type
Authors: Pei Jimin , Kinch Lisa , Grishin Nick V.
Published: November 2019

The human genome harbors a variety of genetic variations. Single-nucleotide changes that alter amino acids in protein-coding regions are one of the major causes of human phenotypic variation and diseases. These single-amino acid variations (SAVs) are routinely found in whole genome and exome sequencing. Evaluating the functional impact of such genomic alterations is crucial for diagnosis of genetic disorders. We developed DeepSAV, a deep-learning convolutional neural network to differentiate disease-causing and benign SAVs based on a variety of protein sequence, structural and functional properties. Our method outperforms most stand-alone programs and has similar predictive power as some of the best available. We transformed DeepSAV scores of rare SAVs observed in the general population into a mutation severity measure of protein-coding genes. This measure reflects a gene’s tolerance to deleterious missense mutations and serves as a useful tool to study gene-disease associations. Genes implicated in cancer, autism, and viral interaction are found by this measure as intolerant to mutations, while genes associated with a number of other diseases are scored as tolerant. Among known disease-associated genes, those that are mutation-intolerant are likely to function in development and signal transduction pathways, while those that are mutation-tolerant tend to encode metabolic and mitochondrial proteins.
A generalizable multivariate brain pattern for interpersonal guilt
Authors: Yu Hongbo , Koban Leonie , Chang Luke J. , Wagner Ullrich , Krishnan Anjali , Vuilleumier Patrik , Zhou Xiaolin , Wager Tor D.
Published: November 2019

Feeling guilty when we have wronged another is a crucial aspect of prosociality, but its neurobiological bases are elusive. Although multivariate patterns of brain activity show promise for developing brain measures linked to specific emotions, it is less clear whether brain activity can be trained to detect more complex social emotional states such as guilt. Here, we identified a distributed Guilt-Related Brain Signature (GRBS) across two independent neuroimaging datasets that used interpersonal interactions to evoke guilt. This signature discriminated conditions associated with interpersonal guilt from closely matched control conditions in a cross-validated training sample (N = 24; Chinese population) and in an independent test sample (N = 19; Swiss population). However, it did not respond to observed or experienced pain, or recalled guilt. Moreover, the GRBS only exhibited weak spatial similarity with other brain signatures of social affective processes, further indicating the specificity of the brain state it represents. These findings provide a step towards developing biological markers of social emotions, which could serve as important tools to investigate guilt-related brain processes in both healthy and clinical populations.
FastMulRFS: Fast and accurate species tree estimation under generic gene duplication and loss models
Authors: Molloy Erin K. , Warnow Tandy
Published: November 2019

Motivation

Species tree estimation is a basic part of biological research but can be challenging because of gene duplication and loss (GDL), which results in genes that can appear more than once in a given genome. All common approaches in phylogenomic studies either reduce available data or are error-prone, and thus, scalable methods that do not discard data and have high accuracy on large heterogeneous datasets are needed.

Results

We present FastMulRFS, a polynomial-time method for estimating species trees without knowledge of orthology. We prove that FastMulRFS is statistically consistent under a generic model of GDL when adversarial GDL does not occur. Our extensive simulation study shows that FastMulRFS matches the accuracy of MulRF (which tries to solve the same optimization problem) and has better accuracy than prior methods, including ASTRAL-multi (the only method to date that has been proven statistically consistent under GDL), while being much faster than both methods.

Availability

FastMulRFS is available on Github (https://github.com/ekmolloy/fastmulrfs).
Human HMGN1 and HMGN2 are not required for transcription-coupled DNA repair
Authors: Apelt Katja , Zoutendijk Iris , Gout Dennis Y. , van den Heuvel Diana , Luijsterburg Martijn S.
Published: November 2019

Transcription-coupled repair (TCR) removes DNA lesions from the transcribed strand of active genes. Stalling of RNA polymerase II (RNAPII) at DNA lesions initiates TCR through the recruitment of the CSB and CSA proteins. The full repertoire of proteins required for human TCR – particularly in a chromatin context - remains to be determined. Studies in mice have revealed that the nucleosome-binding protein HMGN1 is required to enhance the repair of UV-induced lesions in transcribed genes. However, whether HMGN1 is required for human TCR remains unaddressed. Here, we show that knockout or knockdown of HMGN1, either alone or in combination with HMGN2, does not render human cells sensitive to UV light or Illudin S-induced transcription-blocking DNA lesions. Moreover, transcription restart after UV irradiation was not impaired in HMGN-deficient cells. In contrast, TCR-deficient cells were highly sensitive to DNA damage and failed to restart transcription. Furthermore, GFP-tagged HMGN1 was not recruited to sites of UV-induced DNA damage under conditions were GFP-CSB readily accumulated. In line with this, HMGN1 did not associate with the TCR complex, nor did TCR proteins require HMGN1 to associate with DNA damage-stalled RNAPII. Together, our findings suggest that HMGN1 and HMGN2 are not required for human TCR.
Combined model-free and model-sensitive reinforcement learning in non-human primates
Authors: Miranda Bruno , Malalasekera W. M. Nishantha , Behrens Timothy E , Dayan Peter , Kennerley Steven W.
Published: November 2019

Contemporary reinforcement learning (RL) theory suggests that potential choices can be evaluated by strategies that may or may not be sensitive to the computational structure of tasks. A paradigmatic model-free (MF) strategy simply repeats actions that have been rewarded in the past; by contrast, model-sensitive (MS) strategies exploit richer information associated with knowledge of task dynamics. MF and MS strategies should typically be combined, because they have complementary statistical and computational strengths; however, this tradeoff between MF/MS RL has mostly only been demonstrated in humans, often with only modest numbers of trials. We trained rhesus monkeys to perform a two-stage decision task designed to elicit and discriminate the use of MF and MS methods. A descriptive analysis of choice behaviour revealed directly that the structure of the task (of MS importance) and the reward history (of MF and MS importance) significantly influenced both choice and response vigour. A detailed, trial-by-trial computational analysis confirmed that choices were made according to a combination of strategies, with a dominant influence of a particular form of model sensitivity that persisted over weeks of testing. The residuals from this model necessitated development of a new combined RL model which incorporates a particular credit assignment weighting procedure. Finally, response vigor exhibited a subtly different collection of MF and MS influences. These results provide new illumination onto RL behavioural processes in non-human primates.
Seeing around corners: Cells create chemotactic gradients to solve mazes and respond to distant cues in complex environments
Authors: Tweedy Luke , Thomason Peter A. , Martin Kirsty , Zagnoni Michele , Machesky Laura M. , Insall Robert H.
Published: November 2019

Chemotaxis, in which cells steer using chemical gradients, drives fundamental biological processes like embryogenesis, metastasis and immune responses. Self-generated chemotaxis, where cells break down abundant attractants to create gradients, is an important but under-studied aspect of physiological navigation. Here we show that self-generated gradients allow cells to navigate arbitrarily complex paths and, remarkably, make accurate choices about pathways they have not yet encountered. This enables cells to solve microfluidic mazes, even with initially homogeneous environments and distant correct destinations. We combine computational models and experiments to understand how cells anticipate environmental features, and how decision accuracy is determined by path complexity, attractant diffusibility and cell speed. This permits mazes that are easy or hard for cells to resolve, despite similar appearances. Counterintuitively, slowly-diffusing attractants can generate a “mirage”, making cells prefer dead ends over correct paths.In vivoenvironments resemble complex mazes, and only self-generated gradients realistically explain cell behaviour.
On species delimitation, hybridization and population structure of cassava whitefly in Africa
Authors: Elfekih S , Tay WT , Polaszek A , Gordon KHJ , Kunz D , Macfadyen S , Walsh TK , Vyskočilová S , Colvin J , De Barro PJ
Published: November 2019

The Bemisia cassava whitefly complex includes species that cause severe crop damage through vectoring cassava viruses in eastern Africa. Currently, the cassava whitefly complex is divided into species and subgroups based on very limited molecular markers that did not allow clear definition of species and population structure. Based on 14,358 genome-wide SNPs from 63 cassava whitefly individuals belonging to sub-Saharan African (SSA1, SSA2 and SSA4) species, and using a well-curated mtCOI gene database, we show clear incongruities in previous taxonomic approaches underpinned by effects from pseudogenes. We show that the SSA4 species is part of the SSA2 species, and that populations of the SSA1 species comprise of south-eastern (Madagascar, Tanzania) and north-western (Nigeria, Democratic Republic of Congo and Burundi) sub-species that show signatures of allopatric incipient speciation, with a hybrid zone separating these adjacent sub-species. These findings provide the first genomic insights into the evolution and molecular ecology of a highly cryptic hemipteran insect complex in African, and allow the systematic use of genomic data in management and control strategies for this important cassava pest.
An assessment of environmental metabarcoding protocols aiming at favouring contemporary biodiversity in inventories of deep-sea communities
Authors: Brandt Miriam I. , Trouche Blandine , Henry Nicolas , Liautard-Haag Cathy , Maignien Lois , de Vargas Colomban , Wincker Patrick , Poulain Julie , Zeppilli Daniela , Arnaud-Haond Sophie
Published: November 2019

The abyssal seafloor covers more than 50% of planet Earth and is a large reservoir of still mostly undescribed biodiversity. It is increasingly under target of resource-extraction industries although being drastically understudied. In such remote and hard-to-access ecosystems, environmental DNA (eDNA) metabarcoding is a useful and efficient tool for studying biodiversity and implementing environmental impact assessments. Yet, eDNA analysis outcomes may be biased towards describing past rather than present communities as sediments contain both contemporary and ancient DNA.

Using commercially available kits, we investigated the impacts of five molecular processing methods on DNA metabarcoding biodiversity inventories targeting prokaryotes (16S-V4V5), unicellular eukaryotes (18S-V4), and metazoans (18S-V1, COI). As the size distribution of ancient DNA is skewed towards small fragments, we evaluated the effect of removing short DNA fragments via size-selection and ethanol reconcentration using DNA extracted from 10 g of sediment at five deep-sea sites. We also compare communities revealed by DNA and RNA co-extracted from 2 g of sediment at the same sites.

Results show that removing short DNA fragments does not affect alpha and beta diversity estimates in any of the biological compartments investigated. Results also confirm doubts regarding the possibility to better describe live communities using environmental RNA (eRNA). With ribosomal loci, RNA, while resolving similar spatial patterns than co-extracted DNA, resulted in significantly higher richness estimates, supporting hypotheses of increased persistence of ribosomal RNA (rRNA) in the environment and unmeasured bias due to over-abundance of rRNA and RNA release. With the mitochondrial locus, RNA detected lower metazoan richness and resolved less spatial patterns than co-extracted DNA, reflecting high messenger RNA lability. Results also highlight the importance of using large amounts of sediment (≥10 g) for accurately surveying eukaryotic diversity.

We conclude that DNA should be favoured over RNA for logistically realistic, repeatable, and reliable surveys, and confirm that large sediment samples (≥10 g) deliver more complete and accurate assessments of benthic eukaryotic biodiversity and that increasing the number of biological rather than technical replicates is important to infer robust ecological patterns.
Correcting reference bias from the Illumina Isaac aligner enables analysis of cancer genomes
Authors: Cornish Alex J. , Chubb Daniel , Frangou Anna , Hoang Phuc H. , Kaiser Martin , Wedge David C. , Houlston Richard S.
Published: November 2019

Estimating the fraction of cancer cells with individual somatic mutations is central to many analyses in cancer genomics, including characterisation of clonal architecture and timing of mutational events. Estimation of these cancer cell fractions (CCFs) is contingent on unbiased assessment of the fraction of reads supporting variant alleles (VAFs). We demonstrate that VAFs computed by the Illumina Isaac pipeline, used in many large-scale sequencing projects including The 100,000 Genomes Project, are biased by the preferential soft clipping of reads supporting non-reference alleles (semi-aligned reads). We show that these biased VAFs can have deleterious effects on downstream analyses reliant on unbiased CCF estimates. While Isaac bias can be corrected through realignment with alternative parameters, this is computationally intensive. We therefore developed FixVAF, a tool for removing bias introduced by soft clipping of semi-aligned reads, facilitating downstream analyses without the need for realignment. FixVAF is freely available at https://github.com/danchubb/FixVAF.

Contact

alex.cornish@icr.ac.uk or daniel.chubb@icr.ac.uk.
PPanGGOLiN: depicting microbial diversity via a partitioned pangenome graph
Authors: Gautreau Guillaume , Bazin Adelme , Gachet Mathieu , Planel Rémi , Burlot Laura , Dubois Mathieu , Perrin Amandine , Médigue Claudine , Calteau Alexandra , Cruveiller Stéphane , Matias Catherine , Ambroise Christophe , Rocha Eduardo PC , Vallenet David
Published: November 2019

The use of comparative genomics for functional, evolutionary, and epidemiological studies requires methods to classify gene families in terms of occurrence in a given species. These methods usually lack multivariate statistical models to infer the partitions and the optimal number of classes and don’t account for genome organization. We introduce a graph structure to model pangenomes in which nodes represent gene families and edges represent genomic neighborhood. Our method, named PPanGGOLiN, partitions nodes using an Expectation-Maximization algorithm based on multivariate Bernoulli Mixture Model coupled with a Markov Random Field. This approach takes into account the topology of the graph and the presence/absence of genes in pangenomes to classify gene families into persistent, cloud, and one or several shell partitions. By analyzing the partitioned pangenome graphs of isolate genomes from 439 species and metagenome-assembled genomes from 78 species, we demonstrate that our method is effective in estimating the persistent genome. Interestingly, it shows that the shell genome is a key element to understand genome dynamics, presumably because it reflects how genes present at intermediate frequencies drive adaptation of species, and its proportion in genomes is independent of genome size. The graph-based approach proposed by PPanGGOLiN is useful to depict the overall genomic diversity of thousands of strains in a compact structure and provides an effective basis for very large scale comparative genomics. The software is freely available athttps://github.com/labgem/PPanGGOLiN.

Author summary

Microorganisms have the greatest biodiversity and evolutionary history on earth. At the genomic level, it is reflected by a highly variable gene content even among organisms from the same species which explains the ability of microbes to be pathogenic or to grow in specific environments. We developed a new method called PPanGGOLiN which accurately represent the genomic diversity of a species (i.e. its pangenome) using a compact graph structure. Based on this pangenome graph, we classify genes by a statistical method according to their occurrence in the genomes. This method allowed us to build pangenomes even for uncultivated species at an unprecedented scale. We applied our method on all available genomes in databanks in order to depict the overall diversity of hundreds of species. Overall, our work enables microbiologists to explore and visualize pangenomes alike a subway map.