bluuebunny/crossref_metadata_2025 huggingface dataset:
ntEdit: scalable genome sequence polishing
Authors: Warren René L , Coombe Lauren , Mohamadi Hamid , Zhang Jessica , Jaquish Barry , Isabel Nathalie , Jones Steven J M , Bousquet Jean , Bohlmann Joerg , Birol Inanç
Published: May 2019

Motivation

In the modern genomics era, genome sequence assemblies are routine practice. However, depending on the methodology, resulting drafts may contain considerable base errors. Although utilities exist for genome base polishing, they work best with high read coverage and do not scale well. We developed ntEdit, a Bloom filter-based genome sequence editing utility that scales to large mammalian and conifer genomes.

Results

We first tested ntEdit and the state-of-the-art assembly improvement tools GATK, Pilon and Racon on controlled Escherichia coli and Caenorhabditis elegans sequence data. Generally, ntEdit performs well at low sequence depths (<20×), fixing the majority (>97%) of base substitutions and indels, and its performance is largely constant with increased coverage. In all experiments conducted using a single CPU, the ntEdit pipeline executed in <14 s and <3 m, on average, on E.coli and C.elegans, respectively. We performed similar benchmarks on a sub-20× coverage human genome sequence dataset, inspecting accuracy and resource usage in editing chromosomes 1 and 21, and whole genome. ntEdit scaled linearly, executing in 30–40 m on those sequences. We show how ntEdit ran in <2 h 20 m to improve upon long and linked read human genome assemblies of NA12878, using high-coverage (54×) Illumina sequence data from the same individual, fixing frame shifts in coding sequences. We also generated 17-fold coverage spruce sequence data from haploid sequence sources (seed megagametophyte), and used it to edit our pseudo haploid assemblies of the 20 Gb interior and white spruce genomes in <4 and <5 h, respectively, making roughly 50M edits at a (substitution+indel) rate of 0.0024.

Availability and implementation

https://github.com/bcgsc/ntedit

Supplementary information

Supplementary data are available at Bioinformatics online.
Homogeneity tests of covariance matrices with high-dimensional longitudinal data
Authors: Zhong Ping-Shou , Li Runze , Santo Shawn
Published: May 2019

This paper deals with the detection and identification of changepoints among covariances of high-dimensional longitudinal data, where the number of features is greater than both the sample size and the number of repeated measurements. The proposed methods are applicable under general temporal-spatial dependence. A new test statistic is introduced for changepoint detection, and its asymptotic distribution is established. If a changepoint is detected, an estimate of the location is provided. The rate of convergence of the estimator is shown to depend on the data dimension, sample size, and signal-to-noise ratio. Binary segmentation is used to estimate the locations of possibly multiple changepoints, and the corresponding estimator is shown to be consistent under mild conditions. Simulation studies provide the empirical size and power of the proposed test and the accuracy of the changepoint estimator. An application to a time-course microarray dataset identifies gene sets with significant gene interaction changes over time.
Duodenojejunal Bypass and Strictureplasty for Diffuse Small Bowel Crohn’s Disease with a Step-by-Step Visual Guide
Authors: Lee Chun Hin Angus , Rieder Florian , Holubar Stefan D
Published: May 2019

Lay Summary

Crohn’s disease is an inflammatory condition of the intestine with an unknown cause and can result in inflammation, narrowing (stricuture) or penetrating disease (fistula that inflammation goes through the wall of the bowel and into another structure). Unfortunately Crohn’s disease can affect anywhere in the gastrointestinal tract, all the way from the mouth to the anus. Sometimes Crohn’s disease can affect the duodenum, the portion of the small intestine just after the stomach. When Crohn’s disease is in the duodenum and causes narrowing, it is difficult to treat medically, and often needs a surgical intervention. When the narrowing is short, less than a few centimeters, the surgeon can do a strictureplasty which means opening the intestine across the stricture and sewing it back shut in the horitzontal direction to make the opening larger. When the narrowing, or stricture, is longer, then the surgeon may have to connect the stomach to another part of the small intestine (gastrojejunostomy) to avoid or bypass the duodenum, or may have to perform a large reconstructive operation to remove that portion of the small intestine. the challenge is that those operations have significant potential complications associated with them. Therefore, sometimes a bypass operation can be done instead to connect the duodenum to the next part of the small intestine, the jejunum. In this manuscript the authors describe this surgical technique is a 38 year old male with Crohn’s disease who was referred with multiple areas of narrowing in his intestine.
Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions
Authors: Johnson Thomas W , Räber Lorenz , di Mario Carlo , Bourantas Christos , Jia Haibo , Mattesini Alessio , Gonzalo Nieves , de la Torre Hernandez Jose M , Prati Francesco , Koskinas Konstantinos , Joner Michael , Radu Maria D , Erlinge David , Regar Evelyn , Kunadian Vijay , Maehara Akiko , Byrne Robert A , Capodanno Davide , Akasaka Takashi , Wijns William , Mintz Gary S , Guagliumi Giulio
Published: May 2019

This consensus document is the second of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near infrared spectroscopy (NIRS)-IVUS. Beyond guidance of stent selection and optimization of deployment, invasive imaging facilitates angiographic interpretation and may guide treatment in acute coronary syndrome. Intravascular imaging can provide additional important diagnostic information when confronted with angiographically ambiguous lesions and allows assessment of plaque morphology enabling identification of vulnerability characteristics. This second document focuses on useful imaging features to identify culprit and vulnerable coronary plaque, which offers the interventional cardiologist guidance on when to adopt an intracoronary imaging-guided approach to the treatment of coronary artery disease and provides an appraisal of intravascular imaging-derived metrics to define the haemodynamic significance of coronary lesions.
Association of Sarcopenia With Performance on Multiple Cognitive Domains: Results From the ELSA-Brasil Study
Authors: Szlejf Claudia , Suemoto Claudia K , Lotufo Paulo A , Benseñor Isabela M
Published: May 2019

Background

Sarcopenia and cognitive impairment share pathophysiological paths and risk factors. Our aim was to investigate the association of sarcopenia and its defining components with cognitive performance in middle-aged and older adults.

Methods

This cross-sectional analysis included 5,038 participants from the ELSA-Brasil Study, aged ≥ 55 years. Muscle mass was evaluated by bioelectrical impedance analysis and muscle strength by handgrip strength. Sarcopenia was defined according to the Foundation for the National Institutes of Health. Cognition was evaluated using delayed word recall test, semantic verbal fluency test, and trail making test version B. Possible confounders included sociodemographic characteristics, lifestyle, and clinical comorbidities.

Results

The frequencies of sarcopenia, low muscle mass, and low muscle strength were 1.8%, 23.3%, and 4.4%, respectively. After adjustment for possible confounders, poorer performance on the verbal fluency test was associated with sarcopenia (β = −0.20, 95% confidence interval [CI] = −0.38; −0.01, p = .03) and low muscle mass (β = −0.08, 95% CI = −0.14; −0.01, p = .02). Low muscle strength was associated with poorer performance in the delayed word recall test (β = −0.14, 95% CI = −0.27; −0.02, p = .02), verbal fluency test (β = −0.14, 95% CI = −0.26; −0.02, p = .03), and trail making test (β = −0.15, 95% CI = −0.27; −0.03, p = .01).

Conclusions

Sarcopenia was associated with poorer performance on the verbal fluency test, and low muscle strength was associated with poorer performance in all cognitive tests in middle-aged and older adults.
The Devil is in the Details: Identifying Aspects of Temperature Variation that Underlie Sex Determination in Species with TSD
Authors: Carter A W , Paitz R T , Bowden R M
Published: May 2019

Most organisms experience thermal variability in their environment; however, our understanding of how organisms cope with this variation is under-developed. For example, in organisms with temperature-dependent sex determination (TSD), an inability to predict sex ratios under fluctuating incubation temperatures in the field hinders predictions of how species with TSD will fare in a changing climate. To better understand how sex determination is affected by thermal variation, we incubated Trachemys scripta eggs using a “heat wave” design, where embryos experienced a male-producing temperature of 25 ± 3°C for the majority of development and varying durations at a female-producing temperature of 29.5 ± 3°C during the window of development when sex is determined. We compared the sex ratios from these incubation conditions with a previous data set that utilized a similar heat wave design, but instead incubated eggs at a male-producing temperature of 27 ± 3°C but utilized the same female-producing temperature of 29.5 ± 3°C. We compared the sex ratio reaction norms produced from these two incubation conditions and found that, despite differences in average temperatures, both conditions produced 50:50 sex ratios after ∼8 days of exposure to female-producing conditions. This emphasizes that sex can be determined in just a few days at female-producing conditions and that sex determination is relatively unaffected by temperatures outside of this short window. Further, these data demonstrate the reduced accuracy of the constant temperature equivalent model (the leading method of predicting sex ratios) under thermally variable temperatures. Conceptualizing sex determination as the number of days spent incubating at female-producing conditions rather than an aggregate statistic is supported by the mechanistic underpinnings of TSD, helps to improve sex ratio estimation methods, and has important consequences for predicting how species with TSD will fare in a changing climate.
Comparison of Gel Larval Diet With Traditional Lucerne Chaff and Carrot Solid Diets for Rearing of Queensland Fruit Fly (Diptera: Tephritidae)
Authors: Mainali Bishwo P , Moadeli Tahereh , Ponton Fleur , Taylor Phillip W
Published: May 2019

Sterile insect technique (SIT) for Queensland fruit fly, Bactrocera tryoni Froggatt, Australia’s most economically damaging fruit fly species, is currently undergoing a major renewal and expansion. SIT relies on efficient and economical mass-rearing procedures that produce high-quality flies. Two solid larval diets, carrot and lucerne chaff, have traditionally been used to rear Queensland fruit fly. Recently, a gel larval diet has been developed to eliminate biological bulking agents from the mass-rearing process, but to date, there has been no direct comparison of gel larval diet with traditional solid diets. In the present study, the performance of flies reared on gel larval diet was compared with the performance of flies reared on carrot and lucerne chaff diets. In addition, to investigate whether the performance of reared flies depends on ancestral diet as well as tested diet, we sourced eggs from a colony maintained on carrot diet and from a colony maintained on a lucerne chaff diet. Overall, the gel diet was as good or better than the solid diets in all quality control parameters, including, egg–larval duration, pupal number, pupal recovery, adult emergence, percentage of fliers, and rate of fliers. Of note, larvae developed faster and pupated more synchronously on the gel diet than on either of the solid diets. At the loading densities used, gel and carrot diets produced less waste than lucerne chaff diet. Gel diets offer a rearing solution for Queensland fruit fly that eliminates biological bulking agents and yields faster and more synchronous larval development without compromising productivity or quality.
Life after public employment retrenchment: evidence from Italian municipalities
Authors: Auricchio Marta , Ciani Emanuele , Dalmazzo Alberto , de Blasio Guido
Published: May 2019

We investigate the interaction between public and private employment at the local level. In contrast to previous literature, which has mainly examined public sector expansions, we provide evidence about the impact of downsizing. Using data from Italian municipalities, the IV strategy we adopt here exploits the fact that the contraction in public employment observed between the last two Censuses (2001–2011) was strongly influenced by the decision made by central government, with little reference to local economic conditions. Our results suggest that exogenous reductions in public employment stimulate the growth of private jobs, mostly in tradables. The change in local prices, especially for housing services, represents a relevant channel for the interplay between the tradable and non-tradable sectors.
Contemporary Associations of Exclusive Cigarette, Cigar, Pipe, and Smokeless Tobacco Use With Overall and Cause-Specific Mortality in the United States
Authors: Inoue-Choi Maki , Shiels Meredith S , McNeel Timothy S , Graubard Barry I , Hatsukami Dorothy , Freedman Neal D
Published: May 2019

Background

A growing proportion of tobacco users in the United States use non-cigarette products including cigars, pipes, and smokeless tobacco. Studies examining the disease and mortality risks of these products are urgently needed.

Methods

We harmonized tobacco use data from 165 335 adults in the 1991, 1992, 1998, 2000, 2005, and 2010 National Health Interview Surveys. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cause-specific mortality occurring through December 31, 2015, were estimated by exclusive use of cigarettes, cigars, pipes, or smokeless tobacco using Cox proportional hazards regression with age as the underlying time metric and never tobacco users as the referent group.

Results

Current use of cigarettes (HR = 2.23, 95% CI = 2.13 to 2.33) and smokeless tobacco (HR = 1.36, 95% CI = 1.17 to 1.59) were each associated with overall mortality. Relative to never tobacco users, higher risks were observed both in daily (HR = 2.34, 95% CI = 2.24 to 2.44) and nondaily (HR = 1.69, 95% CI = 1.54 to 1.86) cigarette smokers, with associations also observed across major smoking-related causes of death. Daily use of smokeless tobacco was also associated with overall mortality (HR = 1.41, 95% CI = 1.20 to 1.66) as was daily use of cigars (HR = 1.52, 95% CI = 1.12 to 2.08). Current smokeless tobacco use was associated with a higher risk of mortality from heart disease and smoking-related cancer, with strong associations observed for cancers of the oral cavity and bladder.

Conclusions

Exclusive daily use of cigarettes, cigars, and smokeless tobacco was associated with higher mortality risk. Tobacco control efforts should include cigars and smokeless tobacco.
A Numeral Oddity
Authors: Gasparri Luca
Published: May 2019

Natural language appears to allow the ascription of properties of numeral symbols to the denotation of number referring phrases. The paper describes the phenomenon and presents two alternative explanations for why it obtains. One combining an intuitive semantics for number referring phrases and a predicate-shifting mechanism, the other assigning number referring phrases a structured denotation consisting of two parts: a mathematical object (the number) and a contextually determined numeral symbol. Some preliminary observations in favor of the second analysis are offered.
Analysis of Risk Factors for Posterior C1 Screw-Related Complication: A Retrospective Study of 358 Posterior C1 Screws
Authors: Yi Ho Jun , Hong Jae Taek , Lee Jong Beom , Park Jong-Hyeok , Lee Jung Jae , Kim Il Sup , Yang Seung Ho , Sung Jae Hoon
Published: May 2019

BACKGROUND

Although C1 screw fixation is becoming popular, only a few studies have discussed about the risk factors and the patterns of C1 screw complications.

OBJECTIVE

To investigate the incidence of C1 screw complications and analyze the risk factors of the C1 screw complications.

METHODS

A total of 358 C1 screws in 180 consecutive patients were analyzed for C1 screw complications. Screw malposition, occipital neuralgia, major complications, and total C1 screw complications were analyzed.

RESULTS

The distribution of C1 screw entry point is as follows: inferior lateral mass, 317 screws (88.5 %); posterior arch (PA), 38 screws (10.7 %); and superior lateral mass, 3 screws (0.8 %). We sacrificed the C2 root for 127 screws (35.5 %). C1 instrumentation induced 3.1 % screw malposition, 6.4 % occipital neuralgia, 0.6 % vascular injury, and 3.4 % major complications. In multivariate analysis, deformity (odds ratio [OR]: 2.10, P = .003), traumatic pathology (OR: 4.97, P = .001), and PA entry point (OR: 3.38, P = .001) are independent factors of C1 screw malposition. C2 root resection can decrease the incidence of C1 screw malposition (OR: 0.38, P = .012), but it is a risk factor of occipital neuralgia (OR: 2.62, P = .034). Advanced surgical experience (OR: 0.09, P = .020) correlated with less major complication.

CONCLUSION

The incidence of C1 screw complications might not be uncommon, and deformity or traumatic pathology and PA entry point could be the risk factors to total C1 screw complications. The PA screw induces more malposition, but less occipital neuralgia. C2 root resection can reduce screw malposition, but increases occipital neuralgia.
Collective Action and Governance Activism*
Authors: Doidge Craig , Dyck Alexander , Mahmudi Hamed , Virani Aazam
Published: May 2019

We examine how an investor collective action organization (ICAO) enhances activism by institutional investors. The ICAO initiated a new form of engagement—private meetings with independent directors to discuss governance proposals. Compared with a single investor acting alone, the ICAO has stronger incentives to engage in activism. Its dollar holdings and voting power are six times larger and predict direct access to the board and the firms it engages. Firms engaged by the ICAO are at least 58% more likely than non-engaged firms to adopt the ICAO’s governance proposals that include adoption of majority voting, say-on-pay, and specific compensation policies. Engaged firms also increase CEO incentive pay. An event study around the announcement of the ICAO’s formation shows a positive impact on value that increases in both dollar holdings and voting power. We conclude that institutional investors improve governance outcomes through collective action.
MONET: a toolbox integrating top-performing methods for network modularisation
Authors: Tomasoni Mattia , Gómez Sergio , Crawford Jake , Zhang Weijia , Choobdar Sarvenaz , Marbach Daniel , Bergmann Sven
Published: May 2019

We define a disease module as a partition of a molecular network whose components are jointly associated with one or several diseases or risk factors thereof. Identification of such modules, across different types of networks, has great potential for elucidating disease mechanisms and establishing new powerful bio-markers. To this end, we launched the “Disease Module Identification (DMI) DREAM Challenge”, a community effort to build and evaluate unsupervised molecular network modularisation algorithms (Choobdar et al., 2018). Here we present MONET, a toolbox providing easy and unified access to the three top methods from the DMI DREAM Challenge for the bioinformatics community.

Availability and Implementation

MONET is a command line tool for Linux, based on Docker and Singularity containers; the core algorithms were written in R, Python, Ada and C++. It is freely available for download at https://github.com/BergmannLab/MONET.git

Contact

mattia.tomasoni@unil.ch (MT); sven.bergmann@unil.ch (SB)
Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons
Authors: Lewis Emily M.A. , Meganathan Kesavan , Baldridge Dustin , Gontarz Paul , Zhang Bo , Bonni Azad , Constantino John N. , Kroll Kristen L.
Published: May 2019

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rarede novomutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk.

Methods

Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of unknown significance inGPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted.

Results

cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes.

Conclusions

We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.
Estimation of a Time-varying Apparent Infection Rate from Plant Disease Progress Curves: A Particle Filter Approach
Authors: dos S Alves Kaique , Moraes Willian B , da Silva Wellington B , Del Ponte Emerson M
Published: May 2019

The parameters of the simplest (two-parameter) epidemiological models that best fit plant disease progress curve (DPC) data are the surrogate for initial inoculum (y0) and the (constant) apparent infection rate (r), both being useful for understanding, predicting and comparing epidemics. The assumption thatris constant is not reasonable and fluctuations are expected due to systematic changes in factors affecting infection (e.g. weather favorability, host susceptibility, etc.), thus leading to a time-varyingr, orr(t). An arrangement of these models (e.g. logistic, monomolecular, etc.) can be used to obtainrbetween two time points, given the disease (y) data are available. We evaluated a data assimilation technique, Particle Filter (PF), as an alternative method for estimatingr(t). Synthetic DPC data for a hypothetical polycyclic epidemics were simulated using the logistic differential equation for scenarios that combined five patterns ofr(t) (constant, increasing, decreasing, random or sinusoidal); five increasing time assessment interval (Δt= 1, 3, 5, 7 or 9 time units - t.u.); and two levels of noise (α = 0.1 or 0.25) assigned toy(t). The analyses of 50 simulated 60-t.u. DPCs showed that the errors of PF-derivedwere lower (RMSE < 0.05) for Δt< 5 t.u. and least affected by the presence of noise in the measure compared with the logit-derivedr(t). The ability to more accurately estimater(t) using the novel method may be useful to increase knowledge of field epidemics and identify within-season drivers that may explainr(t) behaviour.
Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation
Authors: Bhargava Pavan , Mische Leah , Smith Matthew D. , Harrington Emily , Fitzgerald Kathryn C , Martin Kyle , Kim Sol , Reyes Arthur Anthony , Gonzalez-Cardona Jaime , Volsko Christina , Singh Sonal , Varanasi Kesava , Sotirchos Elias S. , Nourbakhsh Bardia , Dutta Ranjan , Mowry Ellen M. , Waubant Emmanuelle , Calabresi Peter A.
Published: May 2019

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases
Authors: Zheng Jie , Haberland Valeriia , Baird Denis , Walker Venexia , Haycock Philip , Hurle Mark , Gutteridge Alex , Erola Pau , Liu Yi , Luo Shan , Robinson Jamie , Richardson Tom G. , Staley James R. , Elsworth Benjamin , Burgess Stephen , Sun Benjamin B. , Danesh John , Runz Heiko , Maranville Joseph C. , Martin Hannah M. , Yarmolinsky James , Laurin Charles , Holmes Michael V. , Liu Jimmy , Estrada Karol , Santos Rita , McCarthy Linda , Waterworth Dawn , Nelson Matthew R. , Hemani Gibran , Smith George Davey , Butterworth Adam S. , Scott Robert A. , Gaunt Tom R.
Published: May 2019

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here, we estimated the effects of 1002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium (LD) is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programmes showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of our approach in identifying and prioritising potential therapeutic targets.
Anterior corpus callosum modulates symmetric forelimb movements during spontaneous food handling behavior of rats
Authors: Igarashi Masakazu , Akamine Yumiko , Wickens Jeffery R
Published: May 2019

Bimanual motor actions, such as threading a needle, require coordination of the movements of each hand according to the state of the other hand. By connecting homologous cortical regions between the two cerebral hemispheres, the corpus callosum is thought to play a key role in such bimanual coordination. However, direct experimental evidence of the contribution of the corpus callosum to natural behaviors requiring bimanual coordination, such as feeding, is lacking. We investigated the hypothesis that the corpus callosum mediates bimanual movements during food-handling behavior. We first traced the forelimb-related components of the motor corpus callosum in Long-Evans rats, and found that the callosal fiber bundle from the forelimb motor areas passes through the anterior part of the corpus callosum. We then confirmed by electrophysiological recordings that blocking the axonal conduction of fibers in the anterior corpus callosum reduced neural transmission between cortical forelimb areas. The causal role of corpus callosum in bimanual coordination was then tested by analyzing forelimb kinematics during object manipulation, before and after blocking axonal conduction in the anterior corpus callosum. We found the frequency of occurrence of symmetric bimanual movements was reduced by inhibition of anterior corpus callosum. In contrast, asymmetric bimanual movement was increased. Our findings suggest that the anterior corpus callosum coordinates the direction of bimanual movement.
Reactive oxygen species (ROS) triggers unconventional secretion of antioxidants and Acb1
Authors: Cruz-Garcia David , Brouwers Nathalie , Malhotra Vivek , Curwin Amy J.
Published: May 2019

Nutrient deprivation triggers the release of signal-sequence-lacking Acb1 and the antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1, in a Grh1 dependent manner. Our data reveal that starvation leads to production of non-toxic levels of reactive oxygen species (ROS). Treatment of cells with N-acetylcysteine (NAC), which sequesters ROS, prevents antioxidants and Acb1 secretion. Starved cells lacking Grh1 are metabolically active, but defective in their ability to regrow upon return to growth conditions. Treatment with NAC restored the Grh1 dependent effect of starvation on cell growth. In sum, starvation triggers ROS production and cells respond by secreting antioxidants and Acb1, which is an important lipogenic signaling molecule in mammalian cells. We suggest that unconventional secretion of antioxidants and Acb1 like activities maintains cells in a form necessary for growth upon their eventual return from starvation to normal conditions.
Does deliberation really need more effort than intuition? A test using event-related brain potential
Authors: Zeng Jianmin , Tang Dinglan , Yu Jia , Zhang Qinglin , Nusbaum Howard
Published: May 2019

Intuition and deliberation are two strategies for problem-solving and decision-making. It is commonly believed that deliberation requires more effort than intuition. However, to date, neural evidence approving or disapproving this point is scarce. To explore this issue, we asked participants to play two well-matched games requiring either deliberation or intuition. Using event-related brain potential (ERP) technique, we found: (1) Deliberation elicited more deflective ERP than intuition during −1000 ~ −500 ms before the response, which is consistent with the common belief. (2) More importantly, intuition evoked more deflective ERP than deliberation during 550 ~ 650 ms after the onset of the stimulus, which suggests that intuition may need more effort than deliberation at early stage, contradicting the common belief.
A general spectral decomposition of causal influences applied to integrated information
Authors: Cohen Dror , Sasai Shuntaro , Tsuchiya Naotsugu , Oizumi Masafumi
Published: May 2019

Quantifying causal influences between elements of a system remains a central topic in many fields of research. In neuroscience, causal influences among neurons, quantified as integrated information, have been suggested to play a critical role in supporting subjective conscious experience. Recent empirical work has shown that the spectral decomposition of causal influences can reveal frequency-specific influences that are not observed in the time-domain. To date however, a spectral decomposition of integrated information has not been put forward. In this paper, we propose a spectral decomposition of integrated information in linear autoregressive processes. Our proposal is based on a general and flexible framework for deriving the spectral decompositions of causal influences in autoregressive processes. We show that the framework can retrieve the spectral decompositions of other well-known measures such as Granger causality. In simulation, we demonstrate a complex interplay between the spectral decomposition of integrated information and other measures that is not observed in the time-domain. We propose that the spectral decomposition of integrated information will be particularly useful when the underlying frequency-specific causal influences are masked in the time-domain. The proposed method opens the door for empirically investigating the relevance of integrated information to subjective conscious experience in a frequency-specific manner.

Author summary

Understanding how different parts of the brain influence each other is fundamental to neuroscience. Integrated information measures overall causal influences in the brain and has been theorized to directly relate to subjective consciousness experience. For example, integrated information is predicted to be high during wakefulness and low during sleep or general anesthesia. At the same time, neural activity is characterized by well-known spectral signatures. For example, there is a prominent increase in low frequency power of neural activity during sleep and general anesthesia. Taking account of the spectral characteristics of neural activity, it is important to separately quantify integrated information at each frequency. In this paper, we propose a method for decomposing integrated information in the frequency domain. The proposed framework is general and can be used to derive the spectral decomposition of other well-known measures such as Granger causality. The spectral decomposition of integrated information we propose will allow empirically investigating the relationship between neural spectral signatures, integrated information and subjective consciousness experience.
Predicting late-onset Alzheimer’s disease from genomic data using deep neural networks
Authors: de Velasco Oriol Javier , Vallejo Edgar E. , Estrada Karol ,   The Alzheimer’s Disease Neuroimaging Initiative
Published: May 2019

Alzheimer’s disease (AD) is the leading form of dementia. Over 25 million cases have been estimated worldwide and this number is predicted to increase two-fold every 20 years. Even though there is a variety of clinical markers available for the diagnosis of AD, the accurate and timely diagnosis of this disease remains elusive. Recently, over a dozen of genetic variants predisposing to the disease have been identified by genome-wide association studies. However, these genetic variants only explain a small fraction of the estimated genetic component of the disease. Therefore, useful predictions of AD from genetic data could not rely on these markers exclusively as they are not sufficiently informative predictors. In this study, we propose the use of deep neural networks for the prediction of late-onset Alzheimer’s disease from a large number of genetic variants. Experimental results indicate that the proposed model holds promise to produce useful predictions for clinical diagnosis of AD.
Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B1-associated DNA Damage
Authors: St. John Nick , Freedland Julian , Baldino Henri , Doyle Frank , Cera Cinzia , Begley Thomas , Fasullo Michael
Published: May 2019

Exposure to the mycotoxin aflatoxin B1 (AFB1) strongly correlates with hepatocellular carcinoma. P450 enzymes convert AFB1into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) DNA adducts, which convert to stable mutagenic AFB1formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB1is a weak mutagen but a potent recombinagen. However, few genes have been identified that confer AFB1resistance. Here, we profiled the yeast genome for AFB1resistance. We introduced the human CYP1A2 into ∼90% of the diploid deletion library, and pooled samples from CYP1A2-expressing libraries and the original library were exposed to 50 μM AFB1for 20 hs. By using next generation sequencing to count molecular barcodes, we identified 85 AFB1resistant genes from the CYP1A2-expressing libraries. While functionally diverse genes, including those that function in proteolysis, actin reorganization, and tRNA modification, were identified, those that function in post-replication DNA repair and encode proteins that bind to DNA damage were over-represented, compared to the yeast genome, at large. DNA metabolism genes included those functioning in DNA damage tolerance, checkpoint recovery and replication fork maintenance, emphasizing the potency of the mycotoxin to trigger replication stress. Among genes involved in error-free DNA damage tolerance, we observed thatCSM2, a member of theCSM2(SHU)complex, functioned in AFB1-associated sister chromatid recombination while suppressing AFB1-associated mutations. These studies thus broaden the number of AFB1resistant genes and have elucidated a mechanism of error-free bypass of AFB1-associated DNA adducts.
DNA sequence is a major determinant of tetrasome dynamics
Authors: Ordu O. , Lusser A. , Dekker N. H.
Published: May 2019

Eukaryotic genomes are hierarchically organized into protein-DNA assemblies for compaction into the nucleus. Nucleosomes, with the (H3-H4)2tetrasome as a likely intermediate, are highly dynamic in nature by way of several different mechanisms. We have recently shown that tetrasomes spontaneously change the direction of their DNA wrapping between left- and right-handed conformations, which may prevent torque build-up in chromatin during active transcription or replication. DNA sequence has been shown to strongly affect nucleosome positioning throughout chromatin. It is not known, however, whether DNA sequence also impacts the dynamic properties of tetrasomes. To address this question, we examined tetrasomes assembled on a high-affinity DNA sequence using freely orbiting magnetic tweezers. In this context, we also studied the effects of mono- and divalent salts on the flipping dynamics. We found that neither DNA sequence nor altered buffer conditions affect overall tetrasome structure. In contrast, tetrasomes bound to high-affinity DNA sequences showed significantly altered flipping kinetics, predominantly via a reduction in the lifetime of the canonical state of left-handed wrapping. Increased mono- and divalent salt concentrations counteracted this behaviour. Thus, our study indicates that high-affinity DNA sequences impact not only the positioning of the nucleosome, but that they also endow the subnucleosomal tetrasome with enhanced conformational plasticity. This may provide a means to prevent histone loss upon exposure to torsional stress, thereby contributing to the integrity of chromatin at high-affinity sites.

STATEMENT OF SIGNIFICANCE

Canonical (H3-H4)2tetrasomes possess high conformational flexibility, as evidenced by their spontaneous flipping between states of left- and right-handed DNA wrapping. Here, we show that these conformational dynamics of tetrasomes cannot be described by a fixed set of rates over all conditions. Instead, an accurate description of their behavior must take into account details of their loading, in particular the underlying DNA sequence.In vivo, differences in tetrasome flexibility could be regulated by modifications of the histone core or the tetrasomal DNA, and as such constitute an intriguing, potentially adjustable mechanism for chromatin to accommodate the torsional stress generated by processes such as transcription and replication.
Developmentally Regulated Genome Editing in Terminally Differentiated N2-Fixing Heterocysts ofAnabaena cylindricaATCC 29414
Authors: Qiu Yeyan , Gu Liping , Tian Shengni , Sidhu Jagdeep , Gibbons Jaimie , Van Den Top Trevor , Gonzalez-Hernandez Jose L. , Zhou Ruanbao
Published: May 2019

Some vegetative cells ofAnabaena cylindricaare programed to differentiate semi-regularly spaced, single heterocysts along filaments. Since heterocysts are terminally differentiated non-dividing cells, with the sole known function for solar-powered N2-fixation, is it necessary for a heterocyst to retain the entire genome (≈7.1 Mbp) from its progenitor vegetative cell? By sequencing the heterocyst genome, we discovered and confirmed that at least six DNA elements (≈0.12 Mbp) are deleted during heterocyst development. The six-element deletions led to the restoration of five genes (nifH1,nifD,hupL,primase P4and a hypothetical protein gene) that were interrupted in vegetative cells. The deleted elements contained 172 genes present in the genome of vegetative cells. By sequence alignments of intactnifgenes (nifH,nifDandhupL) from N2-fixing cyanobacteria (multicellular and unicellular) as well as other N2-fixing bacteria (non-cyanobacteria), we found that interruptednifgenes all contain the conserved core sequences that may be required for phage DNA insertion. Here, we discuss thenifgenes interruption which uniquely occurs in heterocyst-forming cyanobacteria. To our best knowledge, this is first time to sequence the genome of heterocyst, a specially differentiated oxic N2-fixing cell. This research demonstrated that (1) different genomes may occur in distinct cell types in a multicellular bacterium; and (2) genome editing is coupled to cellular differentiation and/or cellular function in a heterocyst-forming cyanobacterium.
Computational and experimental optimization of T cell activation
Authors: Aksoy Bulent Arman , Czech Eric , Paulos Chrystal , Hammerbacher Jeff
Published: May 2019

Bead-based activation is widely-used for ex vivo expansion of T cells for either research or clinical purposes. Despite its wide use, culture conditions that can potentially affect the efficiency of bead-based T cell activation has not been extensively documented. With the help of computationally-driven experimental investigations of basic culturing factors, we found that culture density, bead-to-cell ratio, and debeading time can have a major impact on the efficiency of bead-based T cell activation for short-term cultures. Furthermore, discrepancies across expected and observed activation efficiencies helped discover interesting artifacts of bead-based T cell activation.

Human primary T cells were imaged together with activation beads at 20X magnification after three hours of culturing at varying confluencies and bead-to-cell ratios.
Pseudomonas aeruginosalectin LecB impairs keratinocyte fitness by abrogating growth factor signalling
Authors: Landi Alessia , Mari Muriel , Wolf Tobias , Kleiser Svenja , Gretzmeier Christine , Wilhelm Isabel , Kiritsi Dimitra , Thünauer Roland , Geiger Roger , Nyström Alexander , Reggiori Fulvio , Claudinon Julie , Römer Winfried
Published: May 2019

Lectins are glycan-binding proteins with no catalytic activity and ubiquitously expressed in nature. Numerous bacteria employ lectins to efficiently bind to epithelia, thus facilitating tissue colonisation. Wounded skin is one of the preferred niches forPseudomonas aeruginosa, which has developed diverse strategies to impair tissue repair processes and promote infection.

Here, we analyse the effect of theP. aeruginosafucose-binding lectin LecB on human keratinocytes and demonstrate that it triggers events in the host, upon binding to fucosylated residues on cell membrane receptors, that extend beyond its role as an adhesion molecule. We found that LecB associates with several growth factor receptors and dampens their signalling pathways, leading to the arrest of cell cycle. Additionally, we describe a novel LecB-triggered mechanism to downregulate host cell receptors by showing that LecB leads to insulin-like growth factor receptor 1 internalisation, without receptor activation, and subsequent missorting towards intracellular endosomal compartments.

Overall, these data highlight that LecB is a multitask virulence factor that, through subversion of several host pathways, has a profound impact on keratinocyte proliferation and survival.
Region-specific magnetic fields structure sea turtle populations
Authors: Cameron Sahmorie J.K. , Baltazar-Soares Miguel , Eizaguirre Christophe
Published: May 2019

Philopatry and long distance migrations are common in the animal kingdom, of which sea turtles are flagship examples. Recent studies have suggested sea turtles use the Earth’s magnetic field to navigate across ocean basins to return to their natal area, yet the mechanisms underlying this process remain unknown. If true though, the genetic structure at nesting sites should positively correlate with differences in location-specific magnetic vectors within nesting regions. Here, we confirm this working hypothesis but only in certain regions of the world and for all sea turtle species nesting in those regions. Reversely, where no correlations were found between genetic differentiation and geomagnetic vectors, this was the case for all nesting sea turtle species. Our approach hence reveals parallel but not universal use of geomagnetic cues in sea turtles. We describe magneto-sensing regions as characterized by sharp clines of total and vertical field intensity vectors offering the navigation cues that increase philopatric accuracy and promote genetic structuring among sea turtle populations.