bluuebunny/crossref_metadata_2025 huggingface dataset:
Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens
Authors: Yamamoto Takayuki , Hara Hidetaka , Foote Jeremy , Wang Liaoran , Li Qi , Klein Edwin C. , Schuurman Hendrik Jan , Zhou Hongmin , Li Juan , Tector A. Joseph , Zhang Zhongqiang , Ezzelarab Mohamed , Lovingood Ray , Ayares David , Eckhoff Devin E. , Cooper David K.C. , Iwase Hayato
Published: July 2019

Background.

The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen.

Methods.

Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts.

Results.

The median survival in GroupB was 186 days (range 90–260), which was significantly longer than in GroupA; median 14 days (range 12–32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis.

Conclusions.

Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.
Body Weight Parameters are Related to Morbidity and Mortality After Liver Transplantation: A Systematic Review and Meta-analysis
Authors: Beckmann Sonja , Drent Gerda , Ruppar Todd , Nikolić Nataša , De Geest Sabina
Published: July 2019

Background.

Weight gain and obesity are well-known clinical issues in liver transplantation (LTx). However, their impacts on patient outcomes remain unclear, as only the impact of pre-LTx body mass index (BMI) on survival has been meta-analyzed. We summarized and synthesized the evidence on pre- and post-LTx body weight parameters’ relations with post-LTx outcomes such as survival, metabolic and cardiovascular comorbidities, and healthcare utilization.

Methods.

We followed the Cochrane Handbook for Systematic Reviews of Interventions’ recommendations. Quality was assessed via a 19-item instrument. Odds ratios and 95% confidence intervals were calculated for outcomes investigated in ≥5 studies.

Results.

Our meta-analysis included 37 studies. Patients with pre-LTx BMI ≥ 30 kg/m2 and BMI ≥ 35 kg/m2 had lower overall survival rates than those with pre-LTx normal weight (72.6% and 69.8% versus 84.2%; P = 0.02 and P = 0.03, respectively). Those with pre-LTx BMI ≥ 30 kg/m2 had worse overall graft survival than normal weight patients (75.8% and 85.4%; P = 0.003). Pre-LTx BMI and pre-LTx overweight were associated with new-onset diabetes (P < 0.001 and P = 0.015, respectively), but post-LTx BMI showed no relationship. No associations were evident with healthcare utilization.

Conclusions.

Patients with BMI values ≥30 kg/m2 had worse patient and graft survival than those with normal weight. Few of the reviewed studies examined post-LTx body weight parameters or other relevant outcomes such as cardiovascular comorbidities. High heterogeneity as well as diverse definitions and operationalizations of measurement and outcomes severely impeded comparability.
Diabetogenic Effects of Immunosuppression: An Integrative Analysis
Authors: Bhat Mamatha , Pasini Elisa , Das Aninditee , Baciu Cristina , Angeli Marc , Humar Atul , Watt Kymberly D. , Allard Johane
Published: July 2019

Background.

Posttransplant diabetes mellitus (PTDM) affects up to 50% of solid organ transplant recipients and compromises long-term outcomes. The goal of this study was to investigate how immunosuppressants affect gene expression in a manner that increases diabetes risk, by performing integrative analysis on publicly available, high-throughput gene expression data.

Methods.

All high-throughput gene expression datasets of solid organ transplant recipients were retrieved from the Gene Expression Omnibus. Significantly dysregulated genes and pathways were determined, and those in common with type 2 diabetes were identified. THP-1 and HepG2 cells were exposed in vitro to tacrolimus, and validation of genes involved in insulin signaling and glucose metabolism was performed using specific arrays. These cells were then treated with the hypoglycemic agents, metformin, and insulin to assess for appropriate reversion of specific diabetogenic genes.

Results.

Insulin signaling and secretion were the most commonly dysregulated pathways that overlapped with diabetes in transplant recipients. KRAS, GRB2, PCK2, BCL2L1, INSL3, DOK3, and PTPN1 were among the most significantly upregulated genes in both immunosuppression and diabetes subsets and were appropriately reverted by metformin as confirmed in vitro.

Conclusions.

We discovered that the significantly dysregulated genes in the context of immunosuppression are implicated in insulin signaling and insulin secretion, as a manifestation of pancreatic β-cell function. In vitro validation confirmed key diabetes-related genes in the context of immunosuppression. Further analysis and in vitro validation revealed that metformin optimally reverts diabetogenic genes dysregulated in the context of immunosuppression. The optimal therapeutic management of posttransplant diabetes mellitus needs to be further investigated, taking into account the mechanistic impact of immunosuppressants.
Survival Benefit of Liver Transplantation for Hepatocellular Carcinoma
Authors: Kanneganti Mounika , Mahmud Nadim , Kaplan David E. , Taddei Tamar H. , Goldberg David S.
Published: July 2019

Background.

In the United States, nearly 30% of liver transplants (LT) are performed for hepatocellular carcinoma (HCC). Although overall long-term survival is highest with LT, there are limited data on the incremental survival benefit of LT versus other curative options (resection or ablation) due to shunting of patients towards LT.

Methods.

We performed a retrospective cohort study of patients aged 50–69 with cirrhosis and HCC in the Veterans Health Administration (population enriched with 3 curative treatments) from 2008 to 2016. The cohort was restricted to patients who received LT, resection, or ablation and a calculated model for end-stage liver disease score <15 at HCC diagnosis.

Results.

Among 2129 veterans in the analytic cohort, 658 (26.7%) received LT, 244 (11.5%) underwent resection, and 1317 (61.59%) received ablation. In multivariable models, patients who underwent resection (hazard ratio: 5.42; 95% confidence interval: 4.15-7.08) or ablation (hazard ratio: 5.50; 95% confidence interval: 4.51-6.71) had significantly increased hazards of death. However, in absolute terms, the incremental survival benefit of LT over resection or ablation was small, between 0.02 and 0.03 years at 1 year, 0.32–0.42 years at 3 years, and 1.04–1.24 years at 5 years follow-up. These results were consistent in sensitivity analyses accounting for possible immortal time bias, as well as a cohort restricted to early/intermediate stage HCC.

Conclusions.

Although LT is associated with significantly increased survival compared to resection and ablation, the absolute incremental survival benefit is small over a 5-year time horizon. Optimal selection of patients for LT is critical for maximizing utilization of a scarce resource.
Gender Disparities in Patients With Alcoholic Liver Disease Evaluated for Liver Transplantation
Authors: McElroy Lisa M. , Likhitsup Alisa , Scott Winder Gerald , Saeed Naba , Hassan Ammar , Sonnenday Christopher J. , Fontana Robert J. , Mellinger Jessica
Published: July 2019

Background.

The morbidity and mortality from alcohol-related liver disease (ALD) is increasing in the United States. However, little is known about gender differences in evaluation and listing for liver transplantation (LT) in patients with ALD.

Methods.

This is a retrospective review of adult patients with ALD evaluated for LT at a single transplant center from January 1, 2010, to March 1, 2017. Univariate, multivariate, and time-series analyses were performed.

Results.

Among the 949 patients with ALD evaluated, mean age was 53 years, 84% were Caucasian, and 33% were women. The median model for end-stage liver disease score was similar between the genders. Women were less likely to be listed for LT (10% versus 19%; P < 0.05). The proportion of women not listed due to active substance use was significantly higher versus men (42% versus 35%; P < 0.05), while the frequency of medical contraindications was comparable between the genders. During a median follow-up of 416 days (range: 0–2784), listed women with ALD were less likely to undergo transplantation (42% versus 47%; P < 0.05).

Conclusions.

Men with ALD were 95% more likely to be listed and 105% more likely to be transplanted compared to women with ALD. While men had more lifetime substance use and related consequences, women had more psychiatric comorbidities and were less likely to be listed due to active alcohol and opioid use. Early detection and effective treatment of psychiatric and substance use disorders in women with ALD may improve their transplant eligibility.
Onychomycosis
Authors: Beuscher Tara L. , Kelechi Teresa J.
Published: July 2019

Toenail disorders account for the majority of foot complaints for which adults seek medical care. Onychomycosis, a fungal nail infection, is the most prevalent. Dermatophytes are responsible for the majority of nail infections and cause varying degrees of nail deformities. While several treatment strategies are available, no one approach (topical, systemic, or mechanical) is highly curative. This article reviews causes, diagnosis, and treatment options for onychomycosis and provides patient education tips to prevent and limit the spread of the disease.
The ‘use-by date’ for lithium-ion battery components
Authors: Gorman Scott F. , Pathan Tanveerkhan S. , Kendrick Emma
Published: July 2019

Lithium-ion battery (LIB) manufacturing is based around the slurry tape casting of electrodes followed by the assembly of the dried electrodes into cells with a separator and electrolyte. Many aspects of the manufacturing process can affect the performance of a lithium-ion cell. One of the least understood aspects in academia is the effect of degradation of the materials during the manufacturing processes or the ‘shelf-life’ of the materials and components. Here, we discuss some of the time limitations and degradation issues observed during the manufacturing and testing of the components from an industrially sourced LiNi
0.6
Mn
0.2
Co
0.2
O
2
(NMC-622)//graphite cell, and the affect that the component storage has, upon both the performance and the properties of the materials and cells. The materials are stored either in a dry room, vacuum oven or in a laboratory environment and the effect of the atmosphere upon the degradation components of the electrodes and electrolyte is characterized by analytical surface techniques and electrochemical analysis. We note that all storage affects the electrochemical performance, even storage in a vacuum oven or dry room. We propose that the electrodes and electrolytes should be used immediately after manufacture; however, we propose alternative methods for storage in case this is not possible.

This article is part of a discussion meeting issue ‘Energy materials for a low carbon future’.
Energetic disorder in perovskite/polymer solar cells and its relationship with the interfacial carrier losses
Authors: Yaghoobi Nia Narges , Méndez Maria , di Carlo Aldo , Palomares Emilio
Published: July 2019

Previous reports have observed a direct relationship between the polymer poly(3-hexylthiophene) molecular weight (MW) and the perovskite solar cell (PSC) efficiency. Herein, we analyse how the differences in MW and the differences in energetic disorder influence the interfacial carrier losses in the PSCs under operation conditions and explain the observed differences.

This article is part of a discussion meeting issue ‘Energy materials for a low carbon future'.
Will organic thermoelectrics get hot?
Authors: Campoy-Quiles Mariano
Published: July 2019

The generally low energy density from most heat sources—the Sun, Earth as well as most human activities—implies that solid-state thermoelectric devices are the most versatile heat harvesters since, unlike steam engines, they can be used on a small scale and at small temperature differences. In this opinion piece, we first discuss the materials requirements for the widespread use of thermoelectrics. We argue that carbon-based materials, such as conducting polymers and carbon nanotubes, are particularly suited for large area and low-temperature operation applications, as they are abundant, low-toxicity and easy to process. We combine experimentally observed macro-trends and basic thermoelectric relations to evaluate the major performance limitations of this technology thus far and propose a number of avenues to take the thermoelectric efficiency of organic materials beyond the state of the art. First, we emphasize how charge carrier mobility, rather than charge density, is currently limiting performance, and discuss how to improve mobility by exploiting anisotropy, high persistence length materials and composites with long and well-dispersed carbon nanotubes. We also show that reducing thermal conductivity could double efficiency while reducing doping requirements. Finally, we discuss several ways in which composites could further boost performance, introducing the concept of interface engineering to produce phonon stack-electron tunnel composites.

This article is part of a discussion meeting issue ‘Energy materials for a low carbon future'.
The effect of the genetic liability to autism spectrum disorder on emotion recognition in young unaffected probands from a population-based cohort
Authors: Wendt Frank R , Carvalho Carolina Muniz , Gelernter Joel , Polimanti Renato
Published: July 2019

We investigated how ASD genetic risk relates to neurodevelopmental features (491 traits tested) via polygenic risk scoring (PRS) in 4,309 young non-ASD probands from the Philadelphia Neurodevelopmental Cohort. ASD PRS most strongly associated with the ability to correctly identify angry facial emotions in youths aged 11-17 years (R2=1.06%, p=1.38×10−7) and replicated similarly in older probands (>18 years) (R2=0.55%, p=0.036). The association in 11- to-17-year-old probands was independent of other psychiatric disorders, brain imaging phenotypes, and educational attainment. ASD PRS also associated with proband-reported emotionality and connectedness with others. The proband-reported irritability trait was highly correlated with angry facial emotion recognition (r2=0.159, p=2.74×10−5) but was independently associated with ASD PRS (R2=1.20%, p=1.18×10−4). Several informant-reported (i.e., typically mother-reported) traits were predicted by the proband’s ASD PRS, including duration of fear (R2=0.156%, p=0.001). These data indicate how genetic liability to ASD may influence neurodevelopment in the general population, especially the development of emotional intelligence.
Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: A nationwide study during 1985-2015
Authors: Konstantinoudis Garyfallos , Schuhmacher Dominic , Ammann Roland A , Diesch Tamara , Kuehni Claudia E , Spycher Ben D ,   for the Swiss Paediatric Oncology Group and the Swiss National Cohort Study Group
Published: July 2019

Background

The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. We investigated the spatial variation of childhood cancers in Switzerland using exact geocodes of place of residence.

Methods

We included 5,947 children diagnosed with cancer during 1985-2015 at age 0-15 from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardization to adjust for age and year of diagnosis. We examined whether the modelled spatial variation of risk can be explained by ambient air concentration of NO2, natural background radiation, area-based socio-economic position (SEP), linguistic region, years of existing general cancer registration in the canton or degree of urbanization.

Results

For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for CNS tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was evidence of an association of background radiation and SEP with incidence of CNS tumours, (1.19;0.98-1.40) and (1.6;1-1.13) respectively.

Conclusion

Of the investigated diagnostic groups, childhood CNS tumours show the largest spatial variation in Switzerland. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role.
Impact of a regional educational advertising campaign on harm perceptions of e-cigarettes, prevalence of e-cigarette use, and quit attempts among smokers
Authors: Tattan-Birch Harry , Jackson Sarah E , Ide Charlotte , Bauld Linda , Shahab Lion
Published: July 2019

Background

We evaluated how effective an advertising campaign that was piloted by Cancer Research UK in January/February 2018 was at promoting quit attempts by increasing awareness of the relative harms of e-cigarettes compared with smoking.

Methods

Adults (≥16 years, n = 2217) living in Greater Manchester (campaign region) and Yorkshire & Humber and the North East of England (control regions) completed cross-sectional surveys immediately before and after the campaign period. Surveys measured socio-demographics, perceptions and use of e-cigarettes, and motivation and attempts to quit smoking. We tested interactions between time (pre, post) and region (campaign, control).

Results

36.7% (95% CI 33.0% – 40.6%) of those in the intervention region recognised the campaign. In the general population, interactions were non-significant for all outcomes except for perception of e-cigarettes as effective cessation aids, with smaller increases from pre-to post-campaign in the campaign (49.9% to 54.0%) compared with the control region (40.5% to 55.0%; OR = 0.66, 95% CI 0.45 – 0.98). Among smokers, motivation to quit increased in the intervention region (44.0% to 48.0%) but decreased in the control region (40.5% to 21.5%; OR = 2.97, 95% CI 1.25 – 7.16), with no other significant differences between regions over time. A Bayesian analysis confirmed that non-significant results were inconclusive.

Conclusions

Compared with the control region, the campaign was associated with an increase in smokers’ motivation to quit but a smaller increase in adults’ perception of e-cigarettes as an effective cessation aid. There was insufficient evidence to determine whether the campaign affected other outcomes.
Eye position signals in the dorsal pulvinar during fixation and goal-directed saccades
Authors: Schneider Lukas , Dominguez-Vargas Adan-Ulises , Gibson Lydia , Kagan Igor , Wilke Melanie
Published: July 2019

Most sensorimotor cortical areas contain eye position information thought to ensure perceptual stability across saccades and underlie spatial transformations supporting goal-directed actions. One pathway by which eye position signals could be relayed to and across cortical areas is via the dorsal pulvinar. Several studies demonstrated saccade-related activity in the dorsal pulvinar and we have recently shown that many neurons exhibit post-saccadic spatial preference long after the saccade execution. In addition, dorsal pulvinar lesions lead to gaze-holding deficits expressed as nystagmus or ipsilesional gaze bias, prompting us to investigate the effects of eye position. We tested three starting eye positions (−15°/0°/15°) in monkeys performing a visually-cued memory saccade task. We found two main types of gaze dependence. First, ∼50% of neurons showed an effect of static gaze direction during initial and post-saccadic fixation. Eccentric gaze preference was more common than straight ahead. Some of these neurons were not visually-responsive and might be primarily signaling the position of the eyes in the orbit, or coding foveal targets in a head/body/world-centered reference frame. Second, many neurons showed a combination of eye-centered and gaze-dependent modulation of visual, memory and saccadic responses to a peripheral target. A small subset showed effects consistent with eye position-dependent gain modulation. Analysis of reference frames across task epochs from visual cue to post-saccadic target fixation indicated a transition from predominantly eye-centered encoding to representation of final gaze or foveated locations in non-retinocentric coordinates. These results show that dorsal pulvinar neurons carry information about eye position, which could contribute to steady gaze during postural changes and to reference frame transformations for visually-guided eye and limb movements.

New & Noteworthy

Work on the pulvinar focused on eye-centered visuospatial representations, but position of the eyes in the orbit is also an important factor that needs to be taken into account during spatial orienting and goal-directed reaching. Here we show that dorsal pulvinar neurons are influenced by eye position. Gaze direction modulated ongoing firing during stable fixation, as well as visual and saccade responses to peripheral targets, suggesting involvement of the dorsal pulvinar in spatial coordinate transformations.
Analysis of task-based functional MRI data preprocessed with fMRIPrep
Authors: Esteban Oscar , Ciric Rastko , Finc Karolina , Blair Ross , Markiewicz Christopher J. , Moodie Craig A. , Kent James D. , Goncalves Mathias , DuPre Elizabeth , Gomez Daniel E. P. , Ye Zhifang , Salo Taylor , Valabregue Romain , Amlien Inge K. , Liem Franziskus , Jacoby Nir , Stojić Hrvoje , Cieslak Matthew , Urchs Sebastian , Halchenko Yaroslav O. , Ghosh Satrajit S. , De La Vega Alejandro , Yarkoni Tal , Wright Jessey , Thompson William H. , Poldrack Russell A. , Gorgolewski Krzysztof J.
Published: July 2019

Functional magnetic resonance imaging (fMRI) is a standard tool to investigate the neural correlates of cognition. fMRI noninvasively measures brain activity, allowing identification of patterns evoked by tasks performed during scanning. Despite the long history of this technique, the idiosyncrasies of each dataset have led to the use of ad-hoc preprocessing protocols customized for nearly every different study. This approach is time-consuming, error-prone, and unsuitable for combining datasets from many sources. Here we showcasefMRIPrep(http://fmriprep.org), a robust tool to prepare human fMRI data for statistical analysis. This software instrument addresses the reproducibility concerns of the established protocols for fMRI preprocessing. By leveraging the Brain Imaging Data Structure (BIDS) to standardize both the input datasets —MRI data as stored by the scanner— and the outputs —data ready for modeling and analysis—,fMRIPrepis capable of preprocessing a diversity of datasets without manual intervention. In support of the growing popularity offMRIPrep, this protocol describes how to integrate the tool in a task-based fMRI investigation workflow.
Genetic coupling of signal and preference facilitates sexual isolation during rapid speciation
Authors: Xu Mingzi , Shaw Kerry L.
Published: July 2019

The divergence of sexual signals is ultimately a coevolutionary process: while signals and preferences diverge between lineages, they must remain coordinated within lineages for matings to occur. Divergence in sexual signals makes a major contribution to evolving species barriers. Therefore, the genetic architecture underlying signal-preference coevolution is essential to understanding speciation but remains largely unknown. InLaupalacrickets where male song pulse rate and female pulse rate preference have coevolved repeatedly and rapidly, we tested two contrasting hypotheses for the genetic architecture underlying signal-preference coevolution: linkage disequilibrium between unlinked loci and genetic coupling (pleiotropy of a shared locus or tight physical linkage). Through selective introgression and quantitative trait locus (QTL) fine mapping, we estimated the location of QTL underlying interspecific variation in both female preference and male pulse rate from the same mapping populations. Remarkably, map estimates of the pulse rate and preference loci are 0.06-0.23 cM apart, the strongest evidence to date for genetic coupling between signal and preference loci. As the second pair of co-localizing signal and preference loci in theLaupalagenome, our finding supports an intriguing pattern, pointing to a major role for genetic coupling in the quantitative evolution of a reproductive barrier and rapid speciation inLaupala. Due to its effect on suppressing recombination, a coupled, quantitative genetic architecture offers a powerful and parsimonious genetic mechanism for signal-preference coevolution and the establishment of positive genetic covariance on which the Fisherian runaway process of sexual selection relies.
Lek-associated movement of a putative Ebolavirus reservoir, the Hammer-headed fruit bat (Hypsignathus monstrosus), in northern Republic of Congo
Authors: Olson Sarah H. , Bounga Gerard , Ondzie Alain , Bushmaker Trent , Seifert Stephanie N. , Kuisma Eeva , Taylor Dylan W. , Munster Vincent J. , Walzer Chris
Published: July 2019

The biology and ecology of Africa’s largest fruit bat remains largely understudied and enigmatic despite at least two highly unusual attributes. The acoustic lek mating behavior of the hammer-headed bat (Hypsignathus monstrosus) in the Congo basin was first described in the 1970s. Then in the 2000s, molecular testing implicated this species and other fruit bats as potential reservoir hosts for Ebola virus and it was one of only two fruit bat species epidemiologically linked to the 2008 Luebo, Democratic Republic of Congo, Ebola outbreak. Here we share findings from the first pilot study of hammer-headed bat movement using GPS tracking and accelerometry units and a small preceding radio-tracking trial at an apparent lekking site. The radio-tracking revealed adult males had high rates of nightly visitation to the site compared to females (only one visit) and that two of six females day-roosted ∼100 m west of Libonga, the nearest village that is ∼1.6 km southwest. Four months later, in mid-April 2018, five individual bats, comprised of four males and one female, were tracked from two to 306 days, collecting from 67 to 1022 GPS locations. As measured by mean distance to the site and proportion of nightly GPS locations within 1 km of the site (percent visitation), the males were much more closely associated with the site (mean distance 1.4 km; 51% visitation), than the female (mean 5.5 km; 2.2% visitation). Despite the small sample size, our tracking evidence supports our original characterization of the site as a lek, and the lek itself is much more central to male than female movement. Moreover, our pilot demonstrates the technical feasibility of executing future studies on hammer-headed bats that will help fill problematic knowledge gaps about zoonotic spillover risks and the conservation needs of fruit bats across the continent.
Unexpected complexity of everyday manual behaviors
Authors: Yan Yuke , Goodman James M. , Moore Dalton D. , Solla Sara A. , Bensmaia Sliman J.
Published: July 2019

Abstract

How does the brain control an effector as complex and versatile as the hand? One possibility is that the neural control of the hand is simplified by limiting the space of achievable hand postures. Indeed, hand kinematics can be largely accounted for within a small subspace of postures. This oft replicated finding has been interpreted as evidence that hand postures are confined to this subspace, and that leaving it volitionally is impossible. A prediction from this hypothesis is that measured hand movements that fall outside of this subspace reflect motor or measurement noise. To address this question, we track hand postures of human participants as they perform two distinct tasks – grasping and signing in American Sign Language. We then apply a standard dimensionality reduction technique – principal components analysis – and replicate the finding that hand movements can be largely described within a reduced subspace. However, we show that postural dimensions that fall outside of this subspace are highly structured and task dependent, suggesting that they too are under volitional control. We conclude that hand control occupies a higher dimensional space than previously considered, and propose that controlling the complexity of hand movements is well within the scope of the brain’s computational power.
Nanopore base-calling from a perspective of instance segmentation
Authors: Zhang Yao-zhong , Akdemir Arda , Tremmel Georg , Imoto Seiya , Miyano Satoru , Shibuya Tetsuo , Yamaguchi Rui
Published: July 2019

Background

Nanopore sequencing is a rapidly developing third-generation sequencing technology, which can generate long nucleotide reads of molecules within a portable device in real time. Through detecting the change of ion currency signals during a DNA/RNA fragment’s pass through a nanopore, genotypes are determined. Currently, the accuracy of nanopore base-calling has a higher error rate than short-read base-calling. Through utilizing deep neural networks, the-state-of-the art nanopore base-callers achieve base-calling accuracy in a range from 85% to 95%.

Result

In this work, we proposed a novel base-calling approach from a perspective of instance segmentation. Different from the previous sequence labeling approaches, we formulated the base-calling problem as a multi-label segmentation task. Meanwhile, we proposed a refined U-net model which we call UR-net that can model sequential dependencies for a one-dimensional segmentation task. The experiment results show that the proposed base-caller URnano achieves competitive results compared to recently proposed CTC-featured base-caller Chiron, on the same amount of training and test data for in-domain evaluation. Our results show that formulating the base-calling problem as a one-dimensional segmentation task is a promising approach.

Availability

The source code and data are available at https://github.com/yaozhong/URnano

Contact

yaozhong@ims.u-tokyo.ac.jp

Supplementary information

Supplementary data are available at attachment online.
Disruption of prepulse inhibition is associated with severity of compulsive behavior and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice
Authors: Manning Elizabeth E , Wang Abigail Y , Saikali Linda M , Winner Anna S , Ahmari Susanne E
Published: July 2019

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.
Exploring the phylogeny of rosids with a five-locus supermatrix from GenBank
Authors: Sun Miao , Folk Ryan A. , Gitzendanner Matthew A. , Smith Stephen A. , Germain-Aubrey Charlotte , Guralnick Robert P. , Soltis Pamela S. , Soltis Douglas E. , Chen Zhiduan
Published: July 2019

Current advances in sequencing technology have greatly increased the availability of sequence data from public genetic databases. With data from GenBank, we assemble and phylogenetically investigate a 19,740-taxon, five-locus supermatrix (i.e.,atpB, rbcL, matK, matR, and ITS) for rosids, a large clade containing over 90,000 species, or approximately a quarter of all angiosperms (assuming an estimate of 400,000 angiosperm species). The topology and divergence times of the five-locus tree generally agree with previous estimates of rosid phylogeny, and we recover greater resolution and support in several areas along the rosid backbone, but with a few significant differences (e.g., the placement of the COM clade, as well as Myrtales, Vitales, and Zygophyllales). Our five-locus phylogeny is the most comprehensive DNA data set yet compiled for the rosid clade. Yet, even with 19,740 species, current sampling represents only 16-22% of all rosids, and we also find evidence of strong phylogenetic bias in the accumulation of GenBank data, highlighting continued challenges for species coverage. These limitations also exist in other major angiosperm clades (e.g., asterids, monocots) as well as other large, understudied branches of the Tree of Life, highlighting the need for broader molecular sampling. Nevertheless, the phylogeny presented here improves upon sampling by more than two-fold and will be an important resource for macroevolutionary studies of this pivotal clade.
Diversification of Disease Resistance Receptors by Integrated Domain Fusions in Wheat and its Progenitors
Authors: Andersen Ethan J. , Nepal Madhav P.
Published: July 2019

Pathogenic effectors inhibit plant resistance responses by interfering with intracellular signaling mechanisms. Plant Nucleotide-binding, Leucine-rich repeat Receptors (NLRs) have evolved highly variable effector-recognition sites to detect these effectors. While many NLRs utilize variable Leucine-Rich Repeats (LRRs) to bind to effectors, some have gained Integrated Domains (IDs) necessary for receptor activation or downstream signaling. While a few studies have identified IDs within NLRs, the homology and regulation of these genes have yet to be elucidated. We identified a diverse set of wheat NLR-ID fusion proteins as candidates for NLR functional diversification through ID effector recognition or signal transduction. NLR-ID diversity corresponds directly with the various signaling components essential to defense responses, expanding the potential functions for immune receptors and removing the need for intermediate signaling factors that are often targeted by effectors. ID homologs (>80% similarity) in other grasses indicate that these domains originated as functional, non-NLR-encoding genes and were incorporated into NLR-encoding genes through duplication. Multiple NLR-ID genes encode experimentally verified alternative transcripts that include or exclude IDs. This indicates that plants employ alternative splicing to regulate IDs, possibly using them as baits, decoys, and functional signaling components. Future studies should aim to elucidate differential expression of NLR-ID alternative transcripts.
Active inference, stressors, and psychological trauma: A neuroethological model of (mal)adaptive explore-exploit dynamics in ecological context
Authors: Linson Adam , Parr Thomas , Friston Karl J.
Published: July 2019

This paper offers a formal account of emotional inference and stress-related behaviour, using the notion of active inference. We formulate responses to stressful scenarios in terms of Bayesian belief-updating and subsequent policy selection; namely, planning as (active) inference. Using a minimal model of how creatures or subjects account for their sensations (and subsequent action), we deconstruct the sequences of belief updating and behaviour that underwrite stress-related responses – and simulate the aberrant responses of the sort seen in post-traumatic stress disorder (PTSD). Crucially, the model used for belief-updating generates predictions in multiple (exteroceptive, proprioceptive and interoceptive) modalities, to provide an integrated account of evidence accumulation and multimodal integration that has consequences for both motor and autonomic responses. The ensuing phenomenology speaks to many constructs in the ecological and clinical literature on stress, which we unpack with reference to simulated inference processes and accompanying neuronal responses. A key insight afforded by this formal approach rests on the trade-off between the epistemic affordance of certain cues (that resolve uncertainty about states of affairs in the environment) and the consequences of epistemic foraging (that may be in conflict with the instrumental or pragmatic value of ‘fleeing’ or ‘freezing’). Starting from first principles, we show how this trade-off is nuanced by prior (subpersonal) beliefs about the outcomes of behaviour – beliefs that, when held with unduly high precision, can lead to (Bayes optimal) responses that closely resemble PTSD.
Unlocking the potential of historical abundance datasets to study biomass change in flying insects
Authors: Kinsella Rebecca S. , Thomas Chris D. , Crawford Terry J. , Hill Jane K. , Mayhew Peter J. , Macgregor Callum J.
Published: July 2019

Trends in insect abundance are well-established in some datasets, but far less is known about how abundance measures translate into biomass trends. Moths (Lepidoptera) provide particularly good opportunities to study trends and drivers of biomass change at large spatial and temporal scales, given the existence of long-term abundance datasets. However, data on the body masses of moths are required for these analyses, but such data do not currently exist.

To address this data gap, we collected empirical data in 2018 on the forewing length and dry mass of field-sampled moths, and used these to train and test a statistical model that predicts the body mass of moth species from their forewing lengths (with refined parameters for Crambidae, Erebidae, Geometridae and Noctuidae).

Modelled biomass was positively correlated, with high explanatory power, with measured biomass of moth species (R2 = 0.886 ± 0.0006, across 10,000 bootstrapped replicates) and of mixed-species samples of moths (R2 = 0.873 ± 0.0003), showing that it is possible to predict biomass to an informative level of accuracy, and prediction error was smaller with larger sample sizes.

Our model allows biomass to be estimated for historical moth abundance datasets, and so our approach will create opportunities to investigate trends and drivers of insect biomass change over long timescales and broad geographic regions.
Developing single molecule methods for measuring the pathway proteins ERK, AKT, cyclin d and p70s6k in localized colon cancer in relation to mutation status
Authors: Olsen Dorte Aa. , Thomsen Caroline EB. , Andersen Rikke F. , Madsen Jonna S. , Jakobsen Anders , Brandslund Ivan
Published: July 2019

Background

The aim of this study was to quantify the intracellular pathway proteins ERK, AKT, cyclin d and p70s6k in localized colon cancer tissue to investigate the possible prognostic values and the ability to be used as screening markers for upstream mutations.

Methods

Colon cancer tissue and autologous reference tissue were collected from 176 patients who underwent surgery for colon cancer. Assays for quantifying ERK, AKT, cyclin d and p70s6k proteins were developed using single molecule array (Simoa). KRAS/BRAF/PIK3CA mutation status was determined using droplet digital PCR.

Results

Patients with BRAF mutations had decreased concentrations of ERK (p=0.0002), AKT (p=0.00004) and cyclin d (p=0.001) while no significant differences were found between patients with KRAS mutations and Wild type (Wt) patients. None of the investigated protein concentrations were associated with disease free survival or overall survival, if including all patients. However, when stratifying according to mutation status, significant correlations to overall survival were seen for patients with BRAF mutations and AKT (p=0.003) or ERK (p=0.046) and for patients with KRAS mutations and p70s6k (p=0.04). Furthermore, the combination of genetic mutations, stage 2 disease, and all of the investigated pathway proteins showed significant correlations to overall survival.

Conclusions

There is a strong correlation between pathway protein concentrations and mutational BRAF status. Overall survival in colon cancer patients depend both on gene mutation status and pathway protein concentrations. As significant correlations were found between BRAF mutations and ERK, AKT and cyclin d, concentration measurements of these pathway proteins might be useful as screening for upstream mutations.
In-vitro synergistic antibacterial effect of atorvastatin and ampicillin against resistant Staphylococcus spp and E.coli isolated from bovine mastitis
Authors: Sankar Sriraam , Thangamalai Ramasamy , Padmanaban Sriram , Kannan Porteen , Srinivasan M R , Arunaman C S
Published: July 2019

The colossal rise in antimicrobial resistance has led to treatment failures and so mastitis has become cumbersome to treat. The objective of this study was to evaluate the antibacterial effect of non-antibiotic drug, atorvastatin in combination with antimicrobial, ampicillin against two commonly isolated bacterial species Staphylococcus spp and E. coli from bovine mastitis. Milk samples were collected from mastitis cows, visiting Veterinary Clinical Complex. Bacterial isolation was performed using Eosin Methylene Blue (EMB) agar and Mannitol Salt Agar (MSA), followed by characterization and identification by biochemical tests and gram staining. Genotypic confirmation was done by Polymerase Chain Reaction (PCR) with subsequent screening for resistant genes-mec A, blaTEM. Antibiotic Sensitivity Test (ABST) of the isolates against 12 different antimicrobials, atorvastatin only, and combination of atorvastatin with ampicillin were performed using Kirby-Bauer disc diffusion method. Minimum Inhibitory Concentration (MIC) of ampicillin alone and ampicillin in combination with atorvastatin were determined by modified microdilution method. Staphylococcus spp (77.5%) and E.coli (35%) were the two major pathogens isolated in the current study and multi-drug resistance was observed. Among the antimicrobials, the ampicillin showed 100% resistance against Staphylococcus spp and 85.71% resistance against E. coli. Atorvastatin did not display antibacterial effect as a sole agent but displayed synergistic antibacterial activity with ampicillin. There was an average increase in Minimum Inhibitory Concentration of ampicillin for E.coli and Staphylococcus spp isolates and atorvastatin decreased the Minimum Inhibitory Concentration of ampicillin in combination. The ampicillin shows more resistance against both Staphylococcus spp and E.coli, while atorvastatin improves the effect of ampicillin in-vitro. So, atorvastatin may be combined with ampicillin for the treatment of Gram-positive and Gram-negative infections. However, further studies are required to ascertain the exact mechanism of action of atorvastatin with respect to their antibacterial effect for them to be redeployed as an antimicrobial drug in the future.
Non-canonical localization of RubisCO under high light conditions in the toxic cyanobacteriumMicrocystis aeruginosaPCC7806
Authors: Barchewitz Tino , Guljamow Arthur , Meissner Sven , Timm Stefan , Henneberg Manja , Baumann Otto , Hagemann Martin , Dittmann Elke
Published: July 2019

The frequent production of the hepatotoxin microcystin and its impact on the life-style of bloom-forming cyanobacteria are poorly understood. Here we report that microcystin interferes with the assembly and the subcellular localization of RubisCO, inMicrocystis aeruginosaPCC7806. Immunofluorescence, electron microscopic and cellular fractionation studies revealed a pronounced heterogeneity in the subcellular localization of RubisCO. At high cell density, RubisCO particles are largely separate from carboxysomes inM. aeruginosaand relocate to the cytoplasmic membrane under high-light conditions. We hypothesize that the binding of microcystin to RubisCO promotes its membrane association and enables an extreme versatility of the enzyme. Steady-state levels of the RubisCO CO2fixation product 3-phosphoglycerate are significantly higher in the microcystin-producing wild type. We also detected noticeable amounts of the RubisCO oxygenase reaction product secreted into the medium that may support the mutual interaction ofM. aeruginosawith its heterotrophic microbial community.
Using a lentiviral Tet-regulated miR-E shRNA dual color vector to evaluate gene function in human leukemic stem cells in vivo
Authors: Maat Henny , Jaques Jennifer , Vellenga Edo , Huls Gerwin , van den Boom Vincent , Schuringa Jan Jacob
Published: July 2019

RNA interference is a powerful tool to study loss-of-gene function in leukemic cells. Still, in order to identify effective novel treatment strategies to target and eradicate leukemic stem cells (LSCs), it is critically important to study gene function in a well-controlled and time-dependent manner. We implemented a lentiviral Tet-regulated miR-E shRNA dual color vector in our in vitro and in vivo human leukemia models. Thus, we were able to efficiently introduce doxycycline-inducible and reversible gene repression and trace and isolate transduced miR-E shRNA expressing cells over time. As proof of concept we focused on the non-canonical PRC1.1 Polycomb complex, which we previously identified to be essential for LSCs (1). Here, we show that inducible downmodulation of PCGF1 strongly impaired the growth of primary MLL-AF9 cells. Next, a Tet-regulated miR-E PCGF1 human xenograft MLL-AF9 leukemia mouse model was established, which revealed that early knockdown of PCGF1 at the onset of leukemia development significantly reduced peripheral blood chimerism levels and improved overall survival. In contrast, knockdown of PCGF1 when leukemia was already firmly established in the bone marrow proved insufficient to enhance overall survival. Despite these findings, FACS analysis of MLL-AF9/miR-E PCGF1/CD45+/GFP+ populations suggested that particularly cells with inefficient PCGF1 knockdown contributed to leukemogenesis. In conclusion, by building in vivo xenograft leukemia inducible RNAi models, we show that timing of gene knockdown critically impacts on the efficacy of leukemia treatment and that clonal drift still plays a major role in the escape of LSCs.