bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of Arrhythmogenicity in Hypertrophic Cardiomyopathy: Insight from Noninvasive Electrocardiographic Imaging
Authors: Perez-Alday Erick A. , Haq Kazi T. , German David M. , Hamilton Christopher , Johnson Kyle , Phan Francis , Rogovoy Nichole M. , Yang Katherine , Wirth Ashley , A.Thomas Jason , Dalouk Khidir , Fuss Cristina , Ferencik Maros , Heitner Stephen , Tereshchenko Larisa G.
Published: July 2019

Background

Mechanisms of arrhythmogenicity in hypertrophic cardiomyopathy (HCM) are not well understood.

Objective

To characterize an electrophysiological substrate of HCM in comparison to ischemic cardiomyopathy (ICM), or healthy individuals.

Methods

We conducted a prospective case-control study. The study enrolled HCM patients at high risk for ventricular tachyarrhythmia (VT) (n=10; age 61±9 y; left ventricular ejection fraction (LVEF) 60±9%), and three comparison groups: healthy individuals (n=10; age 28±6 y; LVEF>70%), ICM patients with LV hypertrophy (LVH) and known VT (n=10; age 64±9 y; LVEF 31±15%), and ICM patients with LVH and no known VT (n=10; age 70±7y; LVEF 46±16%). All participants underwent 12-lead ECG, cardiac CT or MRI, and 128-electrode body surface mapping (BioSemi ActiveTwo, Netherlands). Non-invasive voltage and activation maps were reconstructed using the open-source SCIRun (University of Utah) inverse problem-solving environment.

Results

In the epicardial basal anterior segment, HCM patients had the greatest ventricular activation dispersion [16.4±5.5 vs. 13.1±2.7 (ICM with VT) vs. 13.8±4.3 (ICM no VT) vs. 8.1±2.4 ms (Healthy); P=0.0007], the largest unipolar voltage [1094±211 vs. 934±189 (ICM with VT) vs. 898±358 (ICM no VT) vs. 842±90 µV (Healthy); P=0.023], and the greatest voltage dispersion [median(interquartile range) 215(161-281) vs. 189(143-208) (ICM with VT) vs. 158(109-236) (ICM no VT) vs. 110(106-168)µV (Healthy); P=0.041]. Differences were also observed in other endo-and epicardial basal and apical segments.

Conclusion

HCM is characterized by a greater activation dispersion in basal segments, a larger voltage, and a larger voltage dispersion through LV.
Robustifying genomic classifiers to batch effects via ensemble learning
Authors: Zhang Yuqing , Johnson W. Evan , Parmigiani Giovanni
Published: July 2019

Genomic data are often produced in batches due to practical restrictions, which may lead to unwanted variation in data caused by discrepancies across processing batches. Such “batch effects” often have negative impact on downstream biological analysis and need careful consideration. In practice, batch effects are usually addressed by specifically designed software, which merge the data from different batches, then estimate batch effects and remove them from the data. Here we focus on classification and prediction problems, and propose a different strategy based on ensemble learning. We first develop prediction models within each batch, then integrate them through ensemble weighting methods. In contrast to the typical approach of removing batch effects from the merged data, our method integrates predictions rather than data. We provide a systematic comparison between these two strategies, using studies targeting diverse populations infected with tuberculosis. In one study, we simulated increasing levels of heterogeneity across random subsets of the study, which we treat as simulated batches. We then use the two methods to develop a genomic classifier for the binary indicator of disease status. We evaluate the accuracy of prediction in another independent study targeting a different population cohort. We observed a turning point in the level of heterogeneity, after which our strategy of integrating predictions yields better discrimination in independent validation than the traditional method of integrating the data. These observations provide practical guidelines for handling batch effects in the development and evaluation of genomic classifiers.
Volumetric Segmentation of Cell Cycle Markers in Confocal Images
Authors: Khan Faraz Ahmad , Voß Ute , Pound Michael P , French Andrew P
Published: July 2019

I.

ABSTRACT

Understanding plant growth processes is important for many aspects of biology and food security. Automating the observations of plant development – a process referred to as plant phenotyping – is increasingly important in the plant sciences, and is often a bottleneck. Automated tools are required to analyse the data in images depicting plant growth. In this paper, a deep learning approach is developed to locate fluorescent markers in 3D timeseries microscopy images. The approach is not dependant on marker morphology; only simple 3D point location annotations are required for training. The approach is evaluated on an unseen timeseries comprising several volumes, capturing growth of plants. Results are encouraging, with an average recall of 0.97 and average F-score of 0.78, despite only a very limited number of simple training annotations. In addition, an in-depth analysis of appropriate loss functions is conducted. To accompany [the finally-published] paper we are releasing the 4D point annotation tool used to generate the annotations, in the form of a plugin for the popular ImageJ (Fiji) software. Network models will be released online.
Functional cortico-subcortical reorganization after complete hemispheric disconnection for intractable epilepsy
Authors: Blauwblomme Thomas , Demertzi Athena , Tacchela Jean-Marc , Fillon Ludovic , Bourgeois Marie , Lositto Emma , Eisermann Monika , Marinazzo Daniele , Raimondo Federico , Alcauter Sarael , Van De Steen Frederik , Colenbier Nigel , Laureys Steven , Dangouloff-Ros Volodia , Naccache Lionel , Boddaert Nathalie , Nabbout Rima
Published: July 2019

Hemispherotomy is a treatment for drug-resistant epilepsy with the whole hemisphere involved in seizure onset. As recovery mechanisms are still debated, we characterize functional reorganization with multimodal MRI in two children operated on the right hemisphere (RH). We found that interhemispheric functional connectivity was abolished in both patients. The healthy left hemispheres (LH) displayed focal hyperperfusion in motor and limbic areas, and preserved network-level organization. The disconnected RHs were hypoperfused despite sustained network-level organization. Functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. The classification probability of the RH corresponding to a minimally conscious state was smaller than for the LH. We conclude that after hemispherotomy, neurological rehabilitation is sustained by cortical disinhibition and reinforcement of connectivity driven by subcortical structures in the remaining hemisphere. Our results highlight the effect of vascularization on functional connectivity and raise inquiries about the conscious state of the isolated hemisphere.
Network analysis of the papaya orchard virome from two agroecological regions of Chiapas, Mexico
Authors: Alcalá-Briseño Ricardo I. , Casarrubias-Castillo Kena , López-Ley Diana , Garrett Karen A. , Silva-Rosales Laura
Published: July 2019

The study of complex ecological interactions - such as those among host, pathogen, and vector communities - can help to explain host ranges and the emergence of novel pathogens. The analysis of community structures using bipartite networks describe the associations between two trophic levels, for example plants and pollinators, or hosts and parasitoids. Bipartite networks represent interactions (links) occurring only between nodes in different levels - in our case, between viruses and hosts. We evaluated the viromes of papaya orchards (papaya, weeds, and insects) from intensive production of papaya in the Pacific Coastal Plain and the Central Depression of Chiapas, Mexico. Samples of papaya cultivar Maradol, which, like most cultivars, is susceptible to papaya ringspot virus (PRSV), were categorized by symptoms by local farmers (papaya ringspot symptoms, non-PRSV symptoms, or no symptoms). These analyses revealed the presence of 61 viruses, where only four species were shared among both physiographic regions. Nearly 52 complete viral genome sequences were recovered, of which 16 showed homology to known viruses, and 36 shared similarities with different genera includingPotyvirus,Comovirus, andTombusvirus(RNA viruses), andBegomovirusandMastrevirus(DNA viruses). We analyzed the network of associations between viruses and host-location combinations, and described ecological properties of the network, such as asymmetry in interactions and nestedness compared to null models. Understanding the network structure informs management strategies, and advances understanding of interactions of hosts and viruses in the agroecological landscape.

Importance

Virus-virus interactions in plants can modify host symptoms. As a result, disease management strategies may be unsuccessful if they are based solely on visual assessment and diagnostic assays for known individual viruses. Papaya ringspot virus is an important limiting factor for papaya production, and likely has interactions with other viruses that are not yet known. Using high-throughput sequencing, we recovered known and novel RNA and DNA viruses from papaya orchards in Chiapas, Mexico, categorized by host and, in the case of papaya, symptom type: asymptomatic papaya, papaya with ringspot virus symptoms, papaya with non-ringspot symptoms, weeds, and insects. Using network analysis, we demonstrated virus associations within and among host types, and described the ecological community patterns. Recovery of viruses from weeds and asymptomatic papaya suggests the need for additional management attention. These analyses contribute to the understanding of the community structure of viruses in the agroecological landscape.
Caspase-8 Modulates Angiogenesis By Regulating A Cell Death Independent Pathway In Endothelial Cells
Authors: Tisch Nathalie , Freire-Valls Aida , Yerbes Rosario , Paredes Isidora , La Porta Silvia , Wang Xiaohong , Martín-Pérez Rosa , Castro Laura , Wong Wendy Wei-Lynn , Coultas Leigh , Strilic Boris , Gröne Hermann-Josef , Hielscher Thomas , Mogler Carolin , Adams Ralf , Heiduschka Peter , Claesson-Welsh Lena , Mazzone Massimiliano , López-Rivas Abelardo , Schmidt Thomas , Augustin Hellmut G. , de Almodovar Carmen Ruiz
Published: July 2019

During developmental angiogenesis blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) have reduced retinal angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptorinteracting serine/threonine-protein kinase 3 (RIPK3) and destabilization of VE-cadherin at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR), resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs is beneficial, as pathological neovascularization was reduced in Casp-8ECkopups. Taken together, we identify that Casp-8 signals in a cell-death independent manner in ECs during postnatal and pathological blood vessel formation.
Plasma-derived HIV Nef+ exosomes persist in ACTG384 study participants despite successful virological suppression
Authors: Raymond Andrea D. , Lang Michelle J. , Chu Jane , Campbell-Sims Tamika , Khan Mahfuz , Bond Vincent C. , Pollard Richard B. , Asmuth David M. , Powell Michael D.
Published: July 2019

Human Immunodeficiency Virus (HIV) accessory protein Negative factor (Nef) is detected in the plasma of HIV+ individuals associated with exosomes. The role of Nef+ exosomes (exNef) in HIV pathogenesis is unknown. We perform a retrospective longitudinal analysis to determine correlative clinical associations of exNef plasma levels in ARV-treated HIV+ patients with or without immune recovery. exNef concentration in a subset of AIDS Clinical Trial Group (ACTG) 384 participants with successful virological suppression and with either high (Δ >100 CD4 cell recovery/High Immunological Responders (High-IR) or low (Δ ≤100 CD4 cell recovery/ Low Immunologic Responders (Low-IR) immunologic recovery was measured and compared for study weeks 48, 96, and 144. CD4 recovery showed a negative correlation with exNef at study week 144 (r= −0.3573, *p=.0366). Plasma exNef concentration in high IRs negatively correlated with naïve CD4 count and recovery (r= −0.3249, *p= 0. 0348 (High-IR); r =0.2981, *p= #0.0513 (Low-IR)). However, recovery of CD4 memory cells positively correlated with exNef (r =.4534, *p=.0358) inLow-IRs but not inHigh-IRs. Regimen A (Didanosine, Stavudine, Efavirenz) lowered exNef levels in IRs by 2-fold compared to other regimens. Nef+ exosomes persist in ART-treated HIV+ individuals despite undetectable viral loads, negatively correlates with naive and memory CD4 T cell restoration and may be associated with reduced immunological recovery. Taken together, these data suggest that exNef may represent a novel mechanism utilized by HIV to promote immune dysregulation.
RootNav 2.0: Deep Learning for Automatic Navigation of Complex Plant Root Architectures
Authors: Yasrab Robail , Atkinson Jonathan A , Wells Darren M , French Andrew P , Pridmore Tony P , Pound Michael P
Published: July 2019

We present a new image analysis approach that provides fully-automatic extraction of complex root system architectures from a range of plant species in varied imaging setups. Driven by modern deep-learning approaches,RootNav 2.0replaces previously manual and semi-automatic feature extraction with an extremely deep multi-task Convolutional Neural Network architecture. The network has been designed to explicitly combine local pixel information with global scene information in order to accurately segment small root features across high-resolution images. In addition, the network simultaneously locates seeds, and first and second order root tips to drive a search algorithm seeking optimal paths throughout the image, extracting accurate architectures without user interaction. The proposed method is evaluated on images of wheat (Triticum aestivumL.) from a seedling assay. The results are compared with semi-automatic analysis via the originalRootNavtool, demonstrating comparable accuracy, with a 10-fold increase in speed. We then demonstrate the ability of the network to adapt to different plant species via transfer learning, offering similar accuracy when transferred to anArabidopsis thalianaplate assay. We transfer for a final time to images ofBrassica napusfrom a hydroponic assay, and still demonstrate good accuracy despite many fewer training images. The tool outputs root architectures in the widely accepted RSML standard, for which numerous analysis packages exist (http://rootsystemml.github.io/), as well as segmentation masks compatible with other automated measurement tools.
A cortico-collicular pathway for motor planning in a memory-dependent perceptual decision task
Authors: Duan Chunyu A. , Pan Yuxin , Ma Guofen , Zhou Taotao , Zhang Siyu , Xu Ning-long
Published: July 2019

Survival in a dynamic environment requires animals to plan future actions based on past sensory evidence. However, the neural circuit mechanism underlying this crucial brain function, referred to as motor planning, remains unclear. Here, we employ projection-specific imaging and perturbation methods to investigate the direct pathway linking two key nodes in the motor planning network, the secondary motor cortex (M2) and the midbrain superior colliculus (SC), in mice performing a memory-dependent perceptual decision task. We find dynamic coding of choice information in SC-projecting M2 neurons during motor planning and execution, and disruption of this information by inhibiting M2 terminals in SC selectively impaired decision maintenance. Furthermore, cell-type-specific optogenetic circuit mapping shows that M2 terminals modulate both excitatory and inhibitory SC neurons with balanced synaptic strength. Together, our results reveal the dynamic recruitment of the premotor-collicular pathway as a circuit mechanism for motor planning.
Genomic diversity and global distribution of Saccharomyces eubayanus, the wild ancestor of hybrid lager-brewing yeasts
Authors: Langdon Quinn K. , Peris David , Eizaguirre Juan I. , Opulente Dana A. , Buh Kelly V. , Sylvester Kayla , Jarzyna Martin , Rodríguez María E. , Lopes Christian A. , Libkind Diego , Hittinger Chris Todd
Published: July 2019

S. eubayanus, the wild, cold-tolerant parent of hybrid lager-brewing yeasts, has a complex and understudied natural history. The exploration of this diversity can be used both to develop new brewing applications and to enlighten our understanding of the dynamics of yeast evolution in the wild. Here, we integrate whole genome sequence and phenotypic data of 200 S. eubayanus strains, the largest collection to date. S. eubayanus has a multilayered population structure, consisting of two major populations that are further structured into six subpopulations. Four of these subpopulations are found exclusively in the Patagonian region of South America; one is found predominantly in Patagonia and sparsely in Oceania and North America; and one is specific to the Holarctic ecozone. S. eubayanus is most abundant and genetically diverse in Patagonia, where some locations harbor more genetic diversity than is found outside of South America. All but one subpopulation shows isolation-by-distance, and gene flow between subpopulations is low. However, there are strong signals of ancient and recent outcrossing, including two admixed lineages, one that is sympatric with and one that is mostly isolated from its parental populations. Despite S. eubayanus’ extensive genetic diversity, it has relatively little phenotypic diversity, and all subpopulations performed similarly under most conditions tested. Using our extensive biogeographical data, we constructed a robust model that predicted all known and a handful of additional regions of the globe that are climatically suitable for S. eubayanus, including Europe. We conclude that this industrially relevant species has rich wild diversity with many factors contributing to its complex distribution and biology.
Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration
Authors: Stuebler Antonia G. , Jansen Michaela
Published: July 2019

Bupropion, a FDA-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and non-competitively inhibits nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3) receptors. 5-HT3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system pre- and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on homomeric 5-HT3A and heteromeric mouse 5-HT3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Co-application of bupropion or hydroxybupropion with 5-HT dose-dependently inhibited 5-HT-induced currents in 5-HT3ABRs (IC50 = 866 μM and 505 μM, respectively) but potentiated 5-HT-induced currents at low (30-50 μM) concentrations. The corresponding IC50s for bupropion and hydroxybupropion with 5-HT3AR were 10- and 5-fold lower, respectively (87 μM and 113 μM), and no potentiation was observed. The inhibition of 5-HT3AR and 5-HT3ABR was non-use dependent and voltage-independent, indicating bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, pre-incubation with a low concentration of bupropion that mimics therapeutic drug conditions significantly inhibited 5-HT induced currents in 5-HT3A and even more so 5-HT3AB receptors. In summary, our results indicate that bupropion inhibits 5-HT3ABR, as well as homomeric receptors, and that this inhibition takes place at clinically-relevant concentrations. Inhibition of 5-HT3 receptors by bupropion may contribute to its desired and/or undesired clinical effects.

Significance Statement

5-HT3AB receptors are found in brain areas involved in mood regulation. Clinical studies indicate that antagonizing these receptors was successful in treating mood and anxiety disorders. Some currently clinically available antidepressants and antipsychotics act as antagonists of 5-HT3 receptors. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT3A receptors. The present work provides novel insights into the pharmacological effects bupropion exerts on heteromeric 5-HT3AB receptors. The results advance the knowledge on the clinical effect of bupropion as an antidepressant.
The AGE receptor, OST48 drives podocyte foot process effacement and basement membrane expansion in experimental diabetic kidney disease via promotion of endoplasmic reticulum stress
Authors: Zhuang Aowen , Yap Felicia YT , McCarthy Domenica , Penfold Sally A. , Sourris Karly C. , Coughlan Melinda T. , Schulz Benjamin L , Forbes Josephine M
Published: July 2019

The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection. To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter. Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products. These studies indicate that increased podocyte expression of oligosaccharyltransferase-48kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Eukaryotic virus composition can predict the efficiency of carbon export in the global ocean
Authors: Kaneko Hiroto , Blanc-Mathieu Romain , Endo Hisashi , Chaffron Samuel , Delmont Tom O. , Gaia Morgan , Henry Nicolas , Hernández-Velázquez Rodrigo , Nguyen Canh Hao , Mamitsuka Hiroshi , Forterre Patrick , Jaillon Olivier , de Vargas Colomban , Sullivan Matthew B. , Suttle Curtis A. , Guidi Lionel , Ogata Hiroyuki
Published: July 2019

The biological carbon pump, in which carbon fixed by photosynthesis is exported to the deep ocean through sinking, is a major process in Earth’s carbon cycle. The proportion of primary production that is exported is termed the carbon export efficiency (CEE). Based on in-lab or regional scale observations, viruses were previously suggested to affect the CEE (i.e., viral “shunt” and “shuttle”). In this study, we tested associations between viral community composition and CEE measured at a global scale. A regression model based on relative abundance of viral marker genes explained 67% of the variation in CEE. Viruses with high importance in the model were predicted to infect ecologically important hosts. These results are consistent with the view that the viral shunt and shuttle functions at a large scale and further imply that viruses likely act in this process in a way dependent on their hosts and ecosystem dynamics.
PgRC: Pseudogenome based Read Compressor
Authors: Kowalski Tomasz , Grabowski Szymon
Published: July 2019

Motivation

The amount of sequencing data from High-Throughput Sequencing technologies grows at a pace exceeding the one predicted by Moore’s law. One of the basic requirements is to efficiently store and transmit such huge collections of data. Despite significant interest in designing FASTQ compressors, they are still imperfect in terms of compression ratio or decompression resources.

Results

We present Pseudogenome-based Read Compressor (PgRC), an in-memory algorithm for compressing the DNA stream, based on the idea of building an approximation of the shortest common superstring over high-quality reads. Experiments show that PgRC wins in compression ratio over its main competitors, SPRING and Minicom, by up to 18 and 21 percent on average, respectively, while being at least comparably fast in decompression.

Availability

PgRC can be downloaded from https://github.com/kowallus/PgRC.

Contact

tomasz.kowalski@p.lodz.pl
Optogenetics reveals Cdc42 local activation by scaffold-mediated positive feedback and Ras GTPase
Authors: Lamas Iker , Merlini Laura , Vještica Aleksandar , Vincenzetti Vincent , Martin Sophie G
Published: July 2019

The small GTPase Cdc42 is critical for cell polarization. Scaffold-mediated positive feedback regulation was proposed to mediate symmetry-breaking to a single active zone in budding yeast cells. In rod-shaped fission yeast S. pombe cells, active Cdc42-GTP localizes to both cell poles, where it promotes bipolar growth. Here, we implement the CRY2-CIBN optogenetic system for acute light-dependent protein recruitment to the plasma membrane, which allowed to directly demonstrate positive feedback. Indeed, optogenetic recruitment of constitutively active Cdc42 leads to co-recruitment of the GEF Scd1, in a manner dependent on the scaffold protein Scd2. We show that Scd2 function is completely bypassed and positive feedback restored by an engineered interaction between the GEF and a Cdc42 effector, the Pak1 kinase. Remarkably, such re-wired cells are viable and grow in a bipolar manner even when lacking otherwise essential Cdc42 activators. Interestingly, these cells reveal that Ras1 GTPase plays a dual role in localizing and activating the GEF, thus potentiating the feedback. We conclude that scaffold-mediated positive feedback, gated by Ras activity, is minimally required for rod-shape formation.
Shared genetic underpinnings between genetic generalized epilepsy and background EEG oscillations
Authors: Stevelink Remi , Luykx Jurjen J. , Lin Bochao D. , Leu Costin , Lal Dennis , Smith Alexander , Schijven Dick , Carpay Johannes A. , Rademaker Koen , Baldez Roiza A. Rodrigues , Devinsky Orrin , Braun Kees P.J. , Jansen Floor E. ,   ILAE Consortium on Complex Epilepsies,   Epi25 Collaborative, Smit Dirk , Koeleman Bobby P.C.
Published: July 2019

Objective

Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.

Methods

Confounding factors, including the heterogeneous etiology of epilepsies and medication effects hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a GWAS on epilepsy (n=12,803 people with epilepsy and 24,218 controls) with that from a GWAS on background EEG (n=8,425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta and theta. We replicated our findings in an independent epilepsy replication dataset (n=4851 people with epilepsy and 20,428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores and Mendelian randomization analyses.

Results

Our analyses show strong genetic correlations between genetic generalized epilepsy (GGE) with background EEG oscillations, primarily with the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.

Significance

Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic work-up of epilepsy.
Infant diet promotesBifidobacteriumcommunity cooperation within a single ecosystem
Authors: Lawson Melissa AE , O’Neill Ian J , Kujawska Magdalena , Wijeyesekera Anisha , Flegg Zak , Chalklen Lisa , Hall Lindsay J
Published: July 2019

Diet-microbe interactions play an important role in modulating the early life microbiota, withBifidobacteriumstrains and species dominating the gut microbiota of breast-fed infants. Here, we sought to explore how infant diet drives distinct bifidobacterial community composition and dynamics within individual infant ecosystems. Genomic characterisation of 19 strains isolated from breast-fed infants revealed a diverse genomic architecture enriched in carbohydrate metabolism genes, which was distinct to each strain, but collectively formed a pangenome across infants. Presence of gene clusters implicated in digestion of human milk oligosaccharides (HMOs) varied between species, with growth studies indicating within infant differences in the ability to utilise 2’FL and LNnT HMOs between strains. We also performed cross-feeding experiments using metabolic products from growth on 2’FL or LNnT for non-HMO degrading isolates, these compounds were identified to include fucose, galactose, acetate and N-acetylglucosamine. These data highlight the cooperative nature of individual bifidobacterial ‘founder’ strains within an infant ecosystem, and how sharing resources maximises nutrient consumption from the diet. We propose that this social behaviour contributes to the diversity and dominance ofBifidobacteriumin early life and suggests avenues for development of new diet and microbiota based therapies to promote infant health.
Comparison of Chemotherapy Effects on Mechanical Sensitivity and Food-Maintained Operant Responding in Male and Female Rats
Authors: Legakis LP , Diester CM , Townsend EA , Karim-Nejad L , Negus SS
Published: July 2019

Objective

Chemotherapies of varying classes often cause neuropathy and debilitating chemotherapy-induced neuropathic pain (CINP) sufficient to limit treatment and reduce quality of life for many patients battling cancer. There are currently no effective preventative or alleviative treatments for CINP. Preclinical models have been developed to test candidate CINP treatments; however, studies using these models rarely provide direct comparisons of effects of different chemotherapies or assess the degree to which chemotherapies produce clinically relevant signs of pain-depressed behavior.

Methods

Male and female Sprague-Dawley rats received four injections of vehicle, paclitaxel, oxaliplatin, vincristine, or bortezomib on alternate days. Mechanical hypersensitivity, body weight, and food-maintained operant responding were evaluated before, during, and for up to 42 days after initiation of treatment. Morphine potency and effectiveness to reverse chemotherapy-induced effects were also evaluated.

Results

All four chemotherapies produced dose-dependent and sustained mechanical hypersensitivity in all rats. Vincristine and oxaliplatin produced transient weight loss and decreases in food-maintained operant responding in all rats, whereas paclitaxel and bortezomib produced lesser or no effect. At four weeks after treatment, operant responding was depressed only in paclitaxel-treated males. Morphine reversed mechanical hypersensitivity in all rats but failed to reverse paclitaxel-induced depression of operant responding in males.

Conclusions

Chemotherapy treatments sufficient to produce sustained mechanical hypersensitivity failed to produce sustained or morphine-reversible behavioral depression in rats. Insofar as pain-related behavioral depression is a cardinal sign of CINP in humans, these results challenge the presumption that these chemotherapy-dosing regimens are sufficient to model clinically relevant CINP in rats.
Regulation of neuronal mRNA splicing and Tau isoform ratio by ATXN3 through deubiquitylation of splicing factors
Authors: Neves-Carvalho Andreia , Duarte-Silva Sara , Silva Joana M. , Meireles-Costa Liliana , Monteiro-Fernandes Daniela , Correia Joana S. , Rodrigues Beatriz , Heetveld Sasja , Almeida Bruno , Savytska Natalia , Da Silva Jorge Diogo , Teixeira-Castro Andreia , Sotiropoulos Ioannis , Carvalho Ana Luísa , Heutink Peter , Li Ka Wan , Maciel Patrícia
Published: July 2019

The ubiquitylation/deubiquitylation balance in cells is maintained by deubiquitylating enzymes, including ATXN3. The precise role of this protein, mutated in spinocerebellar ataxia type 3 (SCA3), remains elusive, as few substrates for its deubiquitylating activity were identified. Here, we characterized the ubiquitome of neuronal cells lacking ATXN3, and found altered polyubiquitylation in a large proportion of proteins involved in RNA metabolism, including splicing factors. Using transcriptomic analysis and reporter minigenes we confirmed that splicing was globally altered in these cells. Among the candidate targets of ATXN3 was SRSF7 (9G8), a key regulator of MAPT (Tau) exon 10 splicing. Loss-of-function of ATXN3 led to reduced SRSF7 levels and a deregulation of MAPT exon 10 splicing, resulting in a decreased 4R/3R-Tau ratio. Similar alterations were found in cellular models of expanded polyQ ATXN3 and SCA3 patient brains, pointing to a relevant role of this mechanism in SCA3, and establishing a previously unsuspected link between two key proteins involved in different neurodegenerative disorders.
Collagen hydrogel confinement of amyloid-βaccelerates aggregation and reduces cytotoxic effects
Authors: Simpson Laura W. , Szeto Gregory L. , Boukari Hacene , Good Theresa A. , Leach Jennie B.
Published: July 2019

Alzheimer’s disease (AD) is the most common form of dementia and is associated with the accumulation of amyloid-β (Aβ), a peptide whose aggregation has been associated with neurotoxicity. Drugs targeting Aβ have shown great promise in 2Din vitromodels and mouse models, yet preclinical and clinical trials for AD have been highly disappointing. We propose that currentin vitroculture systems for discovering and developing AD drugs have significant limitations; specifically, that Aβ aggregation is vastly different in these 2D cultures carried out on flat plastic or glass substrates vs. in a 3D environment, such as brain tissue, where Aβ confinement very likely alters aggregation kinetics and thermodynamics. In this work, we identified attenuation of Aβ cytotoxicity in 3D hydrogel culture compared to 2D cell culture. We investigated Aβ structure and aggregation in solution vs. hydrogel using Transmission Electron Microscopy (TEM), Fluorescence Correlation Spectroscopy (FCS), and Thioflavin T (ThT) assays. Our results reveal that the equilibrium is shifted to stable β-sheet aggregates in hydrogels and away from the relatively unstable/unstructured presumed toxic oligomeric Aβ species in solution. Volume exclusion imparted by hydrogel confinement stabilizes unfolded, presumably toxic species, promoting stable extended β-sheet fibrils. These results, taken together with the many recent reports that 3D hydrogel cell cultures enable cell morphologies and epigenetic changes that are more similar to cellsin vivocompared to 2D cultures, strongly suggest that AD drugs should be tested in 3D culture systems as a step along the development pathway towards new, more effective therapeutics.
Listeria monocytogenesexploits the MICOS complex subunit Mic10 to promote mitochondrial fragmentation and cellular infection
Authors: Carvalho Filipe , Spier Anna , Chaze Thibault , Matondo Mariette , Cossart Pascale , Stavru Fabrizia
Published: July 2019

Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and non-physiological cues. We previously showed that infection with the human bacterial pathogenListeria monocytogeneselicits transient mitochondrial fission and a drop in mitochondrial-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved inL. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficientL. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a post-transcriptional regulation. We showed that Mic10 is necessary forL. monocytogenes-induced mitochondrial network fragmentation, and that it contributes toL. monocytogenescellular infection independently of MICOS proteins Mic13, Mic26 and Mic27. Together,L. monocytogenesinfection allowed us to uncover a role for Mic10 in mitochondrial fission.

Importance

Pathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed thatListeria monocytogenesinfection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response toL. monocytogenesinfection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important forL. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used byL. monocytogenesto hijack mitochondria to optimize host infection.
Minor QTLs mining through the combination of GWAS and machine learning feature selection
Authors: Zhou Wei , Bellis Emily S. , Stubblefield Jonathan , Causey Jason , Qualls Jake , Walker Karl , Huang Xiuzhen
Published: July 2019

Introduction

Minor QTLs mining has a very important role in genomic selection, pathway analysis and trait development in agricultural and biological research. Since most individual loci contribute little to complex trait variations, it remains a challenge for traditional statistical methods to identify minor QTLs with subtle phenotypic effects. Here we applied a new framework which combined the GWAS analysis and machine learning feature selection to explore new ways for the study of minor QTLs mining.

Results

We studied the soybean branching trait with the 2,137 accessions from soybean (Glycine max) diversity panel, which was sequenced by 50k SNP chips with 42,080 valid SNPs. First as a baseline study, we conducted the GWAS GAPIT analysis, and we found that only one SNP marker significantly associated with soybean branching was identified. We then combined the GWAS analysis and feature importance analysis with Random Forest score analysis and permutation analysis. Our analysis results showed that there are 36,077 features (SNPs) identified by Random Forest score analysis, and 2,098 features (SNPs) identified by permutation analysis. In total, there are 1,770 features (SNPs) confirmed by both of the Random Forest score analysis and the permutation analysis. Based on our analysis, 328 branching development related genes were identified. A further analysis on GO (gene ontology) term enrichment were applied on these 328 genes. And the gene location and gene expression of these identified genes were provided.

Conclusions

We find that the combined analysis with GWAS and machine learning feature selection shows significant identification power for minor QTLs mining. The presented research results on minor QTLs mining will help understand the biological activities that lie between genotype and phenotype in terms of causal networks of interacting genes. This study will potentially contribute to effective genomic selection in plant breeding and help broaden the way of molecular breeding in plants.
Root and shoot competition lead to contrasting competitive outcomes under water stress: A Meta-analysis
Authors: Foxx Alicia J. , Fort Florian
Published: July 2019

Background

Competition is a critical process that shapes plant communities and interacts with environmental constraints. Though important to natural communities and agricultural systems, there are surprising knowledge gaps related to mechanisms that belie those processes: the contribution of different plant parts on competitive outcomes and the effect of environmental constraints on these contributions.

Objective

Studies that partition competition into root-only and shoot-only interactions assess whether plant parts impose different competitive intensities using physical partitions and serve as an important way to fill knowledge gaps. Given predicted drought escalation due to climate change, we focused meta-analytic techniques on the effects of water supply and competitive outcomes.

Methods

We searched Web of Science for peer-reviewed studies and found 2042 results. From which six suitable studies with 92 effect sizes on 10 species were identified to test these effects.

Results

Water availability and competition treatment (root-only, shoot-only, and full plant competition) significantly interact to affect plant growth responses (p < 0.0001). Root-only and full plant competition are more intense in low water availability conditions than shoot-only competition. Shoot-only competition in high-water availability was the most intense showing the opposite pattern. These results also show that the intensity of full competition is similar to root-only competition and that low-water availability intensifies root competition while weakening shoot competition.

Conclusions

These results emphasize the importance of root competition and these patterns of competition may shift in a changing climate, creating further urgency for further filling knowledge gaps to address issues of drought on plant interactions and communities.
Long-term protection of rhesus macaques from Zika virus reinfection
Authors: Moreno Gage K. , Newman Christina M. , Koenig Michelle R. , Mohns Mariel S. , Weiler Andrea M. , Rybarczyk Sierra , Vosler Logan J. , Pomplun Nicholas , Schultz-Darken Nancy , Rakasz Eva , Dudley Dawn M. , Friedrich Thomas C. , O’Connor David H.
Published: July 2019

By the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome (CZS). Guillain-Barré syndrome (GBS) in ZIKV infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity, however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV two years after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies (nAbs) that protect from detectable plasma viremia following rechallenge and persist for at least 27 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.

Author Summary

ZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the drop in ZIKV cases since the 2015-16 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. While pre-existing herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV two years prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. While this work establishes a new minimal length of protective immunity, additional studies are necessary to define the maximum length of protective immunity following ZIKV infection.
Crystal structure and Hirshfeld surface analysis of 2,5-dibromoterephthalic acid ethylene glycol monosolvate
Authors: Khotchasanthong Kenika , Jittirattanakun Siripak , Jiajaroen Suwadee , Theppitak Chatphorn , Chainok Kittipong
Published: July 2019

The title compound, C8H4Br2O4·C2H6O2, crystallizes with one-half of a 2,5-dibromoterephthalic acid (H2Br2tp) molecule and one-half of an ethylene glycol (EG) molecule in the the asymmetric unit. The whole molecules are generated by application of inversion symmetry. The H2Br2tp molecule is not planar, with the dibromobenzene ring system inclined by a dihedral angle of 18.62 (3)° to the carboxylic group. In the crystal, the H2Br2tp and EG molecules are linked into sheets propagating parallel to (\overline{1}01) through O—H...O hydrogen bonds, thereby forming R
4
4 (12) and R
4
4 (28) graph-set motifs. Br...O and weak π–π stacking interactions are also observed. Hirshfeld surface analysis was used to confirm the existence of these interactions.