bluuebunny/crossref_metadata_2025 huggingface dataset:
The prospective association of objectively measured sleep and cerebral white matter microstructure in middle-aged and older persons
Authors: Kocevska Desana , Tiemeier Henning , Lysen Thom S , de Groot Marius , Muetzel Ryan L , Van Someren Eus J W , Ikram M Arfan , Vernooij Meike W , Luik Annemarie I
Published: July 2019

Study Objectives

Poor sleep may destabilize axonal integrity and deteriorate cerebral white matter. In middle-aged and older adults sleep problems increase alongside structural brain changes, but the temporal relation between these processes is poorly understood. We studied longitudinal associations between sleep and cerebral white matter microstructure.

Methods

One thousand one persons (59.3 ± 7.9 years, 55% women) were followed across 5.8 years (3.9–10.8). Total sleep time (TST, hours), sleep efficiency (SE, percentage), sleep onset latency (SOL, minutes), and wake after sleep onset (WASO, minutes) were measured at baseline using a wrist-worn actigraph. White matter microstructure (global and tract-specific fractional anisotropy [FA] and mean diffusivity [MD]) was measured twice with diffusion tensor imaging (DTI).

Results

Poor sleep was associated with worse white matter microstructure up to 7 years later but did not predict trajectories of DTI over time. Longer TST was associated with higher global FA (β = 0.06, 95% CI: 0.01 to 0.12), but not with MD. Persons with higher SE had higher global FA (β = 0.01, 95% CI: 0.002 to 0.01) and lower MD (β = −0.01, 95% CI: −0.01 to −0.0004). Consistently, those with more WASO had lower global FA (β = −0.003, 95% CI: −0.005 to −0.001) and higher MD (β = 0.002, 95% CI: 0.0004 to 0.004). Global findings seemed to be driven by microstructural alterations in the cingulum, anterior forceps of corpus callosum, projection and association tracts.

Conclusions

Middle-aged and older persons with more WASO, lower SE and shorter TST have worse microstructure of cerebral white matter. Microstructural alterations are most pronounced projection and association tracts, in the cingulum, and in the anterior forceps of corpus callosum.
Acceleration of chemical shift encoding-based water fat MRI for liver proton density fat fraction and T2* mapping using compressed sensing
Authors: Lohöfer Fabian K. , Kaissis Georgios A. , Müller-Leisse Christina , Franz Daniela , Katemann Christoph , Hock Andreas , Peeters Johannes M. , Rummeny Ernst J. , Karampinos Dimitrios , Braren Rickmer F.
Published: July 2019

Objectives

To evaluate proton density fat fraction (PDFF) and T2* measurements of the liver with combined parallel imaging (sensitivity encoding, SENSE) and compressed sensing (CS) accelerated chemical shift encoding-based water-fat separation.

Methods

Six-echo Dixon imaging was performed in the liver of 89 subjects. The first acquisition variant used acceleration based on SENSE with a total acceleration factor equal to 2.64 (acquisition labeled as SENSE). The second acquisition variant used acceleration based on a combination of CS with SENSE with a total acceleration factor equal to 4 (acquisition labeled as CS+SENSE). Acquisition times were compared between acquisitions and proton density fat fraction (PDFF) and T2*-values were measured and compared separately for each liver segment.

Results

Total scan duration was 14.5 sec for the SENSE accelerated image acquisition and 9.3 sec for the CS+SENSE accelerated image acquisition. PDFF and T2* values did not differ significantly between the two acquisitions (paired Mann-Whitney and paired t-test P>0.05 in all cases). CS+SENSE accelerated acquisition showed reduced motion artifacts (1.1%) compared to SENSE acquisition (12.3%).

Conclusion

CS+SENSE accelerates liver PDFF and T2*mapping while retaining the same quantitative values as an acquisition using only SENSE and reduces motion artifacts.

Strengths of this study

Compressed sensing allows accelerated imaging with reduction of motion artifacts without alteration of quantitative measurements

Robust results in fat and iron quantification in a heterogeneous patient cohort

Limitations of this study

No histopathological validation of the MR findings was performed

The study was not performed at different field strengths
Machine learning to predict early recurrence after oesophageal cancer surgery
Authors: Rahman Saqib A , Walker Robert C , Lloyd Megan A , Grace Ben L , van Boxel Gijs I , Kingma Feike , Ruurda Jelle P , van Hillegersberg Richard , Harris Scott , Parsons Simon , Mercer Stuart , Griffiths Ewen A , O’Neill J.Robert , Turkington Richard , Fitzgerald Rebecca C , Underwood Timothy J ,   On behalf of the OCCAMS Consortium, the full list of contributors is displayed in acknowledgements
Published: July 2019

Objective

To develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multi-national cohort.

Summary Background Data

Early cancer recurrence after oesophagectomy is a common problem with an incidence of 20-30% despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. Machine learning techniques potentially allow more accurate prognostication and have been applied in this study.

Methods

Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in 6 UK and 1 Dutch oesophago-gastric units were analysed. Using clinical characteristics and post-operative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and XG boost (XGB). Finally, a combined (Ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model.

Results

In total 812 patients were included. The recurrence rate at less than 1 year was 29.1%. All of the models demonstrated good discrimination. Internally validated AUCs were similar, with the Ensemble model performing best (ELR=0.785, RF=0.789, XGB=0.794, Ensemble=0.806). Performance was similar when using internal-external validation (validation across sites, Ensemble AUC=0.804). In the final model the most important variables were number of positive lymph nodes (25.7%) and vascular invasion (16.9%).

Conclusions

The derived model using machine learning approaches and an international dataset provided excellent performance in quantifying the risk of early recurrence after surgery and will be useful in prognostication for clinicians and patients.

DRAFT VISUAL ABSTRACT

Icons taken fromwww.flaticon.com, made by ‘Freepik’, ‘smashicons’, and ‘prettycons’. Reproduced under creative commons attribution license

MINI-ABSTRACT

Early recurrence after surgery for adenocarcinoma of the oesophagus is common. We derived a risk prediction model using modern machine learning methods that accurately predicts risk of early recurrence using post-operative pathology
Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2
Authors: Altas Bekir , Ju Anes , Solís Hugo Cruces , Karaca Samir , Winchenbach Jan , Kaplan Öyküm , Schwark Manuela , Wieser Georg L. , Chaugule Viduth K. , Majoul Irina , Hassan Mohamed A. , Goel Rashi , Wojcik Sonja M. , Pichler Andrea , Mitkovski Miso , de Hoz Livia , Urlaub Henning , Jahn Olaf , Saher Gesine , Rhee JeongSeop , Kawabe Hiroshi
Published: July 2019

Nedd4-2 is an E3 ubiquitin ligase, missense mutation of which is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity, and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.

CONDENSED TITLE

Ubiquitination of Astrocytic Channels by Nedd4-2

Ubiquitination is a key regulatory machinery for protein expression. Our present work provides evidence that astrocytic ion channel proteostasis coordinated by an E3 ubiquitin ligase Nedd4-2 is of particular importance for the maintenance of neuronal network activity.
The flagellar substrate specificity switch protein FlhB assembles onto the extra-membrane export gate to regulate type three secretion
Authors: Kuhlen Lucas , Johnson Steven , Zeitler Andreas , Bäurle Sandra , Deme Justin C. , Debo Rebecca , Fisher Joseph , Wagner Samuel , Lea Susan M.
Published: July 2019

Export of proteins through type three secretion systems (T3SS) is critical for motility and virulence of many major bacterial pathogens. Proteins are transported through an export gate complex consisting of three proteins (FliPQR in flagellar systems, SctRST in virulence systems) that were initially annotated as membrane proteins, but which we have recently shown assemble into an extra-membranous helical assembly. A fourth putative membrane protein (FlhB/SctU) is essential to the export process, and also functions to “switch” secretion substrate specificity once the growing hook/needle structures reach their determined length. Here we present the structure of an export gate containing the switch protein from a Vibrio polar flagellar system at 3.2 Å resolution by cryo-electron microscopy. The structure reveals that the FlhB/SctU further extends the helical export gate assembly with its four putative transmembrane helices adopting an out-of-membrane location, wrapped around the other export gate components at the base of the structure. The unusual topology of the switch protein helices creates a loop that wraps around the bottom of the closed export gate complex. Structure-informed mutagenesis suggests that this loop is critical in gating secretion and we propose that a series of conformational changes in the type 3 secretion system trigger opening of the export gate through the interactions between FlhB/SctU and FliPQR/SctRST.
Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen
Authors: Avramovska Ognenka , Hickman Meleah A.
Published: July 2019

Organismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogenCandida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploidC. albicansfollowing exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-of-heterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploidC. albicanscompared to diploidC. albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.
Low level of expression of C-terminally truncated human FUS causes extensive changes in spinal cord transcriptome of asymptomatic transgenic mice
Authors: Lysikova Ekaterina A. , Funikov Sergei , Rezvykh Alexander P. , Chaprov Kirill D. , Kukharsky Michail S. , Ustyugov Alexey A. , Deykin Alexey V. , Flyamer Ilya. A. , Boyle Shelagh , Bachurin Sergey O. , Ninkina Natalia , Buchman Vladimir L.
Published: July 2019

Mutations in a gene encoding RNA-binding protein FUS was linked to familial forms of amyotrophic lateral sclerosis (ALS). C-terminal truncations of FUS are associated with aggressive forms of ALS. However, motor neurons are able to tolerate permanent production of pathogenic truncated form of FUS protein until its accumulation in the cytoplasm of neurones does not reach a critical threshold.

In order to identify how the nervous system responds to pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low level of neuronal expression of a highly aggregation prone and pathogenic form of C-terminally truncated FUS. In contrast to mice with substantially higher level of expression of the same FUS variant that develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any sign of pathology even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice comparing to the wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating to potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective target for therapy of FUS-ALS and possibly, other forms of ALS.
Epigenetic signatures of chronic social stress in stress-susceptible animals
Authors: O’Toole Nicholas , Zhang Tie-Yuan , Wen Xianglan , Diorio Josie , Silveira Patricia P. , Labonté Benoit , Nestler Eric J. , Meaney Michael J.
Published: July 2019

Exposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene andCacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with ß-catenin as the hub gene of a network that included the ß-catenin-related WNT/frizzled signaling pathway as well as bothEsr1andDcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed ‘WNT signaling’ as the top pathway, which features ß-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.
A non-acidic method using hydroxyapatite and phosphohistidine monoclonal antibodies allows enrichment of phosphopeptides containing non-conventional phosphorylations for mass spectrometry analysis
Authors: Adam K. , Fuhs S. , Meisenhelder J. , Aslanian A. , Diedrich J. , Moresco J. , La Clair J. , Yates J.R. , Hunter T.
Published: July 2019

Four types of phosphate-protein linkage generate nine different phosphoresidues in living organisms. Histidine phosphorylation is a long-time established but largely unexplored post-translational modification, mainly because of the acid-lability of the phosphoramidate bonds. This lability means that standard phosphoproteomic methods used for conventional phosphate esters (phospho-Ser/Thr/Tyr) must be modified to analyze proteins containing the phosphoramidate-amino acids - phospho-His/Arg/Lys. We show that a non-acidic method allows enrichment of non-conventional phosphoresidue-containing peptides from tryptic digests of human cell lines, using hydroxyapatite binding and/or immobilized 1-pHis and 3-pHis monoclonal antibodies for enrichment. 425 unique non-conventional phosphorylation sites (i.e. pHis, pLys and pArg) were detected with a high probability of localization by LC-MS/MS analysis and identified using a customized MaxQuant configuration, contributing to a new era of study in post-translational modification and cell signaling in humans. This is the first fully non-acidic method for phosphopeptide enrichment which uses immunoaffinity purification and remains compatible with mass spectrometry analysis for a wider coverage of potential protein phosphorylation events.
Myf6/MRF4 is a Myogenic Niche Regulator Required for the Maintenance of the Muscle Stem Cell Pool
Authors: Lazure Felicia , Blackburn Darren M. , Karam Nabila , Sahinyan Korin , Sharanek Ahmad , Nguyen Duy , Corchado Aldo H. , Lepper Christoph , Najafabadi Hamed S. , Perkins Theodore J. , Jahani-Asl Arezu , Soleimani Vahab
Published: July 2019

In metazoans, skeletal muscle evolved to contract and produce force. However, recent experimental evidence suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins, including ligands for downstream activation of key signaling pathways such as EGFR, STAT3 and VEGFR. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce key myokines such as EGF, VEGFA and LIF. Consequently, although Myf6 knockout mice are born with a normal muscle stem cell compartment, they undergo progressive reduction in their stem cell pool during postnatal life. Mechanistically, muscle stem cells from the Myf6 knockout animals show defects in activation of EGFR and STAT3 signaling, upregulate the p38 MAP kinase pathway and spontaneously break from quiescence. Exogenous application of recombinant EGF and LIF rescue the defects in the muscle stem cell pool of Myf6 knockout animals. Finally, skeletal muscles of mice lacking Myf6 have a significantly reduced ability to sustain donor-engrafted muscle stem cells. Taken together, our data uncovers a novel role for Myf6 in regulating the expression of niche factors and myokines to maintain the skeletal muscle stem cell pool in adult mice.
Continuous Endoglin (CD105) Overexpression Disrupts Angiogenesis and Facilitates Tumor Cell Metastasis
Authors: Ollauri-Ibáñez Claudia , Núñez-Gómez Elena , Egido-Turrión Cristina , Silva-Sousa Laura , Rodríguez-Barbero Alicia , López-Novoa José M. , Pericacho Miguel
Published: July 2019

Angiogenesis is a complex process essential for tumor growth. For this reason, high levels of pro-angiogenic molecules, such as endoglin (CD105), are supposed to be related to greater tumor growth that lead to a poor cancer prognosis. However, we demonstrate here that defects in angiogenesis that can be attributed to high levels of endoglin, lead to development and worsening of cancer disease. Steady endoglin overexpression disrupts the correct stabilization of the endothelium and the recruitment of mural cells. In consequence, endoglin overexpression gives rise to altered vessels that promote the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.
Tumors Exploit Dedicated Intracellular Vesicles to Program T cell Responses
Authors: Roberts Edward W. , Ruhland Megan K. , Cai En , Mujal Adriana M. , Marchuk Kyle , Beppler Casey , Nam David , Serwas Nina K. , Binnewies Mikhail , Krummel Matthew F.
Published: July 2019

In order to drive productive tumor-infiltrating lymphocyte (TIL) function, myeloid populations must direct antigens to the lymph node, including to resident antigen-presenting cells (APCs) that have never touched the tumor. It has long been supposed that APCs trade antigens with one another, but the dominant cell biology underlying that remains unknown. We used in vitro and in vivo assays together with lattice light sheet and multiphoton imaging to show that myeloid cells carry tumor antigen-laden vesicles that they ‘trade’ with one another as they reach distant sites. This accounts for the majority of antigen displayed to T cells and provides tumors with a mechanism to access APCs that differentially direct T cell activation away from memory phenotypes. This work defines efficient cell biology that drives the first steps of TIL generation and represents a new frontier for engineering tumoral immunity.
Hemispheric asymmetries in resting-state EEG and fMRI are related to approach and avoidance behaviour, but not to eating behaviour or BMI
Authors: Morys Filip , Janssen Lieneke , Cesnaite Elena , Beyer Frauke , Garcia-Garcia Isabel , Kube Jana , Kumral Deniz , Liem Franziskus , Mehl Nora , Mahjoory Keyvan , Schrimpf Anne , Gaebler Michael , Margulies Daniel , Villringer Arno , Neumann Jane , Nikulin Vadim , Horstmann Annette
Published: July 2019

Much of our behaviour is driven by two motivational dimensions – approach and avoidance. These have been related to frontal hemispheric asymmetries in clinical and resting-state EEG studies: approach was linked to higher activity of the left relative to the right hemisphere, while avoidance was related to the opposite pattern. Increased approach behaviour, specifically towards unhealthy foods, is also observed in obesity and has been linked to asymmetry in the framework of the right-brain hypothesis of obesity. Here, we aimed to replicate previous EEG findings of hemispheric asymmetries for self-reported approach/avoidance behaviour and to relate them to eating behaviour. Further, we assessed whether resting fMRI hemispheric asymmetries can be detected and whether they are related to approach/avoidance, eating behaviour, and BMI. We analysed 3 samples: Sample 1 (n=117) containing EEG and fMRI data from lean participants, and Samples 2 (n=89) and 3 (n=152) containing fMRI data from lean, overweight, and obese participants. While in Sample 1 approach in women was related to EEG and fMRI hemispheric asymmetries, in Samples 2 and 3 this effect was not significant. Here, hemispheric asymmetries were neither related to BMI nor eating behaviour. Our study partly replicates previous EEG findings regarding hemispheric asymmetries and indicates that this relationship could also be captured using fMRI. Our findings suggest that eating behaviour and obesity are likely to be mediated by mechanisms not directly relating to frontal asymmetries in neuronal activation quantified with EEG and fMRI.
Spatially-extended nucleation-aggregation-fragmentation models for the dynamics of prion-like neurodegenerative protein-spreading in the brain and its connectome
Authors: Fornari Sveva , Schäfer Amelie , Kuhl Ellen , Goriely Alain
Published: July 2019

The prion-like hypothesis of neurodegenerative diseases states that the accumulation of misfolded proteins in the form of aggregates is responsible for tissue death and its associated neurodegenerative pathology and cognitive decline. Some disease-specific misfolded proteins can interact with healthy proteins to form long chains that are transported through the brain along axonal pathways. Since aggregates of different sizes have different transport properties and toxicity, it is important to follow independently their evolution in space and time. Here, we model the spreading and propagation of aggregates of misfolded proteins in the brain using the general Smoluchowski theory of nucleation, aggregation, and fragmentation. The transport processes considered here are either anisotropic diffusion along axonal bundles or discrete Laplacian transport along a network. In particular, we model the spreading and aggregation of both amyloid-βandτmolecules in the brain connectome. We show that these two models lead to different size distributions and different propagation along the network. A detailed analysis of these two models reveals the existence of four different stages with different dynamics and invasive properties.
CELLULOSE SYNTHASE INTERACTIVE1- and Microtubule-Dependent Cell Wall Architecture Is Required for Acid Growth inArabidopsis Hypocotyls
Authors: Xin Xiaoran , Lei Lei , Zheng Yunzhen , Zhang Tian , Pingali Sai Venkatesh , O’Neill Hugh , Cosgrove Daniel J. , Li Shundai , Gu Ying
Published: July 2019

Auxin-induced cell elongation relies in part on the acidification of the cell wall, a process known as acid growth that presumably triggers expansin-mediated wall loosening via altered interactions between cellulose microfibrils. Cellulose microfibrils are a major determinant for anisotropic growth and they provide the scaffold for cell wall assembly. Little is known about how acid growth depends on cell wall architecture. To explore the relationship between acid growth-mediated cell elongation and plant cell wall architecture, two mutants (jia1-1andcsi1-3) that are defective in cellulose biosynthesis and cellulose microfibril organization were analyzed. The study revealed that cell elongation is dependent on CSI1-mediated cell wall architecture but not on the overall crystalline cellulose content. We observed a correlation between loss of crossed-polylamellate walls and loss of auxin- and fusicoccin-induced cell growth incsi1-3. Furthermore, induced loss of crossed-polylamellate walls via disruption of cortical microtubule mimics the effect ofcsi1in acid growth. We hypothesize that CSI1- and microtubule-dependent crossed-polylamellate walls are required for acid growth inArabidopsishypocotyls.
Variation and inheritance of small RNAs in maize inbreds and F1 hybrids
Authors: Crisp Peter A. , Hammond Reza , Zhou Peng , Vaillancourt Brieanne , Lipzen Anna , Daum Chris , Barry Kerrie , de Leon Natalia , Buell C. Robin , Kaeppler Shawn M. , Meyers Blake C. , Hirsch Candice N. , Springer Nathan M.
Published: July 2019

Small RNAs (sRNAs) regulate gene expression, play important roles in epigenetic pathways, and have been hypothesised to contribute to hybrid vigor in plants. Prior investigations have provided valuable insights into associations between sRNAs and heterosis, often using a single hybrid genotype or tissue. However, our understanding of the role of sRNAs and their potential value to plant breeding are limited by an incomplete picture of sRNA variation between diverse genotypes and development stages. Here, we provide a deep exploration of sRNA variation and inheritance among a panel of 108 maize samples spanning five tissues from eight inbred parents and 12 hybrid genotypes, covering a spectrum of heterotic groups, genetic variation, and levels of heterosis for various traits. We document substantial developmental and genotypic influences on sRNA expression, with varying patterns for 21-nt, 22-nt and 24-nt sRNAs. We provide a detailed view of the distribution of sRNAs in the maize genome, revealing a complex make-up that also shows developmental plasticity, particularly for 22-nt sRNAs. sRNAs exhibited substantially more variation between inbreds as compared to observed variation for gene expression. In hybrids, we identify locus-specific examples of non-additive inheritance, mostly characterised as partial or complete dominance, but rarely outside the parental range. However, the global abundance of 21-nt, 22-nt and 24-nt sRNAs varies very little between inbreds and hybrids, suggesting that hybridization affects sRNA expression principally at specific loci rather than on a global scale. This study provides a valuable resource for understanding the potential role of sRNAs in hybrid vigor.

One-sentence summary

Characterizing the roles of development and genotype in driving expression variation of different small RNA populations in maize inbreds and their F1 hybrids.
Induced and primed defence responses of Fragaria vesca to Botrytis cinerea infection
Authors: Badmi Raghuram , Zhang Yupeng , Tengs Torstein , Brurberg May Bente , Krokene Paal , Fossdal Carl Gunnar , Hytönen Timo , Thorstensen Tage
Published: July 2019

1.

Strawberry is a high-value crop that suffers huge losses from diseases such as grey mould caused by the necrotrophic fungal pathogen Botrytis cinerea. Pesticides are heavily used to protect the strawberry crop, which raises environmental and human health concerns and promotes the evolution of pesticide resistant strains. Upregulating or priming the plants’ defences may be a more environmentally sustainable way of increasing disease resistance. Using Fragaria vesca as a model for the commercially grown octaploid strawberry Fragaria × ananassa, we investigated the transcriptional reprogramming of strawberry upon B. cinerea infection and the effectiveness of four priming chemicals in protecting strawberry against grey mould. First, we found that the transcriptional reprogramming of strawberry upon B. cinerea infection overlapped substantially with the transcriptome responses induced by Phytophthora cactorum (Toljamo et al., 2016), including the genes involved in jasmonic acid (JA), salicylic acid (SA), ethylene (ET) and terpenoid pathways. Furthermore, we investigated the effectiveness of previously identified priming chemicals in protecting strawberry against B. cinerea. The level of upregulated or primed resistance depended on the priming chemical itself (β-aminobutyric acid (BABA), methyl jasmonate (MeJ), (R)-β-homoserine (RBH), prohexadione-calcium (ProCa)) and the application method used (foliar spray, soil drench, seed treatment). Overall, RBH effectively primed strawberry defences against B. cinerea, whereas BABA and ProCa were not effective and MeJ showed mixed effects. Our results not only identify ways to effectively upregulate or prime strawberry defences against B. cinerea, but also provide novel insights about strawberry defences that may be applied in future crop protection schemes.
Spatial arrangement drastically changes the neural representation of multiple visual stimuli that compete in more than one feature domain
Authors: Wiesner Steven , Baumgart Ian W. , Huang Xin
Published: July 2019

Natural scenes often contain multiple objects and surfaces. However, how neurons in the visual cortex represent multiple visual stimuli is not well understood. Previous studies have shown that, when multiple stimuli compete in one feature domain, the evoked neuronal response is biased toward the stimulus that has a stronger signal strength. Here we investigate how neurons in the middle temporal (MT) cortex of macaques represent multiple stimuli that compete in more than one feature domain. Visual stimuli were two random-dot patches moving in different directions. One stimulus had low luminance contrast and moved with high coherence, whereas the other had high contrast and moved with low coherence. We found that how MT neurons represent multiple stimuli depended on the spatial arrangement of the stimuli. When two stimuli were overlapping, MT responses were dominated by the stimulus component that had high contrast. When two stimuli were spatially separated within the receptive fields, the contrast dominance was abolished. We found the same results when using contrast to compete with motion speed. Our neural data and computer simulations using a V1-MT model suggest that the contrast dominance found with overlapping stimuli is due to normalization occurring at an input stage fed to MT, and MT neurons cannot overturn this bias based on their own feature selectivity. The interaction between spatially separated stimuli can largely be explained by normalization within MT. Our results revealed new rules on stimulus competition and highlighted the impact of hierarchical processing on representing multiple stimuli in the visual cortex.

SIGNIFICANCE STATEMENT

Previous studies have shown that the neural representation of multiple visual stimuli can be accounted for by a divisive normalization model. By using multiple stimuli that compete in more than one feature domain, we found that luminance contrast has a dominant effect in determining competition between multiple stimuli when they were overlapping but not spatially separated. Our results revealed that neuronal responses to multiple stimuli in a given cortical area cannot be simply predicted by the population neural responses elicited in that area by the individual stimulus components. To understand the neural representation of multiple stimuli, rather than considering response normalization only within the area of interest, one must consider the computations including normalization occurring along the hierarchical visual pathway.
Evidence for mutation-order speciation inSenecio lautus
Authors: Melo Maria C. , James Maddie E. , Roda Federico , Bernal-Franco Diana , Wilkinson Melanie J. , Liu Huanle , Walter Greg M. , Ortiz-Barrientos Daniel
Published: July 2019

In a number of animal species, divergent natural selection has repeatedly and independently driven the evolution of reproductive isolation between populations adapted to contrasting, but not to similar environments1. This process is known as parallel ecological speciation, and examples in plants are enigmatically rare2. Here, we perform a comprehensive test of the ecological speciation hypothesis in an Australian wildflower where parapatric populations found in coastal sand dunes (Dune ecotype) and headlands (Headland ecotype) have repeatedly and independently diverged in growth habit. Consistent with a role for divergent natural selection driving the evolution of reproductive isolation, we found that Dune populations with erect growth habit were easy to transplant across sand dunes, were largely interfertile despite half-a-million years of divergence, and were reproductively isolated from equally divergent Headland populations with prostrate growth habit. However, we unexpectedly discovered that both extrinsic and intrinsic reproductive isolation has evolved between prostrate Headland populations, suggesting that populations evolving convergent phenotypes can also rapidly become new species. Mutation-order speciation2, where the random accumulation of adaptive alleles create genetic incompatibilities between populations inhabiting similar habitats, provides a compelling explanation for these complex patterns of reproductive isolation. Our results suggest that natural selection can drive speciation effectively, but environmental and genetic complexity might make parallel ecological speciation uncommon in plants despite strong morphological convergence.
The YdiU Domain Modulates Bacterial Stress Signaling through Mn2+-dependent UMPylation
Authors: Yang Yinlong , Yue Yingying , Song Nannan , Li Cuiling , Yuan Zenglin , Wang Yan , Ma Yue , Li Hui , Zhang Fengyu , Wang Weiwei , Jia Haihong , Li Peng , Li Xiaobing , Wang Qi , Ding Zhe , Dong Hongjie , Gu Lichuan , Li Bingqing
Published: July 2019

Sensing stressful conditions and adjusting cellular metabolism to adapt to the environment is essential for bacteria to survive in variable situations. Here, we describe a new stress-related protein YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine 5’-monophosphate to a protein tyrosine/histidine residue—a novel modification defined as UMPylation. Mn2+serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+-binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. The detailed mechanism is proposed based on Apo-YdiU, YdiU-ATP, YdiU-AMP crystal structures and molecular dynamics simulation models of YdiU-UTP and YdiU-UTP-peptide.In vivodata demonstrate that YdiU effectively protectsSalmonellafrom stress-induced ATP depletion through UMPylation.

Highlights

YdiU involves in stress-resistance ofSalmonella.

YdiU mediates protein UMPylation in a Mn2+-dependent manner.

Structural insights into YdiU-mediated UMPylation.

UMPylation of chaperones by YdiU modulates their function.
Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants
Authors: He Yaoxi , Luo Xin , Zhou Bin , Hu Ting , Meng Xiaoyu , Audano Peter A. , Kronenberg Zev N. , Eichler Evan E. , Jin Jie , Guo Yongbo , Yang Yanan , Qi Xuebin , Su Bing
Published: July 2019

Rhesus macaque (Macaca mulatta) is a widely-studied nonhuman primate. Here we present a high-quality de novo genome assembly of the Chinese rhesus macaque (rheMacS) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), the rheMacS genome assembly improves sequence contiguity by 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). To improve gene annotation, we generated more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to the long-read assembly of ape genomes. We show that many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a set of candidate ASSVs that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. This improved rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.
Mutations in a single signaling pathway allow growth on a different solvent than water
Authors: Kampmeyer Caroline , Johansen Jens V. , Holmberg Christian , Karlson Magnus , Gersing Sarah K. , Bordallo Heloisa N. , Kragelund Birthe B. , Lerche Mathilde H. , Jourdain Isabelle , Winther Jakob R. , Hartmann-Petersen Rasmus
Published: July 2019

Since life is completely dependent on water, it is difficult to gauge the impact of solvent change. To analyze the role of water as a solvent in biology, we replaced water with heavy water (D2O), and investigated the biological effects by a wide range of techniques, using the fission yeastSchizosaccharomyces pombeas model organism. We show that high concentrations of D2O lead to altered glucose metabolism, growth retardation, and inhibition of meiosis. However, mitosis and overall cell viability were only slightly affected. After prolonged incubation in D2O, cells displayed gross morphological changes, thickened cell walls as well as aberrant septa and cytoskeletal organization. RNA sequencing revealed that D2O causes a strong downregulation of most tRNAs and triggers activation of the general stress response pathway. Genetic screens identified several D2O sensitive mutants, while mutants compromised in the cell integrity pathway, including the protein kinase genespmk1,mkh1,pek1andpck2, that control cell wall biogenesis, were more tolerant to D2O. We speculate that D2O affects the phospholipid membrane or cell wall glycans causing an activation of the cell integrity pathway. In conclusion, the effects of solvent replacement are pleiotropic but the D2O-triggered activation of the cell integrity pathway and subsequent increased deposition of cell wall material and septation problems appear most critical for the cell growth defects.
PAWER: Protein Array Web ExploreR
Authors: Fishman Dmytro , Kuzmin Ivan , Adler Priit , Vilo Jaak , Peterson Hedi
Published: July 2019

Protein microarray is a well-established approach for characterizing activity levels of thousands of proteins in a parallel manner. Analysis of protein microarray data is complex and time-consuming, while existing solutions are either outdated or challenging to use without programming skills. The typical data analysis pipeline consists of a data preprocessing step, followed by differential expression analysis, which is then put into context via functional enrichment. Normally, biologists would need to assemble their own workflow by combining a set of unrelated tools to analyze experimental data. Provided that most of these tools are developed independently by various bioinformatics groups, making them work together could be a real challenge. Here we present PAWER, the first online tool for protein microarray analysis. PAWER enables biologists to carry out all the necessary analysis steps in one go. PAWER provides access to state-of-the-art computational methods through a user-friendly interface, resulting in publication-ready illustrations. We also provide an R package for more advanced use cases, such as bespoke analysis workflows. PAWER is freely available at https://biit.cs.ut.ee/pawer.
Multistage activity within a diverse set of epi-drugs against Plasmodium falciparum parasites
Authors: Coetzee Nanika , von Grüning Hilde , van der Watt Mariette , Reader Janette , Birkholtz Lyn-Marié
Published: July 2019

The epigenome of the malaria parasite, Plasmodium falciparum, is associated with control of various essential processes in the parasite including control of proliferation of asexual development as well as sexual differentiation. The unusual nature of the epigenome has prompted investigations of the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity associated with a library of 95 compounds, active against various epigenetic modifiers within cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and non-histone epigenetic modifiers. Moreover, 4 compounds targeting histone acetylation and methylation, show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds.
A rhomboid protease, EhROM1, regulates the submembrane distribution and size of the Gal/GalNAc lectin subunits in the human protozoan parasite, Entamoeba histolytica
Authors: Welter Brenda H. , Temesvari Lesly A.
Published: July 2019

Entamoeba histolytica is a food- and waterborne parasite that is the causative agent of amebic dysentery and amoebic liver abscesses. Adhesion is one of the most important virulence functions as it facilitates motility, colonization of host, destruction of host tissue, and uptake of nutrients by the parasite. One well-characterized parasite cell surface adhesin is the Gal/GalNAc lectin, which binds to galactose or N-acetylgalactosamine residues on host components and is composed of heavy (Hgl), intermediate (Igl), and light (Lgl) subunits. Igl has been shown to be constitutively localized to lipid rafts (cholesterol-rich membrane domains), whereas Hgl and Lgl transiently associate with rafts. When all three subunits are localized to rafts there is an increase in galactose-sensitive adhesion. Thus, submembrane location may regulate the function of this adhesion. Rhomboid proteases are a conserved family of intramembrane proteases that also participate in the regulation of parasite-host interactions. In E. histolytica, one rhomboid protease, EhROM1, cleaves Hgl as a substrate, and knockdown of its expression inhibits parasite-host interactions. Since rhomboid proteases are found within membranes, it is not surprising that lipid composition regulates their activity and enzyme-substrate binding. Given the importance of the lipid environment for both rhomboid proteases and the Gal/GalNAc lectin, we sought to gain insight into the relationship between rhomboid proteases and submembrane location of the lectin in E. histolytica. We demonstrated that EhROM1, itself, is enriched in rafts. Reducing rhomboid protease activity, either pharmacologically or genetically, correlated with an enrichment of Hgl and Lgl in rafts. In a mutant cell line with reduced EhROM1 expression, there was also a significant augmentation of the level of all three Gal/GalNAc subunits on the cell surface and an increase in the molecular weight of Hgl and Lgl. Overall, the study provides insight into the molecular mechanisms governing parasite-host adhesion for this pathogen.
Associated factors and spatial patterns of the epidemic sporotrichosis in a high density human populated area: A cross-sectional study from 2016 to 2018
Authors: Lecca Lívian Otávio , Paiva Marcelo Teixeira , Stefanie Fonseca de Oliveira Camila , Franco Morais Maria Helena , de Azevedo Maria Isabel , de Valgas e Bastos Camila , Keller Kelly Moura , Ecco Roselene , Silva Alves Márcia Regina , Tavares Pais Graziella Coelho , Salvato Lauranne Alves , de Morais Donancio Xaulim Gustavo , Barbosa David Soeiro , Brandão Silvana Tecles , Ferreira de Magalhães Soares Danielle
Published: July 2019

We carried out an epidemiological characterization of human and feline sporotrichosis, between 2016 and 2018, in a high density-populated area in Brazil. Professionals were trained to identify suspected cats and notified vets to interview the owners and collect swabs of the wounds from these animals. Mycological cultures were performed, and colonies identified for Spotrothrix spp. Subsequently, data regarding the outcome from suspected animals were collected. Confirmed cases of human sporotrichosis (56) were also counted and analysed for spatial distribution. Regions with highest prevalence of feline sporotrichosis, had greater frequencies of both human and feline cases. 118 (77.63%) animals were positive. Animals that lived only partially at home were 3.02 times more likely of being positive (OR 3.02, CI 95% 1,96-10,43). The prevalence of feline sporotrichosis was 8.36 ‰ (CI 95%, 5.38 - 9.55 ‰). There was no statistically significant association between environmental variables and positive diagnosis, corroborating the hypothesis that direct transmission by infected cats plays a greater role in the occurrence and continuous outbreaks of sporotrichosis in Brazil. Among the positive animals, 61.90% (CI 95% 58.95 - 64.96) died, being 6.30 times more likely to die than negative animals (p< 0.05, OR 6.30, CI 95% 2,79-14,42). The lethality rate was 55.08% in cats (CI 95% 49.20 - 51.15). The mortality for sporotrichosis was 4.6 ‰ cats (CI 95% 3.4 - 6 ‰). Only 7.62% (CI 95% 7.12 - 8.16) positive cats were treated and cured. Among dead positive animals, 29.23% were inappropriately discarded. This is the first report on the epidemic of sporotrichosis in Minas Gerais, Brazil. The free offer for treatment and veterinary care to these animals should be taken into consideration, as well as the collection and incineration of the dead ones, as measures of public health, followed by the guidance and care for the human patient.