bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning dynamical information from static protein and sequencing data
Authors: Pearce Philip , Woodhouse Francis G. , Forrow Aden , Kelly Ashley , Kusumaatmaja Halim , Dunkel Jörn
Published: August 2018

Many complex processes, from protein folding and virus evolution to brain activity and neuronal network dynamics, can be described as stochastic exploration of a high-dimensional energy landscape. While efficient algorithms for cluster detection and data completion in high-dimensional spaces have been developed and applied over the last two decades, considerably less is known about the reliable inference of state transition dynamics in such settings. Here, we introduce a flexible and robust numerical framework to infer Markovian transition networks directly from time-independent data sampled from stationary equilibrium distributions. Our approach combines Gaussian mixture approximations and self-consistent dimensionality reduction with minimal-energy path estimation and multi-dimensional transition-state theory. We demonstrate the practical potential of the inference scheme by reconstructing the network dynamics for several protein folding transitions, gene regulatory network motifs and HIV evolution pathways. The predicted network topologies and relative transition time scales agree well with direct estimates from time-dependent molecular dynamics data, stochastic simulations and phylogenetic trees, respectively. The underlying numerical protocol thus allows the recovery of relevant dynamical information from instantaneous ensemble measurements, effectively alleviating the need for time-dependent data in many situations. Owing to its generic structure, the framework introduced here will be applicable to high-throughput RNA and protein sequencing datasets and future cryo-electron-microscopy data, and can guide the design of new experimental approaches towards studying complex multiphase phenomena.
Label-free digital holo-tomographic microscopy reveals virus-induced cytopathic effects in live cells
Authors: Yakimovich Artur , Witte Robert , Andriasyan Vardan , Georgi Fanny , Grebera Urs F.
Published: August 2018

Cytopathic effects (CPEs) are a hallmark of infections. CPEs can be observed by phase contrast or fluorescence light microscopy, albeit at the cost of phototoxicity. We report that digital holo-tomographic microscopy (DHTM) reveals distinct patterns of virus infections in live cells with minimal perturbation. DHTM is label-free, and records the phase shift of low energy light passing through the specimen on a transparent surface. DHTM infers a 3-dimensional (3D) tomogram based on the refractive index (RI). By measuring RI and computing the refractive index gradient (RIG) values DHTM unveils on optical heterogeneity in cells upon virus infection. We find that vaccinia virus (VACV), herpes simplex virus (HSV) and rhinovirus (RV) infections progressively and distinctly increased RIG. VACV, but not HSV and RV infection induced oscillations of cell volume, while all three viruses altered cytoplasmic membrane dynamics, and induced apoptotic features akin to the chemical compound staurosporin, but with virus-specific signatures. In sum, we introduce DHTM for quantitative label-free microscopy in infection research, and uncover virus-type specific changes and CPE in living cells at minimal interference.
Spatial neuronal synchronization and the waveform of oscillations: implications for EEG and MEG
Authors: Schaworonkow Natalie , Nikulin Vadim V.
Published: August 2018

Neuronal oscillations are ubiquitous in the human brain and are implicated in virtually all brain functions. Often they are referred to by their frequency content, i.e., α-, β-, γ-oscillations. Although they indeed can be described by a prominent peak in the power spectrum, their waveform is not necessarily sinusoidal and shows a rather complex morphology which needs to be captured with multiple spectral harmonics. Both frequency and temporal descriptions of such non-sinusoidal neuronal oscillations can be utilized. However, in non-invasive EEG/MEG recordings the waveform of oscillations often takes a sinusoidal shape which in turn leads to a rather oversimplified view on oscillatory processes.

In this study, we show in simulations how spatial synchronization can mask non-sinusoidal features of the underlying rhythmic neuronal processes. Consequently, the degree of non-sinusoidality can serve as a measure of spatial synchronization. To confirm this empirically, we show that a mixture of EEG components is indeed associated with more sinusoidal oscillations compared to the waveform of oscillations in each constituent component. Using simulations, we also show that the spatial mixing of the non-sinusoidal neuronal signals strongly affects the amplitude ratio of the spectral harmonics constituting the waveform. This in turn has high relevance for the interpretation of the relative strength of spectral peaks, which is commonly used for inferring neuronal signatures corresponding to specific behavioral states.

Moreover, our simulations show how spatial mixing can affect the strength and even the direction of the amplitude coupling between constituent neuronal harmonics. Consistently with these simulations, we also demonstrate these effects in real EEG recordings. Our findings have far reaching implications for the neu-rophysiological interpretation of neuronal oscillations and cross-frequency interactions, as well as for the unequivocal determination of oscillatory phase.
Interferometric scattering microscopy reveals microsecond nanoscopic protein motion on a live cell membrane
Authors: Taylor Richard W. , Mahmoodabadi Reza Gholami , Rauschenberger Verena , Giessl Andreas , Schambony Alexandra , Sandoghdar Vahid
Published: August 2018

Much of the biological functions of a cell are dictated by the intricate motion of proteins within its membrane over a spatial range of nanometers to tens of micrometers and time intervals of microseconds to minutes. While this rich parameter space is not accessible to fluorescence microscopy, it can be within reach of interferometric scattering (iSCAT) particle tracking. Being sensitive even to single unlabeled proteins, however, iSCAT is easily accompanied by a large speckle-like background, which poses a substantial challenge for its application to cellular imaging. Here, we show that these difficulties can be overcome and demonstrate tracking of transmembrane epidermal growth factor receptors (EGFR) with nanometer precision in all three dimensions at up to microsecond speeds and tens of minutes duration. We provide unprecedented examples of nanoscale motion and confinement in ubiquitous processes such as diffusion in the plasma membrane, transport on filopodia, and endocytosis.
The context-dependent nature of the neural implementation of intentions
Authors: Uithol Sebo , Görgen Kai , Pischedda Doris , Toni Ivan , Haynes John-Dylan
Published: August 2018

Many studies have identified networks in parietal and prefrontal cortex that are involved in intentional action. Yet, knowledge about what these networks exactly encoded is still scarce. In this study we look into the content of those processes. We ask whether the neural representations of intentions are context- and reason-invariant, or whether these processes depend on the context we are in, and the reasons we have for choosing an action. We use a combination of functional magnetic resonance imaging and multivariate decoding to directly assess the context- and reason-dependency of the processes underlying intentional action. We were able to decode action decisions in the same context and for the same reasons from the fMRI data, in line with previous decoding studies. Furthermore, we could decode action decisions across different reasons for choosing an action. Importantly, though, decoding decisions across different contexts was at chance level. These results suggest that for voluntary action, there is considerable context-dependency in intention representations. This suggests that established invariance in neural processes may not reflect an essential feature of a certain process, but that this stable character could be dependent on invariance in the experimental setup, in line with predictions from situated cognition theory.
Fungal growth is affected by and affects pH and redox potential (Eh) of the growth medium
Authors: Bousset L. , Ermel M. , Soglonou B. , Husson O.
Published: August 2018

Fungal plant pathogens live in the specific environment of plants. Understanding of the interaction between pathogens and their host plants might open new ways to control plant diseases. Yet, the specificities of the plant environment and its effects on fungal growth are not yet fully explored. Both pH and Eh play a key role during the interaction between the fungus and its host plants, but often studied independently or at different scales. To decipher the interrelation between plant growth and their soil environment, recent theoretical and methodological advances have been made through the joint characterization of the pH and Eh. This opens the prospect to develop similar methods for fungi. The aim of our study was to investigate whether the methods developed for soil could be transposed to fungi. We first worked on artificial media, assessing the impact of fungal growth on the media in cultures. The growth of all 16 species tested significantly altered either Eh, pH or both in agar media. Measuring Eh reveals that even the species not modifying pH can have an impact on the surrounding environment. Reciprocally, altered media were used to characterize sensitivity of fungal growth to both pH and Eh parameters. The response of the six fungi tested to the modified media was quantitative with a decrease in colony diameter. In addition, colony aspect was repeatedly and thoroughly modified. As a first step towards the same studies in conditions matching the natural environment of fungal pathogens, we tested how the measurement can be performed with fungi growing on oilseed rape plants. In infected plant stems, pH and Eh were significantly altered, in opposite directions for L. maculans and S. sclerotiorum. The observed alcalinisation or acidification correlates with canker length. Our series of experiments indicate that the procedure published for Eh and pH in soil can be extended for measurement in agar media and in infected plants. Further, the joint characterization of both parameters opens the way to a more precise understanding of the impact of fungi on their environment, and conversely, of the environment on fungal growth. The availability of methods for measurement opens the prospect to study combinations of stresses, either on agar media or in plants, and get an understanding of the involvement of pH and Eh modifications in these interactions.
Microsatellite primer development for invasive perennial herb,Gypsophila paniculata(Caryophyllaceae)
Authors: Leimbach-Maus Hailee B. , Parks Syndell R. , Partridge Charlyn G.
Published: August 2018

Premise of the study: Gypsophila paniculataL. (baby’s breath) is an herbaceous perennial that has invaded much of northern and western United States and Canada, outcompeting and crowding out native and endemic species. Microsatellite primers were developed to analyze the genetic structure of invasive populations.

Methods and Results:We have identified 16 polymorphic nuclear microsatellite loci forG. paniculataout of 73 loci that successfully amplified from a primer library created using Illumina sequencing technology. The developed primers amplified microsatellite loci in 3 invasive populations in Michigan. Primers amplified di-, tri-, and tetra-nucleotide repeats.

Conclusions:These markers will be useful in characterizing the genetic structure of invasive populations throughout North America to aid targeted management efforts, and in native Eurasian populations to better understand invasion history. Five of these developed primers also amplified inG. elegans.
Direct observation of rotation-coupled protein diffusion along DNA on the microsecond timescale
Authors: Marklund Emil , Amselem Elias , Kipper Kalle , Zheng Xuan , Johansson Magnus , Deindl Sebastian , Elf Johan
Published: August 2018

Many proteins that bind specific DNA sequences search the genome by combining three dimensional (3D) diffusion in the cytoplasm with one dimensional (1D) sliding on non-specific regions of the DNA1–5. It is however not known how sliding proteins are oriented with respect to DNA in order to recognize specific sequences. Here we measure the polarization of fluorescence emission from single fluorescently labeledlacrepressor (LacI) molecules sliding on stretched DNA. Real-time feedback-coupled confocal single-particle tracking allows us to measure fluorescence correlation of the sliding molecules. We find that the fluctuations in the fluorescence signal on the μs timescale are accurately described by rotation-coupled sliding on DNA. On average, LacI moves ∼50 base pairs per revolution, which is significantly longer than the 10.5 bp helical periodicity of DNA. Our data support a facilitated diffusion model1where the transcription factor (TF) scans the DNA grooves for hydrogen bonding opportunities in a pre-aligned orientation with occasional slippage out of the groove.
CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo
Authors: Rieger Michael A. , King Dana M. , Cohen Barak A. , Dougherty Joseph D.
Published: August 2018

CELF6 is a RNA-binding protein in a family of proteins with roles in human health and disease, however little is known about the mRNA targets or in vivo function of this protein. We utilized CLIP-Seq to identify, for the first time, in vivo targets of CELF6 and identify hundreds of transcripts bound by CELF6 in the brain. We found these are disproportionately mRNAs coding for synaptic proteins. We then conducted functional validation of these targets, testing greater than 400 CELF6 bound sequence elements for their activity, applying a massively parallel reporter assay framework to evaluation of the CLIP data. We also mutated potential binding motifs within these elements and tested their impact. This comprehensive analysis led us to ascribe a previously unknown function to CELF6: we found bound elements were generally repressive of translation, that CELF6 further enhances this repression via decreasing RNA abundance, and this process was dependent on UGU-rich sequence motifs. This greatly extends the known role for CELF6, which had previously been defined only as a splicing factor. We further extend these findings by demonstrating the same function for CELF3, CELF4, and CELF5. Finally, we demonstrate that the CELF6 targets are derepressed in CELF6 mutant mice in vivo, confirming this new role in the brain. Thus, our study demonstrates that CELF6 and other sub-family members are repressive CNS RNA-binding proteins, and CELF6 downregulates specific mRNAs in vivo.
Computational Analysis of Dynamical Fluctuations of Oncoprotein E7 (HPV) for the Hot Spot Residue Identification Using Elastic Network Model
Authors: Malik R. M. , Nazir F. , Fazal S. , Bhatti A. , Ullah M. , Malik S. I. , Kanwal A. , Aziz S. E. , Azam S.
Published: August 2018

Virus proteins after invading human body alter host protein-protein interaction networks, resulting in the creation of new interactions, along with destroying or modifying other interactions or proteins. Topological features of new or modified networks compromise the host system causing increased production of viral particles. The molecular basis for this alteration of proteins interactivity is short linear peptide motifs similar in both virus and humans. These motifs are identified by modular domains, which are the subunits of a protein, in the human body, resulting in stabilization or moderation of these protein interactions Protein molecules can be modeled by elastic network models showing the fluctuations of residues when they are biologically active. We focused our computational study on the binding and competing interactions of the E7 protein of HPV with Rb protein. Our study was based on analysis of dynamic fluctuations of E7 in host cell and correlation analysis of specific residue found in motif of LxCxE, that is the key region in stabilizing interaction between E7 and Rb. Hot spot residue of E7 were also identified which could provide platform for drug prediction in future. Nevertheless, our study validates the role of linear binding motifs LxCxE of E7 of HPV in interacting with Rb as an important event in propagation of HPV in human cells and transformation of infection into cervical cancer.
Dot6 is a major regulator of cell size and a transcriptional activator of ribosome biogenesis in the opportunistic yeast Candida albicans
Authors: Chaillot Julien , Malick Jaideep , Sellam Adnane
Published: August 2018

In most species, size homeostasis appears to be exerted in late G1 phase as cells commit to division, called Start in yeast and the Restriction Point in metazoans. This size threshold couples cell growth to division and thereby establishes long-term size homeostasis. Our former investigations have shown that hundreds of genes markedly altered cell size under homeostatic growth conditions in the opportunistic yeast Candida albicans, but surprisingly only few of these overlapped with size control genes in the budding yeast Saccharomyces cerevisiae. Here, we investigated one of the divergent potent size regulators in C. albicans, the Myb-like HTH transcription factor Dot6. Our data demonstrated that Dot6 is a negative regulator of Start and also acts as a transcriptional activator of ribosome biogenesis (Ribi) genes. Genetic epistasis uncovered that Dot6 interacted with the master transcriptional regulator of the G1 machinery, SBF complex, but not with the Ribi and cell size regulators Sch9, Sfp1 and p38/Hog1. Dot6 was required for carbon-source modulation of cell size and it is regulated at the level of nuclear localization by TOR pathway. Our findings support a model where Dot6 acts as a hub that integrate directly growth cues via the TOR pathway to control the commitment to mitotic division at G1.
Ventral tegmental area astrocytes orchestrate avoidance and approach behavior
Authors: Gomez J. A. , Perkins J. M. , Beaudoin G. M. , Cook N. B. , Quraishi S. A. , Szoeke Erin A , Thangamani K. , Tschumi C. W. , Wanat M. J. , Maroof A. M. , Beckstead M. J. , Rosenberg P. A. , Paladini C. A.
Published: August 2018

The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates approach and avoidance behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, VTA astrocytes facilitate excitation of local GABA neurons to increase inhibition of dopamine neurons. The increased inhibition of dopamine neurons elicits real-time and learned avoidance behavior that is sufficient to impede expression of learned preference for reward. Despite the large number of functions performed by astrocytes, loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct learned avoidance circuit that opposes learned approach behavior.
Progression of recent Mycobacterium tuberculosis exposure to active tuberculosis is a highly heritable complex trait driven by 3q23 in Peruvians
Authors: Luo Yang , Suliman Sara , Asgari Samira , Amariuta Tiffany , Calderon Roger , Lecca Leonid , León Segundo R. , Jimenez Judith , Yataco Rosa , Contreras Carmen , Galea Jerome T. , Becerra Mercedes , Nejentsev Sergey , Martínez-Bonet Marta , Nigrovic Peter A. , Moody D. Branch , Murray Megan B , Raychaudhuri Soumya
Published: August 2018

Among 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% are expected to develop active tuberculosis (TB). Approximately half of these will progress to active TB within the first 18 months after infection, presumably because they fail to mount the initial immune response that contains the local bacterial spread. The other half will reactivate their latent infection later in life, likely triggered by a loss of immune competence due to factors such as HIV-associated immunosuppression or ageing. This natural history suggests that undiscovered host genetic factors may control early progression to active TB. Here, we report results from a large genome-wide genetic study of early TB progression. We genotyped a total of 4,002 active TB cases and their household contacts in Peru and quantified genetic heritability of early TB progression to be 21.2% under the liability scale. Compared to the reported of genome-wide TB susceptibility (15.5%), this result indicates early TB progression has a stronger genetic basis than population-wide TB susceptibility. We identified a novel association between early TB progression and variants located in an enhancer region on chromosome 3q23 (rs73226617, OR=1.19; P < 5×10−8). We used in silico and in vitro analyses to identify likely functional variants and target genes, highlighting new candidate mechanisms of host response in early TB progression.
Genomic data provides new insights on the demographic history and the extent of recent material transfers in Norway spruce
Authors: Chen Jun , li Lili , Milesi Pascal , Jansson Gunnar , Berlin Mats , Karlsson Bo , Aleksic Jelena , Vendramin Giovanni G. , Lascoux Martin
Published: August 2018

Primeval forests are today exceedingly rare in Europe and transfer of forest reproductive material for afforestation and improvement have been very common, especially over the last two centuries. This can be a serious impediment when inferring past population movements in response to past climate changes such as the last glacial maximum (LGM), some 18,000 years ago. In the present study, we genotyped 1,672 individuals from three Picea species (P. abies, P. obovata, and P. omorika) at 400K SNPs using exome capture to infer the past demographic history of Norway spruce and estimate the amount of recent introduction used to establish the Norway spruce breeding program in Southern Sweden. Most of these trees belong to P. abies and originate from the base population of the Swedish breeding program. Others originate from populations across the natural ranges of the three species. Of the 1,499 individuals stemming from the breeding program, a large proportion corresponds to recent introductions. The split of P. omorika occurred 23 million years ago (mya), while the divergence between P. obovata and P. abies began 17.6 mya. Demographic inferences retrieved the same main clusters within P. abies than previous studies, i.e. a vast northern domain ranging from Norway to central Russia, where the species is progressively replaced by Siberian spruce (P. obovata) and two smaller domains, an Alpine domain, and a Carpathian one, but also revealed further subdivision and gene flow among clusters. The three main domains divergence was ancient (15 mya) and all three went through a bottleneck corresponding to the LGM. Approximately 17% of P. abies Nordic domain migrated from P. obovata ~103K years ago, when both species had much larger effective population sizes. Our analysis of genome-wide polymorphism data thus revealed the complex demographic history of Picea genus in Western Europe and highlighted the importance of material transfer in Swedish breeding program.
In SilicoIdentification of Three Types of Integrative and Conjugative Elements (ICEs) inElizabethkingia anophelisStrains Isolated from Around the World
Authors: Xu Jiannong , Pei Dong , Nicholson Ainsley , Lan Yuhao , Xia Qing
Published: August 2018

Elizabethkingia anophelisis an emerging global multidrug-resistant opportunistic pathogen. We assessed the diversity among 13 complete genomes and 23 draft genomes ofE. anophelisderived from various environmental settings and human infections from different geographic regions around the world over past decades from 1950s. Thirty-one of these 36 strains harbor integrative and conjugative elements (ICEs). A total of 52 ICEs were identified, and categorized into three ICE types based on the architecture of signature genes in the conjugation module. The type II and III ICEs were found to integrate into regions adjacent to tRNA genes, while type I ICEs used a variety of integration sites, inserting into intergenic regions or even directly into a gene, sometimes disrupting gene function. Integrases such as tyrosine recombinases, serine recombinases and DDE transposases were found in most ICEs. The ICEs carry various cargo genes including transcription regulators and those involved in antibiotic resistance. The CRISPR-Cas system was found in nine strains, including four strains in which CRISPR-Cas machinery and ICEs co-exist. ICE distribution in the strains showed no geographic or temporal patterns. The ICEs inE. anophelisdiffer in gene structure and sequence from CTnDOT, a well-studied ICE prevalent inBacteroidesspp. This is the first set of ICEs identified in the family Flavobacteriaceae. As a prevalent type of mobile genetic elements in various strains ofE. anophelisaround the world, the categorization of ICEs will facilitate further investigations such as virulence, genome epidemiology and adaptation genomics ofE. anophelis.

Importance

Elizabethkingia anophelisis an opportunistic human pathogen, and the genetic diversity between strains from around the world becomes apparent as more genomes are sequenced. The Integrative Conjugative Element (ICE), found in many bacterial species, contains genes for transfer via conjugation and integration into the chromosome, along with various cargo genes. ICEs are identified in 31 of 36 strains and categorized into three types based on architecture of modular genes, integrases, and integration sites. ICE distribution in different strains displays no spatial and temporal patterns. Several ICE-containing strains also possessed CRISPR-Cas units, considered to be the bacterial adaptive immune system providing protection against phage and predatory mobile genetic elements. This co-existence suggests that ICEs are beneficial or at least not harmful to the bacterial cells they inhabit. ICEs as a component of the mobile genetic repertoire enable recipients to resist antibiotics, survive disinfecting agents, and adapt to various ecological niches.
Deep Learning for Quality Control of Subcortical Brain 3D Shape Models
Authors:   The ENIGMA Consortium, Petrov Dmitry , Gutman Boris A. , Kuznetsov Egor , van Erp Theo G.M. , Turner Jessica A. , Schmaal Lianne , Veltman Dick , Wang Lei , Alpert Kathryn , Isaev Dmitry , Zavaliangos-Petropulu Artemis , Ching Christopher R.K. , Calhoun Vince , Glahn David , Satterthwaite Theodore D. , Andreassen Ole Andreas , Borgwardt Stefan , Howells Fleur , Groenewold Nynke , Voineskos Aristotle , Radua Joaquim , Potkin Steven G. , Crespo-Facorro Benedicto , Tordesillas-Gutirrez Diana , Shen Li , Lebedeva Irina , Spalletta Gianfranco , Donohoe Gary , Kochunov Peter , Rosa Pedro G.P. , James Anthony , Dannlowski Udo , Baune Bernhard T. , Aleman Andr , Gotlib Ian H. , Walter Henrik , Walter Martin , Soares Jair C. , Ehrlich Stefan , Gur Ruben C. , Doan N. Trung , Agartz Ingrid , Westlye Lars T. , Harrisberger Fabienne , Riecher-Rössler Anita , Uhlmann Anne , Stein Dan J. , Dickie Erin W. , Pomarol-Clotet Edith , Fuentes-Claramonte Paola , Canales-Rodrguez Erick Jorge , Salvador Raymond , Huang Alexander J. , Roiz-Santiaez Roberto , Cong Shan , Tomyshev Alexander , Piras Fabrizio , Vecchio Daniela , Banaj Nerisa , Ciullo Valentina , Hong Elliot , Busatto Geraldo , Zanetti Marcus V. , Serpa Mauricio H. , Cervenka Simon , Kelly Sinead , Grotegerd Dominik , Sacchet Matthew D. , Veer Ilya M. , Li Meng , Wu Mon-Ju , Irungu Benson , Walton Esther , Thompson Paul M. ,   for the ENIGMA consortium
Published: August 2018

We present several deep learning models for assessing the morphometric fidelity of deep grey matter region models extracted from brain MRI. We test three different convolutional neural net architectures (VGGNet, ResNet and Inception) over 2D maps of geometric features. Further, we present a novel geometry feature augmentation technique based on parametric spherical mapping. Finally, we present an approach for model decision visualization, allowing human raters to see the areas of subcortical shapes most likely to be deemed of failing quality by the machine. Our training data is comprised of 5200 subjects from the ENIGMA Schizophrenia MRI cohorts, and our test dataset contains 1500 subjects from the ENIGMA Major Depressive Disorder cohorts. Our final models reduce human rater time by 46-70%. ResNet outperforms VGGNet and Inception for all of our predictive tasks.
Superresolution architecture of pluripotency guarding adhesions
Authors: Stubb Aki , Guzmán Camilo , Närvä Elisa , Aaron Jesse , Chew Teng-Leong , Saari Markku , Miihkinen Mitro , Jacquemet Guillaume , Ivaska Johanna
Published: August 2018

Human pluripotent stem cells (hPSC) can generate almost all adult cell lineages. While it is clear that key transcriptional programmes are important elements for maintaining pluripotency, the equally essential requirement for cell adhesion to specific extracellular matrix components remains poorly defined. Our recent observation that hPSC colonies form unusually large “cornerstone” focal adhesions (FA), distinct from parental somatic cells, that are lost following differentiation, emphasises the potential of these atypical FA as gatekeepers of pluripotency. Here, using nanopatterns, we further demonstrate that physical restriction of adhesion size, in hPSC colonies, is sufficient to trigger differentiation. Using superresolution two-colour interfero-metric photo-activated localization microscopy (iPALM), we examined the three-dimensional architecture of these cornerstone adhesions and report vertical lamination of FA proteins with three main structural peculiarities: 1) integrin β5 and talin are present at high density, at the edges of cornerstone FA, adjacent to a vertical kank-rich protein wall. 2) Vinculin localises higher than expected with respect to the substrata and displays a head-above-tail orientation, and 3) surprisingly, actin and α-actinin are present in two discrete layers, a previously undescribed localisation for these proteins. Finally, we report that depletion of kanks diminishes FA patterning, and actin organisation within the colony, indicating a key role for kanks in hPSC colony architecture.
Eco-evolutionary agriculture: a study in crop rotations
Authors: Bargués-Ribera Maria , Gokhale Chaitanya S.
Published: August 2018

Since its origins, thousands of years ago, agriculture has been challenged by the presence of evolving plant pathogens. In response, current practices have started relying on computational tools to design efficient prospective planning, but further efforts for multi-criteria assessment are needed. Here, we present a methodology for developing cultivation strategies optimal for control or eradication of pathogens. This approach can integrate both, traditionally used criteria in crop rotations and the analysis of host-pathogen coevolution systems where hosts are artificially selected. Our analysis shows that prospective planning can maximise cash yield in the long run by investing consecutively in soil quality during initial sea-sons. Importantly, rational application of crop rotation patterns can minimise yield loss in infected fields, despite the evolution of pathogen virulence. Our results provide strategies for optimal resource investment for increased food production and lead to further insights into minimisation of pesticide use in a society demanding efficient agriculture.
Pat1 promotes processing body assembly by enhancing the phase separation of the DEAD-box ATPase Dhh1 and RNA
Authors: Sachdev Ruchika , Hondele Maria , Linsenmeier Miriam , Vallotton Pascal , Mugler Christopher F. , Arosio Paolo , Weis Karsten
Published: August 2018

Processing bodies (PBs) are cytoplasmic mRNP granules that assemble via liquid-liquid phase separation and are implicated in the decay or storage of mRNAs. How PB assembly is regulated in cells remains unclear. We recently identified the ATPase activity of the DEAD-box protein Dhh1 as a key regulator of PB dynamics and demonstrated that Not1, an activator of the Dhh1 ATPase and member of the CCR4-NOT deadenylase complex inhibits PB assemblyin vivo[Mugler et al., 2016]. Here, we show that the PB component Pat1 antagonizes Not1 and promotes PB assembly via its direct interaction with Dhh1. Intriguingly,in vivoPB dynamics can be recapitulatedin vitro, since Pat1 enhances the phase separation of Dhh1 and RNA into liquid droplets, whereas Not1 reverses Pat1-Dhh1-RNA condensation. Overall, our results uncover a function of Pat1 in promoting the multimerization of Dhh1 on mRNA, thereby aiding the assembly of large multivalent mRNP granules that are PBs.
The effect of community dialogues and sensitization on patient reporting of adverse events in rural Uganda: uncontrolled before-after study
Authors: Ndagije Helen Byomire , Manirakiza Leonard , Kajungu Dan , Galiwango Edward , Kusemererwa Donna , Olsson Sten , Spinewine Anne , Speybroeck Niko
Published: August 2018

Background

The patients that experience adverse events are in the best position to report them, only if they were empowered to do so. Systematic community engagement and support to patients in a rural setting to monitor any potential harm from medicines should provide evidence for patient safety.

Methods

This paper describes an uncontrolled before and after study aimed at assessing the effect of a community engagement strategy, the Community Dialogues and Sensitization (CDS) intervention between January and April 2017, on the knowledge, attitude and practice of reporting adverse drug events by community members in the two eastern Ugandan districts. A representative cross-sectional baseline household survey was done prior to the intervention in September 2016 (n=1034) and the end-line survey (n=827) in July 2017.

Results

After implementation of the CDS intervention, there was an overall 20% (95% CI=16- 25) increase in awareness about adverse drug events in the community. The young people (15- 24 years) demonstrated a 41% (95% CI =31-52) increase and the un-educated showed a 50% (95% CI=37-63) increase in awareness about adverse drug events. The attitudes towards reporting increased overall by 5% in response to whether there was a need to report ADEs (95% CI =3-7). An overall 115% (95% CI =137-217) increase in the population that had ever experienced ADEs was also reported.

Conclusion

Our evaluation shows that the CDS intervention increases knowledge, improves attitudes by catalyzing discussions among community members and health workers on health issues and monitoring safety of medicines.
Biogeography of the savanna-like vegetation in hot dry valleys in southwestern China with reference to their floristic origin and evolution
Authors: Zhu Hua , Yan Lichun
Published: August 2018

Savanna-like vegetation and dry thickets occur in hot dry valleys across southwestern China. Here, the flora and biogeography of these vegetations are studied. Native seed plants of 3,217 species from 1,038 genera in 163 families are recorded from the hot dry valleys in SW China. The biogeographical elements with a tropical distribution contribute 57.18%, but the ones with a temperate distribution contribute 36.45% of the total genera of the flora. This shows that the flora has proliferated by temperate elements via their evolution, although the flora occur in tropical habitats in the hot dry valleys. Floristic divergence across these hot dry valleys is obvious. The floras in the Yuanjiang (the upper reaches of the Red River) and the Nujiang (the upper reaches of the Salween River) valleys are dominated by tropical elements (77.26% and 74.49 of the total genera, respectively), but the flora of the Jinshajiang (the upper reaches of the Yangtze River) valley is composed of half tropical (47.27%) and half temperate (44.96%) genera. Regarding floristic similarities, the Jinshajiang shows the highest similarity to the Yuanjiang although these river valleys are located a great distance from each other. Our results could be well explained from the geological events since the Cenozoic, such as the uplift of Himalayas, the extrusion of Indochina, the river capture of the Jinshajiang separating from the Yuanjiang, and the northward movement of the Burma Plate. Further floristic comparison between the flora in hot dry valleys of SW China and southern Africa supports the consideration that the flora of savanna-like vegetations of SW China could have floristic affinity to African savannas over the course of its evolutionary history by the Indian Plate from southern Africa colliding with Eurasia in the Cenozoic.
Electrical Fields Induced Inside the Rat Brain with Skin, Skull, and Dural Placements of the Current Injection Electrode
Authors: Asan Ahmet S. , Gok Sinan , Sahin Mesut
Published: August 2018

Transcranial electrical stimulation (tES) is rapidly becoming an indispensable clinical tool with its different forms. Animal data are crucially needed for better understanding of the underlying mechanisms of tES. For reproducibility of results in animal experiments, the electric fields (E-Fields) inside the brain parenchyma induced by the injected currents need to be predicted accurately. In this study, we measured the electrical fields in the rat brain perpendicular to the brain surface, i.e. vertical electric field (VE-field), when the stimulation electrode was placed over the skin, skull, or dura mater through a craniotomy hole. The E-field attenuation through the skin was a few times larger than that of the skull and the presence of skin substantially reduced the VE-field peak at the cortical surface near the electrode. The VE-field declined much quicker in the gray matter underneath the pial surface than it did in the white matter, and thus the large VE-fields were contained mostly in the gray matter. The transition at the gray/white matter border caused a significant peak in the VE-field, as well as at other local inhomogeneties. A conductivity value of 0.57 S/m is predicted as a global value for the whole brain by matching our VE-field measurements to the field profile given by analytical equations for volume conductors. Finally, insertion of the current return electrode into the shoulder, submandibular, and hind leg muscles had virtually no effects on the measured E-field amplitudes in the cortex underneath the epidural electrodes.
Over-expression of the photoperiod response regulatorZmCCT10modifies plant architecture, flowering time and inflorescence morphology in maize
Authors: Stephenson Elizabeth , Estrada Stacey , Meng Xin , Ourada Jesse , Muszynski Michael G. , Habben Jeffrey E. , Danilevskaya Olga N.
Published: August 2018

Maize originated as a tropical plant that required short days to transition from vegetative to reproductive development.ZmCCT10[CO, CONSTANS, CO-LIKEandTIMING OF CAB1(CCT) transcription factor family] is a photoperiod regulator and was identified as a major QTL controlling photoperiod sensitivity in maize. We modulated expression ofZmCCT10in transgenic maize using two constitutive promoters which cause differing expression levels. Transgenic plants over expressingZmCCT10with either promoter was delayed in their transition from vegetative to reproductive development but were not affected in their change from juvenile-to-adult vegetative growth. Strikingly, transgenic plants containing the stronger expressing construct had a very prolonged period of vegetative growth accompanied with dramatic modifications to plant architecture that impacted both vegetative and reproductive traits. These plants did not produced ears, but tassels were heavily branched, and more than half of the transgenic plants showed conversion of shoot apices into “bushy tops”, which were composed of vegetative reversion plantlets. Analysis of expression modules controlling the floral transition and meristem identity linked these networks to photoperiod dependent regulation, whereas phase change modules appeared to be photoperiod independent. Results from this study clarified the influence of the photoperiod pathway on vegetative and reproductive development and allowed to fine-tune the flowering time model for maize.
Temporally varying isotopic niche overlap of the invasive ctenophore Mnemiopsis leidyi with other zooplanktivores in the western Dutch Wadden Sea
Authors: Walraven Lodewijk van , Looijengoed Wouter van , Sarina Jung A. , Langenberg Victor T. , van der Veer Henk W.
Published: August 2018

The invasive ctenophore Mnemiopsis leidyi can be a major predator of zooplankton in areas where it has been introduced. In this study, the possible competition of M. leidyi with native macroplankton and nekton in the western Dutch Wadden Sea was investigated in March–August, 2011 by determining and comparing isotopic niches of zooplanktivores. Stable carbon and nitrogen isotope signatures were determined from tissue samples of fish, scyphozoa, hydromedusa, ctenophores, crustaceans and cephalopods. δ15N of M. leidyi was positively related to ctenophore size, suggesting that small ctenophores occupied a lower trophic level than large ones. A cluster analysis showed that in the spring and early summer period, when M. leidyi densities are low, average δ13C and δ15N ratios of the invasive M. leidyi were similar to those of most other gelatinous zooplankton and pelagic fish species sampled. At the beginning of the bloom period in August there was no overlap in isotopic niche of M. leidyi with that of any other pelagic zooplanktivore. During this month the population consisted mainly of larvae and juveniles with lower δ15N ratios. At present, M. leidyi appears not to be a significant competitor for other gelatinous zooplankton and fish species because the period of high diet overlap with other consumers was also the period in which M. leidyi was least abundant.
Access to and use of preventive intermittent treatment for Malaria during pregnancy: a qualitative study in Chókwè district, Southern Mozambique
Authors: Arnaldo Paulo , Cambe Isabel , Magasso Amílcar , Chicumbe Sérgio , Rovira-Vallbona Eduard , Rosanas-Urgell Anna , Enosse Sónia M.
Published: August 2018

Background

Malaria remains a significant health problem in Mozambique, particularly to pregnant women and children less than five years old. Intermittent preventive treatment is recommended for malaria prevention in pregnancy (IPTp). Despite the widespread use and cost-effectiveness of this intervention, the coverage remains low. In this study, we aimed to explore the factors limiting the access and use of IPTp-SP in Chókwè district.

Methods and findings

We used qualitative research methods through semi-structured interviews to collect data from 46 pregnant women and four health care staff from Chókwè, a rural area of southern Mozambique. Data were transcribed, manually coded and analysed using content and thematic method. Participants were not aware of pregnancy-related risks of malaria infection or the benefit of malaria prevention in pregnancy. Late and infrequently antenatal care (ANC) attendance, concerns about the long waiting time at ANC consultations,plus reluctance to disclose the pregnancy early, emerged as driving factors for inadequate IPTp delivery.

Conclusions

Pregnant women experience substantial barriers to receive adequate IPTp-SP dosing for malaria prevention. Poor awareness, non-compliance with ANC attendance and poor attitude of health care staff were main barriers to IPTp-SP delivery. There is a need to strengthen actions that improve awareness about malaria and prevention among pregnant women, as well as quality services across the ANC services in order to increase IPTp-SP uptake.
A natural history model for planning prostate cancer testing: calibration and validation using Swedish registry data
Authors: Karlsson Andreas , Jauhiainen Alexandra , Gulati Roman , Eklund Martin , Grönberg Henrik , Etzioni Ruth , Clements Mark
Published: August 2018

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history.

An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register.

After calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC.

Using the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55–69 years was predicted to reduce prostate cancer incidence by 0.11% with no increase in the mortality rate. The model is open source and suitable for planning for effective prostate cancer screening into the future.

Author summary

A naïve perspective is that cancer screening is simple: people are screened, some cancers are detected early, and cancer mortality rates decline. However, the mathematics for screening becomes difficult quickly, it is hard to infer causation from observational data, and even large randomised screening studies provide limited evidence. Simulations are therefore important for planning cancer screening.

We found an older US prostate cancer natural history model to be poorly suited for contemporary Sweden. We therefore re-implemented and re-calibrated the US model using data from Swedish registries.

Our revised model, the Stockholm “Prostata” model, provides predictions similar to those observed in the detailed Swedish registers on prostate cancer incidence and mortality. By modelling the mechanisms of the screening effect, we can predict the benefits and harms under a range of screening interventions.