bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanics of CaMKII-actin networks
Authors: Khan Shahid , Downing Kenneth H. , Molloy Justin E.
Published: May 2018

Calcium calmodulin dependent kinase (CaMKII) has an important role in dendritic spine remodelling upon synaptic stimulation. Using fluorescence video microscopy and image analysis, we investigated the architectural dynamics of rhodamine-phalloidin stabilized F-actin networks cross-linked by CaMKII. We used automated image analysis to identify F-actin bundles and cross-over junctions and developed a dimensionless metric to characterize network architecture. Similar networks were formed by three different CaMKII species with ten-fold length difference in the linker region between the kinase domain and holoenzyme hub; implying linker length is not a primary determinant of F-actin binding. Electron micrographs showed that, at physiological molar ratios, single CaMKII holoenzymes cross-linked multiple F-actin filaments in random networks, whereas at higher CaMKII / F-actin ratios filaments bundled. Light microscopy established that random networks resisted macromolecular crowding, with polyethylene glycol mimicking cytoplasmic osmolarity, and blocked ATP-powered compaction by myosin-2 mini-filaments. Importantly, the networks disassembled following addition of calcium calmodulin and were then rapidly spaced into compacted foci by myosin motors or, more slowly, aggregated by crowding. Single molecule TIRF microscopy showed CaMKII dissociation from surface-immobilized G-actin exhibited a mono-exponential dwell-time distribution, whereas CaMKII bound to F-actin networks had a long-lived fraction, trapped at cross-over junctions. Release of CaMKII from F-actin, triggered by calcium calmodulin did not require ATP (hence phosphorylation) and was too rapid to measure with video-rate imaging. The residual bound-fraction was reduced substantially upon addition of an NMDA receptor peptide analogue. These results provide mechanistic insights to CaMKII-actin interactions at the collective network and single molecule level. Our findings argue that CaMKII-actin networks in dendritic spines are stable enough to protect the basal network architecture against physical stress but once CaMKII is disengaged by calcium calmodulin and sequestered by receptors at the synapse; F-actin compaction by myosin motors stabilizes the expanded spine compatible with the recorded times.
Measurement of infection efficiency of a major wheat pathogen using time-resolved imaging of disease progress
Authors: Karisto P. , Dora S. , Mikaberidze A.
Published: May 2018

Infection efficiency is a key epidemiological parameter that determines the proportion of pathogen spores able to infect and cause lesions once they have landed on a susceptible plant tissue. In this study, we present an improved method to measure infection efficiency of Zymoseptoria tritici using a replicated greenhouse experiment. Z. tritici is a fungal pathogen that infects wheat leaves and causes Septoria tritici blotch (STB), a major disease of wheat worldwide.

We devised an original experimental setup, where we (i) attached living wheat leaves to metal plates allowing for time-resolved imaging of disease progress in planta. Since lesions were continuously appearing, expanding and merging during the period of up to three weeks, daily measurements were necessary for accurate counting of lesions. We also (ii) used reference membranes to characterize the density and the spatial distribution of inoculated spores on leaf surfaces. In this way, we captured the relationship between the number of lesions and the number of viable spores deposited on the leaves and estimated the infection efficiency of about 4 % from the slope of this relationship.

Our study provides a proof of principle for an accurate and reliable measurement of infection efficiency of Z. tritici. The method opens opportunities for determining the genetic basis of the component of quantitative resistance that suppresses infection efficiency. This knowledge would improve breeding for quantitative resistance against STB, a control measure considered more durable than deployment of major resistance genes.
Equivalence of the Erlang Seir Epidemic Model and the Renewal Equation
Authors: Champredon David , Dushoff Jonathan , Earn David J.D.
Published: May 2018

Most compartmental epidemic models can be represented using the Euler-Lotka renewal equation (RE). The value of the RE is not widely appreciated in the epidemiological modelling community, perhaps because its equivalence to standard models has not been presented rigorously in non-trivial cases. Here, we provide analytical expressions for the intrinsic generation interval distribution that must be used in the RE in order to yield epidemic dynamics that are identical to those of the susceptible-exposed-infectious-recovered (SEIR) compartmental model with Erlang-distributed latent and infectious periods. This class of models includes the standard (exponentially-distributed) SIR and SEIR models as special cases.
The apical region of the herpes simplex virus major capsid protein promotes capsid maturation
Authors: Ruhge Laura L. , Huet Alexis G. E. , Conway James F. , Smith Gregory A.
Published: May 2018

The herpesvirus capsid assembles in the nucleus as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown, but it is dependent upon activation of the VP24 internal protease. Scaffold cleavage triggers angularization of the shell and its decoration with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and mature angularized capsid, the apical region of the major capsid protein (VP5) is surface exposed. We investigated whether the VP5 apical region contributes to intracellular transport dynamics following entry into primary sensory neurons and also tested the hypothesis that conserved negatively-charged amino acids in the apical region contribute to VP26 acquisition. To our surprise neither hypothesis proved true. Instead, mutation of glutamic acid residues in the apical region delayed viral propagation and induced focal capsid accumulations in nuclei. Examination of capsid morphogenesis based on epitope unmasking, capsid composition, and ultrastructural analysis indicated that these clusters consisted of procapsids. The results demonstrate that, in addition to established events that occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis and maturation.
The potassium channel KCNJ13 is essential for smooth muscle cytoskeletal organization during mouse tracheal tubulogenesis
Authors: Yin Wenguang , Kim Hyun-Taek , Wang ShengPeng , Gunawan Felix , Wang Lei , Kishimoto Keishi , Zhong Hua , Roman Dany , Preussner Jens , Guenther Stefan , Graef Viola , Buettner Carmen , Grohmann Beate , Looso Mario , Morimoto Mitsuru , Mardon Graeme , Offermanns Stefan , Stainier Didier Y.R.
Published: May 2018

Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13 mutant trachea phenotypes. These results provide insights into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Agent-Based Modeling Reveals Possible Mechanisms for Observed Aggregation Cell Behaviors inMyxococcus xanthus
Authors: Zhang Zhaoyang , Igoshin Oleg A. , Cotter Christopher R. , Shimkets Lawrence J.
Published: May 2018

Myxococcus xanthusis a soil bacterium that serves as a model system for biological self-organization. Cells form distinct, dynamic patterns depending on environmental conditions. An agent-based model (ABM) was used to understand howM. xanthuscells aggregate into multicellular mounds in response to starvation. In this model, each cell is modeled as an agent, represented by a point-particle and characterized by its position and moving direction. At low agent density, the model recapitulates the dynamic patterns observed by experiments and a previous biophysical model. To study aggregation at high cell density, we extended the model based on the recent experimental observation that cells exhibit biased movement towards aggregates. We tested two possible mechanisms for this biased movement and demonstrate that a chemotaxis model with adaptation can reproduce the observed experimental results leading to the formation of stable aggregates. Furthermore, our model reproduces the experimentally observed patterns of cell alignment around aggregates.

Author summary

Collective self-organization of cells into multicellular structures is important for lifestyle of many bacterial species.Myxococcus xanthusbacterium is a model system for studying this self-organization. In this work, we investigate how in response to starvationM. xanthuscells aggregate into multicellular mounds. A recent study identified the key cellular behaviors that are necessarily for the aggregation but the mechanisms of these behaviors remained unclear. To uncover these mechanisms, we developed a computational model that simulates interactions among a large number of cells. The results demonstrate that the observed bias in the cell reversal times as they move towards the aggregates can be explained by chemotaxis model. In this model cells secrete a chemical signal and respond to it via a partially-adapting biochemical network. The resulting aggregation dynamics are in good agreement with the experiments. Furthermore, chemotaxis signaling model reproduces the experimentally observed patterns of cell alignment around aggregates. On the other hand, an alternative model, based on contact-dependent signaling between cells, fails to aid in aggregation. Thus our models make important predictions about the cellular interactions that drives multicellular aggregation and can serve as a basis to investigate a wider range of developmental mutant strains.
Dorsal/NF-κB exhibits a dorsal-to-ventral mobility gradient in the Drosophila embryo
Authors: Al Asafen Hadel , Clark Natalie M. , Goyal Etika , Jacobsen Thomas , Dima Sadia Siddika , Chen Hung-Yuan , Sozzani Rosangela , Reeves Gregory T.
Published: May 2018

Morphogen-mediated patterning is a highly dynamic developmental process. To obtain an accurate understanding of morphogen gradient formation and downstream gene expression, biophysical parameters such as protein mobilities must be quantifiedin vivo. The dorsal-ventral (DV) patterning of earlyDrosophilaembryos by the NF-κB homolog Dorsal (Dl) is an excellent system for understanding morphogen gradient formation. Dl gradient formation is controlled by the inhibitor Cactus/IκB (Cact), which regulates the nuclear import and diffusion of Dl protein. However, quantitative measurements of Dl mobility and binding are currently lacking. Here, we use scanning fluorescence correlation spectroscopy to quantify the mobility of GFP-tagged Dl. We find that the DNA binding of Dl-GFP, which affects its mobility, varies along the DV axis, with highest DNA binding on the ventral side. Moreover, we also observe that the time scale for Dl-GFP to exit the nucleus is longer in the ventral and lateral regions of the embryo, which is consistent with stronger DNA binding. Using analysis of mutant alleles ofdltagged with GFP, we conclude that Dl-GFP/Cact interactions in the nuclei are responsible for the variation in Dl-GFP/DNA binding along the DV axis, which impacts our understanding of the spatial range of the Dl gradient and the robustness and precision of downstream gene expression. Thus, our results highlight the complexity of morphogen gradient dynamics and the ability of quantitative measurements of biophysical interactions to drive biological discovery.
A high-density carbon fiber neural recording array technology
Authors: Massey Travis L , Santacruz Samantha R , Hou Jason F , Pister Kristofer SJ , Carmena Jose M , Maharbiz Michel M
Published: May 2018

Objective: Microwire and Utah-style neural recording arrays are the predominant devices used for cortical neural recording, but the implanted electrodes cause a significant adverse biological response and suffer from well-studied performance degradation. Recent work has demonstrated that carbon fiber electrodes do not elicit this same adverse response, but these existing designs are not practically scalable to hundreds or thousands of recording sites. We present technology that overcomes these issues while additionally providing fine electrode pitch for spatial oversampling.

Approach: We present a 32-channel carbon fiber monofilament-based intracortical neural recording array fabricated through a combination of bulk silicon microfabrication processing and microassembly. This device represents the first truly two-dimensional carbon fiber neural recording array. The density, channel count, and size scale of this array are enabled by an out-of-plane microassembly technique in which individual fibers are inserted through metallized and isotropically conductive adhesive-filled holes in an oxide-passivated microfabricated silicon substrate.

Main results: Five-micron diameter fibers are spaced at a pitch of 38 microns, four times denser than state of the art one-dimensional arrays. The fine diameter of the carbon fibers affords both minimal cross-section and nearly three orders of magnitude greater lateral compliance than standard tungsten microwires. Typical 1 kHz impedances are on the order of hundreds of kiloohms, and successful in vivo recording is demonstrated in the motor cortex of a rat. 22 total units are recorded on 20 channels, with unit SNR ranging from 0.85 to 4.2.

Significance: This is the highest density microwire-style electrode array to date, and this fabrication technique is scalable to a larger number of electrodes and allows for the potential future integration of microelectronics. Large-scale carbon fiber neural recording arrays are a promising technology for reducing the inflammatory response and increasing the information density, particularly in neural recording applications where microwire arrays are already used.
Acute-phase CD4+ T cell responses targeting invariant viral regions are associated with control of live-attenuated simian immunodeficiency virus
Authors: Sutton Matthew S. , Ellis-Connell Amy , Moriarty Ryan V. , Balgeman Alexis J. , Gellerup Dane , Barry Gabrielle , Weiler Andrea M. , Friedrich Thomas C. , O’Connor Shelby L.
Published: May 2018

We manipulated SIVmac239Δnef, a model of MHC-independent viral control, to evaluate characteristics of effective cellular responses mounted by Mauritian cynomolgus macaques (MCMs) who express the M3 MHC haplotype that has been associated with poor control of pathogenic SIV. We created SIVΔnef-8x to test the hypothesis that effective SIV-specific T cell responses targeting invariant viral regions can emerge in the absence of immunodominant CD8+ T cell responses targeting variable epitopes, and that control is achievable in individuals lacking known protective MHC alleles. Full proteome IFNγ ELISPOT assays identified six newly targeted immunogenic regions following SIVΔnef-8x infection of M3/M3 MCMs. We deep sequenced circulating virus and found that four of the six newly targeted regions rarely accumulated mutations. Six animals infected with SIVΔnef-8x targeted at least one of the four invariant regions and had a lower set point viral load compared to two animals that did not target any invariant regions. We found that MHC class II molecules restricted all four of the invariant peptide regions, while the two variable regions were restricted by MHC class I molecules. Therefore, in the absence of immunodominant CD8+ T cell responses that target variable regions during SIVmac239Δnef infection, individuals without ‘protective’ MHC alleles developed predominantly CD4+ T cell responses specific for invariant regions that may improve control of virus replication. Our results provide some evidence that antiviral CD4+ T cells during acute SIV infection can contribute to effective viral control and should be considered in strategies to combat HIV infection.

Importance

Studies defining effective cellular immune responses to human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have largely focused on a rare population that express specific MHC class I alleles and control virus replication in the absence of antiretroviral treatment. This leaves in question whether similar effective immune responses can be achieved in the larger population. The majority of HIV-infected individuals mount CD8+ T cell responses that target variable viral regions that accumulate high-frequency escape mutations. Limiting T cell responses to these variable regions and targeting invariant viral regions, similar to observations in rare ‘elite controllers’, may provide an ideal strategy for the development of effective T cell responses in individuals with diverse MHC genetics. Therefore, it is paramount to determine whether T cell responses can be redirected towards invariant viral regions in individuals without ‘protective’ MHC alleles and if these responses improve control of virus replication.
Two-photon imaging induces brain heating and calcium microdomain hyperactivity in cortical astrocytes
Authors: Schmidt Elke , Oheim Martin
Published: May 2018

Unraveling how neural networks process and represent sensory information and how this cellular dynamics instructs behavioral output is a main goal in current neuroscience. Two-photon activation of optogenetic actuators and fluorescence calcium (Ca2+) imaging with genetically encoded Ca2+ indicators allow, respectively, the all-optical stimulation and readout of activity from genetically identified cell populations. However, these techniques expose the brain to high near-infrared light doses raising the concern of light-induced adverse effects on the biological phenomena being studied. Combing Ca2+ imaging of GCaMP6f-expressing cortical astrocytes as a sensitive readout for photodamage and an unbiased machine-based event detection, we demonstrate the subtle build-up of aberrant microdomain Ca2+ signals in fine astroglial processes. Illumination conditions routinely being used in biological two-photon microscopy (920-nm excitation, 100-fs regime, ten mW average power) increased the frequency of microdomain Ca2+ events, but left their amplitude, area and duration rather unchanged. This increase in local Ca2+ activity was followed by Ca2+ transients in the otherwise silent soma. Ca2+ hyperactivity occurred without overt morphological damage. Surprisingly, at the same average power, continuous-wave 920-nm illumination was as damaging as fs pulses, indicating a linear, heating-mediated (rather than a highly non-linear) damage mechanism. In an astrocyte-specific IP3-receptor knock-out mouse (IP3R2-KO), Near-infrared light-induced Ca2+ microdomains signals persisted in the small processes, underpinning their resemblance to physiological IP3R2-independent Ca2+ signals, while somatic activity was abolished. Contrary to what has generally been believed in the field, shorter pulses and lower average power are advantageous to alleviate photodamage and allow for longer useful recording windows.

SIGNIFICANCE STATEMENT

Imaging the fine structure and function of the brain has become possible with two-photon microscopy that uses ultrashort-pulsed infrared laser light for better tissue penetration. The high peak energy of these light pulses has raised concerns about photodamage resulting from multi-photon processes. Here, we show that the time-averaged rather than the peak laser power matters. At wavelengths and with laser powers now commonly used in neuroscience brain damage occurs as a consequence of direct infrared light absorption, i.e., heating. To counteract brain heating we explore a strategy that uses even shorter, more energetic pulses but a lower time-averaged laser power to produce the same image quality while making two-photon microscopy less invasive.
Ecdysone signaling promotes expression of multifunctional RNA binding proteins essential for ovarian germline stem cell self-renewal inDrosophila
Authors: Finger Danielle S. , Holt Vivian V. , Ables Elizabeth T.
Published: May 2018

Steroid hormones promote stem cell self-renewal in many tissues; however, the molecular mechanisms by which hormone signaling is integrated with niche-derived signals are largely uncharacterized. In theDrosophilaovary, the steroid hormone ecdysone promotes germline stem cell (GSC) self-renewal. Despite strong evidence that ecdysone modulates the reception of bone morphogenetic protein (BMP) signals in GSCs, transcriptional targets of ecdysone signaling that facilitate BMP reception are unknown. Here, we report that ecdysone signaling promotes the expression of the heterogeneous nuclear ribonucleoproteins (hnRNPs)squid,hephaestus,Hrb27C, andHrb87Fin GSCs. These hnRNPs functionally interact with ecdysone signaling to control GSC number and are cell autonomously required in GSCs for their maintenance. We demonstrate that hnRNPs promote GSC self-renewal by binding to transcripts essential for proper BMP signaling, including the BMP receptorsthickveinsandpunt. Our findings support the model that stem cells coordinate local and long-range signals at the transcriptional and post-transcriptional levels to maintain self-renewal in response to physiological demand.

GRAPHICAL ABSTRACT

Ecdysone signaling regulates distinct hnRNPs that bind to BMP signaling targets to control GSC self-renewal.

SUMMARY STATEMENT

Ecdysone signaling promotes expression of heterogeneous ribonucleoproteins that modulate BMP-dependent germline stem cell self-renewal in theDrosophilaovary.
A map of climate change-driven natural selection in Arabidopsis thaliana
Authors: Exposito-Alonso Moises ,   500 Genomes Field Experiment Team, Burbano Hernán A. , Bossdorf Oliver , Nielsen Rasmus , Weigel Detlef
Published: May 2018

Through the lens of evolution, climate change is an agent of natural selection that forces populations to change and adapt, or face extinction. Current assessments of the risk of biodiversity associated with climate change1, however, do not typically take into account the genetic makeup of populations and how natural selection impacts it2. We made use of the extensive genome information in Arabidopsis thaliana and measured how rainfall-manipulation affected the fitness of 517 natural lines grown in Spain and Germany. This allowed us to directly infer selection along the genome3. Natural selection was particularly strong in the hot-dry Spanish location, killing 63% of lines and significantly changing the frequency of ~5% of all genome-wide variants. A significant portion of this climate-driven natural selection over variants was predictable from signatures of local adaptation (R2=29-52%), as genetic variants found in geographic areas with climates more similar to the experimental sites were positively selected. Field-validated predictions across the species range indicated that Mediterranean and Western Siberian populations — at the edges of the species’ environmental limits — currently experience the strongest climate-driven selection. With more frequent droughts and rising temperatures in Europe4, we forecast an increase in directional natural selection moving northwards from the southern end, and putting many native A. thaliana populations at evolutionary risk.
Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9
Authors: Agudelo Daniel , Carter Sophie , Velimirovic Minja , Duringer Alexis , Levesque Sébastien , Rivest Jean-François , Loehr Jeremy , Mouchiroud Mathilde , Cyr Denis , Waters Paula J , Laplante Mathieu , Moineau Sylvain , Goulet Adeline , Doyon Yannick
Published: May 2018

Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.
Putting hands to rest: efficient deep CNN-RNN architecture for chemical named entity recognition with no hand-crafted rules
Authors: Korvigo Ilia , Holmatov Maxim , Zaikovskii Anatolii , Skoblov Mikhail
Published: May 2018

Chemical named entity recognition (NER) is an active field of research in biomedical natural language processing. To facilitate the development of new and superior chemical NER systems, BioCreative released the CHEMDNER corpus, an extensive dataset of diverse manually annotated chemical entities. Most of the systems trained on the corpus rely on complicated hand-crafted rules or curated databases for data preprocessing, feature extraction and output post-processing, though modern machine learning algorithms, such as deep neural networks, can automatically design the rules with little to none human intervention. Here we explored this approach by experimenting with various deep learning architectures for targeted tokenisation and named entity recognition. Our final model, based on a combination of convolutional and stateful recurrent neural networks with attention-like loops and hybrid word-and character-level embeddings, reaches near human-level performance on the testing dataset with no manually asserted rules. To make our model easily accessible for standalone use and integration in third-party software, we’ve developed a Python package with a minimalistic user interface.
Protein biocargo of citrus fruit-derived vesicles reveals heterogeneous transport and extracellular vesicles populations
Authors: Pocsfalvi Gabriella , Turiák Lilla , Ambrosone Alfredo , del Gaudio Pasquale , Puska Gina , Fiume Immacolata , Silvestre Teresa , Vékey Károly
Published: May 2018

Cellular vesicles are membrane-enclosed organelles that transport material inside and outside the cell. Plant-derived vesicles are receiving increasing attention due to their potential as nanovectors for the delivery of biologically active substances. We aimed to expand our understanding about the heterogeneity and the protein biocargo of citrus fruit juice sac cell-derived vesicles. Micro- and nanosized vesicle fractions were isolated from four citrus species,C. sinensis,C. limon,C. paradisiandC. aurantium, characterized using physicochemical methods and protein cargos were compared using label-free quantitative shotgun proteomics. In each sample approximately 600-800 proteins were identified. Orthologues of most of the top-ranking proteins have previously been reported in extracellular vesicles of mammalian origin. Patellin-3-like, clathrin heavy chain, heat shock proteins, 14-3-3 protein, glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase 6 were highly expressed in all citrus vesicle fractions. The presence of membrane channel aquaporin on the other hand characteristic of the nanovesicle fractions. Bioinformatics revealed more than hundred protein orthologues potentially implicated in vesicular trafficking. In particular, CCV, COPI and COPII coat proteins indicates the presence of highly heterogeneous populations of intracellular transport vesicles. Moreover, the different hydrolases and oxidoreductases transported within the citrus fruit-derived vesicles can be responsible for the various biological activities possessed by the preparations.

Abbreviations

EVs

extracellular vesicles;

MVs

microvesicles;

NVs

nanovesicles;

PM

plasma membrane;

UC

ultracentrifugation;

CCV

clathrin coated vesicles;

COPI

coat protein I;

COPII

coat protein II
PP2ARts1enforces a proportional relationship between cell size and growth rate
Authors: Leitao Ricardo M. , Pham Annie , Okobi Quincy , Kellogg Douglas R.
Published: May 2018

Cell size is proportional to growth rate. Thus, cells growing slowly in poor nutrients can be nearly half the size of cells growing rapidly in rich nutrients. The relationship between cell size and growth rate appears to hold across all orders of life, yet the underlying mechanisms are unknown. In budding yeast, most growth occurs during mitosis, and the proportional relationship between cell size and growth rate is therefore enforced primarily by modulating growth in mitosis. When growth is slow, the duration of mitosis is increased to allow more time for growth, yet the amount of growth required to complete mitosis is reduced, leading to birth of small daughter cells. Previous studies found that PP2A associated with the Rts1 regulatory subunit (PP2ARts1) works in a TORC2-dependent feedback loop that sets cell size and growth rate to match nutrient availability. However, it was unknown whether PP2ARts1influences growth in mitosis. Here, we show that PP2ARts1is required for the proportional relationship between cell size and growth rate during mitosis. Moreover, nutrients and PP2ARts1influence the duration of mitosis, and thus the extent of growth in mitosis, via Wee1 and Pds1/securin, two conserved regulators of mitotic progression. Together, the data suggest a model in which the same global signals that set growth rate also set the critical amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for the proportional relationship between size and growth rate.
Extracellular Vesicle-delivered Bone Morphogenetic Proteins: A novel paracrine mechanism during embryonic development
Authors: Draebing Thomas , Heigwer Jana , Juergensen Lonny , Katus Hugo Albert , Hassel David
Published: May 2018

Morphogens including Wnt, Hedgehog and BMP proteins are essential during embryonic development and early induction of organ progenitors. Besides free diffusion to form signalling gradients, extracellular vesicle- (EV-) mediated morphogen transport was identified as a central mechanism for Wnt- and Hh-signalling. Here, we investigated EVs isolated from whole zebrafish embryos as a potential morphogen transport mechanism. Inhibition of EV-secretion during development leads to severe dorsalization phenotypes, reminiscent of disrupted BMP-signalling. Subsequently, we found that EVs isolated from zebrafish embryos at bud stage contain biologically active BMP2/4 protein. Embryos with inhibited EV secretion display reduced Smad1/5/9-phosphorylation and downstream gene expression activity. We further show that BMP-containing EVs are secreted by endodermal cellsin vitro, and inhibition of endodermal-EV releasein vivocauses signs of BMP signalling loss. Our data provides evidence that establishes the transport of BMP2/4 by EVs as an essential but so far undiscovered mechanism in developmental morphogenesis.
Learning list concepts through program induction
Authors: Rule Joshua , Schulz Eric , Piantadosi Steven T. , Tenenbaum Joshua B.
Published: May 2018

Humans master complex systems of interrelated concepts like mathematics and natural language. Previous work suggests learning these systems relies on iteratively and directly revising a language-like conceptual representation. We introduce and assess a novel concept learning paradigm called Martha’s Magical Machines that captures complex relationships between concepts. We model human concept learning in this paradigm as a search in the space of term rewriting systems, previously developed as an abstract model of computation. Our model accurately predicts that participants learn some transformations more easily than others and that they learn harder concepts more easily using a bootstrapping curriculum focused on their compositional parts. Our results suggest that term rewriting systems may be a useful model of human conceptual representations.
Burst Synchronization in A Scale-Free Neuronal Network with Inhibitory Spike-Timing-Dependent Plasticity
Authors: Kim Sang-Yoon , Lim Woochang
Published: May 2018

We are concerned about burst synchronization (BS), related to neural information processes in health and disease, in the Barabasi-Albert scale-free network (SFN) composed of inhibitory bursting Hindmarsh-Rose neurons. This inhibitory neuronal population has adaptive dynamic synaptic strengths governed by the inhibitory spike-timing-dependent plasticity (iSTDP). In previous works without considering iSTDP, BS was found to appear in a range of noise intensities for fixed synaptic inhibition strengths. In contrast, in our present work, we take into consideration iSTDP and investigate its effect on BS by varying the noise intensity. Our new main result is to find occurrence of a Matthew effect in inhibitory synaptic plasticity: good BS gets better via LTD, while bad BS get worse via LTP. This kind of Matthew effect in inhibitory synaptic plasticity is in contrast to that in excitatory synaptic plasticity where good (bad) synchronization gets better (worse) via LTP (LTD). We note that, due to inhibition, the roles of LTD and LTP in inhibitory synaptic plasticity are reversed in comparison with those in excitatory synaptic plasticity. Moreover, emergences of LTD and LTP of synaptic inhibition strengths are intensively investigated via a microscopic method based on the distributions of time delays between the preand the post-synaptic burst onset times. Finally, in the presence of iSTDP we investigate the effects of network architecture on BS by varying the symmetric attachment degree l* and the asymmetry parameter Δl in the SFN.
Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified fromToxoplasma gondii
Authors: Salunke Rahul , Mourier Tobias , Banerjee Manidipa , Pain Arnab , Shanmugam Dhanasekaran
Published: May 2018

The mitochondrial F-type ATP synthase, a multi-subunit nanomotor, is critical for maintaining cellular ATP levels. InToxoplasma gondiiand other apicomplexan parasites, many subunit components, necessary for proper assembly and functioning of this enzyme, appear to be missing. Here, we report the identification of 20 novel subunits ofT. gondiiF-type ATP synthase from mass spectrometry analysis of partially purified monomeric (~600 kDa) and dimeric (>1 MDa) forms of the enzyme. Despite extreme sequence diversification, key FOsubunits, a, b and d, can be identified from conserved structural features. Orthologs for these proteins are restricted to apicomplexan, chromerid and dinoflagellate species. Interestingly, their absence in ciliates indicates a major diversion, with respect to subunit composition of this enzyme, within the alveolate clade. Discovery of these highly diversified novel components of the apicomplexan F-type ATP synthase complex could facilitate the development of novel anti-parasitic agents. Structural and functional characterization of this unusual enzyme complex will advance our fundamental understanding of energy metabolism in apicomplexan species.
The complex geography of domestication of the African riceOryza glaberrima
Authors: Choi Jae Young , Dorph Katherine , Purugganan Michael D.
Published: May 2018

While the domestication history of Asian rice has been extensively studied, details of the evolution of African rice remains elusive. The inner Niger delta has been suggested as the center of origin but molecular data for its support are lacking. Here, we present the most comprehensive analysis to date on the evolutionary and domestication history of African rice. By analyzing whole genome re-sequencing data from 282 individuals in domesticated African riceOryza glaberrimaand its progenitorO. barthii, we hypothesize a non-centric domestication origin for African rice. Our analyses show geographically based population structure inO. glaberrima, as well as significant evidence of admixture between genetic groups. Furthermore, we have evidence that the previously hypothesizedO. barthiiprogenitor populations in West Africa have evolutionary signatures similar to domesticated rice and carried causal domestication mutations, suggesting those progenitors may actually represent feral wild-domesticated hybrid rice. Demography modeling suggested the inlandO. glaberrimahad a protracted period of bottlenecking that preceded the coastal population by 800–1,800 years. Phylogeographic analysis of genes involved in the core domestication process suggests that the origins of causal domestication mutations could be traced to wild progenitors in multiple different locations in West and Central Africa. Based on our evidence, we hypothesizeO. glaberrimawas not domesticated from a single centric location but was rather a diffuse process where multiple regions contributed key alleles for different domestication traits.

Author Summary

For many crops it is not clear how they got domesticated from their wild progenitors. Transition from a wild to domesticated state required a series of genetic changes, and studying the evolutionary origin of these domestication-causing mutations are key to understanding the domestication origins of a crop. Moreover, population relationships within a crop holds insight into the evolutionary history of domestication and whether there was gene flow between different genetic groups. In this study, we investigate the domestication history ofOryza glaberrima, a rice species that was domesticated in West Africa independently from the Asian rice speciesO. sativa. Using genome-wide data from a large sample of domesticated and wild African rice samples we did not find evidence that supported the established domestication model forO. glaberrima—a single domestication origin. Rather, our evidence suggests the domestication process for African rice was initiated in multiple regions of West Africa, caused potentially by the local environmental and cultivation preference of people. Admixture between different genetic groups had facilitated the exchange and spread of core domestication mutations. Hence domestication of African rice was a multi-regional process.
CytoBinning: immunological insights from multi-dimensional data
Authors: Shen Yang , Chaigne-Delalande Benjamin , Lee Richard W.J. , Losert Wolfgang
Published: May 2018

New cytometric techniques continue to push the boundaries of multi-parameter quantitative data acquisition at the single-cell level particularly in immunology and medicine. Sophisticated analysis methods for such ever higher dimensional datasets are rapidly emerging, with advanced data representations and dimensional reduction approaches. However, these are not yet standardized and clinical scientists and cell biologists are not yet experienced in their interpretation. More fundamentally their range of statistical validity is not yet fully established. We therefore propose a new method for the automated and unbiased analysis of high-dimensional single cell datasets that is simple and robust, with the goal of reducing this complex information into a familiar 2D scatter plot representation that is of immediate utility to a range of biomedical and clinical settings. Using publicly available flow cytometry and mass cytometry datasets we demonstrate that this method (termed CytoBinning), recapitulates the results of traditional manual cytometric analyses and leads to new and testable hypotheses.
Thymidylate synthase maintains the de-differentiated state of aggressive breast cancers
Authors: Siddiqui Aarif , Gollavilli Paradesi , Schwab Annemarie , Vazakidou Maria Eleni , Ersan Pelin G , Ramakrishnan Mallika , Pluim Dick , Coggins Si′Ana , Saatci Ozge , Annaratone Laura , Schellens Jan HM , Kim Baek , Asangani Irfan Ahmed , Rasheed Suhail Ahmed Kabeer , Marchiò Caterina , Sahin Ozgur , Ceppi Paolo
Published: May 2018

Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC).In vitro, TS knockdown increased the population of CD24+differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated a repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasizein vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for the maintenance of the EMT/stem-like state by fueling a DPYD-dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC (TNBC), and strongly correlated with worse prognosis. The present study provides therationaleto study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.
Tyrosinase mediated humic substances synthesis by Bacillus aryabhattai TFG5
Authors: Muniraj Iniyakumar , Shameer Syed , Ramachandran Priyadarshini , Uhandi Sivakumar
Published: May 2018

The present investigation aims at understanding the mechanism of Humic Substances (HS) formation and enhancement through tyrosinase produced by Bacillus aryabhattai TFG5. A bacterium isolated from termite mound produced tyrosinase (1.34 U.ml−1) and laccase (2.1 U.ml−1) at 48 and 60 h of fermentation respectively. The protein from B. aryabhattai TFG5 was designated as TyrB and it had a predicted molecular weight of 35.23 kDa. Swiss modelling of protein revealed a bi copper protein with its conserved residues required for activity. Interestingly, TyrB efficiently transformed and polymerized standard phenols besides transforming free phenols of Coir pith Wash Water (CWW). In addition, spectroscopic evidences suggest that TyrB enhanced the HS production from coir pith biomass. Furthermore, degradative products and changes in biomass structure by TyrB analysed through FT-IR suggests that TyrB might follow the polyphenol theory of HS synthesis.
Prevalence and factors associated with Skilled Birth Attendants use among post-partum women in Arusha Tanzania
Authors: Shirima Febronia Lawrence , Komba Aurelia Severine , Msuya Sia E , Mahande Michael Johnson
Published: May 2018

Introduction

Death related to pregnancy complications and delivery remains a public health problem in developing countries including Tanzania where majority of women and newborns die each year due to preventable causes. Delivery with a skilled birth attendant (SBA) is an important intervention to avert maternal and newborn mortality. This study aimed to determine factors influencing skilled birth attendant’s use among postpartum women in Arusha city and Arumeru district in Arusha region.

Methods

This was a cross-sectional study which was conducted from April to July 2017. The study utilized secondary data from the parent study which was conducted in Arusha city and Arumeru district in Arusha region. The parent study aimed to assess knowledge of danger signs in obstetric complication, birth preparedness and utilization of skilled birth attendants among post-partum women in urban and rural Arusha region in Tanzania. Data analysis was performed using SPSS version 20. Chi square statistics was used to determine the association between a set of independent variables and utilization of skilled birth attendance in bivariate analysis. Odds ratios with 95% confidence interval for factors influencing skilled birth attendants’ use were estimated in a multivariable logistic regression models. A p-value of less than 0.05 was considered statistically significant.

Results

A total of 1218 post-partum women were studied. Their mean age was 26.2 (SD 5.9) years. Of these, 1020 used skilled birth attendants during delivery; this corresponds to prevalence of 83.7%. Mother’s education level, area of residence, distance from health facility, frequency of antenatal care and parity were significantly associated utilization of skilled birth attendants during delivery.

Conclusion

The prevalence of skilled birth attendants’ use among postpartum women is high in the studied population compared to the national level. Strategies to create community awareness on important of skilled birth attendants’ use will increase its uptake and my help to reduce both mother and child mortality.
SWI/SNF remains localized to chromatin in the presence of SCHLAP1
Authors: Raab Jesse R. , Smith Keriayn N. , Spear Camarie C. , Manner Carl J. , Calabrese J. Mauro , Magnuson Terry
Published: May 2018

SCHLAP1 is a long-noncoding RNA that is prognostic for progression to metastatic prostate cancer and promotes an invasive phenotype. SCHLAP1 is reported to function by depleting the core SWI/SNF subunit, SMARCB1, from the genome. SWI/SNF is a large, multi-subunit, chromatin remodeling complex that can be combinatorially assembled to yield hundreds to thousands of distinct complexes. Here, we investigated the hypothesis that SCHLAP1 affects only specific forms of SWI/SNF and that the remaining SWI/SNF complexes were important for the increased invasion in SCHLAP1 expressing prostate cells. Using several assays we found that SWI/SNF is not depleted from the genome by SCHLAP1 expression. We find that SCHLAP1 induces changes to chromatin openness but is not sufficient to drive changes in histone modifications. Additionally, we show that SWI/SNF binds many coding and non-coding RNAs. Together these results suggest that SCHLAP1 has roles independent of canonical SWI/SNF and that SWI/SNF broadly interacts with RNA.
Studies of Bending Effects of Microvilli of Leukocyte on Rolling Adhesion
Authors: Wu Tai-Hsien , Qi Dewei
Published: May 2018

It has been widely acknowledged that further understanding about the cell adhesion (e.g., leukocyte rolling adhesion) can help us gain more knowledge about the causes of relevant diseases and design more effective treatments and diagnoses. Although recent simulation studies considered the deformability of the leukocytes, most of them, however, did not consider the bending deformation of microvilli. In this paper, an advanced leukocyte model based on an immersed boundary lattice-Boltzmann lattice-spring model (LLM) and an adhesive dynamics (AD) is presented in details. The flexural stiffness of microvilli is introduced into the model for simulations of leukocyte rolling adhesion. This innovative model is applied to investigate the influences of bending deformation of microvilli on the process of leukocyte rolling adhesion and the underlying mechanism at different shear rates. It is demonstrated that the bending deformation of microvilli can be influenced by the flexural stiffness of microvilli and shear rates, resulting in the different rolling velocity of leukocytes, number of receptor-ligand bonds, and bond forces. The findings clearly indicate that the bending of microvilli plays a crucial role in the dynamics of leukocyte adhesion.