bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural color in Junonia butterflies evolves by tuning scale lamina thickness
Authors: Thayer Rachel C. , Allen Frances I. , Patel Nipam H.
Published: March 2019

In diverse organisms, nanostructures that coherently scatter light create structural color, but how such structures are built remains mysterious. We investigate the evolution and genetic regulation of butterfly scale laminae, which are simple photonic nanostructures. In a lineage of buckeye butterflies artificially selected for blue wing color, we found that thickened laminae caused a color shift from brown to blue. Deletion of the optix wing patterning gene also altered color via lamina thickening, revealing shared genetic regulation of pigments and lamina thickness. Finally, we show how lamina thickness variation contributes to the color diversity that distinguishes sexes and species throughout the genus Junonia. Thus, quantitatively tuning one dimension of scale architecture facilitates both the microevolution and macroevolution of a broad spectrum of hues. Because the lamina is an intrinsic component of typical butterfly scales, our findings suggest that tuning lamina thickness is a readily accessible mechanism to create structural color across the Lepidoptera.
Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases
Authors: Liu Ronghan , Chen Yuehong , Wang Shuya , Cui Yazhou , Zhang Xiangli , Lei Zi-Ning , Hettinghouse Aubryanna , Liu Jody , Fu Wenyu , Chen Zhe-Sheng , Liu Chuanju
Published: March 2019

TNF-α signaling plays a central role in the pathogenesis of various diseases, particularly autoimmune diseases. Screening of a library composed of FDA approved drugs led to the identification of Terfenadine and its active metabolite Fexofenadine as inhibitors of TNF-α signaling. Both Fexofenadine and Terfenadine inhibited TNF/NF-κB signaling in vitro and in vivo, and ameliorated disease symptoms in various autoimmune disease models, including TNF-α transgenic mice, collagen-induced arthritis, and inflammatory bowel disease. Subsequent studies identified cytosolic phospholipase A2 (cPLA2) as a novel target of Fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished Fexofenadine’s anti-TNF activity. Collectively, these findings not only provide new insights into the understanding of Fexofenadine action and underlying mechanism, but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly autoimmune diseases.
Metatranscriptomics as a tool to identify fungal species and subspecies in mixed communities
Authors: Marcelino Vanesa R. , Irinyi Laszlo , Eden John-Sebastian , Meyer Wieland , Holmes Edward C. , Sorrell Tania C.
Published: March 2019

High-throughput sequencing (HTS) enables the generation of large amounts of genome sequence data at a reasonable cost. Organisms in mixed microbial communities can now be sequenced and identified in a culture-independent way, usually using amplicon sequencing of a DNA barcode. Bulk RNA-seq (metatranscriptomics) has several advantages over DNA-based amplicon sequencing: it is less susceptible to amplification biases, it captures only living organisms, and it enables a larger set of genes to be used for taxonomic identification. Using a defined mock community comprised of 17 fungal isolates, we evaluated whether metatranscriptomics can accurately identify fungal species and subspecies in mixed communities. Overall, 72.9% of the RNA transcripts were classified, from which the vast majority (99.5%) were correctly identified at the species-level. Of the 15 species sequenced, 13 were retrieved and identified correctly. We also detected strain-level variation within theCryptococcusspecies complexes: 99.3% of transcripts assigned toCryptococcuswere classified as one of the four strains used in the mock community. Laboratory contaminants and/or misclassifications were diverse but represented only 0.44% of the transcripts. Hence, these results show that it is possible to obtain accurate species- and strain-level fungal identification from metatranscriptome data as long as taxa identified at low abundance are discarded to avoid false-positives derived from contamination or misclassifications. This study therefore establishes a base-line for the application of metatranscriptomics in clinical mycology and ecological studies.
Enhanced replication of mouse adenovirus type 1 following virus-induced degradation of protein kinase R (PKR)
Authors: Goodman Danielle E. , Pretto Carla D. , Krepostman Tomas A. , Carnahan Kelly E. , Spindler Katherine R.
Published: March 2019

Protein kinase R (PKR) plays a major role in activating host immunity during infection by sensing dsRNA produced by viruses. Once activated by dsRNA, PKR phosphorylates the translation factor eIF2α, halting cellular translation. Many viruses have methods of inhibiting PKR activation or its downstream effects, circumventing protein synthesis shutdown. These include sequestering dsRNA or producing proteins that bind to and inhibit PKR activation. Here we describe our finding that in multiple cell types, PKR was depleted during mouse adenovirus type 1 (MAV-1) infection. MAV-1 did not appear to be targeting PKR at a transcriptional or translational level because total PKR mRNA levels and levels of PKR mRNA bound to polysomes were unchanged or increased during MAV-1 infection. However, inhibiting the proteasome reduced the PKR depletion seen in MAV-1-infected cells, whereas inhibiting the lysosome had no effect. This suggests that proteasomal degradation alone is responsible for PKR degradation during MAV-1 infection. Time course experiments indicate that the degradation occurs early after infection. Infecting cells with UV-inactivated virus prevented PKR degradation, whereas inhibiting viral DNA replication did not. Together these results suggest that an early viral gene is responsible. Degradation of PKR is a rare mechanism to oppose PKR activity, and it has only been described in six RNA viruses. To our knowledge, this is the first example of a DNA virus counteracting PKR by degrading it.

Importance

The first line of defense in cells during viral infection is the innate immune system, which is activated by different viral products. PKR is a part of this innate immune system and is induced by interferon and activated by dsRNA produced by DNA and RNA viruses. PKR is such an important part of the antiviral response that many viral families have gene products to counteract its activation or the resulting effects of its activity. Although a few RNA viruses degrade PKR, this method of counteracting PKR has not been reported for any DNA viruses. MAV-1 does not encode virus-associated RNAs, a human adenoviral defense against PKR activation. Instead, MAV-1 degrades PKR, and it is the first DNA virus reported to do so. The innate immune evasion by PKR degradation is a previously unidentified way for a DNA virus to circumvent the host antiviral response.
Opposing modulation of Cx26 gap junctions and hemichannels by CO2
Authors: Nijjar Sarbjit , Maddison Daniel , Meigh Louise , de Wolf Elizabeth , Rodgers Thomas , Cann Martin , Dale Nicholas
Published: March 2019

Cx26 hemichannels open in response to moderate elevations of CO2(PCO255 mmHg) via a carbamylation reaction that depends on residues K125 and R104. Here we investigate the action of CO2on Cx26 gap junctions. Using a dye transfer assay, we found that an elevated PCO2of 55 mmHg greatly delayed the permeation of a fluorescent glucose analogue (NBDG) between HeLa cells coupled by Cx26 gap junctions. However, the mutations K125R or R104A abolished this effect of CO2. Whole cell recordings demonstrated that elevated CO2reduced the Cx26 gap junction conductance (median reduction 5.6 nS, 95% confidence interval, 3.2 to 11.9 nS) but had no effect on Cx26K125Ror Cx31 gap junctions. CO2can cause intracellular acidification, but using 30 mM propionate we found that acidification in the absence of a change in PCO2caused a median reduction in the gap junction conductance of 5.3 nS (2.8 to 8.3 nS). This effect of propionate was unaffected by the K125R mutation (median reduction 7.7 nS, 4.1 to 11.0 nS). pH-dependent and CO2-dependent closure of the gap junction are thus mechanistically independent. Mutations of Cx26 associated with the Keratitis Ichthyosis Deafness syndrome (N14K, A40V and A88V) also abolished the CO2-dependent gap junction closure. Elastic network modelling suggests that the lowest entropy state when CO2is bound, is the closed configuration for the gap junction but the open state for the hemichannel. The opposing actions of CO2on Cx26 gap junctions and hemichannels thus depend on the same residues and presumed carbamylation reaction.
Decomposing information into copying versus transformation
Authors: Kolchinsky Artemy , Corominas-Murtra Bernat
Published: March 2019

In many real-world systems, information can be transmitted in two qualitatively different ways: bycopyingor bytransformation. Copyingoccurs when messages are transmitted without modification, e.g., when an offspring receives an unaltered copy of a gene from its parent.Transformationoccurs when messages are modified systematically during transmission, e.g., when non-random mutations occur during biological reproduction. Standard information-theoretic measures do not distinguish these two modes of information transfer, although they may reflect different mechanisms and have different functional consequences. Starting from a few simple axioms, we derive a decomposition of mutual information into the information transmitted by copying and by transformation. Our decomposition applies whenever the source and destination of the channel have the same set of outcomes, so that a notion of message identity exists, although generalizations to other kinds of channels and similarity notions are explored. Furthermore, copy information can be interpreted as the minimal work needed by a physical copying process, relevant to better understand the physics of replication. We use the proposed decomposition to explore a model of amino acid substitution rates. Our results apply to any system in which the fidelity of copying, rather than simple predictability, is of critical relevance.
The role of feature-based attention in visual serial dependence
Authors: Fritsche Matthias , de Lange Floris P.
Published: March 2019

Perceptual decisions about current sensory input are biased towards input of the recent past – a phenomenon termed serial dependence. Serial dependence may serve to stabilize neural representations in the face of external and internal noise. However, it is unclear under which circumstances previous input attracts subsequent perceptual decisions, and thus, whether serial dependence reflects a broad smoothing or selective stabilization operation. Here, we investigated whether focusing attention on particular features of the previous stimulus modulates serial dependence. We found an attractive bias in orientation estimations when previous and current stimuli had similar orientations, and a repulsive bias when they had dissimilar orientations. The attractive bias was markedly reduced when observers attended to the size, rather than the orientation, of the previous stimulus. Conversely, the repulsive bias for stimuli with large orientation differences was not modulated by feature-based attention. This suggests separate sources of these positive and negative perceptual biases.
GABA-Glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep
Authors: Billwiller Francesca , Castillo Laura , Elseedy Heba , Ivanov Anton Ivanovich , Scapula Jennyfer , Ghestem Antoine , Carponcy Julien , Libourel Paul Antoine , Bras Hélène , Abdelmeguid Nabila ElSayed , Krook-Magnuson Esther , Soltesz Ivan , Bernard Christophe , Luppi Pierre-Hervé , Esclapez Monique
Published: March 2019

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to fully characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.

Significant statement

An increase of theta and gamma power in the dentate gyrus (DG) is an hallmark of paradoxical (REM) sleep (PS) and is suggested to promote learning and memory consolidation by synchronizing hippocampal networks and increasing its outputs to cortical targets. However the neuronal networks involved in such control of DG activity during PS are poorly understood. The present study identifies a population of GABA/Glutamate neurons in the lateral supramammllary nucleus (SuML) innervating the DG that could support such control during PS. Indeed, we show that activation of these SuML-DG projections increase theta power and frequency as well as gamma power in the DG specifically during PS and modulate activity of a subset of DG granule cells.
Exploiting the unwanted: sulphate reduction enables phosphate recovery from energy-rich sludge during anaerobic digestion
Authors: Lippens Celine , De Vrieze Jo
Published: March 2019

Anaerobic digestion is shifting from a single-purpose technology for renewable energy recovery from organic waste streams to a process for integrated resource recovery. The valorisation of high-rate energy- and phosphorus-rich sludge creates the opportunity for their combined recovery. This phosphate is present in a precipitated form in the sludge, and its release into the liquid phase is an important issue before recovery can be achieved. The objective of this research was to exploit the “unwanted” sulphate reduction process for the release of phosphate into the liquid phase during anaerobic digestion, thus, making it available for recovery. Two different treatments were considered,i.e., a control digester and a digester to which sulphate was added, each operated in triplicate for a period of 119 days. The control digester showed stable methane production at 628 ± 103 mL CH4L−1d−1, with a feedstock COD (chemical oxygen demand) conversion efficiency of 89.5 ± 14.6 %. In contrast, the digester with sulphate addition showed a 29.9 ± 15.3 % decrease in methane production, reaching an “inhibited steady state”, but phosphate release into the liquid phase increased with a factor 4.5, compared to the control digester. This inhibited steady state coincided with a clear shift from a Methanosaetaceae to a Methanosarcinaceae dominated methanogenic community. Overall, the sulphate reduction process allows phosphate release during the anaerobic digestion process, yet, at the cost of a reduced methane production rate.
CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors
Authors: Walens Andrea , DiMarco Ashley V. , Lupo Ryan , Kroger Benjamin R. , Damrauer Jeffrey S. , Alvarez James V.
Published: March 2019

Over half of breast cancer related deaths are due to recurrence five or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.
A Truly Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite
Authors: Trevathan James K. , Baumgart Ian W. , Nicolai Evan N. , Gosink Brian A. , Asp Anders J. , Settell Megan L. , Polaconda Shyam R. , Malerick Kevin D. , Brodnick Sarah K. , Zeng Weifeng , Knudsen Bruce E. , McConico Andrea L. , Sanger Zachary , Lee Jannifer H. , Aho Johnathon M. , Suminski Aaron J. , Ross Erika K. , Lujan J. Luis , Weber Douglas J. , Williams Justin C. , Franke Manfred , Ludwig Kip A. , Shoffstall Andrew J.
Published: March 2019

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, we have developed a novel electrode that begins as an uncured, flowable pre-polymer that can be injected around a neuroanatomical target to minimize surgical manipulation. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, we performed detailed electrochemical and microscopy characterization of its material properties and validated the feasibility of using it to electrically stimulate the nervous system in rats and swine. The silicone-metal-particle composite performed very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of being simpler than traditional electrode designs, less invasive, and more cost-effective, the Injectrode has the potential to increase the adoption of neuromodulation therapies for existing and new indications.
Fundamental Theory of the Evolution Force (FTEF): Gene Engineering utilizing Synthetic Evolution Artificial Intelligence (SYN-AI)
Authors: Davis L.K. , Uppu R.M.
Published: March 2019

The effects of the evolution force are observable in nature at all structural levels ranging from small molecular systems to conversely enormous biospheric systems. However, the evolution force and work associated with formation of biological structures has yet to be described mathematically or theoretically. In addressing the conundrum, we consider evolution from a unique perspective and in doing so we introduce “The fundamental Theory of the Evolution Force”. Whereby, the driving force of evolution is defined as a compulsion acting at the matter-energy interface that accomplishes genetic diversity while simultaneously conserving structure and function. By proof of concept, we attempt herein to characterize evolution force associated with genomic building block (GBB) formation utilizing synthetic evolution artificial intelligence (SYN-AI). As part of our methodology, we transform the DNA code into time dependent DNA codes based upon DNA hierarchical structural levels that allow evolution by the exchange of genetic information like the swapping of building blocks in a game of Legos. Notably, we not only theorize and mathematical describe the evolution force herein, but have written a set of 14-3-3 docking genes from scratch.
Modeling mechanisms of tremor reduction for essential tremor using symmetric biphasic DBS
Authors: Lee Shane , Asaad Wael F , Jones Stephanie R
Published: March 2019

Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4–10 Hz movement. For severe, medication refractory cases, deep brain stimulation (DBS) targeting the ventral intermediate nucleus of the thalamus (VIM) can be an effective treatment for cessation of tremor and is thought to work in part by disrupting tremor frequency oscillations (TFOs) in VIM. However, DBS is not universally effective and may be further disrupting cerebellar-mediated activity in the VIM. Here, we applied biophysically detailed computational modeling to investigate whether the efficacy of DBS is affected by the mechanism of generation of TFOs or by the pattern of stimulation. We simulated the effects of DBS using standard, asymmetric pulses as well as biphasic, symmetric pulses to understand biophysical mechanisms of how DBS disrupts TFOs generated either extrinsically or intrinsically. The model results suggested that the efficacy of DBS in the VIM is affected by the mechanism of generation of TFOs. Symmetric biphasic DBS reduced TFOs more than standard DBS in both networks, and these effects were stronger in the intrinsic network. For intrinsic tremor frequency activity, symmetric biphasic DBS was more effective at reducing TFOs. Simulated non-tremor signals were also transmitted during symmetric biphasic DBS, suggesting that this type of DBS may help to reduce side effects caused by disruption of the cerebellothalamocortical pathway. Biophysical details in the model provided a mechanistic interpretation of the cellular and network dynamics contributing to these effects that can be empirically tested in future studies.

Significance Statement

Essential tremor (ET) is a common movement disorder, whose primary symptom is an involuntary rhythmic movement of the limbs or head. An area of the human tha-lamus demonstrates electrical activity that oscillates at the frequencies of tremor, and deep brain stimulation (DBS) in this area can reduce tremor. It is not fully understood how DBS affects tremor frequency activity in the thalamus, and studying different patterns of DBS stimulation may help to clarify these mechanisms. We created a computational model of different shapes of DBS and studied how they reduce different hypothesized generators of tremor frequency activity. A greater understanding of how DBS affects the thalamus may lead to improved treatments to reduce tremor and alleviate side effects in patients with ET.
Modular tissue-specific regulation ofdoublesexunderpins sexually dimorphic development inDrosophila
Authors: Rice Gavin R. , Barmina Olga , Luecke David , Hu Kevin , Arbeitman Michelle , Kopp Artyom
Published: March 2019

The ability of a single genome to produce distinct and often dramatically different male and female forms is one of the wonders of animal development. In most animals, sex-specific phenotypes are shaped by interactions between a sex determination pathway and spatial patterning gene networks. InDrosophila melanogaster, most sexually dimorphic traits are controlled by sex-specific isoforms of thedoublesex(dsx) transcription factor, anddsxexpression is mostly limited to cells that give rise to sexually dimorphic traits. However, it is unknown how this mosaic of “sex-naïve” and “sex-aware” tissues arises. Here, we characterize thecis-regulatory sequences that controldsxexpression in the foreleg, which contains multiple types of sex-specific sensory organs. We find that separate modular enhancers are responsible fordsxexpression in each sexually dimorphic organ. Expression ofdsxin the sex comb is co-regulated by two enhancers with distinct spatial and temporal specificities that are separated by a genitalia-specific enhancer. Thus, the mosaic of sexually dimorphic and monomorphic organs depends on modular regulation ofdsxtranscription by dedicated cell type-specific enhancers.

Summary Statement

We identify the modularcis-regulatory elements that direct expression ofdoublesexin sexually dimorphic structures inDrosophilalegs and genitalia. This regulatory landscape provides insight into how cells obtain their sex-specific identity.
The principle of inverse effectiveness in audiovisual speech perception
Authors: van de Rijt Luuk P.H. , Roye Anja , Mylanus Emmanuel A.M. , Opstal A. John van , van Wanrooij Marc M.
Published: March 2019

We assessed how synchronous speech listening and lip reading affects speech recognition in acoustic noise. In simple audiovisual perceptual tasks, inverse effectiveness is often observed, which holds that the weaker the unimodal stimuli, or the poorer their signal-to-noise ratio, the stronger the audiovisual benefit. So far, however, inverse effectiveness has not been demonstrated for complex audiovisual speech stimuli. Here we assess whether this multisensory integration effect can also be observed for the recognizability of spoken words.

To that end, we presented audiovisual sentences to 18 native-Dutch normal-hearing participants, who had to identify the spoken words from a finite list. Speech-recognition performance was determined for auditory-only, visual-only (lipreading) and auditory-visual conditions. To modulate acoustic task difficulty, we systematically varied the auditory signal-to-noise ratio. In line with a commonly-observed multisensory enhancement on speech recognition, audiovisual words were more easily recognized than auditory-only words (recognition thresholds of −15 dB and −12 dB, respectively).

We here show that the difficulty of recognizing a particular word, either acoustically or visually, determines the occurrence of inverse effectiveness in audiovisual word integration. Thus, words that are better heard or recognized through lipreading, benefit less from bimodal presentation.

Audiovisual performance at the lowest acoustic signal-to-noise ratios (45%) fell below the visual recognition rates (60%), reflecting an actual deterioration of lipreading in the presence of excessive acoustic noise. This suggests that the brain may adopt a strategy in which attention has to be divided between listening and lip reading.
Comparing self- and hetero-metacognition in the absence of verbal communication
Authors: Vuillaume Laurène , Martin Jean-Rémy , Sackur Jérôme , Cleeremans Axel
Published: March 2019

The ability to infer how confident other people are in their decisions is crucial for regulating social interactions. It is unclear whether one can read others’ confidence in absence of verbal communication and whether one can infer it as accurately as for one’s own confidence. To address these questions, we used an auditory task in which participants had to guess the confidence of someone else performing the task or to judge their own confidence in different conditions (i.e., while performing the task themselves or while watching themselves performing the task on a pre-recorded video). Results show that participants are able to guess the confidence of other people as accurately as when judging their own. Crucially, we show that hetero-metacognition is a flexible mechanism relying on different cues according to the context. Our results support the idea that metacognition leverages the same inference mechanisms as involved in theory of mind.
Combined morphological and transcriptomic analyses reveal genetic regulation underlying the species-specific bulbil outgrowth in Dioscorea alata L
Authors: Wu Zhi-Gang , Jiang Wu , Tao Zheng-Ming , Guo Xiu-Zhu , Pan Xiao-Jun , Yu Wen-Hui
Published: March 2019

In yam (Dioscorea spp) species, bulbil at leaf axils is the most striking species-specific axillary structure and exhibits important ecological niches as well as crop yields. Genetic regulation underlying bulbil outgrowth remain largely unclear. We here first characterized the development of bulbil from Dioscorea alata L. using histological analysis and further performed full transcriptional profiling on its key developmental stages. Comprehensive mRNA analyses suggested that long-distance phytohormone signals including auxin, CK and ABA, play critical roles in controlling the initiation of bulbil through coordinately altering expression levels of genes involved in localized hormone metabolism and transport. Sucrose functioned as a novel signal and was required strongly at the early stage of bulbil formation, thus promoting its outgrowth through up-regulating trehalose-6-phophate pathway. GO pathway analysis demonstrated that genes are enriched in biological processes related to light stimuli, cell division, cell wall modification and carbohydrate metabolism. Particularly, some novel genes including dioscorin A/B, starch synthetic enzymes and chitinases showed remarkably high expression levels and strengthened the outgrowth of bulbil. Our data set demonstrated that the initiation of bulbil was highly regulated by a large number of transcriptional regulators. RNA in situ hybridization with MYB, WRKY and NAC transcription factors confirmed their key roles in triggering bulbil initiation. Together, our findings provide a crucial angle for genetic regulation of controlling the unique reproductive development of bulbils. Transcriptome data set can serve as a valuable genomic resource for yam research community or further genetic manipulation to improve bulbil yields.

Highlight

Transcriptomic data identified multiple functional genes and regulators; long-distance signals (auxin, CK, ABA), and sucrose as a novel signal play critical roles in controlling bulbil outgrowth.
Trans-Endothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice
Authors: Williams Ian M , McClatchey P Mason , Bracy Deanna P , Bonner Jeffrey S , Valenzuela Francisco A , Wasserman David H
Published: March 2019

Delivery of insulin to the surface of myocytes is required for skeletal muscle (SkM) insulin action. Previous studies have shown that SkM insulin delivery is reduced in the setting of obesity and insulin resistance (IR). The key variables that control SkM insulin delivery are 1) microvascular perfusion and 2) the rate at which insulin moves across the continuous endothelium of SkM capillaries. Obesity and IR are associated with reduced insulin-stimulated SkM perfusion. Whether an impairment in trans-endothelial insulin transport (EIT) contributes to SkM IR, however, is unknown. We hypothesized that EIT would be delayed in a mouse model of diet-induced obesity (DIO) and IR. Using intravital insulin imaging, we found that DIO male mice have a ~15% reduction in EIT compared to their lean counterparts. This impairment in EIT is associated with a 45% reduction in the density of endothelial vesicles. Despite impaired EIT, hyperinsulinemia sustained delivery of insulin to the interstitial space in DIO male mice. Even with maintained interstitial insulin delivery DIO male mice still showed SkM IR, indicating severe myocyellular IR in this model. Interestingly, there was no difference in EIT, endothelial ultrastructure or SkM insulin sensitivity between lean and high fat diet-fed female mice. These results suggest that, in male mice, obesity results in damage to the capillary endothelium which limits the capacity for EIT.
A peptide of a type I toxin-antitoxin system induces Helicobacter pylori morphological transformation from spiral-shape to coccoids
Authors: Mortaji Lamya El , Tejada-Arranz Alejandro , Rifflet Aline , Boneca Ivo G , Pehau-Arnaudet Gérard , Radicella J. Pablo , Marsin Stéphanie , De Reuse Hilde
Published: March 2019

Toxin-antitoxin systems are found in many bacterial chromosomes and plasmids with roles ranging from plasmid stabilization to biofilm formation and persistence. In these systems, the expression/activity of the toxin is counteracted by an antitoxin, which in type I systems is an antisense-RNA. While the regulatory mechanisms of these systems are mostly well-defined, the toxins’ biological activity and expression conditions are less understood. Here, these questions were investigated for a type I toxin-antitoxin system (AapA1-IsoA1) expressed from the chromosome of the human pathogen Helicobacter pylori. We show that expression of the AapA1 toxin in H. pylori causes growth arrest associated with rapid morphological transformation from spiral-shaped bacteria to round coccoid cells. Coccoids are observed in patients and during in vitro growth as a response to different stress conditions. The AapA1 toxin, first molecular effector of coccoids to be identified, targets H. pylori inner membrane without disrupting it, as visualized by Cryo-EM. The peptidoglycan composition of coccoids is modified with respect to spiral bacteria. No major changes in membrane potential or ATP concentration result from AapA1 expression, suggesting coccoid viability. Single-cell live microscopy tracking the shape conversion suggests a possible association of this process with cell elongation/division interference. Oxidative stress induces coccoid formation and is associated with repression of the antitoxin promoter and enhanced processing of its transcript, leading to an imbalance in favor of AapA1 toxin expression.

Our data support the hypothesis of viable coccoids with characteristics of dormant bacteria that might be important in H. pylori infections refractory to treatment.

Significance Statement

Helicobacter pylori, a gastric pathogen causing 800,000 deaths in the world annually, is encountered both in vitro and in patients as spiral-shaped bacteria and as round cells named coccoids. We discovered that the toxin from a chromosomal type I toxin-antitoxin system is targeting H. pylori membrane and acting as an effector of H. pylori morphological conversion to coccoids. We showed that these round cells maintain their membrane integrity and metabolism, strongly suggesting that they are viable dormant bacteria. Oxidative stress was identified as a signal inducing toxin expression and coccoid formation. Our findings reveal new insights into a form of dormancy of this bacterium that might be associated with H. pylori infections refractory to treatment.
3.1Å structure of yeast RNA polymerase II elongation complex stalled at a cyclobutane pyrimidine dimer lesion solved using streptavidin affinity grids
Authors: Lahiri Indrajit , Xu Jun , Han Bong Gyoon , Oh Juntaek , Wang Dong , DiMaio Frank , Leschziner Andres E
Published: March 2019

Despite significant advances in all aspects of single particle cryo-electron microscopy (cryo-EM), specimen preparation still remains a challenge. During sample preparation, macromolecules interact with the air-water interface, which often leads to detrimental effects such as denaturation or adoption of preferred orientations, ultimately hindering structure determination. Randomly biotinylating the protein of interest and then tethering it to a cryo-EM grid coated with two-dimensional crystals of streptavidin (acting as an affinity surface) can prevent the protein from interacting with the air-water interface. Recently, this approach was successfully used to solve a high-resolution structure of a test sample, a bacterial ribosome. However, the general applicability of this method to samples where interaction with the air-water interface is problematic remains to be determined. Here we report a 3.1Å structure of a RNA polymerase II elongation complex stalled at a cyclobutane pyrimidine dimer lesion (Pol II EC(CPD)) solved using streptavidin grids. Our previous attempt to solve this structure using conventional sample preparation methods resulted in a poor quality cryo-EM map due to Pol II EC(CPD)’s adopting a strong preferred orientation. Imaging the same sample on streptavidin grids led to a high-resolution structure with little anisotropy, showing that streptavidin affinity grids could be used as a general strategy to address challenges posed by interaction with the air-water interface.
PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
Authors: Jain Siddhant U. , Do Truman J. , Lund Peder J. , Rashoff Andrew Q. , Cieslik Marcin , Diehl Katharine L. , Bajic Andrea , Juretic Nikoleta , Deshmukh Shriya , Venneti Sriram , Muir Tom W , Garcia Benjamin A. , Jabado Nada , Lewis Peter W.
Published: March 2019

Polycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing. Diffuse intrinsic pontine gliomas (DIPGs) have extremely low H3K27me3 levels mediated by H3 K27M oncohistone. Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of EZHIP is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that EZHIP directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promote similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at the sites of PRC2 recruitment. Importantly, we find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a potential mechanism for loss of H3K27me3 spreading from CpG islands in vivo. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors– the K27M oncohistone and the EZHIP ‘oncohistone-mimic’– that dysregulate gene silencing to promote tumorigenesis.
Division and adaptation to host nutritional environment of apicomplexan parasites depend on apicoplast lipid metabolic plasticity and host organelles remodelling
Authors: Amiar Souad , Katris Nicholas J. , Berry Laurence , Dass Sheena , Shears Melanie J. , Brunet Camille , Touquet Bastien , Hakimi Mohamed-Ali , McFadden Geoffrey I. , Yamaryo-Botté Yoshiki , Botté Cyrille Y.
Published: March 2019

Apicomplexan parasites are unicellular eukaryotes responsible for major human diseases including malaria and toxoplasmosis. Apicomplexan parasites must obtain and combine lipids both from host cell scavenging andde novosynthesis to maintain parasite propagation and survival within their human host. Major questions on the actual role for each lipid source or how these are regulated upon fluctuating host nutritional conditions remain unanswered. Characterization of an apicoplast acyltransferase TgATS2, shows that the apicoplast provides local (lyso)phosphatidic acid balance, which is required for the recruitment of a novel dynamin (TgDrpC) critical during parasite cytokinesis. Disruption of TgATS2 led parasites to shift metabolic lipid acquisition fromde novosynthesis towards host scavenging. Importantly, both lipid scavenging andde novosynthesis pathways exhibit major metabolic and cellular plasticity upon sensing host lipid-deprived environments through concomitant (i) up-regulation ofde novofatty acid synthesis capacities in the apicoplast, and (ii) parasite-driven host cell remodelling to generate multi-membrane-bound structures from host organelles that are imported towards the parasite.
Tamoxifen Suppresses Pancreatic β-Cell Proliferation in Mice
Authors: Ahn Surl-Hee , Granger Anne , Rankin Matthew M. , Lam Carol J. , Cox Aaron R. , Kushner Jake A.
Published: March 2019

Tamoxifen is a mixed agonist/antagonist estrogen analogue that is frequently used to induce conditional gene deletion in mice using Cre-loxP mediated gene recombination. Tamoxifen is routinely employed in extremely high-doses relative to typical human doses to induce efficient gene deletion in mice. Although tamoxifen has been widely assumed to have no influence upon β-cells, the acute developmental and functional consequences of high-dose tamoxifen upon glucose homeostasis and adult β-cells are largely unknown. We tested if tamoxifen influences glucose homeostasis in male mice of various genetic backgrounds. We then carried out detailed histomorphometry studies of mouse pancreata. We also performed gene expression studies with islets of tamoxifen-treated mice and controls. Tamoxifen had modest effects upon glucose homeostasis of mixed genetic background (F1 B6129SF1/J) mice, with fasting hyperglycemia and improved glucose tolerance but without overt effects on fed glucose levels or insulin sensitivity. Tamoxifen inhibited proliferation of β-cells in a dose-dependent manner, with dramatic reductions in β-cell turnover at the highest dose (decreased by 66%). In sharp contrast, tamoxifen did not reduce proliferation of pancreatic acinar cells. β-cell proliferation was unchanged by tamoxifen in 129S2 mice but was reduced in C57Bl6 genetic background mice (decreased by 59%). Gene expression studies revealed suppression of RNA for cyclins D1 and D2 within islets of tamoxifen-treated mice. Tamoxifen has a cytostatic effect on β-cells, independent of changes in glucose homeostasis, in mixed genetic background and also in C57Bl6 mice. Tamoxifen should be used judiciously to inducibly inactivate genes in studies of glucose homeostasis.
Mobile Phone Based Strategies for Preconception Education in Rural Africa
Authors: Kassa Zemenu Yohannes , Tenaw Zelalem , Astatkie Ayalew , Siyoum Melese , Bekele Gezahegn , Taye Kefyalew , Mekonnen Shewangizaw , Kassaye Zerai
Published: March 2019

Background

prepregnancy health care is vital to alleviate and prevent maternal and neonatal disability and death.

Objective

The purpose of the study was to measure the levels of knowledge and attitude on preconception care and their determinants among women who delivered at government hospitals in a rural setting in southern Ethiopia.

Method

A facility-based cross sectional study was done from January 01 to February 30, 2017 on a sample of 370 women who delivered at government hospitals in Wolayita zone. The mothers were selected using systematic random sampling. The data were collected using structured and pretested interviewer administered questionnaires at the postnatal ward of each hospital. Data were analyzed using bivariate and multivariable techniques.

Results

The result showed that 53% (95% confidence interval [CI]: 47.8%, 58.1%) of mothers who delivered at public hospitals had adequate level of knowledge on preconception care, whereas 54.3% (95% CI: 49.2%, 59.5%) possessed positive attitude to preconception care. Mothers who have radio, planned pregnancy and have participated in community meetings related to preconception care had a meaningfully higher odds of good level of knowledge to preconception care. Ordinal regression showed that women who own mobile phone had at least three times significantly higher odds of positive attitude to preconception care, whereas women who have participated community meetings had lower odds of positive attitude on preconception care.

Conclusion

The results revealed that the levels of mothers’ knowledge and positive attitude on preconception care are low relative to other studies. Using transistor radio and mobile phone have significant effect in improving the knowledge and attitude of reproductive age women on preconception care. Hence, providing community health education based on radio and/or mobile phone messaging could be useful in positively influencing the knowledge and attitude of women on preconception care.
Genetic and antigenic variation of foot-and-mouth disease virus during persistent infection in naturally infected cattle and Asian buffalo in India
Authors: Biswa Jitendra K. , Ranjan Rajeev , Subramaniam Saravanan , Mohapatra Jajati K. , Patidar Sanjay , Sharma Mukesh K. , Bertram Miranda R. , Brito Barbara , Rodriguez Luis L. , Pattnaik Bramhadev , Arzt Jonathan
Published: March 2019

The role of foot-and-mouth disease virus (FMDV) persistently infected ruminants in initiating new outbreaks remains controversial, and the perceived threat posed by such animals hinders international trade in FMD-endemic countries. In this study we report longitudinal analyses of genetic and antigenic variations of FMDV serotype O/ME-SA/Ind2001d sublineage during naturally occurring, persistent infection in cattle and buffalo at an organised dairy farm in India. The proportion of animals from which FMDV RNA was recovered was not significantly different between convalescent (post-clinical) and sub-clinically infected animals or between cattle and buffalo across the sampling period. However, infectious virus was isolated from a higher proportion of buffalo samples and for a longer duration compared to cattle. Analysis of the P1 sequences from recovered viruses indicated fixation of mutations at the rate of 1.816 × 10-2substitution/site/year (s/s/y) (95% CI 1.362-2.31 × 10-2s/s/y). However, the majority of point mutations were transitional substitutions. Within individual animals, the mean dN/dS (ω) value for the P1 region varied from 0.076 to 0.357, suggesting the selection pressure acting on viral genomes differed substantially across individual animals. Statistical parsimony analysis indicated that all of the virus isolates from carrier animals originated from the outbreak virus. The antigenic relationship value as determined by 2D-VNT assay revealed fluctuation of antigenic variants within and between carrier animals during the carrier state which suggested that some carrier viruses had diverged substantially from the protection provided by the vaccine strain. This study contributes to understanding the extent of within-host and within-herd evolution that occurs during the carrier state of FMDV.