bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of the stress hormone cortisol on the metatranscriptome of the oral microbiome
Authors: Duran-Pinedo Ana E. , Solbiati Jose , Frias-Lopez Jorge
Published: June 2018

Imbalances of the microbiome also referred to as microbial dysbiosis, could lead to a series of different diseases. One factor that has been shown to lead to dysbiosis of the microbiome is exposure to psychological stressors. Throughout evolution microorganisms of the human microbiome have developed systems for sensing host-associated signals such as hormones associated with those stressors, enabling them to recognize essential changes in its environment thus changing its expression gene profile to fit the needs of the new environment. The most widely accepted theory explaining the ability of hormones to affect the outcome of an infection involves the suppression of the immune system. Commensal microbiota is involved in stressor-induced immunomodulation, but other biological effects are not yet known. Here we present the impact that cortisol had on the community-wide transcriptome of the oral community. We used a metatranscriptomic approach to obtain first insights into the metabolic changes induced by this stress hormone as well as which members of the oral microbiome respond to the presence of cortisol in the environment. Our findings show that the stress hormone cortisol directly induces shifts in the gene expression profiles of the oral microbiome that reproduce results found in the profiles of expression of periodontal disease and its progression.
Recovered and dead outcome patients caused by influenza A (H7N9) virus infection show different pro-inflammatory cytokine dynamics during disease progress and its application in real-time prognosis
Authors: Liu Yingxia , Wang Xinfa , Zhu Houshun , Ma Jinmin , Lu Zhe , Yuan Jing , Li Jianming , Li Jiandong , Ren Yan , Wen Bo , Ouyang Wenjie , Zheng Haixia , Zou Rongrong , Bi Yuhai , Yin Changcheng , Guo Zhenyu , Sun Wanying , Pei Na , Li Junhua , Zhu Shida , Yang Huanming , Liu Lei , Xu Xun , Liu Siqi , Wang Hui , Li Liqiang
Published: June 2018

The persistent circulation of influenza A(H7N9) virus within poultry markets and human society leads to sporadic epidemics of influenza infections. Severe pneumonia and acute respiratory distress syndrome (ARDS) caused by the virus lead to high morbidity and mortality rates in patients. Hyper induction of pro-inflammatory cytokines, which is known as “cytokine storm”, is closely related to the process of viral infection. However, systemic analyses of H7N9 induced cytokine storm and its relationship with disease progress need further illuminated. In our study we collected 75 samples from 24 clinically confirmed H7N9-infected patients at different time points after hospitalization. Those samples were divided into three groups, which were mild, severe and fatal groups, according to disease severity and final outcome. Human cytokine antibody array was performed to demonstrate the dynamic profile of 80 cytokines and chemokines. By comparison among different prognosis groups and time series, we provide a more comprehensive insight into the hypercytokinemia caused by H7N9 influenza virus infection. Different dynamic changes of cytokines/chemokines were observed in H7N9 infected patients with different severity. Further, 33 cytokines or chemokines were found to be correlated with disease development and 11 of them were identified as potential therapeutic targets. Immuno-modulate the cytokine levels of IL-8, IL-10, BLC, MIP-3a, MCP-1, HGF, OPG, OPN, ENA-78, MDC and TGF-β 3 are supposed to be beneficial in curing H7N9 infected patients. Apart from the identification of 35 independent predictors for H7N9 prognosis, we further established a real-time prediction model with multi-cytokine factors for the first time based on maximal relevance minimal redundancy method, and this model was proved to be powerful in predicting whether the H7N9 infection was severe or fatal. It exhibited promising application in prognosing the outcome of a H7N9 infected patients and thus help doctors take effective treatment strategies accordingly.
Zombi: A phylogenetic simulator of trees, genomes and sequences that accounts for dead lineages
Authors: Davín Adrián A. , Tricou Théo , Tannier Eric , de Vienne Damien M. , Szöllősi Gergely J.
Published: June 2018

Here we present Zombi, a tool to simulate the evolution of species, genomes and sequences in silico, that considers for the first time the evolution of genomes in extinct lineages. It also incorporates various features that have not to date been combined in a single simulator, such as the possibility of generating species trees with a pre-defined variation of speciation and extinction rates through time, simulating explicitly intergenic sequences of variable length and outputting gene tree - species tree reconciliations.

Availability and implementation

Source code and manual are freely available in https://github.com/AADavin/ZOMBI/

Contact

aaredav@gmail.com
A two-locus hybrid incompatibility is widespread, polymorphic, and active in natural populations of Mimulus
Authors: Zuellig Matthew P. , Sweigart Andrea L.
Published: June 2018

Reproductive isolation, which is essential for the maintenance of species in sympatry, is often incomplete between closely related species. In these taxa, reproductive barriers must continue to evolve within species, without being degraded by ongoing gene flow. To better understand this dynamic, we investigated the frequency and distribution of incompatibility alleles at a two-locus, recessive-recessive hybrid lethality system between species of yellow monkeyflower (Mimulus guttatus and M. nasutus) that hybridize in nature. We found that M. guttatus typically carries hybrid lethality alleles at one locus (hl13) and M. nasutus typically carries hybrid lethality alleles at the other locus (hl14). As a result, most naturally formed hybrids will carry incompatible alleles at both loci, with the potential to express hybrid lethality in later generations. Despite this general pattern, we also discovered considerable polymorphism at both hl13 and hl14 within both Mimulus species. For M. guttatus, polymorphism at both loci even occurs within populations, meaning that incompatible allele pairings might also often arise through regular, intraspecific gene flow. By examining genetic variation linked to hl13 and hl14, we discovered that introgression from M. nasutus is a primary driver of this polymorphism within M. guttatus. Additionally, patterns of introgression at the two hybrid lethality loci suggest that natural selection acts to eliminate incompatible allele pairings, providing evidence that even weak reproductive barriers might promote genomic divergence between species.
Re-programming ofPseudomonas syringaepv.actinidiaegene expression during early stages of infection of kiwifruit
Authors: McAtee Peter A. , Brian Lara , Curran Ben , van der Linden Otto , Nieuwenhuizen Niels J. , Chen Xiuyin , Henry-Kirk Rebecca , Stroud Erin A. , Nardozza Simona , Jayaraman Jay , Rikkerink Erik H. A. , Print Cris G. , Allan Andrew C. , Templeton Matthew D.
Published: June 2018

Background

Pseudomonas syringaeis a widespread bacterial species complex that includes a number of significant plant pathogens. Amongst these,P. syringaepv.actinidiae(Psa) initiated a worldwide pandemic in 2008 on cultivars ofActinidia chinensisvar.chinensis. To gain information about the expression of genes involved in pathogenicity we have carried out transcriptome analysis ofPsaduring the early stages of kiwifruit infection.

Results

Gene expression inPsawas investigated during the first five days after infection of kiwifruit plantlets, using RNA-seq. Principal component and heatmap analyses showed distinct phases of gene expression during the time course of infection. The first phase was an immediate transient peak of induction around three hours post inoculation (HPI) that included genes that code for a Type VI Secretion System and nutrient acquisition (particularly phosphate). This was followed by a significant commitment, between 3 and 24 HPI, to the induction of genes encoding the Type III Secretion System (T3SS) and Type III Secreted Effectors (T3SE). Expression of these genes collectively accounted for 6.3% of the bacterial transcriptome at this stage. There was considerable variation in the expression levels of individual T3SEs but all followed the same temporal expression pattern, with the exception of HopAS1, which peaked later in expression at 48 HPI. As infection progressed over the time course of five days, there was an increase in the expression of genes with roles in sugar, amino acid and sulfur transport and the production of alginate and colanic acid. These are both polymers that are major constituents of extracellular polysaccharide substances (EPS) and are involved in biofilm production. Reverse transcription-quantitative PCR (RT-qPCR) on an independent infection time course experiment showed that the expression profile of selected bacterial genes at each infection phase correlated well with the RNA-seq data.

Conclusions

The results from this study indicate that there is a complex remodeling of the transcriptome during the early stages of infection, with at least three distinct phases of coordinated gene expression. These include genes induced during the immediate contact with the host, those involved in the initiation of infection, and finally those responsible for nutrient acquisition.
RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions
Authors: Whitford Whitney , Lehnert Klaus , Snell Russell G. , Jacobsen Jessie C.
Published: June 2018

Background

The popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However the additional source of information from read balance, defined as relative proportion of reads of each allele at each position, has been underutilised in the existing applications.

Results

We present Read Balance Validator (RBV), a bioinformatic tool which uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report.

Conclusions

RBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV
Antiviral viral compound fromStreptomyces ghanaensislike strain against white spot syndrome virus (WSSV) of shrimp
Authors: Rajkumar T. , Manimaran M. , Taju G. , Vimal S. , Majeed S. Abdul , Kannabiran K. , Sivakumar S. , Kumar K.M. , Madhan S. , Sahul Hameed A.S.
Published: June 2018

Actinomycetes isolates collected from different environments were screened for antiviral activity against WSSV. One isolate designated as CAHSH-2 showed antiviral activity against WSSV at the concentration of 0.2 mg per shrimp. The laboratory trial of determining antiviral activity of ethyl acetate extract (EtOAcE) of CAHSH-2 against WSSV was carried out 21 times since 2014. CAHSH-2 isolate which showed antiviral activity was characterized and identified asStreptomyces ghanaensislike strain. Among the five fractions obtained from EtOAcE of potential actinomycetes isolate, F1 was found to have strong antiviral activity. The F1A and F1B sub-fractions from F1 fraction were subjected to GC-MS, FTIR,1H and13C NMR analyses and, the compounds identified were di-n-octyl phthalate and bis (2-methylheptyl) phthalate, respectively. Among these compounds, di-n-octyl phthalate showed strong antiviral activity against WSSV. Molecular docking studies revealed that di-n-octyl phthalate was found to have high binding affinity with VP26 and VP28 proteins of WSSV, whereas the bis (2-methylheptyl) phthalate showed low binding affinity with VP26 and VP28. The antiviral activity of EtOAcE of actinomycetes against WSSV was confirmed by PCR, RT-PCR, Western blot and ELISA. The EA extract of active isolate was found to be non-toxic toArtemia, post-larvae and adultLitopenaeus vannamei.

Importance

White spot syndrome virus (WSSV) is an important shrimp viral pathogen and responsible for huge economic loss to shrimp culture industry worldwide including India. The global loss due to WSSV has been estimated about USD 10 billion and the loss continues at the same extent even now. Various strategies have been followed to prevent or control diseases of aquatic animals. In spite of various preventive and control strategies, WSSV has been still persisting for more than two decades. No control strategies have so far been evolved to put a break to WSSV. In this situation, an attempt was made in the present work to screen some actinomycetes isolates for antiviral activity against WSSV. Among these isolates, one isolate identified asStreptomyces ghanaensislike isolate CAHSH-2 showed activity against WSSV. This article gives the information about the antiviral compound against WSSV and the mechanism of viral inhibition.
Tissue spatial correlation as cancer marker
Authors: Takabayashi Masanori , Majeed Hassaan , Kajdacsy-Balla Andre , Popescu Gabriel
Published: June 2018

We propose a new intrinsic cancer marker in fixed tissue biopsy slides, which is based on the local spatial autocorrelation length obtained from quantitative phase images. The spatial autocorrelation length in a small region of the tissue phase image is sensitive to the nanoscale cellular morphological alterations and can hence inform on carcinogenesis. Therefore, this metric can potentially be used as an intrinsic cancer marker in histopathology. Typically, these correlation length maps are calculated by computing 2D Fourier transforms over image sub-regions – requiring long computational times. In this paper, we propose a more time efficient method of computing the correlation map and demonstrate its value for diagnosis of benign and malignant breast tissues. Our methodology is based on highly sensitive quantitative phase imaging data obtained by spatial light interference microscopy (SLIM).
Ecological network assembly: how the regional metaweb influences local food webs
Authors: Saravia Leonardo A. , Marina Tomás I. , Kristensen Nadiah P. , De Troch Marleen , Momo Fernando R.
Published: June 2018

Local food webs result from a sequence of colonisations and extinctions by species from the regional pool or metaweb, i.e., the assembly process. Assembly is theorised to be a selective process: whether or not certain species or network structures can persist is partly determined by local processes including habitat filtering and dynamical constraints. Consequently, local food web structure should reflect these processes.

The goal of this study was to test evidence for these selective processes by comparing the structural properties of real food webs to the expected distribution given the metaweb. We were particularly interested in ecological dynamics; if the network properties commonly associated with dynamical stability are indeed the result of stability constraints, then they should deviate from expectation in the direction predicted by theory.

To create a null expectation, we used the novel approach of randomly assembling model webs by drawing species and interactions from the empirical metaweb. The assembly model permitted colonisation and extinction, and required a consumer species to have at least one prey, but had no habitat type nor population dynamical constraints. Three data sets were used: (1) the marine Antarctic metaweb, with 2 local food-webs; (2) the 50 lakes of the Adirondacks; and (3) the arthropod community from Florida Keys’ classic defaunation experiment.

Contrary to our expectations, we found that there were almost no differences between empirical webs and those resulting from the null assembly model. Few empirical food webs showed significant differences with network properties, motif representations and topological roles. Network properties associated with stability did not deviate from expectation in the direction predicted by theory.

Our results suggest that — for the commonly used metrics we considered — local food web structure is not strongly influenced by dynamical nor habitat restrictions. Instead, the structure is inherited from the metaweb. This suggests that the network properties typically attributed as causes or consequences of ecological stability are instead a by-product of the assembly process (i.e., spandrels), and may potentially be too coarse to detect the true signal of dynamical constraint.
Revisiting the phylogeny of Ficus (Moraceae): When Next Generation Sequencing corroborates Past Generation Botanists
Authors: Rasplus Jean-Yves , Rodriguez Lillian Jennifer , Tollon-Cordet Christine , Cruaud Astrid
Published: June 2018

Despite their ecological and evolutionary importance, fig trees still lack a resolved phylogeny. We used multiple analytical approaches and 600 conserved RAD-seq loci collected across 40 representative species to infer phylogenetic relationships among the major clades of Ficus. Our results converged on a fully resolved phylogeny that contradicts previous hypotheses by not placing section Pharmacosycea sister to all other fig trees. Instead, we find that subgenus Sycomorus is sister to two clades, one comprising all other gynodioecious sections, and the other containing all monoecious sections. Our results corroborate earlier botanists’ hypotheses and provide a baseline for future classification. We infer the evolution of key traits (growth form, breeding system and pollination mode) and find that, contrary to previous hypotheses, the ancestor of extant fig trees was likely a gynodioecious and actively pollinated tree. Our results open new opportunities to explore diversification patterns in fig trees and better understand their mutualistic interaction with wasps.
Brain regions modulated during covert visual attention in the macaque
Authors: Bogadhi Amarender R. , Bollimunta Anil , Leopold David A. , Krauzlis Richard J.
Published: June 2018

Neurophysiology studies of covert visual attention in monkeys have emphasized the modulation of sensory neural responses in the visual cortex. At the same time, electrophysiological correlates of attention have been reported in other cortical and subcortical structures, and recent fMRI studies have identified regions across the brain modulated by attention. Here we used fMRI in two monkeys performing covert attention tasks to reproduce and extend these findings in order to help establish a more complete list of brain structures involved in the control of attention. As expected from previous studies, we found attention-related modulation in frontal, parietal and visual cortical areas as well as the superior colliculus and pulvinar. We also found significant attention-related modulation in cortical regions not traditionally linked to attention – mid-STS areas (anterior FST and parts of IPa, PGa, TPO), as well as the caudate nucleus. A control experiment using a second-order orientation stimulus showed that the observed modulation in a subset of these mid-STS areas did not depend on visual motion. These results identify the mid-STS areas (anterior FST and parts of IPa, PGa, TPO) and caudate nucleus as potentially important brain regions in the control of covert visual attention in monkeys.
Multiple myeloma immunoglobulin λ translocations portend poor prognosis
Authors: Barwick Benjamin G. , Neri Paola , Bahlis Nizar J. , Nooka Ajay K. , Kaufman Jonathan L. , Gupta Vikas A. , Auclair Daniel , Keats Jonathan J. , Lonial Sagar , Vertino Paula M. , Boise Lawrence H.
Published: June 2018

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed ‘high-risk’. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.
Increased adaptability to rapid environmental change can more than make up for the two-fold cost of males
Authors: Holmes Caroline M. , Nemenman Ilya , Weissman Daniel B.
Published: June 2018

The famous “two-fold cost of sex” is really the cost of anisogamy – why should females mate with males who do not contribute resources to offspring, rather than isogamous partners who contribute equally? In typical anisogamous populations, a single very fit male can have an enormous number of offspring, far larger than is possible for any female or isogamous individual. If the sexual selection on males aligns with the natural selection on females, anisogamy thus allows much more rapid adaptation via super-successful males. We show via simulations that this effect can be sufficient to overcome the two-fold cost and maintain anisogamy against isogamy in populations adapting to environmental change. The key quantity is the variance in male fitness – if this exceeds what is possible in an isogamous population, anisogamous populations can win out in direct competition by adapting faster.
Effective repair of joint cartilage using human pluripotent stem cell-derived tissue
Authors: Gardner Oliver F. W. , Juneja Subhash C. , Whetstone Heather , Nartiss Yulia , Sieker Jakob T. , Veillette Christian , Keller Gordon M. , Craft April M.
Published: June 2018

Adult articular cartilage lacks significant regenerative capacity, and damage to this tissue often leads to progressive joint degeneration (osteoarthritis). We developed strategies to generate articular cartilage from human pluripotent stem cells (hPSCs) as a source of clinically relevant tissues for joint repair1. Previously, we demonstrated that these chondrocytes retain cartilage forming potential following subcutaneous implantation in mice. In this report, we evaluated the potential of human embryonic stem cell (hESC)-derived articular cartilage tissue to repair osteochondral defects created in the rat knee. Following implantation, the hESCderived cartilage maintained a proteoglycan and type II collagen-rich matrix, and was well integrated with native rat tissue at the basal and lateral surfaces. The ability to generate cartilage tissue with integrative and reparative properties from an unlimited and robust cell source represents a significant clinical advance for cartilage repair that can be applied to large animal models and ultimately to patient care.
Multiple optic gland signaling pathways implicated in octopus maternal behaviors and death
Authors: Wang Z Yan , Ragsdale Clifton W
Published: June 2018

0. Summary statement

Octopus optic glands employ a multiplex progression of signaling molecules to regulate maternal behaviors.

1. Abstract

Post-reproductive life in the female octopus is characterized by an extreme pattern of maternal care: the mother cares for her clutch of eggs without feeding until her death. These maternal behaviors are completely eradicated if the optic glands, the octopus analog of the vertebrate pituitary gland, are removed from brooding females. Despite the optic gland’s importance in regulating maternal behavior, the molecular features underlying optic gland function are unknown. Here, we identify major signaling systems of theOctopus bimaculoidesoptic gland. Through behavioral analyses and transcriptome sequencing, we report that the optic gland undergoes remarkable molecular changes that coincide with transitions between behavioral stages. These include the dramatic up- and down-regulation of catecholamine, steroid, insulin, and feeding peptide pathways. Transcriptome analyses in other tissues demonstrate that these molecular changes are not generalized markers of aging and senescence, but instead, specific features of the optic glands. Our results provide strong evidence for the functional conservation of signaling molecules across evolutionarily distant species. For example, elevated levels of insulin growth factor binding proteins are associated with cachexia-like tissue wasting in flies, humans, and, reported here, octopuses. Our study expands the classic optic gland-pituitary gland analogy and indicates that, rather than a single “self-destruct” hormone, the maternal optic glands employ multiple pathways as systemic hormonal signals of behavioral control.
Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission
Authors: Lur Gyorgy , Higley Michael J.
Published: June 2018

A growing body of literature has demonstrated the potential for ketamine in the treatment of major depression. Sub-anesthetic doses produce rapid and sustained changes in depressive behavior, both in patients and rodent models, associated with reorganization of glutamatergic synapses in the prefrontal cortex (PFC). While ketamine is known to regulate NMDA-type glutamate receptors (NMDARs), the full complement of downstream cellular consequences for ketamine administration are not well understood. Here, we combine electrophysiology with 2-photon imaging and glutamate uncaging in acute slices of mouse PFC to further examine how ketamine alters glutamatergic synaptic transmission. We find that four hours after ketamine treatment, glutamatergic synapses themselves are not significantly affected. However, expression levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity disrupts the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, α2 adrenergic receptors and GABABreceptors selectively inhibit AMPA-type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine-induced loss of RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results demonstrate a novel mechanism by which ketamine can influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.
PI(4,5)P2 Binding Sites in the Ebola Virus Matrix Protein Modulate Assembly and Budding
Authors: Johnson Kristen A. , Budicini Melissa R. , Urata Sarah , Bhattarai Nisha , Gerstman Bernard S. , Chapagain Prem P. , Li Sheng , Stahelin Robert V.
Published: June 2018

Ebola virus (EBOV) causes sever hemorrhagic fever in humans, can cause death in a large percentage of those infected, and still lacks FDA approved treatment options. In this study, we investigated how the essential EBOV protein, VP40, forms stable oligomers to mediate budding and assembly from the host cell plasma membrane. An array of in vitro and cellular assays identified and characterized two lysine rich regions that bind to PI(4,5)P2 and serve distinct functions through the lipid binding and assembly of the viral matrix layer. We found that when VP40 binds PI(4,5)P2, VP40 oligomers become extremely stable and long lived. Together, this work characterizes the molecular basis of PI(4,5)P2 binding by VP40, which stabilizes formation of VP40 oligomers necessary for viral assembly and budding. Quercetin, a natural product that lowers PI(4,5)P2 in the plasma membrane, inhibited budding of VP40 VLPs and may inform future treatment strategies against EBOV.
Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis
Authors: Zhang Bin , Babu Kamesh R. , Lim Chun You , Kwok Zhi Hao , Li Jia , Zhou Siqin , Yang Henry , Tay Yvonne
Published: June 2018

RNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.
Mitochondrial citrate transporters CtpA and YhmA are involved in lysine biosynthesis in the white koji fungus,Aspergillus luchuensismut. kawachii
Authors: Kadooka Chihiro , Izumitsu Kosuke , Onoue Masahira , Okutsu Kayu , Yoshizaki Yumiko , Takamine Kazunori , Goto Masatoshi , Tamaki Hisanori , Futagami Taiki
Published: June 2018

Aspergillus luchuensismut. kawachiiproduces a large amount of citric acid during the process of fermenting shochu, a traditional Japanese distilled spirit. In this study, we characterizedA. kawachiiCtpA and YhmA, which are homologous to the yeastSaccharomyces cerevisiaemitochondrial citrate transporters Ctp1 and Yhm2, respectively. CtpA and YhmA were purified fromA. kawachiiand reconstituted into liposomes. The proteoliposomes exhibited only counter-exchange transport activity; CtpA transported citrate using counter substrates especially forcis-aconitate and malate, whereas YhmA transported citrate using a wider variety of counter substrates, including citrate, 2-oxoglutarate, malate,cis-aconitate, and succinate. Disruption ofctpAandyhmAcaused deficient hyphal growth and conidia formation with reduced mycelial weight–normalized citrate production. Because we could not obtain a ΔctpAΔyhmAstrain, we constructed actpA-Sconditional expression strain in the ΔyhmAbackground using the Tet-On promoter system. Knockdown ofctpA-Sin ΔyhmAresulted in a severe growth defect on minimal medium, indicating that double disruption ofctpAandyhmAleads to synthetic lethality; however, we subsequently found that the severe growth defect was relieved by addition of lysine. Our results indicate that CtpA and YhmA are mitochondrial citrate transporters involved in citric acid production and that transport of citrate from mitochondria to the cytosol plays an important role in lysine biogenesis inA. kawachii.

IMPORTANCE

Citrate transport is believed to play a significant role in citrate production by filamentous fungi; however, details of the process remain unclear. This study characterized two citrate transporters fromAspergillus luchuensismut. kawachii. Biochemical and gene disruption analyses showed that CtpA and YhmA are mitochondrial citrate transporters required for normal hyphal growth, conidia formation, and citric acid production. In addition, this study provided insights into the links between citrate transport and lysine biosynthesis. The characteristics of fungal citrate transporters elucidated in this study will help expand our understanding of the citrate production mechanism and facilitate the development and optimization of industrial organic acid fermentation processes.
Fecal pollution explains antibiotic resistance gene abundances in anthropogenically impacted environments
Authors: Antti Karkman , Katariina Pärnänen , Joakim Larsson D.G.
Published: June 2018

Discharge of treated sewage leads to release of antibiotic resistant bacteria, resistance genes and antibiotic residues to the environment. Such pollution can directly contribute to increased morbidity caused by the transmission of resistant fecal pathogens. Residual antibiotics in wastewaters have been speculated to select for resistant bacteria and thereby promote the evolution and emergence of new resistance factors. Increased abundance of antibiotic resistance genes in sewage and sewage-impacted environments may, however, simply be a result of fecal contamination with resistant bacteria rather than caused by an on-site selection pressure. In this study we have disentangled these two alternative scenarios by relating the relative resistance gene abundance to the accompanying extent of fecal pollution in publicly available metagenomic data. This was possible by analyzing the abundance of a newly discovered phage which is exceptionally abundant in, and specific to, human feces. The presence of resistance genes could largely be explained by fecal pollution, with no clear signs of selection in the environment, the only exception being environments polluted by very high levels of antibiotics from manufacturing where selection is evident. Our results demonstrate the necessity to take in to account the fecal pollution levels to avoid making erroneous assumptions regarding environmental selection of antibiotic resistance. The presence or absence of selection pressure has major implications for what the risk scenarios are (transmission versus evolution) and for what mitigations (reducing pathogenic bacteria or selective agents) should be prioritized to reduce health risks related to antibiotic resistance in the environment.
Influence of miR-520e-mediated MAPK signaling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2
Authors: Tian Jing-hui , Liu Wen-dong , Zhang Zhi-yong , Tang Li-hua , Li Dong , Tian Zhao-ju , Lin Shao-wei , Li Ying-jie
Published: June 2018

This paper aims to determine the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EphA2 in HBV-positive HCC tissues and cells were detected. HepG2.2.15 and Huh7 cells transfected with pHBV1.2 were divided into Mock, NC, miR-520e mimic, miR-520e inhibitor, si-EphA2, and miR-520e inhibitor + si-EphA2 groups. MiR-520e, HBV DNA content, HBsAg and HBeAg levels, cell proliferation, apoptosis and protein expression of EphA2 and MAPK pathways were evaluated. Furthermore, rAAV81.3HBV infected-mouse model was established to detect HBV-DNA levels. MiR-520e was up-regulated and EphA2 was down-regulated in HBV-positive HCC tissues and cells (HepG2.2.15 and HepAD38). MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but miR-520e was dose-dependently elevated in Huh7-X, HepG2-X, and HepG2.2.15 cells after interfering HBx. Additionally, miR-520e mimic and si-EphA2 groups were apparently reduced in HBV DNA content, HBsAg and HBeAg levels, cell proliferation, and were enhanced in the expressions of EphA2, MAPK pathways and cell apoptosis. Furthermore, si-EphA2 can reverse the promotion effect of miR-520e inhibitor on the HBV replication and tumor cell growth Up-regulating miR-520e in rAAV81.3HBV infected-mouse resulted in the reduced EphA2 in liver tissues and HBV DNA content in serum. MiR-520e was found to be decreased in HBV-positive HCC tissues and cells, while over-expression of miR-520e blocked MAPK pathways via inhibiting EphA2, ultimately reducing HBV replication and inhibiting tumor cell growth.
Spatiotemporally controlled genetic perturbation for efficient large-scale studies of cell non-autonomous effects
Authors: Chai Andrea , Mateus Ana M. , Oozeer Fazal , Sousa-Nunes Rita
Published: June 2018

Studies in genetic model organisms have revealed much about the development and pathology of complex tissues. Most have focused on cell-intrinsic gene functions and mechanisms. Much less is known about how transformed, or otherwise functionally disrupted, cells interact with healthy ones towards a favorable or pathological outcome. This is largely due to technical limitations. We developed new genetic tools in Drosophila melanogaster that permit efficient multiplexed gain- and loss-of-function genetic perturbations with separable spatial and temporal control. Importantly, our novel tool-set is independent of the commonly used GAL4/UAS system, freeing the latter for additional, non-autonomous, genetic manipulations; and is built into a single strain, allowing one-generation interrogation of non-autonomous effects. Altogether, our design opens up efficient genome-wide screens on any deleterious phenotype. Specifically, we developed tools to study extrinsic effects on neural tumor growth but the strategy presented has endless applications within and beyond neurobiology, and in other model organisms.

Impact statement

A novel genetic strategy for induction of reproducible neural tumors (or any other deleterious phenotype) in a singleDrosophilastock (applicable to other organisms).
A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes
Authors: Boutchueng-Djidjou Martial , Belleau Pascal , Bilodeau Nicolas , Fortier Suzanne , Bourassa Sylvie , Droit Arnaud , Elowe Sabine , Faure Robert L.
Published: June 2018

Despite the identification of many susceptibility genes our knowledge of the underlying mechanisms responsible for complex disease remains limited. Here, we identified a type 2 diabetes disease module in endosomes, and validate it for functional relevance on selected nodes. Using hepatic Golgi/endosomes fractions, we established a proteome of insulin receptor-containing endosomes that allowed the study of physical protein interaction networks on a type 2 diabetes background. The resulting collated network is formed by 313 nodes and 1147 edges with a topology organized around a few major hubs with Cdk2 displaying the highest collective influence. Overall, 88% of the nodes are associated with the type 2 diabetes genetic risk, including 101 new candidates. The Type 2 diabetes module is enriched with cytoskeleton and luminal acidification –dependent processes that are shared with secretion-related mechanisms. We identified new signaling pathways driven by Cdk2 and PTPLAD1 whose expression regulate the association of the insulin receptor with TUBA, TUBB, the actin component ACTB and the endosomal sorting markers Rab5c and Rab11a. Therefore, the interactome of internalized insulin receptors reveals the presence of a type 2 diabetes disease module enriched in new layers of feedback loops required for insulin signaling, clearance and islet biology.

Author Summary

According to the local hypothesis each complex disease can be linked to a well-defined network called the disease module. A disease module can be defined by the topological properties of protein interaction networks. Given the complexity of the whole interaction map the existence of such disease modules remains largely to be tested. Here, we found a type 2 diabetes disease module in insulin receptor-containing endosomes. The disease module contains new pathways that are associated with both insulin signaling, clearance and secretion. Its co-functionality with islets biology may provide a mechanistic rationale for the exploration of personalized medicine and elaborate new drugs.
SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation
Authors: Jankauskaitė Justina , Jiménez-García Brian , Dapkūnas Justas , Fernández-Recio Juan , Moal Iain H.
Published: June 2018

Motivation

Understanding the relationship between the sequence, structure, binding energy, binding kinetics and binding thermodynamics of protein-protein interactions is crucial to understanding cellular signaling, the assembly and regulation of molecular complexes, the mechanisms through which mutations lead to disease, and protein engineering.

Results

We present SKEMPI 2.0, a major update to our database of binding free energy changes upon mutation for structurally resolved protein-protein interactions. This version now contains manually curated binding data for 7085 mutations, an increase of 133%, including changes in kinetics for 1844 mutations, enthalpy and entropy changes for 443 mutations, and 440 mutations which abolish detectable binding.

Availability

The database is available at https://life.bsc.es/pid/skempi2/
Computational enhancement of single-cell sequences for inferring tumor evolution
Authors: Miura Sayaka , Huuki Louise A , Buturla Tiffany , Vu Tracy , Gomez Karen , Kumar Sudhir
Published: June 2018

Motivation: Tumor sequencing has entered an exciting phase with the advent of single-cell techniques that are revolutionizing the assessment of single nucleotide variation (SNV) at the highest cellular resolution. However, state-of-the-art single-cell sequencing technologies produce data with many missing bases (MBs) and incorrect base designations that lead to false-positive (FP) and false-negative (FN) detection of somatic mutations. While computational methods are available to make biological inferences in the presence of these errors, the accuracy of the imputed MBs and corrected FPs and FNs remains unknown.

Results: Using computer simulated datasets, we assessed the robustness performance of four existing methods (OncoNEM, SCG, SCITE, and SiFit) and one new method (BEAM). BEAM is a Bayesian evolution-aware method that improves the quality of single-cell sequences by using the intrinsic evolutionary information in the single-cell data in a molecular phylogenetic framework. Overall, BEAM and SCITE performed the best. Most of the methods imputed MBs with high accuracy, but effective detection and correction of FPs and FNs require sampling a large number of SNVs. Analysis of an empirical dataset shows that computational methods can improve both the quality of tumor single-cell sequences and their utility for biological inference.

Conclusions: Tumor cells descend from pre-existing cells, which creates evolutionary continuity in single-cell sequencing datasets. This information enables BEAM and other methods to correctly impute missing data and incorrect base assignments, but correction of FPs and FNs remains challenging when the number of SNVs sampled is small relative to the number of cells sequenced.

Availability:BEAM is available on the web athttps://github.com/SayakaMiura/BEAM.

Contact:s.kumar@temple.edu
The Chromatin-binding Protein Spn1 contributes to Genome Instability inSaccharomyces cerevisiae
Authors: Thurston Alison K. , Radebaugh Catherine A. , Almeida Adam R. , Argueso Juan Lucas , Stargell Laurie A.
Published: June 2018

Cells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA damage tolerance pathway includes two sub-pathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence sub-pathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. UsingSaccharomyces cerevisiae, we examined the role of Spn1, a chromatin binding and transcription elongation factor, in DNA damage tolerance. Expression of a mutant allele ofSPN1results in increased resistance to the DNA damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological lifespan. We attribute these effects to an increased usage of the template switch branch of the DNA damage tolerance pathway in thespn1strain. This provides evidence for a role of wild type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.