bluuebunny/crossref_metadata_2025 huggingface dataset:
Adsorption of tetracycline on Fe (hydr)oxides: effects of pH and metal cation (Cu
2+
, Zn
2+
and Al
3+
) addition in various molar ratios
Authors: Hsu Liang-Ching , Liu Yu-Ting , Syu Chien-Hui , Huang Mei-Hsia , Tzou Yu-Min , Teah Heng Yi
Published: March 2018

Iron (Fe) (hydr)oxides control the mobility and bioavailability of tetracycline (TC) in waters and soils. Adsorption of TC on Fe (hydr)oxides is greatly affected by polyvalent metals; however, impacts of molar metal/TC ratios on TC adsorptive behaviours on Fe (hydr)oxides remain unclear. Results showed that maximum TC adsorption on ferrihydrite and goethite occurred at pH 5–6. Such TC adsorption was generally promoted by the addition of Cu
2+
, Zn
2+
and Al
3+
. The greatest increase in TC adsorption was found in the system with molar Cu/TC ratio of 3 due to the formation of Fe hydr(oxide)–Cu–TC ternary complexes. Functional groups on TC that were responsible for the complexation with Cu
2+
shifted from phenolic diketone groups at Cu/TC molar ratio < 1 to amide groups at Cu/TC molar ratio ≥ 1. For the addition of Al
3+
, the complexation only took place with phenolic diketone groups, resulting in the enhanced TC adsorption at a molar Al/TC ratio of 1. However, TC adsorption decreased for Al/TC molar ratio > 1 as excess Al
3+
led to the competitive adsorption with Al/TC complexes. For the Zn
2+
addition, no significant correlation was found between TC adsorption capacity and molar Zn/TC ratios.
Total synthesis of rupestine G and its epimers
Authors: Yusuf Abdullah , Zhao Jiangyu , Wang Bianlin , Aibibula Paruke , Aisa Haji Akber , Huang Guozheng
Published: March 2018

Rupestine
G
is a guaipyridine sesquiterpene alkaloid isolated from
Artemisia rupestris
L. The total synthesis of rupestine
G
and its epimers was accomplished employing a Suzuki reaction to build a terminal diene moiety. The diene was further elaborated into the desired guaipyridine structure by a ring-closing metathesis reaction. Over all, rupestine
G
and its three epimers were obtained as a mixture in a sequence of nine linear steps with 18.9% yield. Rupestine
G
and its optically pure isomers were isolated by chiral preparative HPLC and fully characterized by
1
H ,
13
C NMR, HRMS, optical rotation value, and experimental and calculated electronic circular dichroism spectroscopy.
The evolutionary history of polycotylid plesiosaurians
Authors: Fischer V. , Benson R. B. J. , Druckenmiller P. S. , Ketchum H. F. , Bardet N.
Published: March 2018

Polycotylidae is a clade of plesiosaurians that appeared during the Early Cretaceous and became speciose and abundant early in the Late Cretaceous. However, this radiation is poorly understood.Thililua longicollisfrom the Middle Turonian of Morocco is an enigmatic taxon possessing an atypically long neck and, as originally reported, a series of unusual cranial features that cause unstable phylogenetic relationships for polycotylids. We reinterpret the holotype specimen ofThililua longicollisand clarify its cranial anatomy.Thililua longicollispossesses an extensive, foramina-bearing jugal, a premaxilla–parietal contact and carinated teeth. Phylogenetic analyses of a new cladistic dataset based on first-hand observation of most polycotylids recoverThililuaandMauriciosaurusas successive lineages at the base of the earliest Late Cretaceous polycotyline radiation. A new dataset summarizing the Bauplan of polycotylids reveals that their radiation produced an early burst of disparity during the Cenomanian–Turonian interval, with marked plasticity in relative neck length, but this did not arise as an ecological release following the extinction of ichthyosaurs and pliosaurids. This disparity vanished during and after the Turonian, which is consistent with a model of ‘early experimentation/late constraint’. Two polycotylid clades, Occultonectia clade nov. and Polycotylinae, survived up to the Maastrichtian, but with low diversity.
Benefits And Limitations Of Three-Dimensional Printing Technology For Ecological Research
Authors: Behm Jocelyn E. , Waite Brenna R. , Tonia Hsieh S. , Helmus Matthew R.
Published: March 2018

Background

Ecological research often involves sampling and manipulating non-model organisms that reside in heterogeneous environments. As such, ecologists often adapt techniques and ideas from industry and other scientific fields to design and build equipment, tools, and experimental contraptions custom-made for the ecological systems under study. Three-dimensional (3D) printing provides a way to rapidly produce identical and novel objects that could be used in ecological studies, yet ecologists have been slow to adopt this new technology. Here, we provide ecologists with an introduction to 3D printing.

Results

First, we give an overview of the ecological research areas in which 3D printing is predicted to be the most impactful and review current studies that have already used 3D printed objects. We then outline a methodological workflow for integrating 3D printing into an ecological research program and give a detailed example of a successful implementation of our 3D printing workflow for 3D printed models of the brown anole,Anolis sagrei,for a field predation study. After testing two print media in the field, we show that the models printed from the less expensive and more sustainable material (blend of 70% plastic and 30% recycled wood fiber) were just as durable and had equal predator attack rates as the more expensive material (100% virgin plastic).

Conclusions

Overall, 3D printing can provide time and cost savings to ecologists, and with recent advances in less toxic, biodegradable, and recyclable print materials, ecologists can choose to minimize social and environmental impacts associated with 3D printing. The main hurdles for implementing 3D printing – availability of resources like printers, scanners, and software, as well as reaching proficiency in using 3D image software – may be easier to overcome at institutions with digital imaging centers run by knowledgeable staff. As with any new technology, the benefits of 3D printing are specific to a particular project, and ecologists must consider the investments of developing usable 3D materials for research versus other methods of generating those materials.
Comparable affinity of RabGDIα for GTP- and GDP-bound forms of Rab7 supports a four-state transition model for Rab7 subcellular localization
Authors: Kanemitsu-Fujita Akane , Morishita So , Kjaer Svend , Fukuda Mitsunori , Schiavo Giampietro , Nakamura Takeshi
Published: March 2018

Endolysosomal system is linked to almost all aspects of cell life and diseases, and Rab7 occupies a critical node in this crucial pathway. However, there have been conflicting views about the exact role of Rab7 in membrane trafficking, since some studies have reported that Rab7 regulates the trafficking from early to late endosomes, while others highlighted its role in late endosomes to lysosomes progression. In the present study, we have revisited this issue from a new viewpoint. In COS-7 cells, a GDP-bound Rab7 mutant, T22N, was located to vesicular membranes as well as in cytoplasm. Similarly, the GTPase-deficient Q67L mutant of Rab7 resided in cytoplasm as well as on membranes. Additionally, we found that RabGDI interacted with both GTP- and GDP-bound forms of Rab7 in vitro. These results have prompted us to propose a four-state transition model for Rab7. This four-state model matches with our recent findings that Rab7 was initially recruited to macropinosomes in a GDP-bound inactive form and subsequently became activated during endocytic maturation in EGF-stimulated COS-7 cells.
Parasitism effects on coexistence and stability within simple trophic modules
Authors: Prosnier Loïc , Médoc Vincent , Loeuille Nicolas
Published: March 2018

Parasites are important components of food webs. Although their direct effects on hosts are well-studied, indirect impacts on trophic networks, thus on non-host species, remain unclear.

In this study, we investigate the consequences of parasitism on coexistence and stability within a simple trophic module: one predator consuming two prey species in competition. We test how such effects depend on the infected species (prey or predator). We account for two effects of parasitism: the virulence effect (parasites affect the infected species intrinsic growth rate through direct effects on fecundity or mortality) and the interaction effect (increased vulnerability of infected prey or increased food intake of infected predators).

Results show that coexistence is favored when effects have intermediate intensity. We link this result to modifications of direct and apparent competitions among prey species. Given a prey infection, accounting for susceptible-infected population structure highlights that coexistence may also be reduced due to predator-parasite competition.

Parasites affect stability by modulating energy transfer from prey to predator. Predator infection therefore has a stabilizing effect due to increased energy fluxes and/or predator mortality.

Our results suggest that parasites potentially increase species coexistence. Precise predictions however require an assessment of various parasite effects. We discuss the implications of our results for the functioning of trophic networks and the evolution of foraging strategies within food webs.
Climate change and the potential distribution ofXylella fastidiosain Europe
Authors: Godefroid Martin , Cruaud Astrid , Streito Jean-Claude , Rasplus Jean-Yves , Rossi Jean-Pierre
Published: March 2018

The bacteriumXylella fastidiosa (Xf)is a plant endophyte native to the Americas that causes worldwide concern.Xfhas been recently detected in several regions outside its natural range including Europe. In that context, accurate estimates of its response to climate change are required to design cost-efficient and environment-friendly control strategies. In the present study, we collected data documenting the native and invaded ranges of the three main subspecies ofXf: fastidiosa, paucaandmultiplex, as well as two strains ofXfsubsp.multiplexrecently detected in southern France (ST6 and ST7). We fitted bioclimatic species distribution models (SDMs) to forecast their potential geographic range and impact in Europe under current and future climate conditions. According to model predictions, the geographical range ofXfas presently reported in Europe is small compared to the large extent of suitable areas. The European regions most threatened byXfencompass the Mediterranean coastal areas of Spain, Greece, Italy and France, the Atlantic coastal areas of France, Portugal and Spain as well as the south-western regions of Spain and lowlands in southern Italy. Potential distribution of the different subspecies / strains are contrasted but all are predicted to increase by 2050, which could threaten several of the most economically important wine-, olive- and fruit-producing regions of Europe, warranting the design of control strategies. Bioclimatic models also predict that the subspeciesmultiplexmight represent a threat to most of Europe under current and future climate conditions. These results may serve as a basis for future design of a spatially informed European-scale integrated management strategy, including early detection surveys in plants and insect vectors, quarantine measures as well as agricultural practices.
In vivo characterization and quantification of neurofibrillary tau PET radioligand [18F]MK-6240 in humans from Alzheimer’s disease dementia to young controls
Authors: Betthauser Tobey J , Cody Karly A , Zammit Matthew D , Murali Dhanabalan , Converse Alexander K , Barnhart Todd E , Stone Charles K , Rowley Howard A , Johnson Sterling C , Christian Bradley T
Published: March 2018

Tau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer’s disease (AD). This work investigatesin vivokinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [18F]MK-6240 in humans.

Methods

Fifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted magnetic resonance imaging (MRI), and [11C]PiB and [18F]MK-6240 PET imaging. PET data were coregistered to the MRI and time-activity curves were extracted from regions of interest to assess [18F]MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis (LGA) and multilinear reference tissue method (MRTM2)) were investigated for quantification of [18F]MK-6240 distribution volume ratios (DVRs) in a subset of nineteen participants. Stability of DVR methods was evaluated using truncated scan durations. Standard uptake value ratio (SUVR) estimates were compared to DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature.

Results

Standard uptake values in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared to MRTM2. DVR estimates remained stable when truncating the scan duration to 60 minutes. SUVR determined 70-90 minutes post-injection of [18F]MK-6240 indicated linearity near unity when compared to DVR estimates and minimized potential spill-in from uptake outside of the brain. [18F]MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus.

Conclusions

[18F]MK-6240 is a promising PET radioligand forin vivoimaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.
Climate-fire-vegetation interactions and the rise of novel landscape patterns in subalpine ecosystems, Colorado
Authors: Calder W. John , Stefanova Ivanka , Shuman Bryan
Published: March 2018

Wildfire, when coupled with climate change, may catalyze abrupt shifts in forest vegetation patterns and composition. Such vegetation changes may also feedback to further alter the extent and frequency of fires through changes in forest fuels and their continuity.

To test these expectations, we obtained six fossil pollen records from lakes across a subalpine landscape in Colorado. Forests there may have responded to climate change and widespread wildfires ca. 1000 years ago when a previous study indicates >80% of sites on the landscape burned within a century. The fires coincided with regional warming, but the extent of burning declined before the climate cooled again. Potentially, post-fire changes in fuel structure and composition contributed to a decline in burning while the warmth persisted.

Results of cluster analyses of the pollen percentages indicate that large changes between successive sets of samples coincided with the widespread wildfires at five of the six sites. After the wildfires, sagebrush (Artemisia) and other meadow taxa increased as conifers, especially spruce (Picea), declined across the landscape, indicating that the forests opened.

The opening of the forests may have created fuel breaks across the mountain range that limited wildfire after temperatures rose ∼0.5 °C, and the opening became larger as forests opened further during the Little Ice Age (LIA). Pollen assemblages, like those associated with modern bands of meadow and forest at high elevations, known as ribbon forests, only became common across our study sites during the LIA when the effects of the large fires and subsequent cooling interacted.

Synthesis. The transition to open landscapes after widespread wildfire is consistent with the hypothesized vegetation-fire-climate feedbacks and illustrates how climate and fire can interact to rapidly transform landscapes, produce novel vegetation patterns, and further interact with subsequent disturbance regimes.
Mass Amphibian Mortality during Overwintering Related To Fungal Pathogen But Not Larval Environment: An Explanation for Declines?
Authors: Rumschlag Samantha L. , Boone Michelle D.
Published: March 2018

Abstract

Development of infectious diseases within hosts may be shaped by environmental conditions that cause tradeoffs in energetic demands for immune responses against demands for host growth and survival. Environmental conditions may influence these tradeoffs by affecting size of hosts, or tradeoffs may change across seasons, thereby altering the impacts of diseases on hosts. In the present study, we exposed northern leopard frog (Lithobates pipiens) tadpoles to varying larval environments (low leaf litter, high density of conspecifics, 40 µg/L atrazine, caged fish, or control) that influenced size at metamorphosis, a measure of host quality. Subsequently, we exposed these metamorphs of to Batrachochytrium dendrobatidis (Bd), a fungal pathogen linked to worldwide host population declines, at metamorphosis and/or 12 weeks later, prior to overwintering. Bd exposure dramatically reduced survival during overwintering and the effect was strongest when frogs were exposed both at metamorphosis and before overwintering. Larval environments, which determined host size, did not influence effects of Bd. Stage-structured models built to assess the impacts of Bd exposure on host populations suggest that Bd exposure at metamorphosis or before overwintering would reduce annual population growth rates by an average of 19% and 41%, respectively. Our study indicates that northern leopard frog hosts suffered little effects of Bd exposures following metamorphosis and that lower host quality did not hamper a frog’s ability to respond to Bd. Instead, we provide evidence that Bd exposure can reduce survival and result in population size reductions via reduced recruitment from overwintering mortality, providing a plausible mechanism for enigmatic declines of amphibians in temperate regions.
The cellular NMD pathway restricts Zika virus infection and is targeted by the viral capsid protein
Authors: Fontaine KA , Leon KE , Khalid MM , Jimenez-Morales D , Kaye J , Shah P , Finkbeiner S , Krogan N , Ott M
Published: March 2018

Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice2–4. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1)5. Endogenous UPF1 interacted with the viral capsid protein in co-immunoprecipitation experiments and capsid expression post-transcriptionally downregulated UPF1, a process that we confirmed occurs during de novo ZIKV infection. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures. We therefore propose that ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD6,7, which subsequently contributes to neuropathology in vivo.
Brain-Specific Deletion of GIT1 Impairs Cognition and Alters Phosphorylation of Synaptic Protein Networks Implicated in Schizophrenia Susceptibility
Authors: Fass Daniel M. , Lewis Michael C. , Ahmad Rushdy , Szucs Matthew J. , Zhang Qiangge , Fleishman Morgan , Wang Dongqing , Kim Myung Jong , Biag Jonathan , Carr Steven A. , Scolnick Edward M. , Premont Richard T. , Haggarty Stephen J.
Published: March 2018

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and find that these mice have deficits in fear conditioning learning and spatial memory. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.
Complete guide RNA design for CRISPR-mediated regulation of human long noncoding RNA transcription
Authors: Saberi Amir , Zhu Renjun , Kwon Chulan
Published: March 2018

Transcription inhibition and activation of long noncoding RNAs (lncRNAs) mediated by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology provides potential advantages in high-throughput functional genomics studies over RNA interference or overexpression platforms. In this work, we identify over 90,000 lncRNA transcription start sites (TSSs) based on the MiTranscriptome human genome annotation and design single guide RNA (sgRNA) libraries with strong predicted activities and low off-target effects for CRISPR-mediated inhibition and activation (CRISPRi/a) of their transcription. A large fraction of these TSSs correspond to putative genes that are not annotated in common reference genome annotations and have never been functionally studied. Our CRISPRi/a libraries, or their context-dependent subsets, are potentially useful in genome-scale functional studies of human lncRNAs.
Condition-adaptive fused graphical lasso (CFGL): an adaptive procedure for inferring condition-specific gene co-expression network
Authors: Lyu Yafei , Xue Lingzhou , Zhang Feipeng , Koch Hillary , Saba Laura , Kechris Katerina , Li Qunhua
Published: March 2018

Co-expression network analysis provides useful information for studying gene regulation in biological processes. Examining condition-specific patterns of co-expression can provide insights into the underlying cellular processes activated in a particular condition. One challenge in this type of analysis is that the sample sizes in each condition are usually small, making the statistical inference of co-expression patterns highly underpowered. A joint network construction that borrows information from related structures across conditions has the potential to improve the power of the analysis.

One possible approach to constructing the co-expression network is to use the Gaussian graphical model. Though several methods are available for joint estimation of multiple graphical models, they do not fully account for the heterogeneity between samples and between co-expression patterns introduced by condition specificity. Here we develop the condition-adaptive fused graphical lasso (CFGL), a data-driven approach to incorporate condition specificity in the estimation of co-expression networks. We show that this method improves the accuracy with which networks are learned. The application of this method on a rat multi-tissue dataset and The Cancer Genome Atlas (TCGA) breast cancer dataset provides interesting biological insights. In both analyses, we identify numerous modules enriched for Gene Ontology functions and observe that the modules that are upregulated in a particular condition are often involved in condition-specific activities. Interestingly, we observe that the genes strongly associated with survival time in the TCGA dataset are less likely to be network hubs, suggesting that genes associated with cancer progression are likely to govern specific functions, rather than regulating a large number of biological processes. Additionally, we observed that the tumor-specific hub genes tend to have few shared edges with normal tissue, revealing tumor-specific regulatory mechanism.

Author summary

Gene co-expression networks provide insights into the mechanism of cellular activity and gene regulation. Condition-specific mechanisms may be identified by constructing and comparing co-expression networks of multiple conditions. We propose a novel statistical method to jointly construct co-expression networks for gene expression profiles from multiple conditions. By using a data-driven approach to capture condition-specific co-expression patterns, this method is effective in identifying both co-expression patterns that are specific to a condition and that are common across conditions. The application of this method on real datasets reveals interesting biological insights.
Changes in the genetic requirements for microbial interactions with increasing community complexity
Authors: Morin Manon , Pierce Emily C. , Dutton Rachel
Published: March 2018

Microbial community structure and function rely on complex interactions whose underlying molecular mechanisms are poorly understood. To investigate these interactions in a simple microbiome, we introduced E. coli into an experimental community based on a cheese rind and identified the differences in E. coli’s genetic requirements for growth in interactive and non-interactive contexts using Random Barcode Transposon Sequencing (RB-TnSeq) and RNASeq. E. coli’s genetic requirements varied among pairwise growth conditions and between pairwise and community conditions. Our analysis points to mechanisms by which growth conditions change as a result of increasing community complexity and suggests that growth within a community relies on a combination of pairwise and higher order interactions. Our work provides a framework for using the model organism E. coli as a probe to investigate microbial interactions regardless of the genetic tractability of members of the studied ecosystem.
Female ornamentation and the fecundity trade-off in a sex-role reversed pipefish
Authors: Mobley Kenyon B. , Morrongiello John R. , Warr Matthew , Bray Diane , Wong Bob B. M.
Published: March 2018

Female ornaments are a rare occurrence in nature. One explanation for this is that female ornaments are costly to produce and maintain and, therefore, females must trade-off resources related to reproduction to promote ornament expression. Here, we investigate the potential trade-off between female ornamentation and fecundity in the sex-role reversed, wide-bodied pipefish, Stigmatopora nigra. We measured two components of the female ornament, body width and stripe thickness, and tested the relationship between these ornaments and female fecundity and the mean egg size. Both body width and stripe thickness were strongly and positively related to female body size. After controlling for the influence of body size, we found no evidence of a cost of belly width or stripe thickness on female fecundity. Rather, females that have larger ornaments have higher fecundity and thus a greater relative fitness advantage. However, larger females suffered a slight decrease in egg size, consistent with a potential trade-off between egg size and body size, although no relationship between egg size and ornaments was observed. Our results suggest that larger S. nigra females accurately advertise their reproductive value to males, and underscore the importance of investigating the potential mechanisms that promote and maintain honesty of female ornaments.
A translaminar genetic logic for the circuit identity of intracortically-projecting neurons
Authors: Klingler Esther , De la Rossa Andres , Fièvre Sabine , Jabaudon Denis
Published: March 2018

Distinct subtypes of intracortically-projecting neurons (ICPN) are present in all layers, allowing propagation of information within and across cortical columns. How the molecular identities of ICPN relate to their defining anatomical and functional properties is unknown. Here we show that the transcriptional identities of ICPN primarily reflect their input-output connectivities rather than their birth dates or laminar positions. Thus, conserved circuit-related transcriptional programs are at play across cortical layers, which may preserve canonical circuit features across development and evolution.
Wide distributions and cryptic diversity within aMicrostomum(Platyhelminthes) species complex
Authors: Atherton Sarah , Jondelius Ulf
Published: March 2018

Microstomum lineareis a common species of fresh and brackish waters found worldwide. Three genes (18S, CO1, ITS) were sequenced from specimens ofM. linearecollected from four countries and the levels of cryptic diversity and genetic structuring was assessed. Results showedM. linearehas very wide haplotype distributions suggesting higher than expected dispersal capabilities. In addition, three new species were described on the basis of molecular taxonomy:Microstomum artoisisp. nov.,Microstomum tchaikovskyisp. nov., andMicrostomum zicklerorumsp. nov.
Hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing
Authors: Chen Shouwen , Yang Dahai , Wen Ying , Jiang Zhiwei , Zhang Lingzhi , Jiang Jiatiao , Chen Yaozhen , Hu Tianjian , Wang Qiyao , Zhang Yuanxing , Liu Qin
Published: March 2018

Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains uncovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cells (IECs). Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion, gut inflammation, and enterocyte pyroptosis in orally-infected mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.

Significance

Sensing of lipopolysaccharide (LPS) in the cytosol triggers non-canonical inflammasome-mediated innate responses. Recent work revealed that bacterial outer membrane vesicles (OMVs) enables LPS to access the cytosol for extracellular bacteria. However, since intracellular OMVs are generally constrained in endosomes, how OMV-derived LPS gain access to the cytosol remains unknown. Here, we reported that hemolysin largely bound with OMVs and entered cells through dynamin-dependent endocytosis. Intracellular hemolysin significantly impaired OMVs-constrained vacuole integrity and increased OMV-derived LPS exposure to the cytosolic sensor, which promoted non-canonical inflammasome activation and restricted bacterial gut infections. This work reveals the role of hemolysin in promoting non-canonical inflammasome activation and alerting host immune recognition, which provides insights into the more sophisticated biological functions of hemolysin upon infection.
Effects of adaptive harvesting on fishing down processes and resilience changes in predator-prey and tritrophic systems
Authors: Tromeur Eric , Loeuille Nicolas
Published: March 2018

Many world fisheries display a declining mean trophic level of catches. This “fishing down the food web” is often attributed to reduced densities of high-trophic-level species. We show here that the fishing down pattern can actually emerge from the adaptive harvesting of two- and three-species food webs, where changes in fishing patterns are driven by the relative profitabilities of the harvested species. Shifting fishing patterns from a focus on higher trophic levels to a focus on lower trophic levels can yield abrupt changes in the system, strongly impacting species densities. In predator-prey systems, such regime shifts occur when the predator species is highly valuable relative to the prey, and when the top-down control on the prey is strong. Moreover, we find that when the two species are jointly harvested, high adaptation speeds can reduce the resilience of fisheries. Our results therefore suggest that flexibility in harvesting strategies will not necessarily benefit fisheries but may actually harm their sustainability.
ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer
Authors: Iyer Prajish , Shrikhande Shailesh V , Ranjan Malika , Joshi Asim , Prasad Ratnam , Gardi Nilesh , Thorat Rahul , Salunkhe Sameer , Dharavath Bhasker , Sahoo Bikram , Chandrani Pratik , Kore Hitesh , Mohanty Bhabani , Chaudhari Vikram , Choughule Anuradha , Kawle Dhananjay , Chaudhari Pradip , Ingle Arvind , Banavali Shripad , Ramadwar Mukta R , Prabhash Kumar , Barreto Savio George , Dutt Shilpee , Dutt Amit
Published: March 2018

The uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activatingERBB2andKRASsomatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively.In vitroandin vivocell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on theKRASmutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence ofKRAS(G12V), but notKRAS(G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.
Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria
Authors: Day Felix , Karaderi Tugce , Jones Michelle R. , Meun Cindy , He Chunyan , Drong Alex , Kraft Peter , Lin Nan , Huang Hongyan , Broer Linda , Magi Reedik , Saxena Richa , Laisk-Podar Triin , Urbanek Margrit , Hayes M. Geoffrey , Thorleifsson Gudmar , Fernandez-Tajes Juan , Mahajan Anubha , Mullin Benjamin H. , Stuckey Bronwyn G.A. , Spector Timothy D. , Wilson Scott G. , Goodarzi Mark O. , Davis Lea , Obermeyer-Pietsch Barbara , Uitterlinden André G. , Anttila Verneri , Neale Benjamin M , Jarvelin Marjo-Riitta , Fauser Bart , Kowalska Irina , Visser Jenny A. , Anderson Marianne , Ong Ken , Stener-Victorin Elisabet , Ehrmann David , Legro Richard S. , Salumets Andres , McCarthy Mark I. , Morin-Papunen Laure , Thorsteinsdottir Unnur , Stefansson Kari ,   23andMe Research Team, Styrkarsdottir Unnur , Perry John , Dunaif Andrea , Laven Joop , Franks Steve , Lindgren Cecilia M. , Welt Corrine K.
Published: March 2018

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (nearPLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.
De novo transcriptome assembly, annotation, and identification of low-copy number genes in the flowering plant genus Silene (Caryophyllaceae)
Authors: Bertrand Yann J K , Petri Anna , Scheen Anne-Cathrine , Töpel Mats , Oxelman Bengt
Published: March 2018

Phylogenetic methods that rely on information from multiple, unlinked genes have recently been developed for resolving complex situations where evolutionary relationships do not conform to bifurcated trees and are more adequately depicted by networks. Such situations arise when successive interspecific hybridizations in combination with genome duplications have shaped species phylogenies. Several processes such as homoeolog loss and deep coalescence can potentially hamper our ability to recover the historical signal correctly. Consequently the prospect of reconstructing accurate phylogenies lies in the combination of several low-copy nuclear markers that when, used in concert, can provide homoeologs for all the ancestral genomes and help to disentangle gene tree incongruence due to deep coalescence events. Expressed sequence tag (EST) databases represent valuable resource for the identification of genes in organisms with uncharacterized genomes and for development of molecular markers. The genus Silene L. is a prime example of a plant group whose evolutionary history involves numerous events of hybridization and polyploidization. As for many groups there is currently a shortage of low-copy nuclear markers, for which phylogenetic usefulness has been demonstrated. Here, we present two EST libraries for two species of Silene that belong to large phylogenetic groups not previously investigated with next generation technologies. The assembled and annotated transcriptomes are used for identifying low copy nuclear regions, suitable for sequencing.
Identification of microRNA clusters cooperatively acting on Epithelial to Mesenchymal Transition in Triple Negative Breast Cancer
Authors: Cantini L , Bertoli G , Cava C , Dubois T , Zinovyev A , Caselle M , Castiglioni I , Barillot E , Martignetti L
Published: March 2018

MicroRNAs play important roles in many biological processes. Their aberrant expression can have oncogenic or tumor suppressor function directly participating to carcinogenesis, malignant transformation, invasiveness and metastasis. Indeed, miRNA profiles can distinguish not only between normal and cancerous tissue but they can also successfully classify different subtypes of a particular cancer. Here, we focus on a particular class of transcripts encoding polycistronic miRNA genes that yields multiple miRNA components. We describe clustered MiRNA Master Regulator Analysis (ClustMMRA), a fully redesigned release of the MMRA computational pipeline (MiRNA Master Regulator Analysis), developed to search for clustered miRNAs potentially driving cancer molecular subtyping. Genomically clustered miRNAs are frequently co-expressed to target different components of pro-tumorigenic signalling pathways. By applying ClustMMRA to breast cancer patient data, we identified key miRNA clusters driving the phenotype of different tumor subgroups. The pipeline was applied to two independent breast cancer datasets, providing statistically concordant results between the two analysis. We validated in cell lines the miR-199/miR-214 as a novel cluster of miRNAs promoting the triple negative subtype phenotype through its control of proliferation and EMT.
Structure of the herpes-simplex virus portal-vertex
Authors: McElwee Marion , Vijayakrishnan Swetha , Rixon Frazer , Bhella David
Published: March 2018

Herpesviruses include many important human pathogens such as herpes simplex virus, cytomegalovirus, varicella-zoster virus and the oncogenic Epstein-Barr virus and Kaposi-sarcoma associated herpesvirus. Herpes virions contains large icosahedral capsids that have a portal at a unique five-fold vertex, similar to that seen in the tailed bacteriophages. The portal is a molecular motor through which the viral genome enters the capsid during virion morphogenesis. The genome also exits the capsid through the portal-vertex when it is injected through the nuclear-pore into the nucleus of a new host cell to initiate infection. Structural investigations of the herpesvirus portal-vertex have proven challenging, owing to the small size of the tail-like portal-vertex associated tegument (PVAT), and the dense tegument layer that lays between the nucleocapsid and the viral envelope, obscuring the view of the portal-vertex. Here we show the structure of the herpes simplex virus portal-vertex at sub-nanometer resolution, solved by electron cryomicroscopy (cryoEM) and single-particle 3D reconstruction. This led to a number of new discoveries including the presence of two previously unknown portal associated structures that occupy the sites normally taken by the penton and the Ta triplex. Our data revealed that the PVAT is composed of ten copies of the C-terminal domain of pUL25, which are uniquely arranged as two tiers of star-shaped density. Our 3D reconstruction of the portal-vertex also shows that one end of the viral genome extends outside the portal in the manner described for some bacteriophage but not previously seen in any eukaryote viruses. Finally, we show that the viral genome is consistently packed in a highly-ordered left-handed spool to form concentric shells of DNA. Our data provide new insights into the structure of a molecular machine critical to the biology of an important class of human pathogens.
Sustained High- and Low-Frequency Neural Responses to Visual Stimuli in Scalp EEG
Authors: Gerber Edden M. , Deouell Leon Y.
Published: March 2018

What are the neurophysiological correlates of sustained visual processing in the scalp EEG signal? In a previous study using intracranial recordings in humans, we found that presentation of visual stimuli for prolonged durations (up to 1.5 seconds) was associated with two kinds of sustained neural activity patterns: a high-frequency broadband (>30 Hz) response that tracked the duration of the stimulus with high precision in early visual cortex (EVC), and with lesser temporal precision in downstream category-selective areas; and a sustained low-frequency potential shift appearing in a small subset of EVC sites. Using a similar approach of presenting images for variable durations to identify sustained activity, we provide the first comprehensive characterization of the manifestation of sustained visual responses as recorded with EEG. In a series of four experiments, we found that both high- and low-frequency sustained responses can be detected on the scalp. The high frequency activity could be detected with high signal to noise ratio only in a subset of individual subjects, in whom it was unequivocal and highly localized. The low frequency sustained response was sensitive to the size and position of the stimulus in the visual field. Both response types showed strong lateralization for stimuli on the left vs. right visual field, suggesting a retinotopic visual cortical source. However, different scalp topographies and different modulation by stimulus properties suggest that the two types of sustained responses are likely driven by distinct sources, and reflect different aspects of sustained processing in the visual cortex.
Inducible alpha-synuclein overexpression affects human Neural Stem Cells behavior
Authors: Zasso J , Ahmed M , Cutarelli A , Conti L
Published: March 2018

Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinson’s disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step.

Here we present a novel human Tet-on hNSC cell line, in which aSyn timing and level of expression can be tightly experimentally tuned. Induction of aSyn in self-renewing hNSCs leads to progressive formation of aSyn aggregates and impairs their proliferation and cell survival. Furthermore, aSyn induction during the neuronal differentiation process results in impaired neurogenic potential due to enhanced refractoriness to exit self-renewal and to increase of gliogenic vs neurogenic competence. Finally, acute aSyn induction in hNSC-derived dopaminergic neuronal cultures results in cell toxicity.

This novel conditional in vitro cell model system may be a valuable tool for dissecting of aSyn pathogenic effects in hNSCs and neurons and in developing new potential therapeutic strategies.
Monkeys use the rod-dense retinal region rather than the fovea to visually fixate small targets in scotopic vision
Authors: Spivak Oleg , Thier Peter , Barash Shabtai
Published: March 2018

Monkeys appear to visually fixate targets in scotopic conditions. The function fixations fulfill in photopic vision, keeping the target’s image on the fovea, is nullified in scotopic vision, because the fovea, with its cones, is desensitized in dim light. Here we followed the hypothesis that a previously described retinal region, the locus of maximal rod density, functionally replaces the fovea; we found that with dark background, most of the fixations direct the fovea above the target, so that the target’s image appears to fall on the line connecting the fovea with the locus of maximal rod density. There is considerable trial-by-trial variation in the fixation positions along this line. On the whole, the closer the visual conditions are to full scotopic, the higher is this gaze upshift, indicating the closer does the target fall to the locus of maximal rod density. Mesopic background induces low mean upshift. Full (45-min) dark adaptation was essential to achieving high upshift values. There is no analogous photopic effect – 45-min ‘bright adaptation’ did not shift the locus of photopic fixation.