bluuebunny/crossref_metadata_2025_split huggingface dataset:
BayeSuites: An open web framework for massive Bayesian networks focused on neuroscience
Authors: Michiels Mario , Larrañaga Pedro , Bielza Concha 
Published: February 2020

AbstractBayeSuites is the first web framework for learning, visualizing, and interpreting Bayesian networks (BNs) that can scale to tens of thousands of nodes while providing fast and friendly user experience. All the necessary features that enable this are reviewed in this paper; these features include scalability, extensibility, interoperability, ease of use, and interpretability. Scalability is the key factor in learning and processing massive networks within reasonable time; for a maintainable software open to new functionalities, extensibility and interoperability are necessary. Ease of use and interpretability are fundamental aspects of model interpretation, fairly similar to the case of the recent explainable artificial intelligence trend. We present the capabilities of our proposed framework by highlighting a real example of a BN learned from genomic data obtained from Allen Institute for Brain Science. The extensibility properties of the software are also demonstrated with the help of our BN-based probabilistic clustering implementation, together with another genomic-data example.
Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo
Authors: Blackwell Danielle L , Fraser Sherri D , Caluseriu Oana , Vivori Claudia , Tyndall Amanda V , Lamont Ryan E , Parboosingh Jillian S , Innes A Micheil , Bernier François P , Childs Sarah J 
Published: February 2020

AbstractMutations in RNA binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb and neurological symptoms. Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. We show a developmental role for Hnrnpul1 in zebrafish, resulting in reduced craniofacial tendon length, severe adult-onset scoliosis and reduced fin size. We demonstrate a role of Hnrnpul1 in alternative splicing and transcriptional regulation using RNA sequencing. Given its cross-species conservation and role in splicing it would not be surprising if it had a role in human development but the developmental role of this gene in humans has not been explored. Whole exome sequencing detected a frameshift variant inHNRNPUL1in two siblings with congenital limb malformations which remain variants of unknown significance. Zebrafish Hnrnpul1 mutants suggest an important developmental role of hnRNPUL1 and provide motivation for exploring potential conservation of ancient regulatory circuits involving hnRNPUL1 in human development.
First study on age and growth of the deep-water Goblin Shark,Mitsukurina owstoni(Jordan, 1898)
Authors: Caltabellotta Fabio P. , Siders Zachary A. , Cailliet Gregor , Motta Fabio S. , Gadig Otto B. F. 
Published: February 2020

AbstractDue to poorly mineralizing structures, ageing deep-water elasmobranchs requires nonconventional techniques. The aim of the present study was to develop a reliable ageing technique using the vertebral centrum to provide information about the age and growth parameters in the Goblin Shark,Mitsukurina owstoni(Jordan, 1898). One vertebral centrum from an individual measuring 315.2 cm in total length was analysed. A minimum age of 27 years was estimated. By incorporating priors based on the growth of deep-water sharks and an additional likelihood onL∞using data on large male Goblin Sharks, a Bayesian von Bertalanffy growth model was estimated with a maleL∞of 364 cm total length, weigh 215 kg atL∞, grow slowly with akequal to 0.049, mature at 16.5 years, and live up to 55 years. Our results are essential to provide useful life history information, with the aim of elucidating the cryptic ecology and biology of this deep-water shark.
Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility
Authors: Sánchez-Sáez Fernando , Gómez-H Laura , Dunne Orla M. , Gallego-Páramo Cristina , Felipe-Medina Natalia , Sánchez-Martín Manuel , Llano Elena , Pendas Alberto M. , Davies Owen R. 
Published: February 2020

AbstractMeiotic reductional division is dependent on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC is formed of eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine mouse genetics, cellular and biochemical studies to reveal that SYCE1 undergoes multivalent interactions with SC component SIX6OS1. The N-terminus of SIX6OS1 binds and disrupts SYCE1’s core dimeric structure to form a 1:1 complex, whilst their downstream sequences provide a distinct second interface. These interfaces are separately disrupted by SYCE1 mutations associated with non-obstructive azoospermia and premature ovarian failure, respectively. Mice harbouring SYCE1’s POF mutation and a targeted deletion within SIX6OS1’s N-terminus are infertile with failure of chromosome synapsis. We conclude that both SYCE1-SIX6OS1 binding interfaces are essential for SC assembly, thus explaining how SYCE1’s reported clinical mutations give rise to human infertility.
Neutrophils are required during immunization with the pneumococcal conjugate vaccine for protective antibody responses and host defense against infection
Authors: Tchalla Essi Y. I. , Wohlfert Elizabeth A. , Bou Ghanem Elsa N. 
Published: February 2020

AbstractNeutrophils can shape adaptive immunity, however their role in vaccine-induced protection against infectionsin vivoremains unclear. Here, we tested their role in the clinically relevant polysaccharide conjugate vaccine againstStreptococcus pneumoniae(pneumococcus). We antibody depleted neutrophils during vaccination, allowed them to recover, and four weeks later challenged mice with pneumococci. We found that while isotype-treated vaccinated controls were protected against an otherwise lethal infection in naïve mice, full protection was lost upon neutrophil depletion. Compared to vaccinated controls, neutrophil-depleted mice had higher lung bacterial burdens, increased incidence of bacteremia and lower survival rates. Sera from neutrophil-depleted mice had less anti-pneumococcal IgG2c and IgG3, were less efficient at inducing opsonophagocytic killing of bacteria by neutrophilsin vitroand worse at protecting naïve mice against pneumococcal pneumonia. In summary, neutrophils are required during vaccination for optimal host protection, which has important implications for future vaccine design against pneumococci and other pathogens.
Stem Cell Transplantation Rescued A Primary Open-Angle Glaucoma Mouse Model
Authors: Xiong Siqi , Kumar Ajay , Tian Shenghe , Taher Eman E. , Yang Enzhi , Kinchington Paul R. , Xia Xiaobo , Du Yiqin 
Published: February 2020

AbstractGlaucoma is a leading cause of irreversible blindness. In this study, we investigated if exogenous stem cells are able to rescue a glaucoma mouse model with transgenic myocilin Y437H mutation and explored the possible mechanisms. Human trabecular meshwork stem cells (TMSCs) were intracamerally transplanted which reduced mouse intraocular pressure, increased outflow facility, protected the retinal ganglion cells and preserved their function. TMSC transplantation also significantly increased the TM cellularity, promoted myocilin secretion from TM cells into the aqueous humor to reduce endoplasmic reticulum stress, repaired the TM tissue with extracellular matrix modulation and ultrastructural restoration. Co-culturing TMSCs with myocilin mutant TM cells in vitro promoted TMSCs differentiating into phagocytic functional TM cells. RNA sequencing revealed that TMSCs had upregulated genes related to TM regeneration and neuroprotection. Our results uncovered therapeutic potential of TMSCs for curing glaucoma and elucidated possible mechanisms by which TMSCs achieve the treatment effect.
The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development
Authors: Echevarría-Andino Martha L. , Allen Benjamin L. 
Published: February 2020

AbstractThe Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands signal through the canonical receptor PTCH1, and three co-receptors– GAS1, CDON and BOC. Together, these co-receptors are required during embryogenesis to mediate proper HH signaling. Here we investigated the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian craniofacial development. Individual deletion of eitherGas1orCdonresults in variable holoprosencephaly phenotypes, characterized by the failure to divide and form the telencephalon and midfacial structures. In contrast, we find thatBocdeletion results in facial widening consistent with increased HH pathway activity. Additionally, the deletion ofBocin aGas1null background partially rescues the craniofacial defects observed inGas1single mutants; a phenotype that persists over developmental time. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion ofGas1andBoc. Mechanistically, BOC selectively restricts neural crest-derived mesenchymal proliferation. Together, these data indicate that BOC acts as a multi-functional regulator of HH signaling during craniofacial development, alternately promoting or restraining HH pathway activity in a tissue-specific fashion.Summary statementHere we identify dual, tissue-specific roles for the Hedgehog co-receptor BOC in both the promotion and antagonism of Hedgehog signaling during craniofacial development.
Differential Impacts on Host Transcription by ROP and GRA Effectors from the Intracellular ParasiteToxoplasma gondii
Authors: Rastogi Suchita , Xue Yuan , Quake Stephen R. , Boothroyd John C. 
Published: February 2020

ABSTRACTThe intracellular parasiteToxoplasma gondiiemploys a vast array of effector proteins from the rhoptry and dense granule organelles to modulate host cell biology; these effectors are known as ROPs and GRAs, respectively. To examine the individual impacts of ROPs and GRAs on host gene expression, we developed a robust, novel protocol to enrich for ultra-pure populations of a naturally occurring and reproducible population of host cells called uninfected-injected (U-I) cells, whichToxoplasmainjects with ROPs but subsequently fails to invade. We then performed single cell transcriptomic analysis at 1-3 hours post-infection on U-I cells (as well as on uninfected and infected controls) arising from infection with either wild type parasites or parasites lacking the MYR1 protein, which is required for soluble GRAs to cross the parasitophorous vacuole membrane (PVM) and reach the host cell cytosol. Based on comparisons of infected and U-I cells, the host’s earliest response to infection appears to be driven primarily by the injected ROPs, which appear to induce immune and cellular stress pathways. These ROP-dependent pro-inflammatory signatures appear to be counteracted by at least some of the MYR1-dependent GRAs and may be enhanced by the MYR-independent GRAs, (which are found embedded within the PVM). Finally, signatures detected in uninfected bystander cells from the infected monolayers suggests that MYR1-dependent paracrine effects also counteract inflammatory ROP-dependent processes.IMPORTANCEThis work performs the first transcriptomic analysis of U-I cells, captures the earliest stage of a host cell’s interaction withToxoplasma gondii, and dissects the effects of individual classes of parasite effectors on host cell biology.
Prey refuge and morphological defense mechanisms as nonlinear triggers in an intraguild predation food web
Authors: Mendonça J. P. , Gleria Iram , Lyra M. L. 
Published: February 2020

AbstractIntraguild predation (IGP) is a type of interaction in which a top predator simultaneously competes and predates an intermediate prey that shares a third prey species with the top predator. While common in nature, most theoretical population dynamics models proposed in the literature predict that this three species interaction usually leads to extinction of the intermediate prey population. Predator-induced defense as well as refuge mechanisms are widely seen in these systems and should be incorporated in IGP models to promote coexistence. With this aim, we introduce a nonlinear response to the predation of IG-predator on IG-prey modelling both prey refuge and morphological defenses. The phase diagram of species coexistence is obtained as function of the attack efficiency and the degree of nonlinearity of the defense mechanisms. Further we show how the nonlinearity affects the equilibrium populations. We unveil that there is an optimal nonlinearity at which the convergence towards the stationary coexistence regime is the fastest.
A novel assay to isolate and quantify third-stage filarial larvae emerging from individual mosquitoes
Authors: McCrea Abigail R. , Edgerton Elizabeth B. , Oliver Genevieve T. , O’Neill Fiona M. , Nolan Thomas J. , Lok James B. , Povelones Michael 
Published: February 2020

AbstractBackgroundMosquitoes transmit filarial nematodes to both human and animal hosts, resulting in worldwide health and economic consequences. Transmission to a vertebrate host requires that ingested microfilariae develop into infective third-stage larvae capable of emerging from the mosquito proboscis onto the skin of the host during blood feeding. Determining the number of microfilariae that successfully develop to infective third-stage larvae in the mosquito host is key to understanding parasite transmission potential and to developing new strategies to block these worms in their vector.MethodsWe developed a novel method to efficiently assess the number of infective third-stage filarial larvae that emerge from experimentally infected mosquitoes. Following infection, individual mosquitoes were placed in wells of a multi-well culture plate and warmed to 37 °C to stimulate parasite emergence.Aedes aegyptiinfected withDirofilaria immitiswere used to determine infection conditions and assay timing. The assay was also tested withBrugia malayiinfectedAe. aegypti.ResultsApproximately 30% ofAe. aegyptiinfected withD. immitisand 50% of those infected withB. malayiproduce emerging third-stage larvae. OnceD. immitisthird-stage larvae emerge at 13 days post infection, the proportion of mosquitoes producing them, and the number produced per mosquito remain stable until at least day 21. The prevalence and intensity of emerging third-stageB. malayiwere similar on days 12-14 days post infection. Increased uptake ofD. immitismicrofilariae increases the fitness cost to the mosquito but does not increase the number of emerging third-stage larvae.ConclusionsWe provide a new assay with an associated set of infection conditions that will facilitate assessment of the filarial transmission potential of mosquito vectors and promote preparation of uniformly infectious L3 for functional assays. The ability to quantify infection outcome will facilitate analyses of molecular interactions between vectors and filariae, ultimately allowing for the establishment of novel methods to block disease transmission.Graphical Abstract
Recent and rapid anthropogenic habitat fragmentation increases extinction risk for freshwater biodiversity
Authors: Brauer Chris J. , Beheregaray Luciano B. 
Published: February 2020

AbstractAnthropogenic habitat fragmentation is often implicated as driving the current global extinction crisis, particularly in freshwater ecosystems. The genetic signal of recent population isolation can however be confounded by the complex spatial arrangement of dendritic river systems. Consequently, many populations may presently be managed separately based on an incorrect assumption that they have evolved in isolation. Integrating landscape genomics data with models of connectivity that account for landscape structure, we show that the cumulative effects of multiple in-stream barriers have contributed to the recent decline of a freshwater fish from the Murray-Darling Basin, Australia. In addition, individual-based eco-evolutionary simulations further demonstrate that contemporary inferences about population isolation are consistent with the 160-year time frame since construction of in-stream barriers began in the region. Our findings suggest that the impact of very recent fragmentation may be often underestimated for freshwater biodiversity. We argue that proactive conservation measures to reconnect many riverine populations are urgently needed.
Lactobacillus curvatusStrains Specifically Show High Levels of Tolerance to Freeze-Thaw Stress
Authors: Ikai Ryunosuke , Tanabe Koichi , Shima Jun 
Published: February 2020

ABSTRACTTolerance to freeze-thaw stress is an important characteristic in recent fermentation processes. To gain insight into the freeze-thaw tolerance of lactic acid bacteria (LAB), we performed screening experiments and observed that severalLactobacillus curvatusstrains showed high freeze-tolerance even in the absence of cryoprotectants. TheseLb. curvatusstrains also showed high levels of freeze tolerance in a milk fermentation process.Lactobacillus sakei(closely related toLb. curvatus) was not revealed to be a freeze-thaw tolerant strain. These data indicate thatLb. curvatushas specific mechanisms underlying its tolerance to freeze-thaw stress.ImportanceOur findings demonstrate thatLb. curvatusstrains frequently show high levels of freeze-thaw tolerance in both culture and milk and thatLb. curvatusstrains are suitable as a model species for investigations of the molecular mechanisms underlying freeze-thaw tolerance in LAB and for applications in fermentation industries.
An Animal Model to StudyKlebsiella pneumoniaeGastro-Intestinal Colonization and Host-to-Host Transmission
Authors: Young Taylor M. , Bray Andrew S. , Nagpal Ravinder K. , Caudell David L. , Yadav Hariom , Zafar M. Ammar 
Published: February 2020

AbstractAn important yet poorly understood facet in the life cycle of a successful pathogen is the host-to-host transmission. Hospital-acquired infections (HAI) resulting from the transmission of drug-resistant pathogens affect hundreds of millions of patients worldwide.Klebsiella pneumoniae(Kpn), a gram-negative bacterium, is notorious for causing HAI, with many of these infections difficult to treat asKpnhas become multi-drug resistant. Epidemiological studies suggest thatKpnhost-to-host transmission requires close contact and generally occurs through the fecal-oral route. Herein, we describe a murine model that can be utilized to study mucosal (oropharynx and gastrointestinal [GI]) colonization, shedding within feces, and transmission ofKpnthrough the fecal-oral route. Using an oral route of inoculation, and fecal shedding as a marker for GI colonization, we show thatKpncan asymptomatically colonize the GI tract of immunocompetent mice, and modifies the host GI microbiota. Colonization density within the GI tract and levels of shedding in the feces differed among the clinical isolates tested. A hypervirulentKpnisolate was able to translocate from the GI tract and cause hepatic infection that mimicked the route of human infection. Expression of the capsule was required for colonization and, in turn, robust shedding. Furthermore,Kpncarrier mice were able to transmit to uninfected cohabitating mice. Lastly, treatment with antibiotics led to changes in the host microbiota and development of a transient super-shedder phenotype, which enhanced transmission efficiency. Thus, this model can be used to determine the contribution of host and bacterial factors towardsKpndissemination.
ClgR contributes to pulmonary pathology but not bacterial growth inMycobacterium tuberculosisinfection
Authors: Gautam Uma Shankar , Kaushal Deepak 
Published: February 2020

AbstractBackgroundThe Clp proteases regulator, ClgR, is encoded in theMycobacterium tuberculosis(Mtb) genome by Rv2745c gene(clgR).ClgR is required to clear damaged proteins, thereby preventing their accumulation in the cell. It also controls the availability of key enzymes or regulators via conditional degradation mechanism of proteolytic activity in Mtb [1,2].MethodsIt has been previously reported that MtbclgRgene is induced in a sigma factor SigH-dependent manner and a deletion mutant ofclgRis susceptible to growth in a hypoxic environment. Whether hypoxia is indeed a restriction factor and ClgR is required for Mtb growth in that environment remains unelucidated. We began to address this hypothesis in the C57/BL6 mouse model of TB where Mtb infected lungs do not form granuloma and the lung environment is considerably non-hypoxic.ResultsOur results demonstrate that despite not having a deficit in growth in either murine lungs or primary macrophages, in comparison to wild type, theΔclgRmutant failed to induce pulmonary pathology.ConclusionWe propose that ClgR is required for the pathogenesis of Mtb.
CRNKL1 is a highly selective regulator of intron-retaining HIV-1 and cellular mRNAs
Authors: Xiao Han , Wyler Emanuel , Milek Miha , Grewe Bastian , Kirchner Philipp , Ekici Arif , Villela Silva Ana Beatriz Oliveira , Jungnickl Doris , Landthaler Markus , Ensser Armin , Überla Klaus 
Published: February 2020

AbstractThe HIV-1 Rev protein is a nuclear export factor for unspliced and incompletely-spliced HIV-1 RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of the spliceosome which all enhanced expression from the HIV-1 unspliced RNA after CRISPR/Cas knock-down. Depletion of DHX38, WDR70 and four proteins of the Prp19-associated complex (ISY1, BUD31, XAB2, CRNKL1) resulted in a more than 20-fold enhancement of unspliced HIV-1 RNA levels in the cytoplasm. Targeting of CRNKL1, DHX38, and BUD31 affected nuclear export efficiencies of the HIV-1 unspliced RNA to a much larger extent than splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cytoplasmic levels of cellular mRNAs with selectively retained introns. Thus, CRNKL1 dependent nuclear retention seems to be a novel mechanism for the regulation of cytoplasmic levels of intron-retaining cellular mRNAs that is harnessed by HIV-1 to direct its complex splicing pattern.