bluuebunny/crossref_metadata_2025_split huggingface dataset:
APC2 is Critical for Ovarian WNT Signalling Control, Fertility and Tumour Suppression
Authors: Mohamed Noha-Ehssan , Hay Trevor , Reed Karen R. , Smalley Matthew J , Clarke Alan R. 
Published: January 2019

AbstractCanonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate for the first time using constitutive APC2-knockout (Apc2−/−) mice, essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphicApcallele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells, most likely due to its role in regulating WNT-signalling. Importantly, given that the APC2-deficient tumours recapitulate the molecular signature and histological features of human adult GCTs, this APC2-deficient mouse has excellent potential as a pre-clinical model to study ovarian tumour biology and for therapeutic testing.
A comparative analysis of cannabis and tobacco smoke exposure on human airway epithelial cell gene expression, immune phenotype, and response to formoterol and budesonide treatment
Authors: Aguiar Jennifer A. , Huff Ryan D. , Tse Wayne , Stampfli Martin R. , McConkey Brendan J. , Doxey Andrew C. , Hirota Jeremy A. 
Published: January 2019

AbstractGlobal recreational cannabis use is a potentially important public health issue that would benefit from experimental evidence to inform policy, regulations, and individual user practices. Comparative analyses between cannabis and tobacco smoke, the latter long reported to have negative impacts on respiratory health, may help provide context and provide clinically relevant evidence.To address this unmet need we performed a comparative study between cannabis and tobacco smoke exposure in the Calu-3 human airway epithelial cells using concentration-response and pharmacological intervention study designs with outcome measurements of cell viability, epithelial cell barrier function, cytokine profile, and transcriptomics.Our results demonstrate that cannabis smoke exposure reduces epithelial cell barrier function without impacting cell viability, accompanied by a cytokine profile associated with inflammation (elevated IL-6 and IL-8), barrier repair (elevated TGF-α and PDGF-AA) and suppressed antiviral immunity (decreased IP-10 and RANTES). Transcriptomic analyses revealed a cannabis smoke induced signature associated with suppressed antiviral genes and induction of oncogenic and oxidative stress pathways. Similar trends were observed for tobacco smoke exposure. A formoterol/budesonide intervention was unable to prevent cannabis smoke-induced reductions in antiviral pathways or normalize induction of oncogenic and oxidative stress responses.Our results show striking similarities between cannabis and tobacco smoke exposure on impairing barrier function, suppressing antiviral pathways, potentiating of pro-inflammatory mediators, and inducing oncogenic and oxidative stress gene expression signatures. Furthermore, we demonstrate that an intervention with formoterol and budesonide is unable to completely normalized cannabisinduced responses. Collectively our data suggest that cannabis smoke exposure is not innocuous and may possess many of the deleterious properties of tobacco smoke, warranting additional studies to support public policy, government regulations, and individual user practices.
Neuroendocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition
Authors: Sonkin Dmitriy , Vural Suleyman , Thomas Anish , Teicher Beverly A. 
Published: January 2019

AbstractSmall cell lung cancer (SCLC) is an aggressive form of lung cancer with limited therapeutic options, a very high mortality rate and is characterized, in most cases, by neuroendocrine features. A small but important subset of SCLC has intact RB1. However, other characteristics of this subset are not well-defined. To comprehensively assess the underlying genomics of SCLC cell lines with functional RB1, we examined 48 SCLC cell lines from the Cancer Cell Line Encyclopedia (CCLE) collection. Out of these 48 SCLC cell lines, 8 were found to be RB1 WT. We found that RB1 WT SCLC lines are enriched for loss of neuroendocrine lineage markers with CDKN2A inactivation, or CCND1 amplification. Six RB1 WT SCLC cell lines were included in NCI SCLC drug sensitivity screen and two of them were sensitive to CDK4/6 inhibition.
Cue-reactivity in the ventral striatum characterizes heavy cannabis use, whereas reactivity in the dorsal striatum mediates dependent use
Authors: Zhou Xinqi , Zimmermann Kaeli , Xin Fei , Zhao Weihua , Derckx Roelinka , Sassmannshausen Anja , Scheele Dirk , Hurlemann Rene , Weber Bernd , Kendrick Keith M. , Becker Benjamin 
Published: January 2019

AbstractBackgroundAnimal models of addiction suggest that the transition from incentive-driven to habitual and ultimately compulsive drug use is mediated by a shift from ventral to dorsal striatal cue-control over drug seeking. Previous studies in human cannabis users reported elevated trait impulsivity and cue-reactivity in striatal circuits, however, these studies were not able to separate addiction-related from exposure-related adaptations.MethodsTo differentiate the adaptive changes, the present functional magnetic resonance imaging study examined behavioral and neural cue-reactivity in dependent (n = 18) and non-dependent (n = 20) heavy cannabis users and a non-using reference group (n = 44).ResultsIrrespective of dependence status, cannabis users demonstrated elevated trait impulsivity as well as increased ventral striatal reactivity and striato-frontal coupling in response to drug cues. Dependent users selectively exhibited dorsal-striatal reactivity and decreased striato-limbic coupling during cue-exposure. An exploratory analysis revealed that higher ventral caudate cue-reactivity was associated with stronger cue-induced arousal and craving in dependent users, whereas this pattern was reversed in non-dependent users.ConclusionsTogether the present findings suggest that an incentive sensitization of the ventral striatal reward system may promote excessive drug use in humans, whereas adaptations in dorsal striatal systems engaged in habit formation may promote the transition to addictive use.
Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel
Authors: Yin Ying , Wu Mengyu , Hsu Allen L. , Borschel William F. , Borgnia Mario J. , Lander Gabriel C. , Lee Seok-Yong 
Published: January 2019

AbstractThe calcium-permeable transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types 1–3. Channel activation requires binding of both ADP-ribose (ADPR) 2,4–6 and Ca2+ 7. The recently published TRPM2 structures from Danio rerio in the ligand-free and in the ADPR/Ca2+-bound conditions represent the channel in closed and open states, which uncover substantial tertiary and quaternary conformational rearrangements 8. However, it is unclear how these rearrangements occur within the tetrameric channel during channel gating. Here we report two cryo-electron microscopy structures of TRPM2 from the same species in complex with Ca2+ alone, and with both ADPR and Ca2+, determined to an overall resolution of ~3.8 Å and ~4.2 Å respectively. In comparison with the published results, our studies capture TRPM2 in two-fold symmetric intermediate states, offering a glimpse of the structural transitions within the tetramer that bridge the closed and open conformations.
A 2.08 Å resolution structure of HLB5, a novel cellulase from the anaerobic gut bacterium Parabacteroides johnsonii DSM 18315
Authors: Chang Changsoo , Brooke Charles , Piao Hailan , Mack Jamey , Babnigg Gyorgy , Joachimiak Andrzej , Hess Matthias 
Published: January 2019

AbstractCellulases play a significant role in the degradation of complex carbohydrates. In the human gut anaerobic bacteria are essential to the well-being of the host by producing these essential enzymes that convert plant polymers into simple sugars that can then be further metabolized by the host. Here we report the 2.08 Å resolution structure of HLB5, a chemically verified cellulase that was identified previously from an anaerobic gut bacterium and that has no structural cellulase homologues in PDB nor possesses any conserved region typical for enzymes that degrade carbohydrates. We anticipate that the information presented here will facilitate the identification of additional cellulases for which no homologues have been identified until to date and in enhancing our understanding how these novel cellulases bind and hydrolyze their substrates.
Multiple two-photon targeted whole-cell patch-clamp recordings from monosynaptically connected neurons in vivo
Authors: Jouhanneau Jean-Sébastien , Poulet James F.A. 
Published: January 2019

AbstractAlthough we know a great deal about monosynaptic connectivity, transmission and integration in the mammalian nervous system from in vitro studies, very little is known in vivo. This is partly because it is technically difficult to evoke action potentials and simultaneously record small amplitude subthreshold responses in closely (< 150 µm) located pairs of neurons. To address this, we have developed in vivo two-photon targeted multiple (2 – 4) whole-cell patch clamp recordings of nearby neurons in superficial cortical layers 1 to 3. Here we describe a step-by-step guide to this approach in the anesthetised mouse primary somatosensory cortex, including: the design of the setup, surgery, preparation of pipettes, targeting and acquisition of multiple whole-cell recordings, as well as in vivo and post-hoc histology. The procedure takes ∼ 4 hours from start of surgery to end of recording and allows examinations both into the electrophysiological features of unitary excitatory and inhibitory monosynaptic inputs during different brain states as well as the synaptic mechanisms of correlated neuronal activity.
HybridMolDB: a manually curated database dedicated to hybrid molecules for chemical biology and drug discovery
Authors: Li Yecheng , Zhao Chongze , Wei Boyan , Wang Ling 
Published: January 2019

AbstractSummaryHybrid molecule-based drug design is the combination of two or more pharmacophoric moieties from identical or non-identical bioactive molecules, or known identical or non-identical bioactive molecules, into a single chemical entity. This strategy may be used to achieve better affinity and efficacy, or improved properties compared to the parent molecules, to interact with two or multiple targets, to reduce undesirable side effects, to decrease drug-drug interactions or to reduce emergence of drug resistance. The approach offers the prospect of better drugs for the treatment of many human diseases. Research activity in this area is increasing and has attracted many practitioners worldwide. To accelerate the design and discovery of new hybrid molecule-based drugs, it is essential to properly collect and annotate experimental data obtained from known hybrid molecules. To address this need, we have developed HybridMolDB, a manually curated database dedicated to hybrid molecules for chemical biology and drug discovery. It contains structures, manually annotated design protocols, pharmacological data, some physicochemical, ligand efficiency, drug-likeness and ADMET characteristics, and the biological targets of known hybrid molecules. HybridMolDB supports a range of query types, including searches by extensive text, protein sequence, chemical structure similarity and property ranges.AvailabilityHybridMolDB is freely available at http://www.idruglab.com/HybridMolDB/index.php.Contactlingwang@scut.edu.cn.
Kidney organoid reproducibility across multiple human iPSC lines and diminished off target cells after transplantation revealed by single cell transcriptomics
Authors: Subramanian Ayshwarya , Sidhom Eriene-Heidi , Emani Maheswarareddy , Sahakian Nareh , Vernon Katherine , Zhou Yiming , Kost-Alimova Maria , Weins Astrid , Slyper Michal , Waldman Julia , Dionne Danielle , Nguyen Lan T , Marshall Jamie , Rosenblatt-Rosen Orit , Regev Aviv , Greka Anna 
Published: January 2019

AbstractHuman iPSC-derived kidney organoids have the potential to revolutionize discovery, but assessing their consistency and reproducibility across iPSC lines, and reducing the generation of off-target cells remain an open challenge. Here, we used single cell RNA-Seq (scRNA-Seq) to profile 415,775 cells to show that organoid composition and development are comparable to human fetal and adult kidneys. Although cell classes were largely reproducible across iPSC lines, time points, protocols, and replicates, cell proportions were variable between different iPSC lines. Off-target cell proportions were the most variable. Prolongedin vitroculture did not alter cell types, but organoid transplantation under the mouse kidney capsule diminished off-target cells. Our work shows how scRNA-seq can help score organoids for reproducibility, faithfulness and quality, that kidney organoids derived from different iPSC lines are comparable surrogates for human kidney, and that transplantation enhances their formation by diminishing off-target cells.
Human Phageprints: A high-resolution exploration of oral phages reveals globally-distributed phage families with individual-specific and temporally-stable community compositions
Authors: Mahmoudabadi Gita , Homyk Kelsey , Catching Adam , Foley Helen , Tadmor Arbel , Mahmoudabadi Ana , Cheung Allison , Phillips Rob 
Published: January 2019

AbstractMetagenomic studies have revolutionized the study of novel phages. However these studies trade the depth of coverage for breadth. In this study we show that the targeted sequencing of a phage genomic region as small as 200-300 base pairs, can provide sufficient sequence diversity to serve as an individual-specific barcode or “Phageprint”. The targeted approach reveals a high-resolution view of phage communities that is not available through metagenomic datasets. By creating instructional videos and collection kits, we enabled citizen scientists to gather ∼700 oral samples spanning ∼100 individuals residing in different parts of the world. In examining phage communities at 6 different oral sites, and by comparing phage communities of individuals living across the globe, we were able to study the effect of spatial separation, ranging from several millimeters to thousands of kilometers. We found that the spatial separation of just a few centimeters (the distance between two oral sites) can already result in highly distinct phage community compositions. For larger distances, spanning the phage communities of different individuals living in different parts of the world, we did not observe any correlation between spatial distance and phage community composition as individuals residing in the same city did not have any more similar phage communities than individuals living on different continents. Additionally, we found that neither genetics nor cohabitation seem to play a role in the relatedness of phage community compositions across individuals. Cohabitating siblings and even identical twins did not have phage community compositions that were any more similar than those of unrelated individuals. The primary factor contributing to phage community composition relatedness is direct contact between two habitats, as is demonstrated by the similarity between oral phage community compositions of partners. Furthermore, by exploring phage communities across the span of a month, and in some cases several years, we observed highly stable community compositions. These studies consistently point to the existence of remarkably diverse and personal phage families that are stable in time and apparently present in people around the world.
Comparative analysis of beneficial effects of Vancomycin treatment on Th1- and Th2-biased mice and role of gut microbiota
Authors: Ray Pratikshya , Pandey Uday , Aich Palok 
Published: January 2019

AbstractAimsVancomycin, an antibiotic, is used to treat infection of multi-drug resistant strains ofClostridium difficileandStaphylococcus. Post-usage effects of vancomycin may lead to many unwanted effects including perturbation of gut microbiota. Perturbation of the gut microbiota, by Vancomycin, was used to understand the altered metabolic and innate immune profile of C57BL/6(Th1-biased) and BALB/c (Th2-biased) mice.Methods and ResultsFollowing treatment with vancomycin till day 4, we observed reduction in abundance of phyla Firmicutes and Bacteroides and increase in Proteobacteria in the gut for both strains of mice. Results further revealed a significant increase in the phylum Verrucomicrobia, from day 5 onwards following treatment with vancomycin led to decreased inflammation and increased rate of glucose tolerance in the host.ConclusionsContinued dosage of vancomycin was more beneficial in C57BL/6 than BALB/c miceSignificance and Impact of the studyThe current study established that initial doses of vancomycin increased pathogenic bacteria but the continued doses of vancomycin provided significant health-related benefits to the host by decreasing pathogenic load and by increasing beneficial microbes of Verrucomicrobia phylum (A. muciniphila) more in C57BL/6 (Th-1) than BALB/c (Th-2) mice.
A configural model of expert judgement as a preliminary epidemiological study of injury problems: An application to drowning
Authors: Morgan Damian , Ozanne-Smith Joan 
Published: January 2019

AbstractRobust epidemiological studies identifying determinants of negative health outcomes require significant research effort. Expert judgement is proposed as an efficient alternative or preliminary research design for risk factor identification associated with unintentional injury. This proposition was tested in a multi-factorial balanced experimental design using specialist judges (N=18), lifeguards and surfers, to assess the risk contribution to drowning for swimming ability, surf bathing experience, and wave height. All factors provided unique contributions to drowning risk (p<.001). An interaction (p=.02) indicated that occasional surf bathers face a proportionally increased risk of drowning at increased wave heights relative to experienced surf bathers. Although findings were limited by strict criteria, and no gold standard comparison data were available, the study provides new evidence on causal risk factors for a drowning scenario. Countermeasures based on these factors are proposed. Further application of the method may assist in developing new interventions to reduce unintentional injury.
Life on the margin: rainwater tanks facilitate overwintering of the dengue vector,Aedes aegypti, in a sub-tropical climate
Authors: Trewin Brendan J , Darbro Jonathan M , Zalucki Myron P , Jansen Cassie C , Schellhorn Nancy A , Devine Gregor J 
Published: January 2019

AbstractA key determinant of insect persistence in marginal habitats is the ability to tolerate environmental extremes such as temperature.Aedes aegyptiis highly invasive and little is known about the physiological sensitivity of the species to fluctuating temperature regimes at the lower critical threshold. This has implications that limit establishment and persistence of the species in sub-optimal regions. Daily winter temperatures were measured in common Australian larval habitats, replicated in environmental chambers, and used to investigate the effect of fluctuating temperatures on the development and survival of tropical and subtropical strains of AustralianAe. aegypti. Development was slow for all treatments but both strains were able to complete development to the adult stage, suggesting previous models underestimate the potential for the species to persist in eastern Australia. Results suggested that thermal buffering in large volume habitats, and water that persists for greater than 32 days, will facilitate completion of the life cycle during sub-tropical winters. Furthermore, we provide a non-linear estimate of the lower critical temperature ofAe. aegyptithat suggests the current threshold may be incorrect. Our study demonstrates that the current re-introduction of water storage containers such as rainwater tanks, into major Australian population centres will increase the risk ofAe. aegyptiestablishment by permitting year-round development south of its current distribution.
Live applications of norbormide-based fluorescent probes in Drosophila melanogaster
Authors: Forgiarini Alessia , Wang Zifei , D’Amore Claudio , Jay-Smith Morgan , Li Freda Fan , Hopkins Brian , Brimble Margaret A. , Pagetta Andrea , Bersani Sara , Martin Sara De , Napoli Barbara , Bova Sergio , Rennison David , Orso Genny 
Published: January 2019

AbstractIn this study we investigated the performance of two norbormide (NRB)-derived fluorescent probes, NRBMC009 (green) and NRBZLW0047 (red), on dissected, living larvae of Drosophila, to verify their potential application in confocal microscopy imaging in vivo. To this end, larval tissues were exposed to NRB probes alone or in combination with other commercial dyes or GFP-tagged protein markers. Both probes were rapidly internalized by most tissues (except the central nervous system) allowing each organ in the microscope field to be readily distinguished at low magnification. At the cellular level, the probes showed a very similar distribution (except for fat bodies), defined by loss of signal in the nucleus and plasma membrane, and a preferential localization to endoplasmic reticulum (ER) and mitochondria. They also recognized ER and mitochondrial phenotypes in the skeletal muscles of fruit fly models that had loss of function mutations in the atlastin and mitofusin genes, suggesting NRBMC009 and NRBZLW0047 as potentially useful in vivo screening tools for characterizing ER and mitochondria morphological alterations. Feeding of larvae and adult Drosophilae with the NRB-derived dyes led to staining of the gut and its epithelial cells, revealing a potential role in food intake assays. In addition, when flies were exposed to either dye over their entire life cycle no apparent functional or morphological abnormalities were detected. Rapid internalization, a bright signal, a compatibility with other available fluorescent probes and GFP-tagged protein markers, and a lack of toxicity make NRBZLW0047 and, particularly, NRBMC009 one of the most highly performing fluorescent probes available for in vivo microscopy studies and food intake assay in Drosophila.