bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infection with CagA+Helicobacter pyloriinduces epithelial to mesenchymal transition in human cholangiocytes
Authors: Thanaphongdecha Prissadee , Karinshak Shannon E. , Ittiprasert Wannaporn , Mann Victoria H. , Chamgramol Yaovalux , Pairojkul Chawalit , Fox James G. , Suttiprapa Sutas , Sripa Banchob , Brindley Paul J. 
Published: April 2020

AbstractRecent reports suggest that the East Asian liver fluke,Opisthorchis viverrini, infection with which is implicated in opisthorchiasis-associated cholangiocarcinoma, serves as a reservoir ofHelicobacter pylori. The opisthorchiasis-affected cholangiocytes that line the intrahepatic biliary tract are considered to be the cell of origin of this malignancy. Here, we investigated interactionsin vitroamong human cholangiocytes, a CagA-positive strain ofHelicobacter pylori, and the related bacillus,Helicobacter bilis. Exposure to increasing numbers ofH. pyloriat 0, 1, 10, 100 bacilli per cholangiocyte induced phenotypic changes including the profusion of thread-like filopodia and a loss of cell-cell contact, in a dose-dependent fashion. In parallel, following exposure toH. pylori, changes were evident in levels of mRNA expression of epithelial to mesenchymal transition (EMT)-encoding factors including snail, slug, vimentin, matrix metalloprotease, zinc finger E-box-binding homeobox, and the cancer stem cell marker CD44. Transcription levels encoding the cell adhesion marker CD24 decreased. Analysis to quantify cellular proliferation, migration and invasion in real time using the xCELLigence approach revealed that exposure to ≥10H. pyloristimulated migration and invasion by the cholangiocytes through an extracellular matrix. In addition, 10 bacilli of CagA-positiveH. pyloristimulated contact-independent colony establishment in soft agar. These findings support the hypothesis that infection withH. pyloricontributes to the malignant transformation of the biliary epithelium.
The impact of purifying and background selection on the inference of population history: problems and prospects
Authors: Johri Parul , Riall Kellen , Becher Hannes , Excoffier Laurent , Charlesworth Brian , Jensen Jeffrey D. 
Published: April 2020

ABSTRACTCurrent procedures for inferring population history generally assume complete neutrality - that is, they neglect both direct selection and the effects of selection on linked sites. We here examine how the presence of direct purifying selection and background selection may bias demographic inference by evaluating two commonly-used methods (MSMC andfastsimcoal2), specifically studying how the underlying shape of the distribution of fitness effects (DFE) and the fraction of directly selected sites interact with demographic parameter estimation. The results show that, even after masking functional genomic regions, background selection may cause the mis-inference of population growth under models of both constant population size and decline. This effect is amplified as the strength of purifying selection and the density of directly selected sites increases, as indicated by the distortion of the site frequency spectrum and levels of nucleotide diversity at linked neutral sites. We also show how simulated changes in background selection effects caused by population size changes can be predicted analytically. We propose a potential method for correcting for the mis-inference of population growth caused by selection. By treating the DFE as a nuisance parameter and averaging across all potential realizations, we demonstrate that even directly selected sites can be used to infer demographic histories with reasonable accuracy.
Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice
Authors: Maldonado-Devincci Antoniette M. , Makdisi Joseph G. , Hill Andrea M. , Waters Renee C. , Hall Nzia I. , Shobande Mariah , Kumari Anjali 
Published: April 2020

AbstractWith alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. Adolescents are also more prone to substance use disorder during adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence and in young adulthood. The present set of experiments were divided into four stages: (1) chronic intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using an intermittent vapor inhalation with repeated binge pattern ethanol exposure from postnatal day (PND) 28–42. Following this, mice underwent abstinence during late adolescence from PND 43–49 (Experiment 1) or PND 43–69 (Experiment 2). Beginning on PND 49–76 (Experiment 1) or PND 70–97 (Experiment 2), mice were assessed for intermittent voluntary ethanol consumption using a two-bottle drinking procedure over 28 days. Male mice that were exposed to ethanol during adolescence showed increased ethanol consumption during later adolescence (Experiment 1) and in emerging adulthood (Experiment 2), while the female mice showed decreased ethanol consumption. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These data highlight sex-dependent vulnerability to developing substance use disorders in adulthood.Significance StatementCurrently, it is vital to determine the sex-dependent impact of binge alcohol exposure during adolescence, given that until recently females have largely been ignored. Here we show that adolescent male mice that are exposed to binge ethanol during adolescence show long-term changes in behavior in adulthood. In contrast, female mice show a transient decrease in ethanol consumption in adulthood and decreased motor activity spent in the center zone of the open field test. Male mice appear to be more susceptible to the long-term changes in ethanol consumption following binge ethanol exposure during adolescence.
The Past, Present and Future of Elephant Landscapes in Asia
Authors: de Silva Shermin , Wu Tiffany , Nyhus Philip , Thieme Alison , Weaver Ashley , Johnson Josiah , Wadey Jamie , Mossbrucker Alexander , Vu Thinh , Neang Thy , Chen Becky Shu , Songer Melissa , Leimgruber Peter 
Published: April 2020

AbstractHabitat loss drives species’ declines worldwide, but is seldom quantified over centennial timescales. We constructed ecological niche models for Asian elephants based on land-use change between 850-2015, and predictions under six different climate/socioeconomic scenarios from 2015-2099. We find that over 64% of suitable natural habitat across diverse ecosystems was lost over the past three centuries. Average patch size dropped 83% from approximately 99,000 km2to 16,000 km2and the area occupied by the largest patch decreased 83% from ~ 4 million km2(45% of area) to 54,000 km2(~7.5% of area). Over half of current elephant range appears unsuitable. Habitat availability is predicted to decline further this century across all scenarios. The most severe losses occur under RCP3.4-SSP4, representing mid-range emissions but high regional inequities. We conclude that climate change mitigation measures must include policies to ensure inter-regional socioeconomic equity to safeguard landscapes for elephants, humans, and other species.
Baseline Resting-State Functional Connectivity Determines Subsequent Pain Ratings to a Tonic Ecologically Valid Experimental Model of Orofacial Pain
Authors: Ayoub Lizbeth J. , McAndrews Mary Pat , Barnett Alexander J. , Jeremy Ho Ka Chun , Cioffi Iacopo , Moayedi Massieh 
Published: April 2020

ABSTRACTPain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure—the insertion of an elastomeric separator between teeth—which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.
Dopamine D2R upregulation in nucleus accumbens indirect pathway does not affect Pavlovian or Go/No-Go Learning
Authors: Martyniuk Kelly , Dandeneau Michelle , Balsam Peter , Kellendonk Christoph 
Published: April 2020

AbstractVentral striatal dopamine is thought to be important for associative learning. Dopamine exerts its role via activation of dopamine D1 and D2 receptors in the ventral striatum. Upregulation of dopamine D2R in the indirect pathway of the nucleus accumbens (NAc) impairs incentive motivation via inhibiting synaptic transmission to the ventral pallidum. Here, we determined whether upregulation of D2Rs and the resulting impairment in indirect pathway function modulates associative learning in an auditory Pavlovian reward learning task as well as Go/No-Go learning in an operant based reward driven Go/No-Go task. We found that upregulation of D2Rs in indirect pathway neurons of the NAc did not affect Pavlovian learning or the extinction of Pavlovian responses, and neither did it alter No-Go learning. A delay in the Go component of the task however could indicate a deficit in learning though it may be attributed to locomotor hyperactivity of the mice. In combination with previously published findings our data suggest that D2Rs in the NAc core play a specific role in regulating motivation by balancing cost/benefit computations but do not necessarily affect associative learning.
Social isolation stress in adolescence, but not adulthood, produces hypersocial behavior in adult male and female C57BL/6J mice
Authors: Rivera-Irizarry Jean K. , Skelly Mary Jane , Pleil Kristen E. 
Published: April 2020

AbstractChronic stress during the developmental period of adolescence increases susceptibility to many neuropsychiatric diseases in adulthood, including anxiety, affective, and alcohol/substance use disorders. Preclinical rodent models of adolescent stress have produced varying results that are species, strain, sex, and laboratory-dependent. However, adolescent social isolation is a potent stressor in humans that has been reliably modeled in male rats, increasing adult anxiety-like and alcohol drinking behaviors, among others. In this study, we examined the generalizability and sex-dependence of this model in C57BL/6J mice, the most commonly used rodent strain in neuroscience research. We also performed a parallel study using social isolation in adulthood to understand the impact of adult social isolation on basal behavioral phenotypes. We found that six weeks of social isolation in adolescence beginning at postnatal day (PD) 28 produced a hypersocial phenotype in both male and female adults in multiple assays and a female-specific anxiolytic phenotype in the elevated plus maze, but it had no effects in other assays for avoidance behavior, fear conditioning, alcohol drinking, reward or aversion sensitivity, novel object exploration, or forced swim behavior in either sex. In contrast, social isolation in adulthood beginning at PD77 produced an anxiogenic phenotype in the light/dark box but had no effects on any other assays. Altogether, our results suggest that 1) adolescence is a critical period for social stress in C57BL/6J mice, producing aberrant social behavior in a sex-independent manner and 2) chronic individual housing in adulthood does not alter basal behavioral phenotypes that may confound interpretation of behavior following other laboratory manipulations.
Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells
Authors: Offeddu Giovanni S. , Hajal Cynthia , Foley Colleen , Wan Zhengpeng , Ibrahim Lina , Coughlin Mark F. , Kamm Roger D. 
Published: April 2020

ABSTRACTThe glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using anin vitromodel of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Trans-endothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.
The TAT Protein Transduction Domain as an Intra-articular Drug-Delivery Technology
Authors: Mailhiot Sarah E. , Thompson Matthew A. , Eguchi Akiko E. , Dinkel Sabrina E. , Lotz Martin K. , Dowdy Steven F. , June Ronald K. 
Published: April 2020

AbstractObjectiveIntra-articular drug delivery holds great promise for the treatment of joint diseases such as osteoarthritis. The objective of this study was to evaluate the TAT peptide transduction domain (TAT-PTD) as a potential intra-articular drug delivery technology for synovial joints.DesignExperiments examined the ability of TAT conjugates to associate with primary chondrocytes and alter cellular function bothin vitroandin vivo. Further experiments examined the ability of the TAT-PTD to bind to human osteoarthritic cartilage.ResultsThe results show that the TAT-PTD associates with chondrocytes, is capable of delivering siRNA for chondrocyte gene knockdown, and that the recombinant enzyme TAT-Cre is capable of inducingin vivogenetic recombination within the knee joint in a reporter mouse model. Lastly, binding studies show that osteoarthritic cartilage preferentially uptakes the TAT-PTD from solution.ConclusionsThe results suggest that the TAT-PTD is a promising delivery strategy for intra-articular therapeutics.
Analyses of spike protein from first deposited sequences of SARS-CoV2 from West Bengal, India
Authors: Begum Feroza , Mukherjee Debica , Thagriki Dluya , Das Sandeepan , Tripathi Prem Prakash , Banerjee Arup Kumar , Ray Upasana 
Published: April 2020

AbstractIndia has recently started sequencing SARS-CoV2 genome from clinical isolates. Currently only few sequences are available from three states in India. Kerala was the first state to deposit complete sequence from two isolates followed by one from Gujarat. On April 27, 2020, the first five sequences from the state of West Bengal (Eastern India) were deposited on ‘a global initiative on sharing avian flu data’ (GISAID) platform. In this paper we have analysed the spike protein sequences from all these five isolates and also compared for their similarities or differences with other sequences reported in India and with isolates of Wuhan origin. We report one unique mutation at position 723 and the other at 1124 in the S2 domain of spike protein of the isolates from West Bengal only and one mutation downstream of the receptor binding domain at position 614 in S1 domain which was common with the sequence from Gujarat (a state of western part of India). Mutation in the S2 domain showed changes in the secondary structure of the spike protein at region of mutation. We also studied molecular dynamics using normal mode analyses and found that this mutation decreases the flexibility of S2 domain. Since both S1 and S2 are important in receptor binding followed by entry in the host cells, such mutations may define the affinity or avidity of receptor binding.
Passenger-surface microbiome interactions in the subway of Mexico City
Authors: Vargas-Robles Daniela , Gonzalez-Cedillo Carolina , Hernandez Apolinar M. , Alcaraz Luis D. , Peimbert Mariana 
Published: April 2020

AbstractInteraction between hands and the environment permits the interchange of microorganisms. The Mexico City subway is used daily by millions of passengers that get in contact with its surfaces. In this study, we used 16S rRNA gene sequencing to characterize the microbiomes of frequently touched surfaces, also comparing regular and women-only wagons. We also explored the effect of surface cleaning on microbial resettling. Finally, we studied passenger behavior and characterized microbial changes after traveling.Most passengers (99%), showed some type of surface interaction during a wagon trip, mostly with the hands (92%). We found microbiome differences associated with surfaces, probably reflecting diverse surface materials and usage frequency. The platform floor was the most bacterial diverse surface, while the stair handrail and pole were the least diverse ones. After pole cleaning, the resettling of microbial diversity was fast (5-30 minutes); however, it did not resemble the initial composition.After traveling, passengers significantly increased their hand microbial diversity and converged to a similar microbial composition among passengers. Additionally, passenger hand microbiomes resembled subway surfaces in diversity and also in the frequency of potentially pathogenic taxa. However, microbial fingerprints were preserved within passengers after traveling.
The phylogenetic functional conservation ofDrosophilaSeven-In-Absentia (SINA) E3 ligase and its two human paralogs, SIAH1 and SIAH2, inDrosophilaeye development
Authors: Van Sciver Robert E. , Cao Yajun , Tang Amy H. 
Published: April 2020

AbstractSeven-IN-Absentia (SINA) is the most downstream signaling gatekeeper identified thus far in the RAS/EGFR pathway that controls photoreceptor cell fate determination inDrosophila. Underscoring the central importance of SINA is its phylogenetic conservation in metazoans, with over 83% amino acid identities shared betweenDrosophilaSINA and human SINA homologs (SIAHs). SIAH is a major tumor vulnerability in multidrug-resistant and incurable cancer. SIAH inhibition is an effective strategy to shut down the tumor-driving K-RAS/EGFR/HER2 pathway activation that promotes malignant tumor growth and metastatic dissemination. To further delineate the SINA function in the RAS/EGFR pathway, a genetic modifier screen was conducted, and 28 newsinamutant alleles were isolated via ethyl methanesulfonate (EMS) and X-ray mutagenesis. Among them, 26 of the newsinamutants are embryonic, larval, or pupal lethal, and stronger than the five publishedsinamutants (sina1,sina2,sina3,sina4, andsina5) which are early adult lethal. By sequencing the SINA-coding region ofsinaES10,sinaES26,sinaES79, andsinaES473homozygous mutant animals, we identified three invariable amino acid residues in SINA’s RING-domain whose single point mutation ablates SINA function. To demonstrate the functional conservation of this medically important family of RING domain E3 ligases inDrosophila, we established a collection of transgenic lines, expressing either wild type (WT) or proteolysis-deficient (PD) SINA/SIAH inhibitors ofDrosophilaSINAWT/PDand human SIAH1WT/PD/2WT/PDunder tissue-specific GAL4-drivers inDrosophilaeye, wing, and salary gland. Our results showed thatDrosophilaSINA and human SIAH1/2 are functionally conserved. Our bioengineered SINAPD/SIAHPDinhibitors are effective in blocking the RAS-dependent neuronal cell fate determination inDrosophila.
The SecA motor generates mechanical force during protein translocation
Authors: Gupta Riti , Toptygin Dmitri , Kaiser Christian M. 
Published: April 2020

AbstractThe Sec translocon moves proteins across lipid bilayers in all cells. The Sec channel enables passage of unfolded proteins through the bacterial plasma membrane, driven by the cytosolic ATPase SecA. Whether SecA generates mechanical force to overcome barriers to translocation posed by structured substrate proteins is unknown. Monitoring translocation of a folded substrate protein with tunable stability at high time resolution allowed us to kinetically dissect Secdependent translocation. We find that substrate unfolding constitutes the rate-limiting step during translocation. Using single-molecule force spectroscopy, we have also defined the response of the protein to mechanical force. Relating the kinetic and force measurements revealed that SecA generates at least 10 piconewtons of mechanical force to actively unfold translocating proteins, comparable to cellular unfoldases. Combining biochemical and single-molecule measurements has thus allowed us to define how the SecA motor ensures efficient and robust export of proteins that contain stable structure.
Downy Mildew effector HaRxL21 interacts with the transcriptional repressor TOPLESS to promote pathogen susceptibility
Authors: Harvey Sarah , Kumari Priyanka , Lapin Dmitry , Griebel Thomas , Hickman Richard , Guo Wenbin , Zhang Runxuan , Parker Jane , Beynon Jim , Denby Katherine , Steinbrenner Jens 
Published: April 2020

AbstractHyaloperonospora arabidopsidis (Hpa) is an oomycete pathogen causing Arabidopsis downy mildew. Effector proteins secreted from the pathogen into the plant play key roles in promoting infection by suppressing plant immunity and manipulating the host to the pathogen’s advantage. One class of oomycete effectors share a conserved ‘RxLR’ motif critical for their translocation into the host cell. Here we characterize the interaction between an RxLR effector, HaRxL21 (RxL21), and the Arabidopsis transcriptional co-repressor Topless (TPL). We establish that RxL21 and TPL interact via an EAR motif at the C-terminus of the effector, mimicking the host plant mechanism for recruiting TPL to sites of transcriptional repression. We show that this motif, and hence interaction with TPL, is necessary for the virulence function of the effector. Furthermore, we provide evidence that RxL21 uses the interaction with TPL, and its close relative TPL-related 1, to repress plant immunity and enhance host susceptibility to both biotrophic and necrotrophic pathogens.