STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle.

Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The transcription factor signal transducer and activator of transcription (STAT)-3 is important for cell cycle progression and cell survival in response to cytokines and growth factors. STAT3 requires phosphorylation on Ser727, in addition to phosphorylation on Tyr705 to be transcriptionally active. In this study, we show that STAT3 is essential for the HPV life cycle in undifferentiated and differentiated keratinocytes. Primary human keratinocytes containing high-risk HPV18 genomes display enhanced STAT3 phosphorylation compared to normal keratinocytes. Expression of the E6 oncoprotein is sufficient to induce the dual phosphorylation of STAT3 at Ser727 and Tyr705 by a mechanism requiring Janus kinases and members of the MAPK family. E6-mediated activation of STAT3 induces the transcription of STAT3 responsive genes including cyclin D1 and Bcl-xL. Silencing of STAT3 protein expression by siRNA or inhibition of STAT3 activation by small molecule inhibitors, or by expression of dominant negative STAT3 phosphorylation site mutants, results in blockade of cell cycle progression. Loss of active STAT3 impairs HPV gene expression and prevents episome maintenance in undifferentiated keratinocytes and upon differentiation, lack of active STAT3 abolishes virus genome amplification and late gene expression. Organotypic raft cultures of HPV18 containing keratinocytes expressing a phosphorylation site STAT3 mutant display a profound reduction in suprabasal hyperplasia, which correlates with a loss of cyclin B1 expression and increased differentiation. Finally, increased STAT3 expression and phosphorylation is observed in HPV positive cervical disease biopsies compared to control samples, highlighting a role for STAT3 activation in cervical carcinogenesis. In summary, our data provides evidence of a critical role for STAT3 in the HPV18 life cycle

Analysis of the role of 13 major fimbrial subunits in colonisation of the chicken intestines by Salmonella enterica serovar Enteritidis reveals a role for a novel locus

<p>Abstract</p> <p>Background</p> <p><it>Salmonella enterica </it>is a facultative intracellular pathogen of worldwide importance. Over 2,500 serovars exist and infections in humans and animals may produce a spectrum of symptoms from enteritis to typhoid depending on serovar- and host-specific factors. <it>S</it>. Enteritidis is the most prevalent non-typhoidal serovar isolated from humans with acute diarrhoeal illness in many countries. Human infections are frequently associated with direct or indirect contact with contaminated poultry meat or eggs owing to the ability of the organism to persist in the avian intestinal and reproductive tract. The molecular mechanisms underlying colonisation of poultry by <it>S</it>. Enteritidis are ill-defined. Targeted and genome-wide mutagenesis of <it>S</it>. Typhimurium has revealed conserved and host-specific roles for selected fimbriae in intestinal colonisation of different hosts. Here we report the first systematic analysis of each chromosomally-encoded major fimbrial subunit of <it>S</it>. Enteritidis in intestinal colonisation of chickens.</p> <p>Results</p> <p>The repertoire, organisation and sequence of the fimbrial operons within members of <it>S. enterica </it>were compared. No single fimbrial locus could be correlated with the differential virulence and host range of serovars by comparison of available genome sequences. Fimbrial operons were highly conserved among serovars in respect of gene number, order and sequence, with the exception of <it>safA</it>. Thirteen predicted major fimbrial subunit genes were separately inactivated by lambda Red recombinase-mediated linear recombination followed by P22/int transduction. The magnitude and duration of intestinal colonisation by mutant and parent strains was measured after oral inoculation of out-bred chickens. Whilst the majority of <it>S</it>. Enteritidis major fimbrial subunit genes played no significant role in colonisation of the avian intestines, mutations affecting <it>pegA </it>in two different <it>S</it>. Enteritidis strains produced statistically significant attenuation. Plasmid-mediated <it>trans</it>-complementation partially restored the colonisation phenotype.</p> <p>Conclusion</p> <p>We describe the fimbrial gene repertoire of the predominant non-typhoidal <it>S. enterica </it>serovar affecting humans and the role played by each predicted major fimbrial subunit in intestinal colonisation of the primary reservoir. Our data support a role for PegA in the colonisation of poultry by <it>S</it>. Enteritidis and aid the design of improved vaccines.</p

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry

The Second-Generation Guide Star Catalog: Description and Properties

The GSC-II is an all-sky database of objects derived from the uncompressed DSS that the STScI has created from the Palomar and UK Schmidt survey plates and made available to the community. Like its predecessor (GSC-I), the GSC-II was primarily created to provide guide star information and observation planning support for HST. This version, however, is already employed at some of the ground-based new-technology telescopes such as GEMINI, VLT, and TNG, and will also be used to provide support for the JWST and Gaia space missions as well as LAMOST, one of the major ongoing scientific projects in China. Two catalogs have already been extracted from the GSC-II database and released to the astronomical community. A magnitude-limited (R=18.0) version, GSC2.2, was distributed soon after its production in 2001, while the GSC2.3 release has been available for general access since 2007. The GSC2.3 catalog described in this paper contains astrometry, photometry, and classification for 945,592,683 objects down to the magnitude limit of the plates. Positions are tied to the ICRS; for stellar sources, the all-sky average absolute error per coordinate ranges from 0.2" to 0.28" depending on magnitude. When dealing with extended objects, astrometric errors are 20% worse in the case of galaxies and approximately a factor of 2 worse for blended images. Stellar photometry is determined to 0.13-0.22 mag as a function of magnitude and photographic passbands (B,R,I). Outside of the galactic plane, stellar classification is reliable to at least 90% confidence for magnitudes brighter than R=19.5, and the catalog is complete to R=20.Comment: 52 pages, 33 figures, to be published in AJ August 200

Ten simple rules for organizing a bioinformatics training course in low- And middle-income countries

© 2021 Moore et al.Bioinformatics training is required at every stage of a scientist’s research career. Continual bioinformatics training allows exposure to an ever-changing and growing repertoire of techniques and databases, and so biologists, computational scientists, and healthcare practitioners are all seeking learning opportunities in the use of computational resources and tools designed for data storage, retrieval, and analysis. There are abundant opportunities for accessing bioinformatics training for scientists in high-income countries (HICs), with well-equipped facilities and participants and trainers requiring minimal travel and financial costs alongside a range of general advice for developing short bioinformatics training courses [1–3]. However, regionally targeted bioinformatics training in low- and middle-income countries (LMICs) often requires more extensive local and external support, organization, and travel. Due to the limited expertise in bioinformatics in LMICs in general, most bioinformatics training requires a fair amount of collaboration with experts beyond the local community, country, or region. A common model of training, used as the basis of this article, includes a local host collaborating with local, regional, and international experts gathering to train local or regional participants. Recently, there has been a growth of capacity strengthening initiatives in LMICs, such as the Pan African Bioinformatics Network for Human Heredity and Health in Africa (H3ABioNet) Initiative [4–6], the Capacity Building for Bioinformatics in Latin America (CABANA) Project [7], the Asia Pacific BioInformatics Network (APBioNet) [8], and the Wellcome Connecting Science Courses and Conferences program [9]. One of the important strands of these initiatives is a drive to organize and deliver valuable bioinformatics training, but organizing and delivering short bioinformatics training workshops in an LMIC present a unique set of challenges. This paper attempts to build upon the sage advice for organizing bioinformatics workshops with specific guidance for organizing and delivering them in LMICs. It describes the processes to follow in organizing courses taking into consideration the low-resource setting. We should also note that LMICs are not a monolithic group and that setting, context, temporality, and specific location matters. LMICs are a complex regional grouping [10] and should be treated as such; however, we will present some common lessons that we hope will help organizers and trainers of bioinformatics training events in LMICs to navigate the often different, challenging, and rewarding experience.The authors who contributed to this manuscript are funded as follows: BM receives salary support from Wellcome Trust grants [WT108749/Z/15/Z, WT108749/Z/15/A], PC, VR, NM, AG’s salaries are funded in whole, or in part, by the NIH Common Fund H3ABioNet grant [U24HG006941], MC, SLFV, AR, PG, PCL’s salaries were partly funded by the UKRI-BBSRC ‘Capacity building for bioinformatics in Latin America’ (CABANA) grant, on behalf of the Global Challenges Research Fund [BB/P027849/1], JDLR is funded by ISCiii AES [ref. PI18/00591] at the CSIC/USAL (Spain) and by CYTED, RIABIO (Red Iberoamericana 521RT0118), AM’s salary is funded by [WT206194/Z/17/Z], GO is funded by the CABANA grant and SM is funded by the EMBL-EBI

Ketamine effects on memory reconsolidation favor a learning model of delusions.

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence