Sedimentology, palaeontology and diagenesis of the Much Wenlock limestone formation

Lithofacies distribution indicates that the Much Wenlock Limestone Formation of England and South Wales was desposited on a shelf which was flat and gently subsiding in the north, but topographically variable in the south. Limestone deposition in the north began with 12m of alga-rich limestone, which formed an upward shoaling sequence. Deepening then led to deposition of calcareous silty mudstones on the northern shelf. The remainder of the formation in this area formed during a shelf-wide regression, culminating in the production of an E to W younging sandbody. Lithofacies distribution on the southern shelf was primarily controlled by local subsidence. Six bedded lithofacies are recognised which contain 14 brachiopod/bryozoan dominated assemblages, of which 11 are in situ and three consist of reworked fossils. Microfacies analysis is necessary to distinguish assemblages which reflect original communities from those which reflect sedimentary processes. Turbulence, substrate-type, ease of feeding and other organisms in the environment controlled faunal distribution. Reefs were built dominantly by corals, stromatoporoids, algae and crinoids. Coral/stromatoporoid (Type A) reefs are common, particularly on the northern shelf, where they formed in response to shallowing, ultimately growing in front of the advancing carbonate sandbody. Algae dominate Type B and Type C reefs, reflecting growth in areas of poor water circulation. Lithification of the formation began in the marine-phreatic environment with precipitation of aragonite and high Mg calcite, which was subsequently altered to turbid low Mg calcite. Younger clear spars post-date secondary void formation. The pre-compactional clear spars have features which resemble the products of meteoric water diagenesis, but freshwater did not enter the formation at this time. The pre-compactional spars were precipitated by waters forced from the surrounding silty mudstones at shallow burial depths. Late diagenetic products are stylolites, compaction fractures and burial cements

Correlation and high-resolution timing for Paleo-tethys Permian-Triassic boundary exposures in Vietnam and Slovenia using geochemical, geophysical and biostratigraphic data sets

Two Permian-Triassic boundary (PTB) successions, Lung Cam in Vietnam, and Lukač in Slovenia, have been sampled for high-resolution magnetic susceptibility, stable isotope and elemental chemistry, and biostratigraphic analyses. These successions are located on the eastern (Lung Cam section) and western margins (Lukač section) of the Paleo-Tethys Ocean during PTB time. Lung Cam, lying along the eastern margin of the Paleo-Tethys Ocean provides an excellent proxy for correlation back to the GSSP and out to other Paleo-Tethyan successions. This proxy is tested herein by correlating the Lung Cam section in Vietnam to the Lukač section in Slovenia, which was deposited along the western margin of the Paleo-Tethys Ocean during the PTB interval. It is shown herein that both the Lung Cam and Lukač sections can be correlated and exhibit similar characteristics through the PTB interval. Using time-series analysis of magnetic susceptibility data, high-resolution ages are obtained for both successions, thus allowing relative ages, relative to the PTB age at ~252 Ma, to be assigned. Evaluation of climate variability along the western and eastern margins of the Paleo-Tethys Ocean through the PTB interval, using d18O values indicates generally cooler climate in the west, below the PTB, changing to generally warmer climates above the boundary. A unique Black Carbon layer (elemental carbon present by agglutinated foraminifers in their test) below the boundary exhibits colder temperatures in the eastern and warmer temperatures in the western Paleo-Tethys Ocean.ReferencesBalsam W., Arimoto R., Ji J., Shen Z, 2007. Aeolian dust in sediment: a re-examination of methods for identification and dispersal assessed by diffuse reflectance spectrophotometry. International Journal of Environment and Health, 1, 374-402.Balsam W.L., Otto-Bliesner B.L., Deaton B.C., 1995. Modern and last glacial maximum eolian sedimentation patterns in the Atlantic Ocean interpreted from sediment iron oxide content. Paleoceanography, 10, 493-507.Berggren W.A., Kent D.V., Aubry M-P., Hardenbol J., 1995. Geochronology, Time Scales and Global Stratigraphic Correlation. SEPM Special Publication #54, Society for Sedimentary Geology, Tulsa, OK, 386p.Berger A., Loutre M.F., Laskar J., 1992. Stability of the astronomical frequencies over the Earth's history for paleoclimate studies. Science, 255, 560-566.Bloemendal J., deMenocal P., 1989. Evidence for a change in the periodicity of tropical climate cycles at 2.4 Myr from whole-core magnetic susceptibility measurements. Nature, 342, 897-900.Chen J., Shen S-j., Li X-h., Xu Y-g., Joachimski M.M., Bowring S.A., Erwin D.H., Yuan D-x., Chen B., Zhang H., Wang Y., Cao C-q, Zheng Q-f., Mu L., 2016. High-resolution SIMS oxygen isotope analysis on conodont apatite from South China and implications for the end-Permian mass extinction. Palaeogeography, Palaeoclimatology, Palaeoecology, 448, 26-38.Da Silva A-C., Boulvain F., 2002. Sedimentology, magnetic susceptibility and isotopes of a Middle Frasnian carbonate platform: Tailfer Section, Belgium. Facies, 46, 89-102.Da Silva A.-C., Boulvain F., 2005. Upper Devonian carbonate platform correlations and sea level variations recorded in magnetic susceptibility. Palaeogeography, Palaeoclimatology, Palaeoecology, 240, 373-388.Dettinger M.D., Ghil M., Strong C.M., Weibel W., Yiou P., 1995. Software expedites singular-spectrum analysis of noisy time series. EOS. Transactions of the American Geophysical Union, 76, 12-21.Dinarès-Turell J., Baceta J.I., Bernaola G., Orue-Etxebarria X., Pujalte V., 2007. Closing the Mid-Palaeocene gap: Toward a complete astronomically tuned Palaeocene Epoch and Selandian and Thanetian GSSPs at Zumaia (Basque Basin, W Pyrenees). Earth Planetary Science Letters, 262, 450-467.Ellwood B.B., García-Alcalde J.L., El Hassani A., Hladil J., Soto F.M., Truyóls-Massoni M., Weddige K., Koptikova L., 2006. Stratigraphy of the Middle Devonian Boundary: Formal Definition of the Susceptibility Magnetostratotype in Germany with comparisons to Sections in the Czech Republic, Morocco and Spain. Tectonophysics, 418, 31-49.Ellwood B.B., Wang W.-H., Tomkin J.H., Ratcliffe K.T., El Hassani A., Wright A.M., 2013. Testing high resolution magnetic susceptibility and gamma gradiation methods in the Cenomanian-Turonian (Upper Cretaceous) GSSP and near-by coeval section. Palaeogeography, Palaeoclimatology, Palaeoecology, 378, 75-90.Ellwood B.B., Wardlaw B.R., Nestell M.K., Nestell G.P., Luu Thi Phuong Lan, 2017. Identifying globally synchronous Permian-Triassic boundary levels in successions in China and Vietnam using Graphic Correlation. Palaeogeography, Palaeoclimatology, Palaeoecology, 485, 561-571.Ghil M., Allen R.M., Dettinger M.D., Ide K., Kondrashov D., Mann M.E., Robertson A., Saunders A., Tian Y., Varadi F., Yiou P., 2002. Advanced spectral methods for climatic time series. Reviews of Geophysics, 40, 3.1-3.41. http://dx.doi.org/10.1029/2000RG000092.Gradstein F.M., Ogg J.G., Smith A.G., 2004. A geologic Time Scale 2004. Cambridge University Press, England, 589p.Hartl P., Tauxe L., Herbert T., 1995. Earliest Oligocene increase in South Atlantic productivity as interpreted from “rock magnetics” at Deep Sea drilling Site 522. Paleoceanography, 10, 311-326.Imbrie J., Hays J.D., Martinson D.G., McIntyre A., Mix A.C., Morley J.J., Pisias N.G., Prell W.L., Shackleton N.J., 1984. The Orbital Theory of Pleistocene Climate: Support from a Revised Chronology of the Marine Delta 18O Record. In Berger A.L., Imbrie J., Hays J., Kukla G., Saltzman B. (Eds.), Milankovitch and Climate, Part I, Kluwer Academic Publishers, 269-305.Mead G.A., Yauxe L., LaBrecque J.L., 1986. Oligocene paleoceanography of the South Atlantic: paleoclimate implications of sediment accumulation rates and magnetic susceptibility. Paleoceanography, 1, 273-284.Salvador A., (Ed.), 1994. International Stratigraphic Guide: The International Union of Geological Sciences and The Geological Society of America, Inc., 2nd Edition, 214p.Scotese C.R., 2001. Atlas of Earth History, Volume 1, Paleogeography, PALEOMAP Project, Arlington, Texas, 52p.Scotese C.R., 2013. Map Folio 49, Permo-Triassic Boundary (251 Ma), PALEOMAP PaleoAtlas for ArcGIS, Triassic and Jurassic Paleogeographic, Paleoclimatic and Plate Tectonic Reconstructions, PALEOMAP Project, Evanston, IL, 3.Shackleton N.J., Crowhurst S.J., Weedon G.P., Laskar J., 1999. Astronomical calibration of Oligocene-Miocene time. Philosophical Transactions of the Royal Society London, A357, 1907-1929.Shaw A.B., 1964. Time in Stratigraphy. New York, Mc Graw Hill, 365p.Shen S.-Z., Crowley J.L., Wang Y., Bowring S.A., Erwin D.H., Henderson C.M., Ramezani J., Zhang H., Shen Y.,Wang X.-D., Wang W., Mu L., Li W.-Z., Tang Y.-G., Liu X.-L., Liu X.-L., Zeng Y., Jiang Y.-F., Jin Y.-G., 2011a. High-precision geochronologic dating constrains probable causes of Earth’s largest mass extinction. Science, 334, 1367-1372. Doi:10.1126/science.1213454.Swartzendruber L.J., 1992. Properties, units and constants in magnetism. Journal of Magnetic Materials, 100, 573-575.Weedon G.P., Jenkyns H.C., Coe A.L., Hesselbo S.P., 1999. Astronomical calibration of the Jurassic time-scale from cyclostratigraphy in British mudrock formations. Philosophical Transactions of the Royal Society London, A357, 1787-1813.Weedon G.P., Shackleton N.J., Pearson P.N., 1997. The Oligocne time scale and cyclostratigraphy on the Ceara Rise, western equatorial Atlantic. In: Schackleton N.J., Curry W.B., Richter C., and Bralower T.J. (Eds.). Proceedings of the Ocean Drilling Program, Scientific Results, 154, 101-114.Whalen M.T., Day J.E., 2008. Magnetic Susceptibility, Biostratigraphy, and Sequence Stratigraphy: Insights into Devonian Carbonate Platform Development and Basin Infilling, Western Alberta. Papers on Phanerozoic Reef Carbonates in Honor of Wolfgang Schlager. SEPM (Society for Sedimentary Geology) Special Publication, 89, 291-314

Deep EST profiling of developing fenugreek endosperm to investigate galactomannan biosynthesis and its regulation

Galactomannans are hemicellulosic polysaccharides composed of a (1 → 4)-linked β-D-mannan backbone substituted with single-unit (1 → 6)-α-linked D-galactosyl residues. Developing fenugreek (Trigonella foenum-graecum) seeds are known to accumulate large quantities of galactomannans in the endosperm, and were thus used here as a model system to better understand galactomannan biosynthesis and its regulation. We first verified the specific deposition of galactomannans in developing endosperms and determined that active accumulation occurred from 25 to 38 days post anthesis (DPA) under our growth conditions. We then examined the expression levels during seed development of ManS and GMGT, two genes encoding backbone and side chain synthetic enzymes. Based on transcript accumulation dynamics for ManS and GMGT, cDNA libraries were constructed using RNA isolated from endosperms at four ages corresponding to before, at the beginning of, and during active galactomannan deposition. DNA from these libraries was sequenced using the 454 sequencing technology to yield a total of 1.5 million expressed sequence tags (ESTs). Through analysis of the EST profiling data, we identified genes known to be involved in galactomannan biosynthesis, as well as new genes that may be involved in this process, and proposed a model for the flow of carbon from sucrose to galactomannans. Measurement of in vitro ManS and GMGT activities and analysis of sugar phosphate and nucleotide sugar levels in the endosperms of developing fenugreek seeds provided data consistent with this model. In vitro enzymatic assays also revealed that the ManS enzyme from fenugreek endosperm preferentially used GDP-mannose as the substrate for the backbone synthesis

Multiple Signaling Pathways are Activated During Insulin-like Growth Factor-I (IGF-I) Stimulated Breast Cancer Cell Migration

In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44233/1/10549_2005_Article_4626.pd

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials