The histone chaperone Vps75 forms multiple oligomeric assemblies capable of mediating exchange between histone H3–H4 tetramers and Asf1–H3–H4 complexes

Wellcome Trust [094090, 097945, 099149]; Medical Research Council [G1100021]. Funding for open access charge: Wellcome Trust.Vps75 is a histone chaperone that has been historically characterized as homodimer by X-ray crystallography. In this study, we present a crystal structure containing two related tetrameric forms of Vps75 within the crystal lattice. We show Vps75 associates with histones in multiple oligomers. In the presence of equimolar H3-H4 and Vps75, the major species is a reconfigured Vps75 tetramer bound to a histone H3-H4 tetramer. However, in the presence of excess histones, a Vps75 dimer bound to a histone H3-H4 tetramer predominates. We show the Vps75-H3-H4 interaction is compatible with the histone chaperone Asf1 and deduce a structural model of the Vps75-Asf1-H3-H4 (VAH) co-chaperone complex using the Pulsed Electron-electron Double Resonance (PELDOR) technique and cross-linking MS/MS distance restraints. The model provides a molecular basis for the involvement of both Vps75 and Asf1 in Rtt109 catalysed histone H3 K9 acetylation. In the absence of Asf1 this model can be used to generate a complex consisting of a reconfigured Vps75 tetramer bound to a H3-H4 tetramer. This provides a structural explanation for many of the complexes detected biochemically and illustrates the ability of Vps75 to interact with dimeric or tetrameric H3-H4 using the same interaction surface.Publisher PDFPeer reviewe

When do fractured media become seismically anisotropic? Some implications on quantifying fracture properties

Fractures are pervasive features within the Earth's crust and they have a significant influence on the multi-physical response of the subsurface. The presence of coherent fracture sets often leads to observable seismic anisotropy enabling seismic techniques to remotely locate and characterise fracture systems. In this study, we confirm the general scale-dependence of seismic anisotropy and provide new results specific to shear-wave splitting (SWS). We find that SWS develops under conditions when the ratio of wavelength to fracture size (λS/d) is greater than 3, where Rayleigh scattering from coherent fractures leads to an effective anisotropy such that effective medium model (EMM) theory is qualitatively valid. When 1<λS/d<3 there is a transition from Rayleigh to Mie scattering, where no effective anisotropy develops and hence the SWS measurements are unstable. When λS/d<1 we observe geometric scattering and begin to see behaviour similar to transverse isotropy. We find that seismic anisotropy is more sensitive to fracture density than fracture compliance ratio. More importantly, we observe that the transition from scattering to an effective anisotropic regime occurs over a propagation distance between 1 and 2 wavelengths depending on the fracture density and compliance ratio. The existence of a transition zone means that inversion of seismic anisotropy parameters based on EMM will be fundamentally biased. More importantly, we observe that linear slip EMM commonly used in inverting fracture properties is inconsistent with our results and leads to errors of approximately 400% in fracture spacing (equivalent to fracture density) and 60% in fracture compliance. Although EMM representations can yield reliable estimates of fracture orientation and spatial location, our results show that EMM representations will systematically fail in providing quantitatively accurate estimates of other physical fracture properties, such as fracture density and compliance. Thus more robust and accurate quantitative estimates of in situ fracture properties will require improvements to effective medium models as well as the incorporation of full-waveform inversion techniques

Vasopressin in conjunction with norepinephrine in septic shock: A retrospective cohort study from a low middle-income country

Objectives: Guidelines recommend use of norepinephrine as the first-line treatment for fluid-refractory septic shock and if septic shock persists vasopressin may be initiated. Since there are limited data from low middle-income countries with high disease burden of sepsis, we aimed to compare the outcomes of using vasopressin adjunct to norepinephrine in comparison with norepinephrine alone.Design: Retrospective cohort study.Setting: Aga Khan University Hospital, Karachi, Pakistan.Patients: Six-hundred fifty-three patients diagnosed with septic shock from January 2019 to December 2019, with 498 given norepinephrine only and 155 given norepinephrine-vasopressin combination.Interventions: None.Measurements and main results: Primary outcome was in-hospital mortality. Secondary outcomes were duration of vasopressor used, length of hospital stay, length of ICU stay, and days on ventilatory support. After adjustment by multivariable logistic regression, it was found that mortality was not significantly associated with the norepinephrine-vasopressin combination (adjusted odds ratio, 0.633 [95% CI, 0.370-1.081]). However, Sequential Organ Failure Assessment score at admission (1.100 [1.014-1.193]), lactate at admission (1.167 [1.109-1.227]), duration of vasopressor used (1.481 [1.316-1.666]), and level of care (3.025 [1.682-5.441]) were found to be independently associated with the adjunct usage of norepinephrine and vasopressin.Conclusions: The use of norepinephrine-vasopressin combination has remained debatable in literature. Our study showed that although there was no difference in mortality between the two groups, admission Sequential Organ Failure Assessment scores and admission lactate levels were found to be significantly higher in the norepinephrine-vasopressin group. Hence, physicians from Pakistan used the norepinephrine-vasopressin combination in resistant septic shock patients who were sicker to begin with. Furthermore, duration of vasopressor therapy and ICU admission were also significantly higher in the combination group. Considering the recent hyperinflation of vasopressors costs and that most healthcare expenditure for patients in Pakistan is out-of-pocket, this can consequently lead to unwarranted financial burden for patients and their families

Hydrous upwelling across the mantle transition zone beneath the Afar Triple Junction

The mechanisms that drive the upwelling of chemical heterogeneity from the lower to upper mantle (e.g., thermal versus compositional buoyancy) are key to our understanding of whole mantle con- vective processes. We address these issues through a receiver function study on new seismic data from recent deployments located on the Afar Triple Junction, a location associated with deep mantle upwelling. The detailed images of upper mantle and mantle transition zone structure illuminate features that give insights into the nature of upwelling from the deep Earth. A seismic low-velocity layer directly above the mantle transition zone, interpreted as a stable melt layer, along with a prominent 520 km discontinuity sug- gest the presence of a hydrous upwelling. A relatively uniform transition zone thickness across the region suggests a weak thermal anomaly (<100 K) may be present and that upwelling must be at least partly driven by compositional buoyancy. The results suggest that the lower mantle is a source of volatile rich, chemically distinct upwellings that influence the structure of the upper mantle, and potentially the chemis- try of surface lavas

Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast.

The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells' expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non-small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified

E-cigarette marketing in the UK: evidence from adult and youth surveys and policy compliance studies

Electronic cigarettes (e-cigarettes) are battery-powered devices that heat a liquid, usually containing nicotine, to allow users to inhale the vapour. The evidence so far suggests they are far less harmful than smoking and can help people to quit smoking. However, as e-cigarettes are a relatively new product and their long-term effects are unknown, they should not be used by people who have never smoked, particularly young people. In 2016 and 2017, regulations were introduced to help ensure that e-cigarette advertising is socially responsible. This means protecting young people, minimising conflation between e-cigarettes and tobacco, and preventing uptake of e-cigarettes amongst people who don’t smoke or use nicotine. The Tobacco and Related Products Regulations 2016 (TRPR) set rules on how e-cigarettes can be advertised and prohibited marketing in specific media channels. Subsequently, the UK Advertising Standards Authority (ASA), Committee of Advertising Practice (CAP) Code and Broadcast Committee of Advertising Practice (BCAP) Code, updated in 2017, set out further advertising regulations in CAP Code Rule 22 and BCAP Code Rule 33. The overall aim of this report was to assess compliance with and the impact of the current UK e-cigarette marketing regulations. The UK Government is obliged to review and deliver a report on the TRPR within five years of the legislation being enacted, by May 2021. This report will help to inform the Government’s review. This report brings together two complementary studies to provide a description of e-cigarette advertising spend, advertising content, compliance with advertising regulations, and reported noticing and appeal of e-cigarette marketing. Study A (by the Institute for Social Marketing & Health) consisted of an analysis of e-cigarette advertising expenditure in the UK in 2019 and a detailed content analysis of a sample of advertising taken from the same year. Study B consisted of an analysis of survey data from the International Tobacco Control Policy Evaluation Project (ITC Project), which measured reported noticing of e-cigarette marketing by young people (16 to 19-year-olds) between 2017 and 2019, and adults (aged 18 and older) between 2016 and 2018 in a broad range of marketing channels.Additional co-authors: James F Thrasher, Yoo Jin Cho, Catherine Cowell, Tim Coker, Sarah Bullock, Alizee Froguel, Jyotsna Vohr

E-cigarette marketing in the UK: evidence from adult and youth surveys and policy compliance studies

Electronic cigarettes (e-cigarettes) are battery-powered devices that heat a liquid, usually containing nicotine, to allow users to inhale the vapour. The evidence so far suggests they are far less harmful than smoking and can help people to quit smoking. However, as e-cigarettes are a relatively new product and their long-term effects are unknown, they should not be used by people who have never smoked, particularly young people. In 2016 and 2017, regulations were introduced to help ensure that e-cigarette advertising is socially responsible. This means protecting young people, minimising conflation between e-cigarettes and tobacco, and preventing uptake of e-cigarettes amongst people who don’t smoke or use nicotine. The Tobacco and Related Products Regulations 2016 (TRPR) set rules on how e-cigarettes can be advertised and prohibited marketing in specific media channels. Subsequently, the UK Advertising Standards Authority (ASA), Committee of Advertising Practice (CAP) Code and Broadcast Committee of Advertising Practice (BCAP) Code, updated in 2017, set out further advertising regulations in CAP Code Rule 22 and BCAP Code Rule 33. The overall aim of this report was to assess compliance with and the impact of the current UK e-cigarette marketing regulations. The UK Government is obliged to review and deliver a report on the TRPR within five years of the legislation being enacted, by May 2021. This report will help to inform the Government’s review. This report brings together two complementary studies to provide a description of e-cigarette advertising spend, advertising content, compliance with advertising regulations, and reported noticing and appeal of e-cigarette marketing. Study A (by the Institute for Social Marketing & Health) consisted of an analysis of e-cigarette advertising expenditure in the UK in 2019 and a detailed content analysis of a sample of advertising taken from the same year. Study B consisted of an analysis of survey data from the International Tobacco Control Policy Evaluation Project (ITC Project), which measured reported noticing of e-cigarette marketing by young people (16 to 19-year-olds) between 2017 and 2019, and adults (aged 18 and older) between 2016 and 2018 in a broad range of marketing channels

A Cryogenic Silicon Interferometer for Gravitational-wave Detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument able to detect gravitational waves at distances 5 times further away than possible with Advanced LIGO, or at greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby Universe, as well as observing the Universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor