The stratigraphical distribution of Mid-Cretaceous foraminifera near Ventor, Isle of Wight

Ventnor No. 2 Borehole, located near Ventnor, Isle of Wight, penetrated the basal part of the Chalk Group and the Selborne Group before terminating in the upper part of the Lower Greensand Group (Sandrock Formation). The borehole was examined for Foraminifera, and although they were not seen in the Sandrock Formation and Monks Bay Sandstone Formation, the remainder of the borehole yielded moderately low diversity assemblages dominated by agglutinated species. Foraminiferal zones 3–6 (H dentatus to M. fallax/M. rostratum macrofaunal zones) were identified in the Gault Formation and zones 6 (lower) to 6a (M. fallax/M. rostratum to A. briacensis macrofaunal zones) were identified in the Upper Greensand Formation. Assemblages from the overlying West Melbury Marly Chalk Formation were used to identify foraminiferal zones BGS1-BGS3 (M. mantelli and M. dixoni macrofaunal zones)

Meningitis and climate: from science to practice

Meningococcal meningitis is a climate sensitive infectious disease. The regional extent of the Meningitis Belt in Africa, where the majority of epidemics occur, was originally defined by Lapeysonnie in the 1960s. A combination of climatic and environmental conditions and biological and social factors have been associated to the spatial and temporal patterns of epidemics observed since the disease first emerged in West Africa over a century ago. However, there is still a lack of knowledge and data that would allow disentangling the relative effects of the diverse risk factors upon epidemics. The Meningitis Environmental Risk Information Technologies Initiative (MERIT), a collaborative research-to-practice consortium, seeks to inform national and regional prevention and control strategies across the African Meningitis Belt through the provision of new data and tools that better determine risk factors. In particular MERIT seeks to consolidate a body of knowledge that provides evidence of the contribution of climatic and environmental factors to seasonal and year-to-year variations in meningococcal meningitis incidence at both district and national scales. Here we review recent research and practice seeking to provide useful information for the epidemic response strategy of National Ministries of Health in the Meningitis Belt of Africa. In particular the research and derived tools described in this paper have focused at “getting science into policy and practice” by engaging with practitioner communities under the umbrella of MERIT to ensure the relevance of their work to operational decision-making. We limit our focus to that of reactive vaccination for meningococcal meningitis. Important but external to our discussion is the development and implementation of the new conjugate vaccine, which specifically targets meningococcus A

Impact of Isotype on the Mechanism of Action of Agonist Anti-OX40 Antibodies in Cancer: Implications for Therapeutic Combinations

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

The geological setting of the coastal fringes of west Sussex, Hampshire and the Isle of Wight

This guide covers a significant part of southern Hampshire, a part of West Sussex and the Isle of Wight. The region is founded on Cretaceous and Palaeogene bedrock, the younger forming the final phase of sedimentation of the Hampshire Basin. The bedrock is covered by a thick and extensive succession of Quaternary superficial deposits subdivided into a number of units that represent a long Quaternary history as the landscape was denuded through numerous periglacial/ temperate climatic cycles

Equilibrium Grade Inflation with Implications for Female Interest

We estimate an equilibrium model of grading policies where professors set grading policies and students register and study for classes, in part, based on these policies. Professors value enrollment, learning, and student study time, and set policies taking into account how other professors grade. Male and female students value course types, the benefits associated with higher grades, and effort costs differently. We calculate how much of the differences in grading policies across fields is driven by differences in demand for courses in those fields and how much is due to differences in professor preferences across fields. We also decompose differences in female/male course taking across fields driven by differences in i) cognitive skills, ii) valuation of grades, iii) cost of studying, and iv) field preferences. We then run counterfactual simulations to evalaute changes to grading policies. Restrictions on grading policies that equalize grade distributions across classes result in higher (lower) grades in science (non-science) fields but more (less) work being required. As women are willing to study more than men, this restriction on grading policies results in more women pursuing the sciences and more men pursuing the non-sciences