Geochemistry, and carbon, oxygen and strontium isotope composition of brachiopods from the Khuff Formation of Oman and Saudi Arabia GeoArabia

Brachiopods are abundant in the Oman Khuff Formation and similar brachiopod faunas are present at a few horizons in the same formation in Central Saudi Arabia. Following extensive systematic and biostratigraphic studies of these faunas, specimens from the base of the Midhnab Member of the Khuff Formation of Saudi Arabia (Buraydah Quadrangle), and from Member 3 of the Khuff Formation of the Huqf outcrop of Oman were assessed for isotope geochemistry (Sr, O and C). Dating using 87Sr/86Sr alone is not conclusive. Five pristine Oman brachiopods from biostratigraphically well-constrained lower Wordian horizons record a range of 87Sr/86Sr values that form a separate cluster offset from the current Sr isotope seawater curve, which defines the Early Permian and earliest Mid-Permian. The 87Sr/86Sr of the pristine Saudi Arabian brachiopod sits in an area which corresponds to a wide scatter of 87Sr/86Sr in the seawater curve data. However, the Saudi Arabian data does indicate that the Midhnab Member is likely younger than Member 3 of the Khuff Formation of the Huqf outcrop. The well-preserved brachiopod carbonate allows deductions to be made about the palaeotemperature of the Oman Khuff Formation Member 3 seawater using its oxygen isotope composition (\u3b418O). Assuming \u3b418O of seawater < \u20130.5\u2030, then palaeotemperature derived from brachiopods in the Oman horizons would be +25\ub0C, +22\ub0C and +17\ub0C respectively. This is consistent with the trend of shallowing within Member 3, suggested by facie

Making drugs out of sunlight and 'thin air': An emerging synergy of synthetic biology and natural product chemistry

Nature has long served as a rich source of structurally diverse small organic molecules with medicinally relevant biological activities. Despite the historical success of these so-called natural products, the enthusiasm of big pharma to explore these compounds as leads in drug design has waxed and waned. A major contributor to this is their often inherent structural complexity. Such compounds are difficult (often impossible) to access synthetically, a hurdle that can stifle lead development and hinder sustainable large-scale production of promising leads for clinical evaluation. However, in recent years, an emerging synergy between synthetic biology and natural product chemistry offers the potential for a renaissance in our ability to access natural products for drug discovery and development. Advances in genome sequencing, bioinformatics and the maturing of heterologous expression platforms are increasing, enabling the study, and ultimately, the manipulation of plant biosynthetic pathways. The triterpenes are one of the most structurally diverse families of natural products and arguably one of the most underrepresented in the clinic. The plant kingdom is the richest source of triterpene diversity, with >20,000 triterpenes reported so far. Transient expression of genes for candidate enzymes and pathways in amenable plant species is emerging as a powerful and rapid means of investigating and harnessing the plant enzymes involved in generating this diversity. Such platforms also have the potential to serve as production systems in their own right, with the possibility of upscaling these discoveries into commercially useful products using the same overall basic procedure. Ultimately, the carbon source for generation of high-value compounds in plants is photosynthesis. Therefore, we could, with the help of plants, be producing new medicines out of sunlight and ‘thin air’ in green factories in the not too distant future

Transient expression in nicotiana benthamiana leaves for triterpene production at a preparative scale

The triterpenes are one of the largest and most structurally diverse families of plant natural products. Many triterpene derivatives have been shown to possess medicinally relevant biological activity. However, thus far this potential has not translated into a plethora of triterpene-derived drugs in the clinic. This is arguably (at least partially) a consequence of limited practical synthetic access to this class of compound, a problem that can stifle the exploration of structure-activity relationships and development of lead candidates by traditional medicinal chemistry workflows. Despite their immense diversity, triterpenes are all derived from a single linear precursor, 2,3-oxidosqualene. Transient heterologous expression of biosynthetic enzymes in N. benthamiana can divert endogenous supplies of 2,3-oxidosqualene towards the production of new high-value triterpene products that are not naturally produced by this host. Agro-infiltration is an efficient and simple means of achieving transient expression in N. benthamiana. The process involves infiltration of plant leaves with a suspension of Agrobacterium tumefaciens carrying the expression construct(s) of interest. Co-infiltration of an additional A. tumefaciens strain carrying an expression construct encoding an enzyme that boosts precursor supply significantly increases yields. After a period of five days, the infiltrated leaf material can be harvested and processed to extract and isolate the resulting triterpene product(s). This is a process that is linearly and reliably scalable, simply by increasing the number of plants used in the experiment. Herein is described a protocol for rapid preparative-scale production of triterpenes utilizing this plant-based platform. The protocol utilizes an easily replicable vacuum infiltration apparatus, which allows the simultaneous infiltration of up to four plants, enabling batch-wise infiltration of hundreds of plants in a short period of time

Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

YesThe duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation in solid phase synthesis. The synthesis was performed on a large scale and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers. Application to solid phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine but this had no beneficial effects on biological activity.MJS was funded by Novartis and UEA. We thank the EPSRC Mass Spectrometry Service, Swansea. We thank Richard Robinson and Julia Hatto at Novartis for help in the large scale synthesis

Role of Subsurface Geo-Energy Pilot and Demonstration Sites in Delivering Net Zero

Recent research suggests that the effects of climate change are already tangible, making the requirement for net zero more pressing than ever. New emissions targets have been announced in April 2021 by various governments, including by the United Kingdom, United States, and China, prior to the Conference of the Parties (COP26) in Glasgow. Part of the solution for net zero will be geo-energy technologies in the subsurface, these include: mine water geothermal, aquifer thermal energy storage (ATES), enhanced geothermal systems and other thermal storage options, compressed air energy storage (CAES), and carbon dioxide capture and storage (CCS) including bioenergy CCS (BECCS). Subsurface net zero technologies have been studied by geologists at laboratory scale and with models, but also require testing at greater-than laboratory scale and in representative conditions not reproducible in laboratories and models. Test, pilot and demonstration facilities aid rock characterisation process understanding and up-scaling, and thereby provide a bridge between laboratory testing and computer modelling and full-scale operation. Examples of test sites that have progressed technology development include the Otway International Test Centre (Australia, CCS) and the Äspö Hard Rock Laboratory (Sweden, geological radioactive waste disposal). These sites have provided scale up for key research questions allowing science issues of relevance to regulation, licencing and permitting to be examined at scale in controlled environments. Successful operations at such sites allow research to be seen at first hand to inform the public, regulators, supply chain companies and investors that such technologies can work safely and economically. A Geological Society conference on the “Role of subsurface research labs in delivering net zero” in February 2021 considered the value of test sites and gaps in their capability. Gaps were identified in two areas: 1) test facilities to aid the design of low cost, high resolution, unobtrusive seismic and other monitoring for a seismically noisy urban environment with a sensitive human population, for example for ATES in urban areas; and 2) a dedicated through-fault zone test site to understand fault transmissivity and reactivation. Conference participants also recommended investment and development in test sites, shared facilities and risk, joint strategies, data interoperability and international collaboration

Using an extended ICAP-based coding guide as a framework for the analysis of classroom observations

Available online 13 April 2023A coding guide based on the Interactive, Constructive, Active, Passive (ICAP) theory was developed and used to analyze the transcripts from filmed classroom observations. The analysis focused on the lesson tasks used by the 20 participating teachers to promote student cognitive engagement and the links between these tasks and student learning. The results showed that a) only 30% of the lesson tasks were assigned the Constructive and Interactive codes, and b) there were important teacher differences. About half of the teachers provided no or very few opportunities for Constructive or Interactive student cognitive engagement in their lessons.Stella Vosniadou, Michael J. Lawson, Erin Bodner, Helen Stephenson, David Jeffries, I Gusti Ngurah Darmawa

Seasonality fluctuations recorded in fossil bivalves during the early Pleistocene: implications for climate change

Understanding the transformations of the climate system may help to predict and reduce the effects of global climate change. The geological record provides a unique archive that documents the long-term fluctuations of environmental variables, such as seasonal change. Here, we investigate how seasonal variation in seawater temperatures varied in the Mediterranean Sea during the early Pleistocene, approaching the Early-Middle Pleistocene Transition (EMPT) and the beginning of precession-driven Quaternary-style glacial–interglacial cycles. We performed whole-shell and sclerochemical stable isotope analyses (δ18O, δ13C) on bivalves, collected from the lower Pleistocene Arda River marine succession (northern Italy), after checking shell preservation. Our results indicate that seawater temperature seasonality was the main variable of climate change in the Mediterranean area during the early Pleistocene, with the Northern Hemisphere Glaciation (NHG) exerting a control on the Mediterranean climate. We show that strong seasonality (14.4–16.0 °C range) and low winter paleotemperatures (0.8–1.6 °C) were likely the triggers leading to the establishment of widespread populations of so called “northern guests” (i.e., cold water taxa) in the Mediterranean Sea around 1.80 Ma. The shells postdating the arrival of the “northern guests” record a return to lower seasonal variations and higher seawater paleotemperatures, with seasonality increasing again approaching the EMPT; the latter, however, is not associated with a corresponding cooling of mean seawater paleotemperatures, showing that the observed seasonality variation represents a clear signal of progressive climate change in the Mediterranean Sea

On Higher Order Gravities, Their Analogy to GR, and Dimensional Dependent Version of Duff's Trace Anomaly Relation

An almost brief, though lengthy, review introduction about the long history of higher order gravities and their applications, as employed in the literature, is provided. We review the analogous procedure between higher order gravities and GR, as described in our previous works, in order to highlight its important achievements. Amongst which are presentation of an easy classification of higher order Lagrangians and its employment as a \emph{criteria} in order to distinguish correct metric theories of gravity. For example, it does not permit the inclusion of only one of the second order Lagrangians in \emph{isolation}. But, it does allow the inclusion of the cosmological term. We also discuss on the compatibility of our procedure and the Mach idea. We derive a dimensional dependent version of Duff's trace anomaly relation, which in \emph{four}-dimension is the same as the usual Duff relation. The Lanczos Lagrangian satisfies this new constraint in \emph{any} dimension. The square of the Weyl tensor identically satisfies it independent of dimension, however, this Lagrangian satisfies the previous relation only in three and four dimensions.Comment: 30 pages, added reference