A generative network model of neurodevelopmental diversity in structural brain organization

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: James S. McDonnell Foundation (McDonnell Foundation); doi: https://doi.org/10.13039/100000913Funder: Cambridge Commonwealth, European and International Trust (Cambridge Commonwealth, European & International Trust); doi: https://doi.org/10.13039/501100003343Abstract: The formation of large-scale brain networks, and their continual refinement, represent crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. But how does this organization arise, and what mechanisms drive diversity in organization? We use generative network modeling to provide a computational framework for understanding neurodevelopmental diversity. Within this framework macroscopic brain organization, complete with spatial embedding of its organization, is an emergent property of a generative wiring equation that optimizes its connectivity by renegotiating its biological costs and topological values continuously over time. The rules that govern these iterative wiring properties are controlled by a set of tightly framed parameters, with subtle differences in these parameters steering network growth towards different neurodiverse outcomes. Regional expression of genes associated with the simulations converge on biological processes and cellular components predominantly involved in synaptic signaling, neuronal projection, catabolic intracellular processes and protein transport. Together, this provides a unifying computational framework for conceptualizing the mechanisms and diversity in neurodevelopment, capable of integrating different levels of analysis—from genes to cognition

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Metal-organic framework composites for nuclear waste clean-up

Radioactive pertechnetate (TcO4-) has been proven a troublesome fission product from the spent fuel of nuclear reactors. Current reprocessing is not effective at removing TcO4- from effluent resulting in discharges of the anion into watercourses through both authorised and accidental incidents. Metal-organic frameworks (MOFs) have been proposed as candidate adsorbents for TcO4- as a result of their high porosity and the ability to fine tune their properties towards particular applications. The processing of these materials into application specific configurations, such as composites, can enhance the physical properties and aid in recycling of the adsorbent. This project will involve the synthesis of both novel and existing MOFs followed by the processing of these materials into composites that can selectively adsorb TcO4-. We opt wherever possible to use benign reagents, and environmentally sustainable techniques for the synthesis of these materials. As such, we close this thesis by presenting our work in sustainable MOF syntheses. Chapter one introduces the key areas of this project. We discuss the nuclear industry and the need for nuclear waste remediating materials. Metal-organic frameworks and their composites are discussed as well as key literature. We close this chapter by highlighting current materials for pertechnetate remediation and lay out the project aims. In chapter two we present our work into ReO4- remediation, a nonradioactive surrogate of pertechnetate, with the MOF UiO-66-NH2 ¬([Zr6O4(OH)4(BDC-NH2)6]) (BDC-NH2 =aminoterephthalic acid). The MOF undergoes post-synthetic modification (PSM)with excess ethyl isocyanate to generate the MOF UiO-66-(NH2)1.8(NHC(O)NHC2H5)4.2. UiO-66-NH2 is configured into two bio composites, alginate hydrogel beads and cellulose filter papers. The effectiveness of the PSM material and the bio-composites for perrhenate remediation is assessed. We turn our attention to crystal engineering of coordination polymers and MOFs in chapter three. Crystal engineering is applied to investigate the effect that structural isomerism of the organic linker N,N′-bis (pyridylmethyl)urea and the counter anion present in silver cationic coordination polymers plays on the resulting crystal structure and topology. Initial studies suggested that the ortho structural isomer could selectively crystallise ReO4 - over competing anions such as nitrate and sulphate however this was ultimately found to not be the case. Silver coordination polymer stability in the presence of application concentration levels of chloride was found to be not sufficient to warrant ReO4 - remediation studies. Three new zinc-based materials are also synthesised and characterised in chapter three. The urea-based organic linkers4,4′-(carbonylbis (azanediyl)) dibenzoic acid and N,N´-bis(4-pyridylmethyl)urea are used in these materials, two of which are mixed linker systems. This chapter presents a total of 14 crystal structures,11 of which have not been previously reported. In chapter four we investigate sustainable syntheses of calcium-based MOFs. Recycled chicken eggshells as well as polyethylene terephthalate (PET)bottles are used as sustainable sources of calcium and terephthalic acid respectively, for a one-pot synthesis of[Ca(BDC)(H2O)3]. Furthermore, eggshells were used to synthesise the MOFs[Ca(SQ)(H2O)] and [Ca(FU)(H2O)3]. Mechanochemistry is applied to provided largely solventless and sustainable syntheses for the three listed MOFs. <p class="MsoNormal"/

Dataset in support of the thesis &#39;Metal-organic framework composites for nuclear waste clean-up&#39;

Thesis Title: Metal-Organic Framework Composites for Nuclear Waste Clean-Up. This dataset contains all relevant data regarding the associated PhD thesis. This dataset contains: PXRD, SEM, SCXRD, FTIR, TGA, BET, ICP-MS, 1H NMR, mass spectrometry data. The data is labelled through the following format: chapter_section_data-type. </span

Toward sustainable syntheses of Ca-based MOFs

We report the use of benign and green precursors, including waste chicken eggshells and PET (polyethyleneterephthalate) from recycled plastic bottles, for the facile synthesis of a variety of calcium-based metal-organic frameworks (Ca-MOFs), using water based and mechanochemical synthesis techniques

A Shared Receptor Suggests a Common Ancestry between an Insecticidal <i>Bacillus thuringiensis</i> Cry Protein and an Anti-Cancer Parasporin

Cry toxins, produced by the bacterium Bacillus thuringiensis, are of significant agronomic value worldwide due to their potent and highly specific activity against various insect orders. However, some of these pore-forming toxins display specific activity against a range of human cancer cells whilst possessing no known insecticidal activity; Cry41Aa is one such toxin. Cry41Aa has similarities to its insecticidal counterparts in both its 3-domain toxic core structure and pore-forming abilities, but how it has evolved to target human cells is a mystery. This work shows that some insecticidal Cry toxins can enhance the toxicity of Cry41Aa against hepatocellular carcinoma cells, despite possessing no intrinsic toxicity themselves. This interesting crossover is not limited to human cancer cells, as Cry41Aa was found to inhibit some Aedes-active Cry toxins in mosquito larval assays. Here, we present findings that suggest that Cry41Aa shares a receptor with several insecticidal toxins, indicating a stronger evolutionary relationship than their divergent activities might suggest

Toward sustainable syntheses of Ca-based MOFs

We report the use of benign and green precursors, including waste chicken eggshells and PET (polyethyleneterephthalate) from recycled plastic bottles, for the facile synthesis of a variety of calcium-based metal-organic frameworks (Ca-MOFs), using water based and mechanochemical synthesis techniques.<br/

Electronic Data : Toward sustainable syntheses of Ca-based MOFs

Electronic data relating to the publication titled &#39;Toward sustainable syntheses of Ca-based MOFs&#39; by Tom. S. Crickmore, Haamidah Begum Sana, Hannah Mitchell, Molly Clark and Darren Bradshaw, published in Chemical Communications, DOI: 10.1039/D1CC04032D </span

A shared receptor suggests a common ancestry between an insecticidal Bacillus thuringiensis cry protein and an anti-cancer parasporin

Cry toxins, produced by the bacterium Bacillus thuringiensis, are of significant agronomic value worldwide due to their potent and highly specific activity against various insect orders. However, some of these pore-forming toxins display specific activity against a range of human cancer cells whilst possessing no known insecticidal activity; Cry41Aa is one such toxin. Cry41Aa has similarities to its insecticidal counterparts in both its 3-domain toxic core structure and pore-forming abilities, but how it has evolved to target human cells is a mystery. This work shows that some insecticidal Cry toxins can enhance the toxicity of Cry41Aa against hepatocellular carcinoma cells, despite possessing no intrinsic toxicity themselves. This interesting crossover is not limited to human cancer cells, as Cry41Aa was found to inhibit some Aedes-active Cry toxins in mosquito larval assays. Here, we present findings that suggest that Cry41Aa shares a receptor with several insecticidal toxins, indicating a stronger evolutionary relationship than their divergent activities might suggest.</p