Alzheimer’s Research UK

BACKGROUNDIn order to alleviate the growing issue of herbicide resistance, diversification of the herbicide portfolio is necessary. A promising yet underutilized mode‐of‐action is the inhibition of fatty acid thioesterases (FATs), which terminate de novo fatty acid (FA) biosynthesis by releasing FAs from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility by determining the amount and length of FAs present. In this study we report a crystallographic fragment screening approach for the identification of novel chemical matter targeting FATs.RESULTSWe have solved the crystal structure of Arabidopsis thaliana FatA to 1.5 Å and conducted a crystallographic fragment screen which identified 129 unique fragments bound in 141 different poses. Ten fragments demonstrated on‐scale potency, two of these exploiting different interactions to known herbicides. Elaboration of one of the fragments resulted in an improvement of affinity from ~20 μm to ~90 nmKD. Finally, superposition of our crystal structures revealed that some fragments exploit large conformational changes in the substrate binding site.CONCLUSIONWe have fully enabled FatA as a target for rapid, rational hit‐to‐lead development, with robust structural, biophysical and biochemical assays. We provide a set of fragment hits which represent diverse, novel scaffolds that both recapitulate interactions made by current herbicides, and also target novel regions within the active and dimer sites. Our fragments can be readily merged and allow for effective catalogue‐based structure–activity relationship (SAR) exploration. Together these data will accelerate the development of novel, alternative herbicides to combat herbicide resistance. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Introduction: Clinical Data Management (CDM) is a critical aspect of clinical research, and the use of clinical data standards is essential to ensure the quality and consistency of one’s data. Objectives: We aim to obtain a snapshot of practice patterns among CDM professionals at academic institutions regarding the implementation and use of clinical data standards. Methods: A survey of 14 questions on clinical data standards and anonymization was sent to over 300 academic clinical institutions worldwide. Data were obtained from a total of 50 institutions. Results: Sixty-six percent of institutions reported implementing data standards while only 22% of reporting institutions offered data standards training and 20% offered training in anonymization. The findings presented here will be useful to research administrators striving to improve upon and streamline the use, implementation, and training of clinical data standards in academic research today.

The S100 protein family functions as protein–proteininteractionadaptors regulated by Ca2+ binding. Formation of variousS100 complexes plays a central role in cell functions, from calciumhomeostasis to cell signaling, and is implicated in cell growth, migration,and tumorigenesis. We established a suite of biochemical and cellularassays for small molecule screening based on known S100 protein–proteininteractions. From 25 human S100 proteins, we focused our attentionon S100A4 because of its well-established role in cancer progressionand metastasizes by interacting with nonmuscle myosin II (NMII). Weidentified several potent and selective inhibitors of this interactionand established the covalent nature of binding, confirmed by massspectrometry and crystal structures. 5b showed on-targetactivity in cells and inhibition of cancer cell migration. The identifiedS100A4 inhibitors can serve as a basis for the discovery of new cancerdrugs operating via a novel mode of action.

Abstract Mutations inPSEN1cause familial Alzheimer’s disease with almost complete penetrance. Age at onset is highly variable between differentPSEN1mutations and even within families with the same mutation. Current research into late onset Alzheimer’s disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of γ-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations inPSEN1impact inflammatory responses in astrocytes, thereby contributing to disease progression.Here, using iPSC-astrocytes, we show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathologicalPSEN1mutations. Using transcriptomic analyses, we demonstrate thatPSEN1mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with an upregulation of genes coding for regulated intramembrane proteolytic and robust activation of JAK-STAT signalling. Using JAK-STAT2 as an example signalling pathway, we show altered phosphorylation cascades inPSEN1mutant astrocytes, reinforcing the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of γ-secretase to confirm a role for PSEN1/γ-secretase in regulating the astrocytic response to inflammatory stimuli.Together, these data suggest that mutations inPSEN1enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution ofPSEN1mutations to fAD pathogenesis, not only impacting APP and Aβ processing but also altering the cellular response to inflammation.

BackgroundCardiometabolic diseases (CMDs) including type 2 diabetes, heart disease, and stroke have been linked to a higher risk of dementia. We examined whether high levels of cognitive reserve (CR) can attenuate the increased dementia risk and brain pathologies associated with CMDs.MethodsWithin the UK Biobank, 216,178 dementia-free participants aged ≥ 60 were followed for up to 15 years. Baseline CMDs and incident dementia were ascertained from medical records, medication use, and medical history. Latent class analysis was used to generate an indicator of CR (low, moderate, and high) based on education, occupational attainment, confiding in others, social contact, leisure activities, and television watching time. A subsample (n = 13,663) underwent brain MRI scans during follow-up. Volumes of total gray matter (GMV), hippocampus (HV), and white matter hyperintensities (WMHV) were ascertained, as well as mean diffusivity (MD) and fractional anisotropy (FA) in white matter tracts.ResultsAt baseline, 43,402 (20.1%) participants had at least one CMD. Over a mean follow-up of 11.7 years, 6,600 (3.1%) developed dementia. The presence of CMDs was associated with 57% increased risk of dementia (HR 1.57 [95% CI 1.48, 1.67]). In joint effect analysis, the HRs of dementia for people with CMDs and moderate-to-high CR and low CR were 1.78 [1.66, 1.91] and 2.13 [1.97, 2.30]), respectively (reference: CMD-free, moderate-to-high CR). Dementia risk was 17% lower (HR 0.83 [0.77, 0.91], p < 0.001) among people with CMDs and moderate-to-high compared to low CR. On brain MRI, CMDs were associated with smaller GMV (β -0.18 [-0.22, -0.13]) and HV (β -0.13 [-0.18, -0.08]) as well as significantly larger WMHV (β 0.06 [0.02, 0.11]) and MD (β 0.08 [0.02, 0.13]). People with CMDs and moderate-to-high compared to low CR had significantly larger GMV and HV, but no differences in WMHV, MD, or FA.ConclusionsAmong people with CMDs, having a higher level of CR was associated with lower dementia risk and larger gray matter and hippocampal volumes. The results highlight a mentally and socially active life as a modifiable factor that may support cognitive and brain health among people with CMDs.

Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled by monocultures. However, cocultures are difficult to use and analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures to model inflammatory neurodegeneration, live-cell stains, and automated classification of neurons, astrocytes or microglia using open-source software. Out of 227 compounds with known bioactivities, 29 protected against lipopolysaccharide-induced neuronal loss, including drugs affecting adrenergic, steroid, inflammatory and MAP kinase signaling. The screen also identified physiological compounds, such as noradrenaline and progesterone, that protected and identified neurotoxic compounds, such as a TLR7 agonist, that induced microglial proliferation. Most compounds used here have not been tested in a neuron-glia coculture neurodegeneration assay previously. Thus, combining a complex cellular disease model with high-content screening of known compounds and automated image analysis allows identification of important biology, as well as potential targets and drugs for treatment.

Theoretically, ownership of property connotes among other things, ''the right to use, perhaps to abuse save in so far as no damage or harm is caused to the adjoining owners of land or neighborhood". 1 Ownership of property further connotes right to exclusive possession and the unfettered right to alienate, develop or transfer such property or right in it when it is desired. This poser supports the maxim of cuiusestsolum, eiusestusqueadcoelum et ad inferos It arises with respect to a given property. Just like Petroleum Act and Nigeria Constitution, the Mineral Act handed over solid minerals to the government of the federation. Ebonyi State is one of the States in the South Eastern Nigeria with enormous solid minerals. However, Mineral Act took a different dimension in approach of exploration and development of the solid minerals thus, giving local community and local government vis-à-vis the immediate landowners some recognitions or participatory roles in negotiation of leases. But prospective miners must get approvals from Ministry of Mines and Steel Development through its Mining Cadastre Office and not through State Department of Mineral Development. Development and sustainability of state economy through the development of non-oil resources across the nation is hampered due to the uncharitable stance of section 44 (3) of the Constitution of Nigeria. Thus, the 'sacrosanct' of this proviso makes the state's right to develop or participation solely on the collection of tolls and land taxes and not rights of developing the minerals per se to boost the independence of state's economic stand. In this article, the writer is considering the above legal issues and how best states with non-oil minerals can develop them to reduce their dependency on federal monthly allocation. It is also aimed to exploring in-depth, principles or theorems that may be best applied in formulating State's non-oil mineral policies, legislations, proven system integration and reforms in solid mineral management in Nigeria to building a sustainable economic development in Ebonyi State Nigeria. The author will have a quick look at Ebonyi State agricultural prowess and make recommendations. This work adopts a doctrinal methodological approach where relevant primary and secondary data will be required.