The Dementias Platform UK (DPUK) Data Portal.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

Clusters of composition: Elemental content of aquatic organic matter in UK and Faroe peatlands.

Water supply companies with reservoirs in peatland areas need to know how land use and vegetation cover in their supply catchments impact the amount and composition of aquatic organic matter in raw waters. Drinking water treatment processes remove organic matter from potable supplies, but recent increases in concentration and changes in composition have made this more difficult. This study analysed the composition of aquatic organic matter from peatland catchments in the UK and Faroe Islands. Both dissolved organic matter (DOM) and particulate organic matter (POM) compositions varied spatially, but these differences were not consistent as water moved through catchments, from headwaters and peatland pools to lake and reservoir outlets. These data showed that lakes and reservoirs are acting as flocculation hotspots, processing OM, releasing carbon (C), hydrogen (H) and oxygen (O) compounds to the atmosphere, and resulting in OM with higher N content. DOM compositions could be grouped into five clusters, showing that water treatment processes can be maximised to target 'envelopes' or clusters of DOM compositions. Catchment factors such as land use, vegetation cover, percentage peat cover and catchment area are good indicators of OM compositions likely to be present in a reservoir, and can guide water companies to maximise efficiency of their raw water treatment processes.

Specific transport of temozolomide does not override DNA repair-mediated chemoresistance.

Temozolomide (TMZ) a DNA alkylating agent, is the standard-of-care for brain tumors, such as glioblastoma multiforme (GBM). Although the physicochemical and pharmacokinetic properties of TMZ, such as chemical stability and the ability to cross the blood-brain barrier (BBB), have been questioned in the past, the acquired chemoresistance has been the main limiting factor of long-term clinical use of TMZ. In the present study, an L-type amino acid transporter 1 (LAT1)-utilizing prodrug of TMZ (TMZ-AA, 6) was prepared and studied for its cellular accumulation and cytotoxic properties in human squamous cell carcinoma, UT-SCC-28 and UT-SCC-42B cells, and TMZ-sensitive human glioma, U-87MG cells that expressed functional LAT1. TMZ-AA 6 accumulated more effectively than TMZ itself into those cancer cells that expressed LAT1 (UT-SCC-42B). However, this did not correlate with decreased viability of treated cells. Indeed, TMZ-AA 6, similarly to TMZ itself, required adjuvant inhibitor(s) of DNA-repair systems, O6-methylguanine-DNA methyl transferase (MGMT) and base excision repair (BER), as well as active DNA mismatch repair (MMR), for maximal growth inhibition. The present study shows that improving the delivery of this widely-used methylating agent is not the main barrier to improved chemotherapy, although utilizing a specific transporter overexpressed at the BBB or glioma cells can have targeting advantages. To obtain a more effective anticancer prodrug, the compound design focus should shift to altering the major DNA alkylation site or inhibiting DNA repair systems.

Painful Bladder Syndrome/Interstitial Cystitis and High Tone Pelvic Floor Dysfunction.

This article provides an overview of 2 conditions that defy straightforward characterization and treatment: interstitial cystitis/painful bladder syndrome often coexists with high tone pelvic floor dysfunction. These conditions are common in gynecologic patients who present with chronic pelvic pain and are often misdiagnosed due to their syndromic nature and amorphous definitions. Clinicians should maintain a high level of suspicion for these processes in patients with chronic pelvic pain or recurrent urinary tract infection symptoms. Optimal treatment uses a multimodal approach to alleviate symptoms.

A comparison of methods for the extraction of dissolved organic matter from freshwaters.

Studies of dissolved organic matter (DOM) composition have used several different methods to concentrate and extract the DOM from fresh water, but the impact of these methods on the composition of the DOM is relatively unknown, as very few studies use more than one method to compare results. The aim of this study was to use several methods, frequently used in the scientific literature, to concentrate and extract DOM from fresh water and compare the elemental and functional group composition of the extracted DOM. In addition, the cost, in terms of money, resources and time, were assessed for each method. The results showed that the elemental and functional group composition of the extracted DOM varied between methods significantly. The methods that yielded the most similar and reproducible DOM results were rotary evaporation, dry-down at 60 °C and freeze-drying. Although each of these methods required a relatively expensive piece of laboratory equipment, this was a 'one-off' cost, and consumables and time per sample were relatively low. This study highlights the dangers of comparing DOM data from different studies when the DOM has been extracted via different methods. In future, it is recommended that studies of DOM composition report their methods of extraction clearly and consistently, ideally using one (or more) of the methods showing reliable results here.

Tackling gaps in developing life-changing treatments for dementia.

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.

Organic matter properties of Fennoscandian ecosystems: Potential oxidation of northern environments under future change?

The oxidative ratio (OR) of an ecosystem, which reflects the ratio of O2:CO2 associated with ecosystem gas exchanges, is an important parameter in understanding the sink of CO2 represented by the terrestrial biosphere. There is a growing body of ecosystem-based approaches to understand OR; however, there are still a number of unknowns. This study addressed two gaps in our understanding of the oxidation of the terrestrial biosphere: (1) What is the oxidation state of Arctic ecosystems, and in particular permafrost soils? (2) Will coupled climate and land use change cause the terrestrial organic matter oxidation state to change? The study considered eight locations along a transect from southern Sweden to northern Norway and sampled different organic matter types (soil, litter, trees, and herbaceous vegetation) as well as different soil orders (Inceptisols, Spodosols, Histosols, and Gelisols). The study showed that although there was no difference between soil orders, there was a significant effect due to location with OR increasing from 1.03 at the southernmost location to 1.09 in the northernmost location; this increase is independent of soil order or type of organic matter. The pattern of post hoc differences in the OR with latitude suggests that the increase in OR is correlated with the northern limit of arable agriculture. The study suggests that the combined effects of climate and land use change could lead to a decrease in terrestrial organic matter OR and an increase in its oxidation state.

Maximizing the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective.

Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilize scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape [Alzheimer's, Parkinson's, frontotemporal degeneration, amyotrophic lateral sclerosis (ALS), Lewy-body and vascular dementia] were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.

The medicinal chemistry of imidazotetrazine prodrugs.

Temozolomide (TMZ) is the standard first line treatment for malignant glioma, reaching "blockbuster" status in 2010, yet it remains the only drug in its class. The main constraints on the clinical effectiveness of TMZ therapy are its requirement for active DNA mismatch repair (MMR) proteins for activity, and inherent resistance through O6-methyl guanine-DNA methyl transferase (MGMT) activity. Moreover, acquired resistance, due to MMR mutation, results in aggressive TMZ-resistant tumour regrowth following good initial responses. Much of the attraction in TMZ as a drug lies in its PK/PD properties: it is acid stable and has 100% oral bioavailability; it also has excellent distribution properties, crosses the blood-brain barrier, and there is direct evidence of tumour localisation. This review seeks to unravel some of the mysteries of the imidazotetrazine class of compounds to which TMZ belongs. In addition to an overview of different synthetic strategies, we explore the somewhat unusual chemical reactivity of the imidazotetrazines, probing their mechanisms of reaction, examining which attributes are required for an active drug molecule and reviewing the use of this combined knowledge towards the development of new and improved anti-cancer agents.