Would You Live Here? Making the Growth Areas communities of choice

This book aims to promote a better understanding of who will live in the Growth Areas, what their aspirations and needs will be, and how we can meet them

City People: City centre living in the UK

City People examines the size and nature of the city centre living phenomenon, focusing on the historic cores of Dundee, Liverpool and Manchester. It asks why it has happened, who is living in the heart of the city - and how long they plan to stay. It then assesses the economic and social benefits of city centre living

Digital process design to define and deliver pharmaceutical particle attributes

A digital-first approach to produce quality particles of an active pharmaceutical ingredient across crystallisation, washing and drying is presented, minimising material requirements and experimental burden during development. To demonstrate current predictive modelling capabilities, the production of two particle sizes (D90 = 42 and 120µm) via crystallisation was targeted to deliver a predicted, measurable difference in in vitro dissolution performance. A parameterised population balance model considering primary nucleation, secondary nucleation, and crystal growth was used to select the modes of production for the different particle size batches. Solubility prediction aided solvent selection steps which also considered manufacturability and safety selection criteria. A wet milling model was parameterised and used to successfully produce a 90g product batch with a particle size D90 of 49.3µm, which was then used as the seeds for cooling crystallisation. A rigorous approach to minimising physical phenomena observed experimentally was implemented, and successfully predicted the required conditions to produce material satisfying the particle size design objective of D90 of 120µm in a seeded cooling crystallisation using a 5-stage MSMPR cascade. Product material was isolated using the filtration and washing processes designed, producing 71.2g of agglomerated product with a primary particle D90 of 128µm. Based on experimental observations, the population balance model was reparametrised to increase accuracy by inclusion of an agglomeration terms for the continuous cooling crystallisation. The dissolution performance for the two crystallised products is also demonstrated, and after 45minutes 104.0mg of the D90 of 49.3µm material had dissolved, compared with 90.5mg of the agglomerated material with D90 of 128µm. Overall, 1513g of the model compound was used to develop and demonstrate two laboratory scale manufacturing processes with specific particle size targets. This work highlights the challenges associated with a digital-first approach and limitations in current first-principles models are discussed that include dealing ab initio with encrustation, fouling or factors that affect dissolution other than particle size

Neuroprotective activity of ursodeoxycholic acid in CHMP2B Intron5 models of frontotemporal dementia

Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2BIntron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2BIntron5. Rescue of CHMP2BIntron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders

Integrated continuous process design for crystallisation, spherical agglomeration, and filtration of lovastatin

Purpose This work seeks to improve the particle processability of needle-like lovastatin crystals and develop a small-footprint continuous MicroFactory for its production. Methods General conditions for optimal spherical agglomeration of lovastatin crystals and subsequent product isolation are developed, first as batch processes, and then transferred to continuous MicroFactory operation. Results Methyl isobutyl ketone is a suitable bridging liquid for the spherical agglomeration of lovastatin. Practical challenges including coupling unit operations and solvent systems; mismatched flow rates and inconsistent suspension solid loading were resolved. The successful continuous production of lovastatin spherical agglomerates (D50 = 336 µm) was achieved. Spherical agglomeration increased the density of the bulk lovastatin powder and improved product flowability from poor to good, whilst maintaining lovastatin tablet performance. Conclusion A continuous, integrated MicroFactory for the crystallisation, spherical agglomeration, and filtration of lovastatin is presented with improved product particle processability. Up to 16,800 doses of lovastatin (60 mg) can be produced per day using a footprint of 23 m2

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio