Systematic Review of miRNA as Biomarkers in Alzheimer's Disease.

Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the accumulation of amyloid-beta plaques and hyperphosphorylated tau in the brain causing a progressive decline in cognitive impairment. Small non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. A systematic review was conducted to extract all miRNA found to be significantly deregulated in the peripheral blood. These deregulated miRNAs were cross-referenced against the miRNAs deregulated in the brain at Braak Stage III. This resulted in a panel of 10 miRNAs (hsa-mir-107, hsa-mir-26b, hsa-mir-30e, hsa-mir-34a, hsa-mir-485, hsa-mir200c, hsa-mir-210, hsa-mir-146a, hsa-mir-34c, and hsa-mir-125b) hypothesised to be deregulated early in Alzheimer's disease, nearly 20 years before the onset of clinical symptoms. After network analysis of the 10 miRNAs, they were found to be associated with the immune system, cell cycle, gene expression, cellular response to stress, neuron growth factor signalling, wnt signalling, cellular senescence, and Rho GTPases

Re-thinking and re-positioning ‘being in the moment’ within a continuum of moments : introducing a new conceptual framework for dementia studies

This article draws upon six social research studies completed by members of the Dementia and Ageing Research Team at The University of Manchester and their associated networks over an eight-year period [2011-2019] with the aim of constructing a definition of ‘being in the moment’ and situating it within a continuum of moments that could be used to contextualise and frame the lived experience of dementia. Using the approach formulated by Pound et al.(2005) to synthesising qualitative studies, we identified this continuum of moments as comprising four sequential and inter-linked steps: i) ‘Creating the moment’, defined as the processes and procedures necessary to enable being in the moment to take place. The time necessary for this to occur can range from fleeting to prolonged; ii) ‘Being in the moment’, which refers to the multi-sensory processes involved in a personal or relational interaction and embodied engagement. Being in the moment can be sustained through creativity and flow; iii) ‘Ending the moment’, defined as when a specific moment is disengaged. This can be triggered by the person(s) involved consciously or subconsciously, or caused by a distraction in the environment or suchlike; and iv) ‘Reliving the moment’, which refers to the opportunity for the experience(s) involved in ‘being in the moment’ to be later remembered and shared, however fragmentary, supported or full the recall

Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development

The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation

Structure of S. aureus HPPK and discovery of a new inhibitor

The first structural and biophysical data on the folate pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), from the pathogenic bacterium Staphylococcus aureus is presented. HPPK is the second essential enzyme in the folate biosynthesis pathway, responsible for catalysing pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl- 7,8-dihydropterin, HMDP). In-silico screening led to the discovery of a substrate competitive inhibitor, San1, which was subsequently co-crystallised with HPPK. A 1.65 Å resolution x-ray structure showed this to bind at the pterin site sharing many of the key intermolecular interactions of the substrate. ITC and SPR measurements yielded an equilibrium binding constant, Kd, of ~13 μM for San1. An IC50 of ~12 μM was determined by means of a new convenient tri-enzyme-coupled spectrophotometric assay. ITC and SPR further showed that the San1 inhibitor has no requirement for magnesium or ATP cofactor for competitive binding to the substrate site. According to 15N heteronuclear NMR measurements, the fast motion of the pterin loop (L2) is partially dampened in the ternary complex between SaHPPK, HMDP and , -methylene adenosine 5-triphosphate (AMPCPP), but the ATP loop (L3) remains mobile on the μs timescale. In contrast, for the SaHPPK/San1/AMPCPP ternary complex, loop L2 becomes rigid on the fast timescale and loop L3 becomes more ordered which are supported by a large entropic penalty associated with San1 binding as revealed by ITC. Backbone assignments and chemical shift perturbations implicate the sulphur in San1 as a likely important loop L2/L3 stabilizing mediato

Does pre-existing cognitive impairment impact on amount of stroke rehabilitation received? An observational cohort study

© The Author(s) 2019. Objective: To examine whether stroke survivors in inpatient rehabilitation with pre-existing cognitive impairment receive less therapy than those without. Design: Prospective observational cohort. Setting: Four UK inpatient stroke rehabilitation units. Participants: A total of 139 stroke patients receiving rehabilitation, able to give informed consent/had an individual available to act as personal consultee. In total, 33 participants were categorized with pre-existing cognitive impairment based on routine documentation by clinicians and 106 without. Measures: Number of inpatient therapy sessions received during the first eight weeks post-stroke, referral to early supported discharge, and length of stay. Results: On average, participants with pre-existing cognitive impairment received 40 total physiotherapy and occupational therapy sessions compared to 56 for those without (mean difference = 16.0, 95% confidence interval (CI) = 2.9, 29.2), which was not fully explained by adjusting for potential confounders (age, sex, National Institutes of Health Stroke Scale (NIHSS), and pre-stroke modified Rankin Scale (mRS)). While those with pre-existing cognitive impairment received nine fewer single-discipline physiotherapy sessions (95% CI = 3.7, 14.8), they received similar amounts of single-discipline occupational therapy, psychology, and speech and language therapy; two more non-patient-facing occupational therapy sessions (95% CI = –4.3, –0.6); and nine fewer patient-facing occupational therapy sessions (95% CI = 3.5, 14.9). There was no evidence to suggest they were discharged earlier, but of the 85 participants discharged within eight weeks, 8 (42%) with pre-existing cognitive impairment were referred to early supported discharge compared to 47 (75%) without. Conclusion: People in stroke rehabilitation with pre-existing cognitive impairments receive less therapy than those without, but it remains unknown whether this affects outcomes

An ultracold molecular beam for testing fundamental physics

We use two-dimensional transverse laser cooling to produce an ultracold beam of YbF molecules. Through experiments and numerical simulations, we study how the cooling is influenced by the polarization configuration, laser intensity, laser detuning and applied magnetic field. The ultracold part of the beam contains more than $2 \times 10^5$ molecules per shot and has a temperature below 200 $\mu$K, and the cooling yields a 300-fold increase in the brightness of the beam. The method can improve the precision of experiments that use molecules to test fundamental physics. In particular, the beam is suitable for measuring the electron electric dipole moment with a statistical precision better than $10^{-30}$ e cm.Comment: 25 pages, 14 figures. Trajectory simulations added and results compared to experiment; other minor revision

Defining simple and comprehensive assessment units for CO2 storage in saline formations beneath the UK North Sea and continental shelf

In the UK, by far the largest CO2 storage opportunities lie offshore. The North Sea in particular has a long and complex geological history, with potential reservoirs geographically widespread and occurring at multiple stratigraphic levels. Diverse storage estimates have been made, using a range of working methods, and yielding different values, e.g. SCCS (2009); Bentham (2006). Consequently the UK Storage Appraisal Project (UKSAP), commissioned and funded by the Energy Technologies Institute (ETI), is undertaking the most comprehensive assessment to date, using abundant legacy seismic and borehole data. This study has a remit to use best current practice, consistent between locations, to calculate the CO2 storage capacity of the entire UK Continental Shelf (UKCS) within saline aquifers and hydrocarbon fields. The potential storage formations have been subdivided into units for assessment, and filtered to remove units with only a small estimated storage capacity to concentrate resources on more viable units. The size of potential storage units approximate to a power law distribution, similar to that of hydrocarbon fields, with a large number of small units and a small number of large units

Geologically constrained evolutionary geomechanical modelling of diapir and basin evolution: a case study from the Tarfaya basin, West African coast

We systematically incorporate burial history, sea floor geometry and tectonic loads from a sequential kinematic restoration model into a 2D evolutionary geomechanical model that simulates the formation of the Sandia salt diapir, Tarfaya basin, NW African Coast. We use a poro-elastoplastic description for the sediment behaviour and a viscoplastic description for the salt. Sedimentation is coupled with salt flow and regional shortening to determine the sediment porosity and strength and to capture the interaction between salt and sediments. We find that temporal and spatial variation in sedimentation rate is a key control on the kinematic evolution of the salt system. Incorporation of sedimentation rates from the kinematic restoration at a location east of Sandia leads to a final geomechanical model geometry very similar to that observed in seismic reflection data. We also find that changes in the variation of shortening rates can significantly affect the present-day stress state above salt. Overall, incorporating kinematic restoration data into evolutionary models provides insights into the key parameters that control the evolution of geologic systems. Furthermore, it enables more realistic evolutionary geomechanical models, which, in turn, provide insights into sediment stress and porosity

Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B

CD8+ T cells are essential for host defense to intracellular bacterial pathogens such as Mycobacterium tuberculosis (Mtb), Salmonella species, and Listeria monocytogenes, yet the repertoire and dominance pattern of human CD8 antigens for these pathogens remains poorly characterized. Tuberculosis (TB), the disease caused by Mtb infection, remains one of the leading causes of infectious morbidity and mortality worldwide and is the most frequent opportunistic infection in individuals with HIV/AIDS. Therefore, we undertook this study to define immunodominant CD8 Mtb antigens. First, using IFN-γ ELISPOT and synthetic peptide arrays as a source of antigen, we measured ex vivo frequencies of CD8+ T cells recognizing known immunodominant CD4+ T cell antigens in persons with latent tuberculosis infection. In addition, limiting dilution was used to generate panels of Mtb-specific T cell clones. Using the peptide arrays, we identified the antigenic specificity of the majority of T cell clones, defining several new epitopes. In all cases, peptide representing the minimal epitope bound to the major histocompatibility complex (MHC)-restricting allele with high affinity, and in all but one case the restricting allele was an HLA-B allele. Furthermore, individuals from whom the T cell clone was isolated harbored high ex vivo frequency CD8+ T cell responses specific for the epitope, and in individuals tested, the epitope represented the single immunodominant response within the CD8 antigen. We conclude that Mtb-specific CD8+ T cells are found in high frequency in infected individuals and are restricted predominantly by HLA-B alleles, and that synthetic peptide arrays can be used to define epitope specificities without prior bias as to MHC binding affinity. These findings provide an improved understanding of immunodominance in humans and may contribute to a development of an effective TB vaccine and improved immunodiagnostics