Engineering Solutions To The Characterisation Of Clinical Disorders Of Upper Eyelid Movement

This project is about improving functioning in patients with ptosis associated with poor levator palpebrae superioris (LPS) function. LPS is a highly specialised muscle responsible for raising the eyelid. Defective LPS may cause the eyelid to droop uncontrollably, thereby covering the visual axis and affecting vision. The current method of correction relies heavily on the experience of the surgeon. Rarely, the implanted materials are at risk of exposure, infection, rejection. More commonly, the ability to completely shut the eyelids is impaired, leading to the danger of corneal exposure that can lead to severe pain and sight-threatening complications. Many patients will require repeat surgeries for correction in the future. One reason for such mechanical failure includes the lack of understanding of the mechanical characteristics of the muscle involved in blinking, and the current surgical suspension material used in replacing it. This lack of a scientific basis means that ptosis is a major challenge in ophthalmic surgery. The aim of this work will include analysing and characterising LPS and blinking dynamics, in the hope of improving future clinical procedures and perhaps provide insights on surgical materials. Two separate approaches are running in parallel to investigate blinking dynamics: to define the mechanical characteristics and properties of the muscles involved in blinking, a new apparatus was designed and constructed to measure the force in eyelid closure, particularly the maximum force of contraction and natural force of closure. On another aspect, a high-speed camera was used at Moorfields Eye Hospital to record and analyse blinking in 32 patients with ptosis, thyroid eye disease and Blepharospasm. The collected and analysed data are used to investigate how eye blinking dynamics in diseased patients are different from healthy individuals and to attempt to separate them from controls using a modelling system. In addition, the blinking dynamics of dermatochalasis patients before and after blepharoplasty surgery were also compared with healthy individuals using high-speed camera and later advanced statistical analysis

Analysis of blink dynamics in patients with blepharoptosis

Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy

Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of antithrombotic therapy in preventing cognitive decline in people with small vessel disease on neuroimaging but without dementia

Simulating biosignatures from pre-oxygen photosynthesising life on TRAPPIST-1e

This is the author accepted manuscript. The final version is available on open access from Oxford University Press via the DOI in this recordData availability: The model output used for this study will be made available following this work’s acceptance for publicationIn order to assess observational evidence for potential atmospheric biosignatures on exoplanets, it will be essential to test whether spectral fingerprints from multiple gases can be explained by abiotic or biotic-only processes. Here, we develop and apply a coupled 1D atmosphere-ocean-ecosystem model to understand how primitive biospheres, which exploit abiotic sources of H2 , CO and O2 , could influence the atmospheric composition of rocky terrestrial exoplanets. We apply this to the Earth at 3.8 Ga and to TRAPPIST-1e. We focus on metabolisms that evolved before the evolution of oxygenic photosynthesis, which consume H2 and CO and produce potentially detectable levels of CH4 . O2 -consuming metabolisms are also considered for TRAPPIST-1e, as abiotic O2 production is predicted on M-dwarf orbiting planets. We show that these biospheres can lead to high levels of surface O2 (approximately 1–5 %) as a result of CO consumption, which could allow high O2 scenarios, by removing the main loss mechanisms of atomic oxygen. Increasing stratospheric temperatures, which increases atmospheric OH can reduce the likelihood of such a state forming. O2 -consuming metabolisms could also lower O2 levels to around 10 ppm and support a productive biosphere at low reductant inputs. Using predicted transmission spectral features from CH4 , CO, O2 /O3 and CO2 across the hypothesis space for tectonic reductant input, we show that biotically-produced CH4 may only be detectable at high reductant inputs. CO is also likely to be a dominant feature in transmission spectra for planets orbiting M-dwarfs, which could reduce the confidence in any potential biosignature observations linked to these biospheres.Science and Technology Facilities Council (STFC)UK Research and InnovationJohn Templeton FoundationLeverhulme TrustHill Family ScholarshipInstitute of Physic

Calcium signals can freely cross the nuclear envelope in hippocampal neurons: somatic calcium increases generate nuclear calcium transients

<p>Abstract</p> <p>Background</p> <p>In hippocampal neurons, nuclear calcium signaling is important for learning- and neuronal survival-associated gene expression. However, it is unknown whether calcium signals generated by neuronal activity at the cell membrane and propagated to the soma can unrestrictedly cross the nuclear envelope to invade the nucleus. The nuclear envelope, which allows ion transit via the nuclear pore complex, may represent a barrier for calcium and has been suggested to insulate the nucleus from activity-induced cytoplasmic calcium transients in some cell types.</p> <p>Results</p> <p>Using laser-assisted uncaging of caged calcium compounds in defined sub-cellular domains, we show here that the nuclear compartment border does not represent a barrier for calcium signals in hippocampal neurons. Although passive diffusion of molecules between the cytosol and the nucleoplasm may be modulated through changes in conformational state of the nuclear pore complex, we found no evidence for a gating mechanism for calcium movement across the nuclear border.</p> <p>Conclusion</p> <p>Thus, the nuclear envelope does not spatially restrict calcium transients to the somatic cytosol but allows calcium signals to freely enter the cell nucleus to trigger genomic events.</p

Truth after post-truth: for a Strong Programme in Discourse Studies

Contemporary post-truth discourses put the constructivist foundations of Discourse Studies to a test. According to critical observers, discourse analysts have been playing into the hands of Trump, Brexit and right-wing populists by politicising scientific knowledge and undermining the idea of scientific truth. In order to respond to these concerns, this article outlines a Strong Programme in Discourse Studies. While the Strong Programme insists on truths as discursive constructions, in no way does it claim that all ideas have the same truth value or that an idea can become true because somebody wants it to be true. The Strong Programme makes the case for discourse research that is constructivist (it asks how truths are constructed practically) without being relativist (all ideas do not have the same normative quality). Taking inspiration from debates in Science and Technology Studies of the 1970s, the Strong Programme formulates principles for discourse researchers dealing with conflicting truth claims. Discourse analytical explanations of truths of first-order participants and of second-order observers should be symmetrical, heterogeneous, multi-perspectival and reflexive. The Strong Programme discourse research is grounded in the founding traditions of ?French? and ?Critical? Discourse Studies, which have struggled over questions of truth and reality since the beginning. While critically interrogating the structuralist heritage of these strands, the Strong Programme insists on the practices of making and unmaking ideas through language use no matter whether they appear as true or false to participants and observers. Discourse Studies are encouraged to critically reflect on how hierarchies between knowledges are not only represented but, through their representation, also constituted through discursive practices

Focus on the management of thunderclap headache: from nosography to treatment

Thunderclap headache (TCH) is an excruciating headache characterized by a very sudden onset. Recognition and accurate diagnosis of TCH are important in order to rule out the various, serious underlying brain disorders that, in a high percentage of cases, are the real cause of the headache. Primary TCH, which may recur intermittently and generally has a spontaneous, benign evolution, can thus be diagnosed only when all other potential underlying causes have been excluded through accurate diagnostic work up. In this review, we focus on the management of TCH, paying particular attention to the diagnostic work up and treatment of the condition

Polymorphisms of the TUB Gene Are Associated with Body Composition and Eating Behavior in Middle-Aged Women

BACKGROUND: The TUB gene, encoding an evolutionary conserved protein, is highly expressed in the hypothalamus and might act as a transcription factor. Mutations in TUB cause late-onset obesity, insulin-resistance and neurosensory deficits in mice. An association of common variants in the TUB gene with body weight in humans has been reported. METHODS/FINDINGS: The aim was to investigate the relationship of single nucleotide polymorphisms (SNPs) of the TUB gene (rs2272382, rs2272383 and rs1528133) with both anthropometry and self-reported macronutrient intake from a validated food frequency questionnaire. These associations were studied in a population-based, cross-sectional study of 1680 middle-aged Dutch women, using linear regression analysis. The minor allele C of the rs1528133 SNP was significantly associated with increased weight (+1.88 kg, P = 0.022) and BMI (+0.56 units, P = 0.05). Compared with non-carriers, both AG heterozygotes and AA homozygotes of the rs2272382 SNP derived less energy from fat (AG: -0.55+/-0.28%, P = 0.05, AA: -0.95+/-0.48%, P = 0.047). However, both genotypes were associated with an increased energy intake from carbohydrates (0.69+/-0.33%, P = 0.04 and 1.68+/-0.56%, P = 0.003, respectively), mainly because of a higher consumption of mono- and disaccharides. Both these SNPs, rs2272382 and rs1528133, were also associated with a higher glycemic load in the diet. The glycemic load was higher among those with AG and AA genotypes for the variant rs2272382 than among the wild types (+1.49 (95% CI: -0.27-3.24) and +3.89 (95% CI: 0.94-6.85) units, respectively). Carriers of the minor allele C of rs1528133 were associated with an increased glycemic load of 1.85 units compared with non-carriers. CONCLUSIONS: Genetic variation of the TUB gene was associated with both body composition and macronutrient intake, suggesting that TUB might influence eating behavior

p73: A Multifunctional Protein in Neurobiology

p73, a transcription factor of the p53 family, plays a key role in many biological processes including neuronal development. Indeed, mice deficient for both TAp73 and ΔNp73 isoforms display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus. TAp73 expression increases in parallel with neuronal differentiation and its ectopic expression induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines and neural stem cells, suggesting that it has a pro-differentiation role. In contrast, ΔNp73 shows a survival function in mature cortical neurons as selective ΔNp73 null mice have reduced cortical thickness. Recent evidence has also suggested that p73 isoforms are deregulated in neurodegenerative pathologies such as Alzheimer’s disease, with abnormal tau phosphorylation. Thus, in addition to its increasingly accepted contribution to tumorigenesis, the p73 subfamily also plays a role in neuronal development and neurodegeneration

Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10−27and−30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research