Isoperimetric problems in the variational calculus of Euler and Lagrange

AbstractHistorians have documented the main development of the calculus of variations in the 18th century. Although we have a clear overall picture of this subject there is in the literature no connected historical account of the more specialized research carried out during the period on problems of extremization under constraint. Concentrating on the work of Leonhard Euler and Joseph Louis Lagrange between 1738 and 1806, the present study attempts to identify and draw together the different threads that make up this story

Plio-Pleistocene Stratigraphy and Tectonic Evolution of the Northern Ohara Depression-Wakarara Range, North Island, New Zealand

Development of the Ohara Depression and uplift of the Ruahine and Wakarara Ranges followed an increase of the convergence rate between the Pacific and Australian plates. The Ohara Depression is a trough of Plio-Pleistocene sediments that crops out between the Ruahine and Wakarara Ranges. Two episodes of uplift during the late Pliocene and Pleistocene are recorded in the geologic record. Initial uplift occurred in the late Pliocene followed by subsidence through the early Pleistocene. The greatest uplift occurred during the mid-Pleistocene, and is recorded by deposition of a 200-250 m-thick conglomerate unit. Although compressional structures are present within and to the east of the Ohara Depression, there is a partitioning of strain between the eastern front of the Wakarara Range and the Ohara Depression. Coast-perpendicular shortening dominates along the eastern Wakarara Range front and translation accompanied by coast-parallel shortening occurs within the Ohara Depression and along the Ruahine and Mohaka faults. Within the northern Ohara Depression, the Big Hill fault transfers motion from the Ruahine fault to the Mohaka fault. The Mohaka fault serves as a boundary between the two strain domains, shielding the part of the Ohara Depression west of the Wakarara Range from contraction

Design and development of novel mTOR and SRC family kinase inhibitors via a phenotypic drug discovery approach

Traditionally, drug discovery programs have focused on prioritising compounds by their affinity to a specific target in isolation, which was hypothesised to be the cause of a particular disease. Through chemical inhibition, the disease could, thus, be prevented or at the very least, controlled. These hypotheses require significant validation before drug screening can begin which relates to lengthy and expensive programs. Furthermore, drug screening against a single target in isolation is not a realistic model of cellular behaviour and is not appropriately tailored to more complex diseases such as cancer. Phenotypic drug discovery, on the other hand, bypasses any involvement of known targets, instead focusing on the desired outcome – the phenotype. In this way, drugs are biased by their potency on the phenotype and not against any particular targets. The molecular mechanism of action need not be known at all, however, it can be useful to later reveal the target(s) involved by various deconvolution methods. This thesis describes a cooperative ligand based phenotypic drug discovery approach, undertaken in order to develop more suitable small molecule drugs for cancer treatment. For this purpose, the promiscuous pyrazolopyrimidine inhibitor PP1 was chosen as a starting model compound. Modification of PP1 on the N1 position allowed a series of water solubilising groups to be incorporated into the pyrazolopyrimidine scaffold which created an initial 12-membered library. Testing against MCF7 breast cancer cells and looking at phenotypic end points such as cell proliferation, cell mobility and cell cycle, generated early target-agnostic structure/anti-proliferative activity relationships. These early results, along with compounds published in recent literature, were used to generate further libraries. Profiling lead compounds against a selection of 18 kinases known to be targeted by PP1, showed the compounds were inhibiting either SRC family or mTOR kinases which enabled the creation of two, structure specific, groups of inhibitors. Further lead optimisation led to the rapid discovery of preclinical candidates with excellent drug-like properties and potencies in both cellular assays and against their respective targets. Compounds also showed improved selectivity profiles compared to PP1 and commonly known inhibitors of SRC and mTOR kinases. Reported, herein, is the discovery of the first sub-nanomolar SRC inhibitor which does not inhibit the kinase ABL and shows excellent properties suitable for further preclinical development

Automatic Stroke Lesion Segmentation With Limited Modalities

MRI Brain image segmentation is a valuable tool in the diagnosis and treatment of many different types of brain damage. There is a strong push for development of computerized segmentation algorithms that can automate this process because segmentation by hand requires a great deal of effort by a highly skilled professional. While hand segmentation is currently considered the gold standard, it is not without flaws; for example, segmentation by two different people can provide slightly different results, and segmentation by hand is labor intensive. Due to these flaws, It is desirable to make this process more consistent and more efficient through computer automation. This project investigates four promising approaches for the automatic segmentation of brain MRIs containing stroke lesions found in recent literature. Two of these algorithms are designed to use multiple modalities of the same patient during segmentation, while the other two are designed to handle one specific modality. The robustness of each to limited, or different, image sequences than they were originally designed for will be tested by applying each to two datasets that contain 24 and 36 patients with chronic stroke lesions. These tests concluded that performance for the multi modal algorithms does tend to decrease as input modalities are removed, however it also revealed that FLAIR imaging in particular seems to be especially valuable for segmenting stroke lesions. In both multi-modal algorithms while there was an overall drop in Dice scores, any testing that included FLAIR images performed significantly better than any other tests. The single channel algorithms had difficulty segmenting any modalities different from the specific one that they were designed for, and were generally unable to detect very small lesions

Relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localised prostate cancer : a systematic review and mixed treatment comparison meta-analysis

© 2013 The Authors. BJU International © 2013 BJU International.Peer reviewedPublisher PD

Interactions Between Marine Benthic Invertebrates and Sediments in Intertidal and Deep Sea Environments

Section I investigated the potential use of Mytilus edulis as an environmentally friendly method of protecting intertidal soft sedimentary coastal zones. The section comprises of four main experiments and one set of joint experiments conducted with BSc Honours students. Experiment 1 was a preliminary study of the attachment of Mytilus edulis on to sand (particle size < 500mum), gravel (particle size range between 4mm and 8mm) and a 1:1 mix of sand and gravel. The results showed that in general mussels on gravel produce more threads than mussels on bare sand. This also means that potentially mussels on sand with underlying gravel will be less likely to be washed away by currents as they will attach to underlying gravel thus anchoring themselves. Experiment 2 developed the findings of experiment 1. The experiment involved allowing Mytilus edulis to form clumps on gravel and sand substrates in the laboratory, along with mussels stored in buckets as an un-clumped condition. The mussels from the laboratory were then transported to an intertidal bay, Ardmore Bay in the Clyde Estuary. The results showed that fewer mussels were lost from gravel substrates on the shore than from sand substrates. The effectiveness of using Mytilus edulis as a way of protecting intertidal soft sedimentary coastal zones can be determined by the numbers of mussels remaining on top of the sediment. The more mussels covering the sediment surface will mean that less of the sediment's surface is exposed to currents that would cause erosion. The results would indicate that some kind of artificial substrate is required to allow mussels to remain in situ on a sandy intertidal coastal zone. Experiment 3 was designed to investigate a novel artificial substrate to allow mussels to be introduced to intertidal soft sedimentary environments. The chosen substrate was plastic mesh with fibres measuring 1mm and 2mm and a square aperture measuring 14mm x 14mm. The experiment was conducted in the laboratory to measure the attachment force of the mussels' byssus threads. The results showed that there was no difference in the attachment strength of mussels on to plastic netting or on to other mussels' shells. This suggests that the attachment onto plastic netting would be as secure as the attachments made in the large mussel beds present along most coastlines in the intertidal zone. So this type of substrate could potentially be used to introduce mussels onto intertidal soft sedimentary environments in an attempt physically to reduce erosion. Experiment 4 developed the research of experiment 3. The plastic mesh was used in place of the gravel used in experiment 2. The results were similar to those found in experiment 2. Mussels that had been exposed to the plastic mesh substrate prior to being laid on to the field sand were less likely to be washed away by currents. The result shows that the method and the substrate used in this experiment have a potential to be developed into a large-scale method of environmentally friendly method of protecting intertidal soft sedimentary environments. The set of joint field experiments simply develops the work conducted in experiments 1 to 4 and investigates aspects not covered in experiments 1 to 4. Experimental set 1 investigated the attachments on and around isolated boulders within a 30m x 10m transect line at both the upper and lower intertidal on Ardmore Bay. There were three experiments conducted within this set. The experiments showed that in general there were more mussels lost from the lower intertidal site than the upper intertidal site. This highlights the need for a suitable substrate to allow mussels to withstand higher energy environments. Experimental set 2 investigated the behaviour of mussels laid on to sand substrate on the shore. The mussels were laid with no space between mussels, 1cm gap between mussels and pre-clumped. The results of the three experiments in the set showed differences to those of experiment 2 and 3. The results showed that mussels that had been allowed to form clumps in the laboratory lost fewer mussels than those simply placed on to the sand on the shore. Again, this serves to re-emphasise the need for a suitable artificial substrate to allow mussels to remain in high-energy environments. Section II investigates the affects of an Oxygen minimum zone present off the coast of Oman in the Arabian Sea. The study focuses on the biological mixing, geochemistry and geotechnical properties of the sediments of the area. The parameters measured were Eh, pH, shear strength, biological mixing, water content, carbonate and total organic matter of the sediment samples. Sediment samples from box cores taken at sites both within and below the OMZ were compared. The samples from within the OMZ showed low redox conditions and high carbonate. The geotechnical properties and biological mixing structures within the OMZ also differed to those outside the OMZ. The differences were related to the level of anoxic conditions and water depth

Faecal haemoglobin and faecal calprotectin as indicators of bowel disease in patients presenting to primary care with bowel symptoms

OBJECTIVE: In primary care, assessing which patients with bowel symptoms harbour significant disease (cancer, higher-risk adenoma or IBD) is difficult. We studied the diagnostic accuracies of faecal haemoglobin (FHb) and faecal calprotectin (FC) in a cohort of symptomatic patients. DESIGN: From October 2013 to March 2014, general practitioners were prompted to request FHb and FC when referring patients with bowel symptoms to secondary care. Faecal samples were analysed for haemoglobin (EIKEN OC-Sensor io) and calprotectin (BÜHLMANN Calprotectin ELISA). Patients triaged to endoscopy were investigated within 6 weeks. All clinicians and endoscopists were blind to the faecal test results. The diagnostic accuracies of FHb and FC for identification of significant bowel disease were assessed. RESULTS: 1043 patients returned samples. FHb was detectable in 57.6% (median 0.4 µg/g, 95% CI 0.4 to 0.8; range 0–200). FC at 50 µg/g or above was present in 60.0%. 755 patients (54.6% women, median age 64 years (range 16–90, IQR 52–73)) returned samples and completed colonic investigations. 103 patients had significant bowel disease; the negative predictive values of FHb for colorectal cancer, higher-risk adenoma and IBD were 100%, 97.8% and 98.4%, respectively. Using cut-offs of detectable FHb and/or 200 µg/g FC detected two further cases of IBD, one higher-risk adenoma and no additional cancers. CONCLUSIONS: In primary care, undetectable FHb is a good ‘rule-out’ test for significant bowel disease and could guide who requires investigation

Effect of carbohydrate feeding on the bone metabolic response to running

Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO·kg body mass-1·h-1) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (VO2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P=0.028; P1NP: P=0.021; IL-6: P=0.036), although there was no difference in the short-term response (β-CTX: P=0.856; P1NP: P=0.721; IL-6: P=0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover

Just find it: The Mymo approach to recommend running shoes

Wearing inappropriate running shoes may lead to unnecessary injury through continued strain upon the lower extremities; potentially damaging a runner’s performance. Many technologies have been developed for accurate shoe recommendation, which centre on running gait analysis. However, these often require supervised use in the laboratory/shop or exhibit too high a cost for personal use. This work addresses the need for a deployable, inexpensive product with the ability to accurately assess running shoe-type recommendation. This was achieved through quantitative analysis of the running gait from 203 individuals through use of a tri-axial accelerometer and tri-axial gyroscope-based wearable (Mymo). In combination with a custom neural network to provide the shoe-type classifications running within the cloud, we experience an accuracy of 94.6 in classifying the correct type of shoe across unseen test data