A physically meaningful method for the comparison of potential energy functions

In the study of the conformational behavior of complex systems, such as proteins, several related statistical measures are commonly used to compare two different potential energy functions. Among them, the Pearson's correlation coefficient r has no units and allows only semi-quantitative statements to be made. Those that do have units of energy and whose value may be compared to a physically relevant scale, such as the root mean square deviation (RMSD), the mean error of the energies (ER), the standard deviation of the error (SDER) or the mean absolute error (AER), overestimate the distance between potentials. Moreover, their precise statistical meaning is far from clear. In this article, a new measure of the distance between potential energy functions is defined which overcomes the aforementioned difficulties. In addition, its precise physical meaning is discussed, the important issue of its additivity is investigated and some possible applications are proposed. Finally, two of these applications are illustrated with practical examples: the study of the van der Waals energy, as implemented in CHARMM, in the Trp-Cage protein (PDB code 1L2Y) and the comparison of different levels of the theory in the ab initio study of the Ramachandran map of the model peptide HCO-L-Ala-NH2.Comment: 30 pages, 7 figures, LaTeX, BibTeX. v2: A misspelling in the author's name has been corrected. v3: A new application of the method has been added at the end of section 9 and minor modifications have also been made in other sections. v4: Journal reference and minor corrections adde

Traumatic posterior urethral fistula to hip joint following gunshot injury: a case report

<p>Abstract</p> <p>Introduction</p> <p>Urinary system fistula to the hip joint is a rare complication. We report a case of delayed posterior urethral fistula to the hip joint following penetrating gunshot wound injury.</p> <p>Case presentation</p> <p>A 37-year-old Iranian Balochi male was shot with a firearm in the superior part of his right pelvis. He underwent primary closure on the same day. Ten months later, he developed urinary retention. He underwent retrograde urethrography and antegrade cystography which showed a stricture measuring 5 cm in length. There was also a history of progressive pain in the right hip joint accompanied by low grade fever which started 2 months after the initial injury. Hip X-ray showed evidence of an acetabular cavity and femoral head destruction diagnostic of complicated septic arthritis. The patient subsequently underwent reconstructive surgery for the urethral stricture and urethral fistula via a transperineal approach followed by total hip arthroplasty.</p> <p>Conclusion</p> <p>Hip joint contamination with urine following a urethro-acetabular fistula can lead to severe and disabling complications such as septic arthritis. We recommend that every clinician should keep these fistulas in mind as a complication of penetrating urethral injury and every attempt should be made for their early diagnosis and prompt treatment.</p

Lamb Wave Propagation in Thermally Damaged Composites

The use of composites in primary and secondary structures of aerospace vehicles is important for increased performance with little weight penalty. Determining the response to thermal damage is necessary for a complete understanding of the total use environment of these materials. The objective of the research presented here is to provide a method of quantifying the amount of thermal damage in composite materials. Components which have non-visible damage, but have degraded performance on the order of several percent, are of interest. At this level of damage the safety margin designed into the structure may be compromised

Supporting perinatal anxiety in the digital age; a qualitative exploration of stressors and support strategies

Background The period surrounding childbirth is one of profound change, which can often be experienced as stressful and overwhelming. Indeed, around 20% of women may experience significant levels of anxiety in the perinatal period. However, most women experiencing perinatal anxiety (PNA) go unrecognised and untreated. The Internet offers a potentially scalable solution to improve access to support, however a dearth of research in this area means that work is needed to better understand women’s experience of PNA, so that potential targets for intervention can be identified and possible barriers to support overcome. This study aimed to qualitatively explore women’s experience of anxiety triggers and support in the perinatal period; and gain insight into what online support is acceptable for women with PNA. Methods Women who were either pregnant or within one-year postpartum were invited to participate in focus groups across the UK. Focus groups were used to allow a diversity of perspectives to be heard, while simultaneously promoting the identification and prioritisation of important support needs and solutions. Interviews were transcribed and thematically analysed. Results Five key themes emerged in relation to women’s experience with PNA: holding unrealistic expectations of birth and motherhood; stigma; the importance of peer support; uncertainty and poor maternal confidence; and a lack of mental health support and knowledge. Perinatal women felt under-supported and poorly prepared for motherhood. A mismatch between their expectations and the reality of their experience, alongside a pressure to be the ‘perfect mum’ was the primary source of their anxiety. Furthermore, stigma associated with PNA may have exacerbated these issues and led to help-seeking avoidance. Overall, women felt these issues could be addressed via online support, through the delivery of more realistic information, providing psychoeducation about PNA symptoms and management, and the inclusion of authentic peer experiences. Thus, delivering evidence-based information and interventions online may provide a solution that is acceptable to this cohort. Conclusions This work provides unique insight into potential sources of anxiety for women in the perinatal period, while also offering potential internet-based support solutions that are likely to be acceptable and helpful for women with PNA

So Small, So Loud: Extremely High Sound Pressure Level from a Pygmy Aquatic Insect (Corixidae, Micronectinae)

To communicate at long range, animals have to produce intense but intelligible signals. This task might be difficult to achieve due to mechanical constraints, in particular relating to body size. Whilst the acoustic behaviour of large marine and terrestrial animals has been thoroughly studied, very little is known about the sound produced by small arthropods living in freshwater habitats. Here we analyse for the first time the calling song produced by the male of a small insect, the water boatman Micronecta scholtzi. The song is made of three distinct parts differing in their temporal and amplitude parameters, but not in their frequency content. Sound is produced at 78.9 (63.6–82.2) SPL rms re 2.10−5 Pa with a peak at 99.2 (85.7–104.6) SPL re 2.10−5 Pa estimated at a distance of one metre. This energy output is significant considering the small size of the insect. When scaled to body length and compared to 227 other acoustic species, the acoustic energy produced by M. scholtzi appears as an extreme value, outperforming marine and terrestrial mammal vocalisations. Such an extreme display may be interpreted as an exaggerated secondary sexual trait resulting from a runaway sexual selection without predation pressure

Efficacy and complications of neurosurgical treatment of acromegaly

The aim of the study was to evaluate the frequency of occurrence of pituitary failure following neurosurgery and the efficacy of transsphenoidal tumour resection in acromegalic patients. We retrospectively evaluated 85 patients (60 female and 25 male), of mean age 43.9 ± 13.2 years, treated by transsphenoidal neurosurgery. Macroadenoma and microadenoma of pituitary were found in 66 (77.6%) and 19 (22.4%) of these patients, respectively. Criteria of cure following neurosurgery were: basal GH < 2.5 μg/l, GH at 120 min in OGTT < 1.0 μg/l and serum concentration of IGF-1 within normal ranges for age and sex. After surgery 32 patients (37.6%) were cured and 53 patients (62.4%) required somatostatin analogue treatment. In patients cured by surgery, lower levels of basal GH (P < 0.05), IGF-1 (P < 0.001), GH at 120 min in OGTT and smaller size of pituitary tumour (P < 0.05) were found at diagnosis, as compared to patients in whom surgery was unsuccessful. Significant correlation between basal serum level of GH at diagnosis and size of pituitary tumour was found (P < 0.001). Invasive tumours were found in 45 of 53 (84.9%) patients not cured and in only 8 of 32 (25.0%) patients cured (P < 0.001). Impaired function of pituitary anterior lobe after surgery was observed in 30% and 4% of patients with macro- and microadenoma, respectively (P < 0.05). The efficacy of neurosurgery is affected by concentration of basal serum GH and IGF-1, GH at 120 min in OGTT, tumour size and invasiveness. Hypopituitarism after surgery is more frequent in patients with macroadenoma. Pituitary insufficiency, as a consequence of surgery, was found in 21% of patients with normal pituitary function prior to operation

Effects of Perfluorocarbons on surfactant exocytosis and membrane properties in isolated alveolar type II cells

<p>Abstract</p> <p>Background</p> <p>Perfluorocarbons (PFC) are used to improve gas exchange in diseased lungs. PFC have been shown to affect various cell types. Thus, effects on alveolar type II (ATII) cells and surfactant metabolism can be expected, data, however, are controversial.</p> <p>Objective</p> <p>The study was performed to test two hypotheses: (I) the effects of PFC on surfactant exocytosis depend on their respective vapor pressures; (II) different pathways of surfactant exocytosis are affected differently by PFC.</p> <p>Methods</p> <p>Isolated ATII cells were exposed to two PFC with different vapor pressures and spontaneous surfactant exocytosis was measured. Furthermore, surfactant exocytosis was stimulated by either ATP, PMA or Ionomycin. The effects of PFC on cell morphology, cellular viability, endocytosis, membrane permeability and fluidity were determined.</p> <p>Results</p> <p>The spontaneous exocytosis was reduced by PFC, however, the ATP and PMA stimulated exocytosis was slightly increased by PFC with high vapor pressure. In contrast, Ionomycin-induced exocytosis was decreased by PFC with low vapor pressure. Cellular uptake of FM 1-43 - a marker of membrane integrity - was increased. However, membrane fluidity, endocytosis and viability were not affected by PFC incubation.</p> <p>Conclusions</p> <p>We conclude that PFC effects can be explained by modest, unspecific interactions with the plasma membrane rather than by specific interactions with intracellular targets.</p

Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of α1-Antitrypsin: implications for disease and drug design

The common Z mutant (Glu342Lys) of α1-antitrypsin results in the formation of polymers that are retained within hepatocytes. This causes liver disease whilst the plasma deficiency of an important proteinase inhibitor predisposes to emphysema. The Thr114Phe and Gly117Phe mutations border a surface cavity identified as a target for rational drug design. These mutations preserve inhibitory activity but reduce the polymerisation of wild-type native α1-antitrypsin in vitro and increase secretion in a Xenopus oocyte model of disease. To understand these effects, we have crystallised both mutants and solved their structures. The 2.2 Å structure of Thr114Phe α1-antitrypsin demonstrates that the effects of the mutation are mediated entirely by well-defined partial cavity blockade and allows in silico screening of fragments capable of mimicking the effects of the mutation. The Gly117Phe mutation operates differently, repacking aromatic side chains in the helix F–β-sheet A interface to induce a half-turn downward shift of the adjacent F helix. We have further characterised the effects of these two mutations in combination with the Z mutation in a eukaryotic cell model of disease. Both mutations increase the secretion of Z α1-antitrypsin in the native conformation, but the double mutants remain more polymerogenic than the wild-type (M) protein. Taken together, these data support different mechanisms by which the Thr114Phe and Gly117Phe mutations stabilise the native fold of α1-antitrypsin and increase secretion of monomeric protein in cell models of disease

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD