Conformational Choices for the Stereochemically Constrained gamma-Amino Acid Residue Gabapentin: Theoretical Studies and Correlation With Experimental Results

Gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn) is an achiral, conformationally constrained gamma amino acid residue. A survey of available crystal structures of Gpn peptides reveals that the torsion angles about the C-gamma-C-beta (theta(1)) and C-beta-C-alpha(theta(2)) bonds are overwhelmingly limited to gauche, gauche (g(+)g(+)/g(-)g(-)) conformations. The Gpn residue forms C-7 and C-9 hydrogen bonds in which the donor and acceptor atoms come from the flanking peptide units. In combination with alpha amino acid residues alpha gamma and gamma alpha segments can adopt C-12 hydrogen bonded structures. The conformational choices available to the Gpn residue have been probed using energy calculations, adopting a grid search strategy. Ramachandran phi-psi maps have been constructed for fixed values of theta(1) and theta(2), corresponding to the gauche and trans conformations. The sterically allowed and energetically favorable regions of conformational space have been defined and experimental observations compared. C-7 and C-9 hydrogen bonded conformational families have been identified using a grid search approach in which theta(1) and theta(2) values are varied over a range of +/- 10 degrees about ideal values at 1 degrees intervals. The theoretical analysis together with experimental observations for 59 Gpn residues from 35 crystal structures permits definition of the limited range of conformational possibilities at this gamma amino acid residue. .

Experimental studies of lipped channel beams subject to web crippling under two-flange load cases

Lipped channel beams (LCBs) are commonly used as flexural members such as floor joists and bearers in the construction 6 industry. These thin-walled LCBs are subjected to specific buckling and failure modes, one of them being web crippling. Despite considerable 7 research in this area, some recent studies have shown that the current web crippling design rules are unable to predict the test capacities under 8 end-two-flange (ETF) and interior-two-flange (ITF) load conditions. In many instances, web crippling predictions by the available design 9 standards such as AISI S100, AS/NZS 4600 and Eurocode 3 Part 1-3 are inconsistent, i.e., unconservative in some cases, although they 10 are conservative in other cases. Hence, experimental studies consisting of 36 tests were conducted in this research to assess the web crippling 11 behavior and capacities of high-strength LCBs under two-flange load cases (ETF and ITF). Experimental results were then compared with the 12 predictions from current design rules. Comparison of the ultimate web crippling capacities from tests showed that the design equations are 13 very unconservative for LCB sections under the ETF load case and are conservative for the ITF load case. Hence, improved equations were 14 proposed to determine the web crippling capacities of LCBs based on the experimental results from this study. Current design equations do 15 not provide the direct strength method (DSM) provisions for web crippling. Hence, suitable design rules were also developed under the DSM 16 format using the test results and buckling analyses using finite-element analyses.

Experimental studies on web crippling strength of hollow flange channels under EOF and IOF load cases

LiteSteel beam (LSB) is a hollow flange channel made from cold-formed steel using a patented manufacturing process involving simultaneous cold-forming and dual electric resistance welding. LSBs are currently used as floor joists and bearers in buildings. However, there are no appropriate design standards available due to its unique hollow flange geometry, residual stress characteristics and initial geometric imperfections arising from manufacturing processes. Recent research studies have focused on investigating the structural behaviour of LSBs under pure bending, predominant shear and combined actions. However, web crippling behaviour and strengths of LSBs still need to be examined. Therefore, an experimental study was undertaken to investigate the web crippling behaviour and strengths of LSBs under EOF (End One Flange) and IOF (Interior One Flange) load cases. A total of 23 web crippling tests were performed and the results were compared with the current AS/NZS 4600 and AISI S100 design standards, which showed that the cold-formed steel design rules predicted the web crippling capacity of LSB sections very conservatively under EOF and IOF load cases. Therefore, suitably improved design equations were proposed to determine the web crippling capacity of LSBs based on experimental results. In addition, new design equations were also developed under the Direct Strength Method format. This paper presents the details of this experimental study on the web crippling behaviour and strengths of LiteSteel beams under EOF and IOF load cases and the results.

Experimental and numerical studies of hollow flange channel beams subject to web crippling under ETF and ITF load cases

This paper presents the details of experimental and numerical studies on the web crippling behaviour of hollow flange channel beams, known as LiteSteel beams (LSB). The LSB has a unique shape of a channel beam with two rectangular hollow flanges, made using a unique manufacturing process. Experimental and numerical studies have been carried out to evaluate the behaviour and design of LSBs subject to pure bending actions, predominant shear actions and combined actions. To date, however, no investigation has been conducted into the web crippling behaviour and strength of LSB sections under ETF and ITF load conditions. Hence experimental studies consisting of 28 tests were first conducted in this research to assess the web crippling behaviour and strengths of LSBs under two flange load cases (ETF and ITF). Experimental web crippling capacity results were then compared with the predictions from AS/NZS 4600 and AISI S100 design rules, which showed that AS/NZS 4600 and AISI S100 design equations are very unconservative for LSBs under ETF and ITF load cases. Hence improved equations were proposed to determine the web crippling capacities of LSBs. Finite element models of the tested LSBs were then developed, and used to determine the elastic buckling loads of LSBs under ETF and ITF load cases. New equations were proposed to determine the corresponding elastic buckling coefficients of LSBs. Finally suitable design rules were also developed under the Direct Strength Method format using the test results and buckling analysis results from finite element analyses.

Experimental investigation of die wear in small-batch hammer-forging under unlubricated conditions

Wear of dies is a serious problem in the forging industry. The materials used for the dies are generally expensive steel alloys and the dies require costly heat treatment and surface finishing operations. Degeneration of the die profile implies rejection of forged components and necessitates resinking or replacement of the die. Measures which reduce wear of the die can therefore aid in the reduction of production costs. The work reported here is the first phase of a study of the causes of die wear in forging production where the batch size is small and the machine employed is a light hammer. This is a problem characteristic of the medium and small scale area of the forging industry where the cost of dies is a significant proportion of the total capital investment. For the same energy input and under unlubricated conditions, die wear has been found to be sensitive to forging temperature; in cold forging the yield strength of the die material is the prime factor governing the degeneration of the die profile, whilst in hot forging the wear resistance of the die material is the main factor which determines the rate of die wear. At an intermediate temperature, such as that characteristic of warm forging, the die wear is found to be less than that in both cold and hot forging. This preliminary study therefore points to the fact that the forging temperature must be taken into account in the selection of die material. Further, the forging industry must take serious note of the warm forging process, as it not only provides good surface finish, as claimed by many authors, but also has an inherent tendency to minimize die wear.

Which One Is Preferred: Myers-Saito Cyclization of Ene-Yne-Allene or Garratt-Braverman Cyclization of Conjugated Bisallenic Sulfone? A Theoretical and Experimental Study

A competitive scenario between Myers-Saito (MS) and Garraff-Braverman (GB) cyclization has been created in a molecule. High-level computations indicate a preference for GB over MS cyclization. The activation energies for the rate-determining steps of the GB and MS cyclizations were found to be the same (24.4 kcal/mol) at the B3LYP/6-31G* level of theory; thus, from the kinetic point of view, both reactions are feasible. However, the main biradical intermediate GB2 of the GB reaction is 6.2 kcal/mol lower in energy than the biradical MS2, which is the main intermediate of MS reaction, so GB cyclization is thermodynamically favored over MS cyclization. To verify the prediction by computational techniques, bisenediynyl sulfones 1-4 and bisenediynyl sulfoxide 17 were synthesized. Under basic conditions, these molecules isomerized to a system possessing both the ene-yne-allene and the bisallenic sulfone. The isolation of only one product, identified as the corresponding naphthalene- or benzene-fused sulfone 8-11, indicated the occurrence of GB cyclization as the sole reaction pathway. No product corresponding to the MS cyclization pathway could be isolated. Though the theoretical prediction showed a preference for the GB pathway over the MS pathway, the exclusive preference for GB over MS cyclization is very striking. Further analysis showed that the intramolecular self-quenching nature of the GB pathway may play an important role in the complete preference for this reaction. Apart from the mechanistic studies, these sulfones showed DNA cleavage activity that had an inverse relation with the reactivity order. Our findings are important for the design of artificial DNA-cleaving agents.

Positional cloning and pathway analysis of the asthma susceptibility gene, NPSR1

In the present study, we identified a novel asthma susceptibility gene, NPSR1 (neuropeptide S receptor 1) on chromosome 7p14.3 by the positional cloning strategy. An earlier significant linkage mapping result among Finnish Kainuu asthma families was confirmed in two independent cohorts: in asthma families from Quebec, Canada and in allergy families from North Karelia, Finland. The linkage region was narrowed down to a 133-kb segment by a hierarchial genotyping method. The observed 77-kb haplotype block showed 7 haplotypes and a similar risk and nonrisk pattern in all three populations studied. All seven haplotypes occur in all three populations at frequences > 2%. Significant elevated relative risks were detected for elevated total IgE (immunoglobulin E) or asthma. Risk effects of the gene variants varied from 1.4 to 2.5. NPSR1 belongs to the G protein-coupled receptor (GPCR) family with a topology of seven transmembrane domains. NPSR1 has 9 exons, with the two main transcripts, A and B, encoding proteins of 371 and 377 amino acids, respectively. We detected a low but ubiquitous expression level of NPSR1-B in various tissues and endogenous cell lines while NPSR1-A has a more restricted expression pattern. Both isoforms were expressed in the lung epithelium. We observed aberrant expression levels of NPSR1-B in smooth muscle in asthmatic bronchi as compared to healthy. In an experimental mouse model, the induced lung inflammation resulted in elevated Npsr1 levels. Furthermore, we demonstrated that the activation of NPSR1 with its endogenous agonist, neuropeptide S (NPS), resulted in a significant inhibition of the growth of NPSR1-A overexpressing stable cell lines (NPSR1-A cells). To determine which target genes were regulated by the NPS-NPSR1 pathway, NPSR1-A cells were stimulated with NPS, and differentially expressed genes were identified using the Affymetrix HGU133Plus2 GeneChip. A total of 104 genes were found significantly up-regulated and 42 down-regulated 6 h after NPS administration. The up-regulated genes included many neuronal genes and some putative susceptibility genes for respiratory disorders. By Gene Ontology enrichment analysis, the biological process terms, cell proliferation, morphogenesis and immune response were among the most altered. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), were verified and confirmed by quantitative reverse-transcriptase-PCR. In conclusion, we identified a novel asthma susceptibility gene, NPSR1, on chromosome 7p14.3. NPS-NPSR1 represents a novel pathway that regulates cell proliferation and immune responses, and thus may have functional relevance in the pathogenesis of asthma.

Project Energise: Using participatory approaches and real time computer prompts to reduce occupational sitting and increase work time physical activity in office workers

Objectives This efficacy study assessed the added impact real time computer prompts had on a participatory approach to reduce occupational sedentary exposure and increase physical activity. Design Quasi-experimental. Methods 57 Australian office workers (mean [SD]; age = 47 [11] years; BMI = 28 [5] kg/m2; 46 men) generated a menu of 20 occupational ‘sit less and move more’ strategies through participatory workshops, and were then tasked with implementing strategies for five months (July–November 2014). During implementation, a sub-sample of workers (n = 24) used a chair sensor/software package (Sitting Pad) that gave real time prompts to interrupt desk sitting. Baseline and intervention sedentary behaviour and physical activity (GENEActiv accelerometer; mean work time percentages), and minutes spent sitting at desks (Sitting Pad; mean total time and longest bout) were compared between non-prompt and prompt workers using a two-way ANOVA. Results Workers spent close to three quarters of their work time sedentary, mostly sitting at desks (mean [SD]; total desk sitting time = 371 [71] min/day; longest bout spent desk sitting = 104 [43] min/day). Intervention effects were four times greater in workers who used real time computer prompts (8% decrease in work time sedentary behaviour and increase in light intensity physical activity; p < 0.01). Respective mean differences between baseline and intervention total time spent sitting at desks, and the longest bout spent desk sitting, were 23 and 32 min/day lower in prompt than in non-prompt workers (p < 0.01). Conclusions In this sample of office workers, real time computer prompts facilitated the impact of a participatory approach on reductions in occupational sedentary exposure, and increases in physical activity.

An Experimental Study on Energy Absorption Behavior of Polyurethane Foams

This article is concerned with a study on the energy absorption behavior of polyurethane (PU) foams such as flexible high resilience (HR), flexible viscoelastic (VE) and semi-rigid (SR) foams as a function of the overall foam density. Foam samples were prepared in the form of cubes by mixing appropriate polyol and isocyanate compounds produced by Huntsman International India Pvt. Ltd. in varying proportions leading to a range of densities for each type of foam. The cubical samples were tested under compressive load in a standard UTM. Based on the measured load-displacement behaviors, variations of peak load and energy-absorption attributes with respect to density are plotted for each type of foam and the possible existence of an optimum foam density is shown.

Postoperative Volume Therapy in Cardiac Surgery : Effects on Hemostatic and Circulatory Variables

Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.

Microsurgical Aneurysm Model in Rats and Mice: Development of Endovascular Treatment and Optimization of Magnetic Resonance Imaging

The rupture of a cerebral artery aneurysm causes a devastating subarachnoid hemorrhage (SAH), with a mortality of almost 50% during the first month. Each year, 8-11/100 000 people suffer from aneurysmal SAH in Western countries, but the number is twice as high in Finland and Japan. The disease is most common among those of working age, the mean age at rupture being 50-55 years. Unruptured cerebral aneurysms are found in 2-6% of the population, but knowledge about the true risk of rupture is limited. The vast majority of aneurysms should be considered rupture-prone, and treatment for these patients is warranted. Both unruptured and ruptured aneurysms can be treated by either microsurgical clipping or endovascular embolization. In a standard microsurgical procedure, the neck of the aneurysm is closed by a metal clip, sealing off the aneurysm from the circulation. Endovascular embolization is performed by packing the aneurysm from the inside of the vessel lumen with detachable platinum coils. Coiling is associated with slightly lower morbidity and mortality than microsurgery, but the long-term results of microsurgically treated aneurysms are better. Endovascular treatment methods are constantly being developed further in order to achieve better long-term results. New coils and novel embolic agents need to be tested in a variety of animal models before they can be used in humans. In this study, we developed an experimental rat aneurysm model and showed its suitability for testing endovascular devices. We optimized noninvasive MRI sequences at 4.7 Tesla for follow-up of coiled experimental aneurysms and for volumetric measurement of aneurysm neck remnants. We used this model to compare platinum coils with polyglycolic-polylactic acid (PGLA) -coated coils, and showed the benefits of the latter in this model. The experimental aneurysm model and the imaging methods also gave insight into the mechanisms involved in aneurysm formation, and the model can be used in the development of novel imaging techniques. This model is affordable, easily reproducible, reliable, and suitable for MRI follow-up. It is also suitable for endovascular treatment, and it evades spontaneous occlusion.