Significance We reconstructed the 3D foot movements of guineafowl traversing a granular substrate from biplanar X-rays, and then incorporated those kinematics into a discrete element simulation. Digital track models permitted visualization of in vivo track formation at the surface and at virtual bedding planes for the first time. Application of these volumetric data to fossil dinosaur tracks uncovered the developmental origin of previously enigmatic features. A "track ontogeny" perspective helps integrate limb and substrate dynamics into the interpretation of track morphology, from which foot anatomy cannot be read directly. Locomotion over deformable substrates is a common occurrence in nature. Footprints represent sedimentary distortions that provide anatomical, functional, and behavioral insights into trackmaker biology. The interpretation of such evidence can be challenging, however, particularly for fossil tracks recovered at bedding planes below the originally exposed surface. Even in living animals, the complex dynamics that give rise to footprint morphology are obscured by both foot and sediment opacity, which conceals animal–substrate and substrate–substrate interactions. We used X-ray reconstruction of moving morphology (XROMM) to image and animate the hind limb skeleton of a chicken-like bird traversing a dry, granular material. Foot movement differed significantly from walking on solid ground; the longest toe penetrated to a depth of ∼5 cm, reaching an angle of 30° below horizontal before slipping backward on withdrawal. The 3D kinematic data were integrated into a validated substrate simulation using the discrete element method (DEM) to create a quantitative model of limb-induced substrate deformation. Simulation revealed that despite sediment collapse yielding poor quality tracks at the air–substrate interface, subsurface displacements maintain a high level of organization owing to grain–grain support. Splitting the substrate volume along "virtual bedding planes" exposed prints that more closely resembled the foot and could easily be mistaken for shallow tracks. DEM data elucidate how highly localized deformations associated with foot entry and exit generate specific features in the final tracks, a temporal sequence that we term "track ontogeny." This combination of methodologies fosters a synthesis between the surface/layer-based perspective prevalent in paleontology and the particle/volume-based perspective essential for a mechanistic understanding of sediment redistribution during track formation.


Current data regarding the anatomy, biostratigrahpy, ecology, and phylogeny of the basal plioplatecarpine Ectenosaurus clidastoides (FHSM VP-401), the most complete specimen available, is reviewed. The most noticeable autapomorphies of this species include an elongated snout, a long frontal bone, a quadrate with fused processes and high tympanic crest, vertically-ridged teeth, and a set of seven carpal bones. VP-401 is designated the neotype for E. clidastoides due to the loss the holotype skeleton. E. clidastoides was most likely a piscivore due its small teeth with unserrated carinae, variable angles of curvature, pointed tips, and slender to robust shape. Ectenosuarus relied on ambush tactics and maneuverability to capture its prey because of the slow speeds its body generated. Prey was swallowed whole using a highly kinetic skull. E. clidastoides inhabited a part of the Western Interior Sea between the end of the Coniacian and the earliest Campanian. Fauna contemporaneous with E. clidastoides consisted mostly of inoceramid bivalves and a large variety of osteihthyans, in addition to small variety of other invertebrates and reptiles, and one bird.


Mask metrology has long been separated into critical dimension (CD) vs. pattern placement (Registration) in terms of both the parametric definitions as well as measurement techniques applied. The combined effect of measured CD and placement errors on mask-to-mask overlay (OL) is hard to model let alone calculate in definitive terms. As device size continues to shrink, novel lithography solutions being considered for 45nm technology node and beyond such as double exposure and patterning techniques are projected to tighten the overlay requirement much faster than originally anticipated. Electron optics is generally the preferred solution for small feature size in-die sampling by virtue of its high image resolution, measurement precision, low cross-field distortion and absence of tool induced shift. In this paper we propose to examine and identify the key elements of a new approach in applying electron optics to a mask metrology system that combines CD and pattern placement. We will then present the results from our experiments with a prototype wide field scanning electron microscope (WFSEM) using reticle with optical proximity correction (OPC) features.


Histidine kinases are key components of regulatory networks in bacteria. Although many of these enzymes are bifunctional, mediating both phosphorylation and dephosphorylation of downstream targets, the molecular details of this central regulatory switch are unclear. We showed recently that the universal second messenger cyclic di–guanosine monophosphate (c-di-GMP) drives Caulobacter crescentus cell cycle progression by forcing the cell cycle kinase CckA from its default kinase into phosphatase mode. We use a com,lbination of structure determination, modeling, and functional analysis to d,ölemonstrate that c-di-GMP reciprocally regulates the two antagonistic CckA activities through noncovalent cross-linking of the catalytic domain with the dimerization histidine phosphotransfer (DHp) domain. We demonstrate that both c-di-GMP and ADP (adenosine diphosphate) promote phosphatase activity and propose that c-di-GMP stabilizes the ADP-bound quaternary structure, which allows the receiver domain to access the dimeric DHp stem for dephosphorylation. In silico analyses predict that c-di-GMP control is widespread among bacterial histidine kinases, arguing that it can replace or modulate canonical transmembrane signaling


Background Anti-TNF drugs show high inter-individual variability in efficacy and toxicity. Currently there are no genetic, biochemical or environmental markers to predict response to treatment. Purpose To assess the influence of gene polymorphism rs2230229 TRAILR1 as a genetic marker in response to treatment with infliximab in patients diagnosed with Crohn's disease (CD). Will it enable us to predict response and improve the effectiveness of the drug? Materials and Methods Prospective observational study of all patients diagnosed with CD treated with infliximab at our hospital. The assessment of response to infliximab was performed using as criteria of clinical response a decreased questionnaire score CDAI (Crohn Disease Activity Index) at the 4th dose. Subsequently patients were considered to have responded if their CDAI decreased by 70 points or more with respect the baseline and at least 25% on the total score and clinical remission was achieved by a CDAI of less than 150 points. Biological response criteria were defined such as patient responders, partial responders or non-responders according to variation in levels of C-reactive protein (CRP) with regard to baseline at 3, 6 and 12 months. To detect polymorphism KASPAR probes were used in a PCR-based allele-specific competitive FRET technology using a computer and a real time PCR of Aplied Biosystems 7500F in 96-well plate. All patients included in the study received a starting dose of infliximab 5 mg/kg at 0, 2 and 6 weeks after the start and then a maintenance dose every 8 weeks. Statistical analyses were performed with Epidat 3.1 and the level of significance was indicated by a p value of less than 0.05. Results The study included a total of 40 patients. The mean age of the patients was 38.66 ± 13.98 years and 61.1% were female. The distribution for genotypes was 81.6% AA, 15.8% GA and 2.6% GG. Significant correlation wasn't found between genotypes or alleles of this polymorphism and clinical response to infliximab. Instead, statistically significant differences were shown for approximately 6 months of treatment when comparing patients with genotypes GG and GA/AA and a positive response (p = 0.047) when considering the biological response. Similarly patients with a G allele had a more frequent negative response than those with the A allele (p = 0.043). On the other hand, significant correlation was found between patients carrying the A allele and the positive response, at 3, 6 and 12 months based on biological response distribution. Conclusions The results of our study show an association of this polymorphism with response to infliximab. Worst response rates are observed in patients carrying allele G diagnosed with CD. We need more studies on this polymorphism and with a larger sample size to confirm these findings. No conflict of interest.


'Thunder days' are simple records of thunderstorm activity, logging whether a human observer heard thunder on a particular day or not. Despite their low dynamic range and inherent subjectivity, thunder days are invaluable as the only long‐term observations of thunderstorm occurrence, with some records stretching back into the nineteenth century. Thunder days, however, are potentially susceptible to false positives, particularly from explosions. Thus one might expect UK thunder days to show anomalously high counts on New Year's Eve and the days around 5 November, Bonfire Night, both of which are celebrated with large firework displays across the country. It is demonstrated that UK Met Office records of thunder days between 1980 and 2010 do not show any significant increase in thunder reporting around 5 November or 31 December. In fact, the days around 5 November exhibit the largest reduction in the amount of reported thunder relative to annual climatology. While meteorological variability cannot be completely ruled out, this result is suggestive of observer bias; it is speculated that human observers, armed with a priori knowledge of the likelihood of false positives, 'second guess' themselves to a greater degree around 5 November than the rest of the year. In fact, the data suggest they should trust in their ability to correctly discriminate between thunder and fireworks.


The term "social entrepreneurship" is being adopted and used more extensively, but its meaning is not widely understood. In particular, the scope of social entrepreneurship in both business and the voluntary sector has not been mapped effectively. This paper seeks to do this. It begins by defining social entrepreneurs and social entrepreneurship. Then, using projects considered for a charter award under the Duke of York's Community Initiative, it looks at what social entrepreneurs do and achieve for the community, at the wide scope of their world, and at the help that is available and needed. The paper includes two case studies of successful social entrepreneurs as a means of drawing out a number of important issues and lessons. It provides a new map for understanding the complexity and the many facets of the world of the social entrepreneur and the voluntary sector. It questions whether the UK government's stated desire for an "explosive act" of volunteering can happen without more substantial support, and concludes that whilst the growth of this sector is urgent and vital, a number of hurdles remain to be overcome.


Abstract. Deliberate injection of aerosol particles into the stratosphere is a potential climate engineering scheme. Particles injected into the stratosphere would scatter solar radiation back to space, thereby reducing the temperature at the Earth's surface and hence the impacts of global warming. Minerals such as TiO2 or SiO2 are among the potentially suitable aerosol materials for stratospheric particle injection due to their greater light-scattering ability than stratospheric sulfuric acid particles. However, the heterogeneous reactivity of mineral particles towards trace gases important for stratospheric chemistry largely remains unknown, precluding reliable assessment of their impacts on stratospheric ozone, which is of key environmental significance. In this work we have investigated for the first time the heterogeneous hydrolysis of ClONO2 on TiO2 and SiO2 aerosol particles at room temperature and at different relative humidities (RHs), using an aerosol flow tube. The uptake coefficient, γ(ClONO2), on TiO2 was ∼ 1.2 × 10−3 at 7 % RH and remained unchanged at 33 % RH, and increased for SiO2 from ∼ 2 × 10−4 at 7 % RH to  ∼ 5 × 10−4 at 35 % RH, reaching a value of  ∼ 6 × 10−4 at 59 % RH. We have also examined the impacts of a hypothetical TiO2 injection on stratospheric chemistry using the UKCA (United Kingdom Chemistry and Aerosol) chemistry–climate model, in which heterogeneous hydrolysis of N2O5 and ClONO2 on TiO2 particles is considered. A TiO2 injection scenario with a solar-radiation scattering effect very similar to the eruption of Mt Pinatubo was constructed. It is found that, compared to the eruption of Mt Pinatubo, TiO2 injection causes less ClOx activation and less ozone destruction in the lowermost stratosphere, while reduced depletion of N2O5 and NOx in the middle stratosphere results in decreased ozone levels. Overall, no significant difference in the vertically integrated ozone abundances is found between TiO2 injection and the eruption of Mt Pinatubo. Future work required to further assess the impacts of TiO2 injection on stratospheric chemistry is also discussed.


The invention relates to a photovoltaic cell (1) having an absorbent photovoltaic material, said cell comprising a front face substrate (10), especially a transparent glass substrate, having, on a main surface, a transparent electrode coating (100) consisting of a thin-film stack that includes a metallic functional layer (40), especially one based on silver, and at least two antireflection coatings (20, 60), characterized in that the antireflection coating (20) placed beneath the metallic functional layer (40) in the direction of the substrate has an optical thickness equal to about one eighth of the maximum absorption wavelength of the photovoltaic material and the antireflection coating (60) placed above the metallic functional layer (40) on the opposite side from the substrate has an optical thickness equal to about one half of the maximum absorption wavelength of the photovoltaic material.


The aim of thesis was to try and establish the effects that nepotism practice and HRM practise had on player satisfaction in G.A.A clubs. Firstly the researcher conducted a review of literature and found a significant amount of material on the effects of both practice in a business context.

The researcher then decided to conduct a review of the literature in relation to the practice within sporting organisations. It was found that nepotism was present in sporting organisations. There was little or no evidence of the application of HRM in sports But there seem to be a lot of evidence in relation to the effects that both had on employee satisfaction. So it came apparent to the researcher that sporting organisations may have similar effects in relation to its members but mainly its players.

It was from this anecdotal and empirical evidence that the researcher drew the research questions. The surveys were conducted thought out Ireland. There were 5 different regions involved, participants from Munster, Connaught, Leinster, Dublin and Ulster. This was in order to obtain a good sample size but also to get an in-depth insight into both practices, it was decided to conduct both quantitative and qualitative research Questionnaires were used with 143 respondents from 11 different clubs. One group interview of 4 ex-players was then conducted for a clearer insight.

The results were significant, both sets of results showed that nepotism was having a significant negative effect on player satisfaction whilst HRM practices were having or would have a significant positive effect on player satisfaction. The findings were that player satisfaction was effecting intention to quit (commitment), but that the reputation of the club seemed not be effected by this.

The research was very significant, because one of the main issues for the clubs was lack of commitment. Here the researcher has identified a possible solution to this problem that could improve team performance. It also shows that HRM is applicable to many different organisations and not just business firms.


Traditional inventory models focus on risk-neutral decision makers, i.e., characterizing replenishment strategies that maximize expected total profit, or equivalently, minimize expected total cost over a planning horizon. In this paper, we propose a framework for incorporating risk aversion in multiperiod inventory models as well as multiperiod models that coordinate inventory and pricing strategies. We show that the structure of the optimal policy for a decision maker with exponential utility functions is almost identical to the structure of the optimal risk-neutral inventory (and pricing) policies. These structural results are extended to models in which the decision maker has access to a (partially) complete financial market and can hedge its operational risk through trading financial securities. Computational results demonstrate that the optimal policy is relatively insensitive to small changes in the decision-maker's level of risk aversion.


Grazing can have considerable ecological impacts when managed inappropriately, however livestock production is a significant contributor to global food security and the removal of land from production is not always a viable option. Grazing management practices that incorporate periods of planned rest (i.e. strategic-rest grazing) may be an alternative to grazing exclusion or continuous grazing that could achieve ecological and animal production outcomes simultaneously. We conducted a meta-analysis of global literature to investigate how strategic-rest grazing mediates ecological (i.e., plant richness and diversity), biophysical (plant biomass and ground cover) and production response variables (animal weight gain and animal production per hectare) compared to continuously grazed or ungrazed areas. Overall, total ground cover and animal production per hectare were significantly greater under strategic-rest grazing than continuous grazing management, but biomass, plant richness, plant diversity and animal weight gain did not differ between grazing treatments. Increasing the length of rest relative to graze time under strategic-rest grazing was associated with an increase in plant biomass, ground cover, animal weight gain and animal production per hectare when compared to continuous grazing. Synthesis and applications. Understanding both the ecological and animal production trade-offs associated with different grazing management strategies is essential to make informed decisions about best-management practices for the world's grazing lands. We show that incorporating periods of rest into grazing regimes improves ground cover and animal production per hectare and that these benefits are more pronounced with increases in the length of time land is rested for. This extended rest also improves biomass production and weight gain compared to continuous grazing systems. Based on these meta-analyses, we recommend that future research considers the duration of rest compared to graze time in comparisons of grazing systems.


With the increasing demand for high speed turbomachinery, the dynamic analysis of rotor bearing system has become very important. Foil bearings with their exceptional feature of negligible wear has gained a very important place in the field of turbomachinery but the nonlinearities present in the bearing call for the dynamic analysis of these bearings. In the present work, a dynamic modeling approach and parametric identification scheme of a single disc rotor mounted on foil bearings is presented. Rotor is analyzed with conventional lumped parameter model. The time varying bearing forces are obtained by solving compressible Reynold's equation using finite difference scheme and the convergence is checked using Gauss Sidle method. Effects of number of bump foils, foil thickness and bump pitch at different speeds of operation of rotor are studied on the dynamic response of rotor. For solving dynamic equations, Newmark method is employed using Matlab. A solid model of the rotor is prepared and then it is analyzed to obtain various critical speeds of the system and to obtain mode shapes at those speeds. A generalized model is developed based on radial basis neural networks to predict the foil thickness and bump pitch from a given frequency response of the rotor. Also a scaled model of shaft, disc and bearing system is fabricated for testing.


I read with interest the article "Clinical Implications of Barrett's Esophagus" by Crooks and Lichtenstein 1 in theArchives. In the "Medical Therapy of Barrett's Esophagus" section, the authors comment, "It is unclear whether it is necessary or desirable to make all patients with Barrett's esophagus achlorhydric, which is now possible with the use of proton pump inhibitors." I believe what the authors intend to imply is that it is possible to increase the intraesophageal pH level to above 4 for longer periods in patients treated with proton pump inhibition, but the use of proton pump inhibitors, even in large doses, will not render most patients truly achlorhydric over a given 24-hour period. Crooks and Lichtenstein correctly point out that there were no data to suggest whether maintaining intraesophageal pH above 4 allows reversion of Barrett's epithelium to squamous epithelium to occur more readily. However, in a recent survey involving


Diabetes is associated with significant morbidity and mortality. The majority of disease burden is attributed to long-term complications. Screening tests to detect and therapies to treat early forms of diabetes complications are available, but few diabetes patients receive screening at the recommended levels. This report investigated the prevalence and correlates of screening in a cohort of type 1 diabetes patients. The study population was the Pittsburgh Epidemiology of Diabetes Complications study cohort. Screening tests assessed included the HbA1c test, dilated eye exam, foot exam, fasting lipid profile, and urine protein screen. The aims were to: 1) identify the frequency and trends in screening; 2) identify general correlates of screening as well as to evaluate the influence of patient behavior and health care access factors on receipt of screening tests and examine the association between clinical risk of developing complications and receipt of screening tests to detect complications. Reported screening rates varied widely between individual tests, and optimal screening, the use of all tests, was reported by the fewest subjects. Overall, screening in this population is improving over time. The strongest general correlates of screening were specialist care, weekly blood sugar testing, and gender. A more in depth analysis of screening predictors was aimed at determining whether patient or health care access level factors have a stronger influence on screening was conducted. Health care access factors that specifically included specialist care, intensive insulin therapy, and number of physician visits were found to have a stronger influence on screening compared to patient level factors. Finally, this study found that overall, screening does not appear to be associated with clinical risk of developing complications.Based upon this research, areas in need of improvement include optimal screening rates and targeting screening endeavors towards patients at clinical risk for developing complications, and interventions that incorporate access factors may have the strongest impact. The findings of this report have public health significance and have implications for diabetes preventive care. The data from this research can be used to design interventions and policies that improve screening rates, and reduce subsequent morbidity and mortality associated with chronic complications.


Domain adaptation has the potential to overcome the expensive or even infeasible la-beling of target data by transferring knowledge from a labeled source domain. In this work, we address domain adaptation in the context of point cloud-based 3D human pose estimation, whose clinical applicability is severely limited by a lack of labeled training data. Unlike the mainstream approach of domain-invariant feature learning, we propose to guide the learning process in the target domain through weak supervision, based on prior knowledge about human anatomy. We embed this prior knowledge into a novel loss function that encourages network predictions to match the statistics of an anatomically plausible skeleton. Specifically, we formulate three loss functions that penalize asymmetric limb lengths, implausible joint angles, and implausible bone lengths. We evaluate the method on a public lying pose dataset (SLP), adapting from uncovered patients in the source to covered patients in the target domain. Our method outperforms diverse state-of-the-art domain adaptation techniques and improves the baseline model by 26 % while reducing the gap to a fully supervised model by 54 %. Source code is available at https://github.com/multimodallearning/da-3dhpe-anatomy .


The question of whether migration can be an equilibrating force in the labour market is an important criterion for an optimal currency area. It is of particular interest currently in the context of high and rising levels of labour market disparities, in particular within the Eurozone where there is no exchange-rate mechanism available to play this role. We shed some new light on this question by comparing pre- and post-crisis migration movements at the regional level in both Europe and the United States, and their association with asymmetric labour market shocks. We find that recent migration flows have reacted quite significantly to the EU enlargements in 2004 and 2007 and to changes in labour market conditions, particularly in Europe. Indeed, in contrast to the pre-crisis situation and the findings of previous empirical studies, there is tentative evidence that the migration response to the crisis has been considerable in Europe, in contrast to the United States where the crisis and subsequent sluggish recovery were not accompanied by greater interregional labour mobility in reaction to labour market shocks. Our estimates suggest that, if all measured population changes in Europe were due to migration for employment purposes – i.e. an upper-bound estimate – up to about a quarter of the asymmetric labour market shock would be absorbed by migration within a year. However, in the Eurozone the reaction mainly stems from migration of thirdcountry nationals. Even within the group of Eurozone nationals, a significant part of the free mobility stems from immigrants from third countries who have taken on the nationality of their Eurozone host country.


Abstract This work illustrates reactor physics applications of the predictive modeling of coupled multiphysics systems (PMCMPS), formulated by Cacuci (2014), by means of the benchmarks Godiva (a bare uranium sphere) and Jezebel-239 and Jezebel-240 (bare plutonium spheres). The PMCMPS methodology was ab initio developed in the response space, to reduce as much as possible the computational memory requirements for predictive modeling of very large systems involving not only many model parameters but also many model responses. The model parameters considered in this work include individual cross sections for each material, nuclide, reaction type, and energy group, giving the following totals: 2241 parameters for Jezebel-239, 1458 parameters for Jezebel-240, and 2916 parameters for Godiva. Eight responses were considered for Jezebel-239 (the effective multiplication factor; the center core fission rates for 233U, 238U, 237Np, and 239Pu; and the center core radiative capture rates for 55Mn, 93Nb, and 63Cu). Three responses (the effective multiplication factor and the center core fission rates for 233U and 237Np) were selected for Jezebel-240, and eleven responses were selected for Godiva (the reaction rate types listed for Jezebel-239, along with the radiative capture rates for 107Ag, 127I, and 81Br). The PMCMPS methodology ensures that increasing the amount of information yields more accurate predictions, with smaller predicted uncertainties, as long as the considered information is consistent. This fact is amply illustrated in this work, which shows that the interdependence of responses that were measured in more than one benchmark is stronger than for responses that were measured in a single benchmark. More generally, the consideration of the complete information, including couplings, provided jointly by all three benchmarks (as opposed to consideration of the benchmarks as separate systems) leads to more accurate predictions of nominal values for responses and model parameters, yielding larger reductions in the predicted uncertainties that accompany the predicted mean values of responses and model parameters.


An overview is given of the direct modulation performance of high-speed semiconductor lasers, The high-speed response characteristics are described using a cascaded two-port model of the laser. This model separates the electrical parasitics from the intrinsic laser and enables these subsections to be considered separately. The presentation concentrates on the small-signal intensity modulation and frequency modulation responses, and the large-signal switching transients and chirping. Device-dependent limitations on high-speed performance are explored and circuit modeling techniques are briefly reviewed.


Responsive Multithreaded Processor (RMTP) has the Simultaneous Multithreading (SMT) architecture with priority for distributed real-time processings, called prioritized SMT architecture. In RMTP, execution efficiencies of tasks executing in threads except the highest priority thread fluctuate by multiple combinations of tasks executing simultaneously. Therefore, it is difficult to guarantee the schedulability of tasks. Many real-time scheduling algorithms having only real-time part is not well suited to the prioritized SMT architecture. Because they cannot make use of the remaining times of threads except the highest priority thread. In contrast, semi-fixed-priority scheduling has an optional part which is a non-real-time part and improves the quality of the result so that semi-fixed-priority scheduling is well suited to the prioritized SMT architecture. This paper evaluates the performance of semi-fixedpriority scheduling on prioritized SMT processors. Experimental evaluations show that semi-fixed-priority scheduling is well suited to prioritized SMT processors.


In 1985, the authors reported the development of a semiempirical dielectric model for soils, covering the frequency range between 1.4 and 18 GHz. The model provides expressions for the real and imaginary parts of the relative dielectric constant of a soil medium in terms of the soil's textural composition (sand, silt, and clay fractions), the bulk density and volumetric moisture content of the soil, and the dielectric constant of water at the specified microwave frequency and physical temperature. This communication provides similar expressions for the 0.3-1.3-GHz range. Upon comparing experimental results measured in this study with predictions based on the semiempirical model, it was found that the model underpredicts the real part of the dielectric constant for high-moisture cases and underestimates the imaginary part for all soils and moisture conditions. A small linear adjustment has been introduced to correct the expression for the real part and a new equation was generated for the effective conductivity to correct the expression for the imaginary part. In addition, dielectric measurements were made to evaluate the dependence of the dielectric constant on clay type. The results show significant variations for the real part and large variations for the imaginary part among soils with the same clay fractions but with clays of different specific surface areas. >


Gravitational collapse of the cylindrical elongated cloud is studied by numerical magnetohydrodynamical simulations. In the infinitely long cloud in hydrostatic configuration, small perturbations grow by the gravitational instability. The most unstable mode indicated by a linear perturbation theory grows selectively even from a white noise. The growth rate agrees with that calculated by the linear theory. First, the density-enhanced region has an elongated shape, i.e., prolate spheroidal shape. As the collapse proceeds, the high-density fragment begins to contract mainly along the symmetry axis. Finally, a spherical core is formed in the non-magnetized cloud. In contrast, an oblate spheroidal dense disk is formed in a cloud in which the magnetic pressure is nearly equal to the thermal one. The radial size of the disk becomes proportional to the initial characteristic density scale-height in the r-direction. As the collapse proceeds, a slowly contracting dense part is formed (<∼ 10% in mass) inside of the fast contracting disk. And this is separated from other part of the disk whose inflow velocity is accelerated as reaching the center of the core. From arguments on the Jeans mass and the magnetic critical mass, it is concluded that the fragments formed in a cylindrical elongated cloud can not be supported against the self-gravity and it will eventually collapse. Subject Headings: Interstellar: Matter — Interstellar: Magnetic Fields — Hydromagnetics — Stars: Formation


The world is increasingly becoming . one. It is, at the same time, one endangered ecosystem and one thriving market place with material and spiritual goods on competitive display. And the good and evil things of life cannot easily be sorted out. The world is becoming one also in the sense that it is better understood today than it was in earlier times, that the material good and the spiritual good, though seemingly belonging to different realms of fact defined by their respective modes of existence, together constitute effectively one and the same reality: the modem world of science, technology, computerized administration and power, that calls upon humankind to struggle for a 'just, participatory and sustainable society' * , and to strive for a society of the future that will be the world over both long-lived and worth living. The Second European Conference on Science and Religion, held on 10-13th. March, 1988, on the campus of the Universiteit Twente, Enschede, The Netherlands, was meant to be a modest market place, a forum, where standpoints and opinions could be presented and criticized. It was meant to offer an opportunity to meet and to make acquaintances in the expectation that the exchange of thoughts would lead to new conceptual horizons that would challenge what so far had been considered as hard fact or what until now had been looked upon as a distinctive feature of a well-established view either of the kingdom of the sciences or of the realm of religion.


A detailed study of the factors determining the linewidth (and hence resolution) in 1H solid-state magic-angle spinning NMR is described. Although it has been known from the early days of magic-angle spinning (MAS) that resolution of spectra from abundant nuclear spins, such as 1H, increases approximately linearly with increasing sample rotation rate, the difficulty of describing the dynamics of extended networks of coupled spins has made it difficult to predict a priori the resolution expected for a given sample. Using recently developed, highly efficient methods of numerical simulation, together with experimental measurements on a variety of test systems, we propose a comprehensive picture of 1H resolution under MAS. The "homogeneous" component of the linewidth is shown to depend primarily on the ratio between an effective local coupling strength and the spin rate, modified by geometrical factors which loosely correspond to the "dimensionality" of the coupling network. The remaining "inhomogeneous" component of the natural linewidth is confirmed to have the same properties as in dilute-spin NMR. Variations in the NMR frequency due to chemical shift effects are shown to have minimal impact on 1H resolution. The implications of these results for solid-state NMR experiments involving 1H and other abundant-spin nuclei are discussed.


BACKGROUND
Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive drugs. However, prolonged use at a medium or high dose is hampered by side effects of which the metabolic side effects are most evident. Relatively little is known about their effect on gene-expression in vivo, the effect on cell subpopulations and the relation to the efficacy and side effects of GCs.

AIM
To identify and compare prednisolone-induced gene signatures in CD4⁺ T lymphocytes and CD14⁺ monocytes derived from healthy volunteers and to link these signatures to underlying biological pathways involved in metabolic adverse effects.

MATERIALS & METHODS
Whole-genome expression profiling was performed on CD4⁺ T lymphocytes and CD14⁺ monocytes derived from healthy volunteers treated with prednisolone. Text-mining analyses was used to link genes to pathways involved in metabolic adverse events.

RESULTS
Induction of gene-expression was much stronger in CD4⁺ T lymphocytes than in CD14⁺ monocytes with respect to fold changes, but the number of truly cell-specific genes where a strong prednisolone effect in one cell type was accompanied by a total lack of prednisolone effect in the other cell type, was relatively low. Subsequently, a large set of genes was identified with a strong link to metabolic processes, for some of which the association with GCs is novel.

CONCLUSION
The identified gene signatures provide new starting points for further study into GC-induced transcriptional regulation in vivo and the mechanisms underlying GC-mediated metabolic side effects.


Abstract:The South-South Cooperation (SSC) strategy advocates that Global South states cooperate within international organizations to gain bargaining leverage and advance their interests in global governance. The SSC agenda advances a multipolar international system, multilateral negotiations, and mutual economic development, especially for less developed states. This research examines qualitative and quantitative documentation of SSC leadership of Brazil and India in the World Trade Organization's Dispute Settlement Body. The analysis uses case studies of each actor's profile in trade disputes and cross-tabulations of their success, both individually and collectively against Global North states. The findings support the proposition that Global South states have relatively high rates of success, especially when they collaborate in disputes against the Global North. This research extends the institutional analysis of SSC to the Dispute Settlement Body as an arena for rule-based decision making and adds a qualitative analysis of the SSC leadership and a quantitative analysis of categorical data of trade disputes. The conclusion summarizes the findings and suggests areas for future research.


In this work, the effects of atmospheric-pressure plasma treatment of polyimide films on surface and dielectric characteristics were studied by using X-ray photoelectron spectroscopy (XPS), surface free energies, and dielectric spectrometer. The total surface free energies and dielectric constants of plasma treated polyimide film were deareased with increasing the treatment time, which was mainly due to a lower London-dispersive component, while the specific component was increased. This could be attributed to an increase of the polar fluorine groups of polyimide per unit surface area. And the fluorine content of the polyimide film was increased with increasing the amount of the treatment time, resulting in decreasing dielectric constant of the film. It was found that the replacement of fluorine led to the decrease of the local electronic polarizability of polyimide, or to the increase of the free volume, which could be attributed to the relatively large volume of fluorine.


In the last years, there has been growing a large increase in digital imaging techniques, and their applications became more and more pivotal in many critical scenarios. Conversely, hand in hand with this technological boost, imaging forgeries have increased more and more along with their level of precision. In this view, the use of digital tools, aiming to verify the integrity of a certain image, is essential. Indeed, insurance is a field that extensively uses images for filling claim requests and a robust forgery detection is essential. This paper proposes an approach which aims to introduce a full-automated system for identifying potential splicing frauds in images of car plates by overcoming traditional problems using artificial neural networks (ANN). For instance, classic fraud-detection algorithms are impossible to fully automatize whereas modern deep learning approaches require vast training datasets that are not available most of the time. The method developed in this paper uses Error Level Analysis (ELA) performed on car license plates as an input for a trained model which is able to classify license plates in either original or forged.


A fundamental incongruity has emerged between continually rising costs and what energy consumers have learned to expect as minimum energy needs. Public policy is beginning to recognize this incongruity. Policymakers are no longer focussing only on controlling utility costs, but have recently begun to question what levels of energy consumption constitute "minimum" energy needs, and whether non-traditional utility service options may be used to meet those needs. Public policy faces an uphill battle. The expectations of consumers are deeply rooted and are a logical outcome of the early economics of the industry. Finding equitable and efficient solutions to the inherent conflict between costs and needs is the challenge of public policy today, and will be throughout the 1980s.


ABSTRACT In response to herbivory, poplar produces among other compounds the volatile alcohol 2-phenylethanol and its corresponding glucoside 2-phenylethyl-β-D-glucopyranoside. While the free alcohol is released only upon herbivory, the glucoside accumulates also in undamaged leaves, but increases after herbivore feeding. Recently we showed that 2-phenylethanol and its glucoside are biosynthesized via separate pathways in Populus trichocarpa. The phenylacetaldehyde synthase PtAAS1 plays a central role in the de novo formation of herbivory-induced volatile 2-phenylethanol, while the phenylalanine decarboxylase PtAADC1 initiates a pathway responsible for the herbivory-induced production of 2-phenylethyl-β-D-glucopyranoside. Besides PtAAS1, P. trichocarpa possesses another aromatic aldehyde synthase PtAAS2 with in vitro enzymatic activity comparable to that of PtAAS1. However, in contrast to PtAAS1, which is exclusively expressed in herbivory-damaged leaves, PtAAS2 was found to be expressed at constant levels in both damaged and undamaged leaves. Thus it has been hypothesized that PtAAS2 provides phenylacetaldehyde as substrate for the constitutive formation of 2-phenylethyl-β-D-glucopyranoside in undamaged P. trichocarpa trees. By generating RNAi-mediated AAS2 knockdown plants, we show here that despite the similar activities of PtAAS1 and PtAAS2 in vitro, the latter enzyme does not contribute to the biosynthesis of 2-phenylethyl-β-D-glucopyranoside in planta. Based on the recent finding that phenylpyruvic acid accumulates in undamaged poplar leaves, the constitutive formation of the glucoside may now be suggested to proceed via the Ehrlich pathway, which begins with the conversion of phenylalanine into phenylpyruvic acid.


THE past quarter century has witnessed an explosion in the understanding of pain, characterized by the elucidation of anatomic pathways, and the identification of receptors, ion channels, and neurotransmitters that are involved in the transmission of nociceptive information from primary sensory neurons in the dorsal root ganglion (DRG) to the brain. In parallel, it has become apparent that the emergence of chronic pain, an important and difficult-to-treat condition, involves defined alterations in nociceptive processing in the peripheral nervous system, at the level of the spinal cord, and in the brain. But despite advances in basic and clinical sciences and the concentrated efforts of many academic and pharmaceutical research laboratories, the development of novel effective treatments for chronic pain has been disappointingly slow. In part, the challenge to the development of pain therapeutics is a predictable result of the parsimonious use by the nervous system of a limited repertoire of neurotransmitters, receptors, and ion channels at multiple sites and in many pathways subserving different functions. Therefore, potent small molecules designed to interrupt nociceptive neurotransmission often have "off-target" adverse effects resulting from actions of these molecules in pathways subserving other, non–painrelated functions. In response, several groups have begun to explore the possibility of using gene transfer to achieve analgesic effects, and in this issue of the Journal, Tzabazis et al. present the results of a study of gene transfer using a herpes simplex virus (HSV)–based vector that significantly extends the range of gene transfer in the treatment of pain. The rationale for applying gene transfer techniques to the treatment of pain is based on the presumption that expression of transgene products (usually short-lived potent peptides) in a restricted anatomical distribution may be used to reduce pain perception through modulation of nociceptive neurotransmission at an identified site, with off-target effects limited by the limited anatomic distribution of transgene expression. Transduction of meninges accomplished by intrathecal injection of "naked" plasmid or liposome-encapsulated DNA, or by injection of recombinant viral vectors created from adenovirus or adenoassociated virus to express inhibitory neurotransmitters (e.g., beta endorphin) or antiinflammatory cytokines (e.g., interleukin 2 or interleukin 10) has been shown to reduce pain-related behaviors in several animal models of inflammatory and neuropathic pain. These analgesic effects are presumed to result from modulation of neurotransmission at the synapse between the central afferents of first-order nociceptive neurons (whose cell bodies lie in the DRG) onto secondorder neurons located in the dorsal horn of spinal cord. Modulation of nociceptive neurotransmission at that synapse in the spinal cord can also be achieved by peripheral inoculation of vectors created from recombinant HSV, relying on the natural neurotropism of HSV to achieve efficient transport from the periphery to sensory neurons in the DRG. Reduction of pain related behaviors using HSV-based vectors has been demonstrated in models of chronic inflammatory and neuropathic pain with vectors expressing enkephalin, glutamic acid decarboxylase (to produce gamma amino butyric acid), glial cell–derived neurotrophic factor, interleukin 4, and the truncated soluble tumor necrosis factor receptor. In the current report, Tzabazis et al. used a recombinant HSV-based vector encoding an antisense sequence to the calcitonin gene–related peptide (CGRP) gene. They demonstrate that application of the vector to the skin resulted in a significant reduction in CGRP expression in primary afferents in the DRG, producing a significant attenuation in thermal C-fiber hyperalgesia after topical application of capsaicin. CGRP is expressed in 45–70% of lumbar DRG neurons, a majority of which are nociceptors. Although the precise role of CGRP in nociception has not been established, spinal delivery of CGRP antagonists has previously been shown to reduce pain-related behaviors in a variety of models, and in the mouse, strain-related differences in sensitivity to noxious heat correlates with strain-dependent differences in CGRP expression and sensitivity. In contrast to the transient effects produced by spinal delivery of CGRP antagonists, HSV-mediated knockdown of CGRP expression resulted in an analgesic effect that persisted for 12 weeks. An advantage to gene transfer of an antisense sequence is that no foreign gene products are released from the transduced neurons, although it will be crucial to demonstrate in future studies that HSV-mediated knockdown of gene expression by this antisense expressing vector is limited to CGRP. Nonetheless, the observation by Tzabazis et al. that the HSV vector produced a significant reduction in CGRP gene expression in a majority of nociceptor afferents in the DRG after superficial application to the skin is impressive, and extension of this work to an animal model of chronic pain would serve as an important preclinical step in the development of a treatment for chronic pain. This Editorial View accompanies the following article: Tzabazis AZ, Pirc G, Votta-Velis E, Wilson SP, Laurito CE, Yeomans DC: Antihyperalgesic effect of a recombinant herpes virus encoding antisense for calcitonin gene–related peptide. ANESTHESIOLOGY 2007; 106:1196–203.


Background: The province of British Columbia (BC) has been recognized for successful SARS-CoV-2 control, with surveillance data showing amongst the lowest case and death rates in Canada. We estimate sero-prevalence for two periods flanking the start (March) and end (May) of first-wave mitigation measures in BC. Methods: Serial cross-sectional sampling was conducted using anonymized residual sera obtained from an outpatient laboratory network, including children and adults in the Greater Vancouver Area (population ~3 million) where community attack rates were expected to be highest. Screening used two chemiluminescent immuno-assays for spike (S1) and nucleocapsid antibodies. Samples sero-positive on either screening assay were assessed by a third assay targeting the S1 receptor binding domain plus a neutralization assay. Age-standardized sero-prevalence estimates were based on dual-assay positivity. The May sero-prevalence estimate was extrapolated to the source population to assess surveillance under-ascertainment, quantified as the ratio of estimated infections versus reported cases. Results: Serum collection dates spanned March 5-13 and May 15-27, 2020. In March, two of 869 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.28% (95%CI=0.03-0.95). Neither specimen had detectable neutralizing antibodies. In May, four of 885 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.55% (95%CI=0.15-1.37%). All four specimens had detectable neutralizing antibodies. We estimate ~8 times more infections than reported cases. Conclusions: Less than 1% of British Columbians had been infected with SARS-CoV-2 when first-wave mitigation measures were relaxed in May 2020. Our findings indicate successful suppression of community transmission in BC, but also substantial residual susceptibility. Further sero-survey snapshots are planned as the pandemic unfolds.


TES (Transform-Expand-Sample) is a versatile class of stationary stochastic processes which can model arbitrary marginals, a wide variety of autocorrelation functions, and a broad range of sample path behaviors. TES parameters are of two kinds: the rst kind is used for the exact tting of the empirical distribution (histogram), while the second kind is used for approximating the empirical autocorrelation function. Parameters of the rst kind are easy to determine algorithmically, but those of the second kind require a hard heuristic search on a large parametric function space. This paper describes an algorithmic procedure which can replace the heuristic search, thereby largely automating TES modeling. The algorithm is cast in nonlinear programming setting with the objective of minimizing a weighted sum of squared diierences between the empirical autocorrelations and their candidate TES model counterparts. It combines a brute-force search with Steepest-Descent nonlinear programming using Zou-tendijk's Feasible Direction Method. Finally, we illustrate the eecacy of our approach via three examples: two from the domain of VBR (Variable Bit Rate) compressed video, and one representing results from a laser intensity experiment.


With the rapid rise of social media content, the question how people navigate to and from social media becomes important in order to understand what new tools and approaches are most beneficial to allow users to discover and interact with this social media data. In this study we analyze session log data to describe navigation patterns involving these sites. Our findings suggest that there are distinct patterns of insular navigation behavior around social media, with blogs being the most transitory in the way users interact with them.


Abstract We describe two caddisflies from mid-Cretaceous Burmese amber, with unusual hair fan modifications on the legs: Cretaganonema dongi nov. gen. et nov. sp. (Calamoceratidae) possesses greatly elongated hind legs with hairtufts at the tarsal apex; Cretahelicopsyche liuyani nov. gen. et nov. sp. (Helicopsychidae) bears a hair-fan on the tibia of the middle legs. The functions of the leg modifications in the fossils are unknown, possibilities are briefly discussed. The species described here represent the third known calamoceratid and the first helicopsychid from the Cretaceous, thus increasing our scant knowledge on the Cretaceous Trichoptera biota and their adaptations.


This paper analyses the ways in which eight national Danish news brands label their online editorial-looking advertising with labels, logos, bylines, and explanatory disclaimer texts. The practices are different and uneven, and whilst they largely comply with current legislation on labelling of advertising, they do little to help users build schemas and literacy to understand and handle this new form of advertising. The paper concludes by pointing to a number of questions that should be explored in future research on the ability of readers to recognise editorial-looking advertising as advertising.


Using the racial integration of national labor unions as a case study, I find that courts played an important and meaningfully autonomous role in integrating unions while elected officials largely failed to act. Courts, unlike elected officials, offered civil rights groups relatively easy access to the legal agenda. In response to thousands of cases in federal courts, judges rewrote key civil rights statutes, oversaw the implementation of their rulings, and used attorneys' fees and damage awards to impose significant financial costs on resistant unions. Court power was the product of multiple and historically contingent forces that involved the interaction of elected officials, civil rights activists, and the legal community. Elected officials delegated to the courts the power to enforce civil rights laws and tacitly endorsed procedural changes that augmented the courts' institutional powers and the legal community's professional influence. In response, judges and lawyers promoted and implemented a civil rights agenda far beyond the endorsement of elected officials. An historical–institutional approach helps explain how courts achieved and wielded independent power and the consequences of their action for civil rights, labor unions, and the American state.Thanks for very helpful comments go to Amy Bridges, Kerstin Carlson, Malcolm Feeley, Beth Garrett, Howard Gillman, Mark Graber, Jeff Haydu, David Karol, Ken Kersch, David Mayhew, Jim Morone, Shehzad Nadeem, Ruth O'Brien, Corey Robin, Pam Singh, John Skrentny, Mark Tushnet, Rick Valelly, Keith Whittington, Janelle Wong, the APSR reviewers, and Lee Sigelman. The University of California's Institute for Labor and Employment provided generous financial assistance.


Whilst next generation sequencing is frequently used to whole genome sequence bacteria from cultures, it is rarely achieved direct from sample, and even more rarely performed in a clinically relevant time frame. To demonstrate the potential of direct from blood sequencing a bacteraemia model was developed, using defibrinated horse blood to model whole human blood infections. Sample processing included removal of erythrocytes and lysis of white blood cells, before rapid and accurate none targeted amplification. The rapid approach to allow direct from sample sequencing, allowed greater than 92% genome coverage of pathogens of interest whilst limiting the sequencing of host genome (less than 7% of all reads). Analysis of de novo assembled reads allowed accurate genotypic antibiotic resistance prediction. The sample processing would be easily applicable to multiple sequencing platforms. Overall this model provides evidence that it is currently possible to rapidly produce whole genome bacterial data from low cell number sterile site infections.


Investigational NO-related therapeutic agents span the range from prodrugs that elevate NO levels, to scavengers of NO, and inhibitors of endogenous NO synthesis. Related agents that influence nitrogen oxides, in addition to NO itself, are also to be considered. Organic nitrates have been used for over 130 years in cardiovascular therapy and hybrid nitrates continue to lead the way in clinical development for an increasing range of disease states. Selectivity for inhibition of NO synthase (NOS) isoforms is a continuing goal. Conversely, N-hydroxyarginine derivatives are substrates for NOS and represent a new NO donor class. Diazeniumdiolate (NONOate) NO donors have been essential for understanding of NO biology and are being developed as NO donor and HNO donor prodrugs including as photolabile sources. N-Hydroxyurea has been used as a cancer drug for decades and is approved for sickle cell disease treatment, but also provides a lead compound for design of NO and HNO donors. Nitroaliphatics and nitrosoaliphatics also represent chemical classes that include NO donors and exhibit biological activity that mimics that of NO. Nitroprusside has been in use since the 1920's and metal ion complexes continue to be explored, including as caged NO donors. Clear and exciting opportunities exist for new therapies based upon NO-related drugs. Despite the extensive clinical use of NO donor drugs and the role of NOS activation in the action of several prescription medications, challenges remain to the development of new NO-related therapeutics, but these are surmountable and are outweighed by the opportunities.


In 1989, the then eight largest CPA firms entered a partnership with the American Accounting Association (AAA) leadership to form the Accounting Education Change Commission (AECC) to provide leadership in changing accounting education so it will be responsive to the needs of those entering a variety of career paths and to address the educational needs of the principal stakeholders in accounting education. This article examines the developments over the past decade and a half in the United States and uses the eight proposed initiatives of the institutions receiving grantsfromAECC as a benchmark for implementation by a Hong Kong academic institution. The environmental difference between the United States and Hong Kong is pointed out. The Government of Hong Kong Special Administrative Region has directed all tertiary institutions to commence a four-year undergraduate degree programme (currently three years) within five years. If the Departments of Accounting of these institutions see the merit of the U.S. accounting education reform and particularly, the initiatives of AECC, then the latter used as a benchmark in programme development by a


In this paper we present a technique for the modelling and animation of cartoon hair. In our approach the primary shape and motion of the hair is defined by an animated NURBS volume, along whose surface are generated clumps of hair geometry. The basis of these hair clumps is formed by key hair curves that are grown along the isocurves of the originating surface and which follow its motion. Particle dynamics are applied to each key hair and blended with initial animation using springs. Profile curves are then extruded along the length of the hey hairs to create the geometry details of the hairdo. The finished animated hairdo is rendered nonphotorealistically in cartoon style shading


In this paper, I deploy an argument that I have developed in a number of recent papers to show that the most influential version of legal positivism - that associated with H.L.A. Hart - fails. The argument's engine is a requirement that a constitutive account of legal facts must meet. According to this rational-relation requirement, it is not enough for a constitutive account of legal facts to specify non-legal facts that modally determine the legal facts. The constitutive determinants of legal facts must provide reasons for the obtaining of the legal facts (in a sense of "reason" that I develop). I show that the Hartian account is unable to meet this requirement. That officials accept a rule of recognition does not by itself constitute a reason why the standards specified in that rule are part of the law of the community. I argue that it is false that understanding the explanatory significance of officials' acceptance of a rule is part of our reflective understanding of the nature of law. A second project of the paper is to respond to a family of objections that challenge me to explain why normative facts and descriptive facts together are better placed to provide reasons for legal facts than descriptive facts alone. A unifying theme of the objections is that explanations have to stop somewhere; descriptive facts, it is suggested, are no worse a stopping place than normative facts. The paper also spells out a consequence of the rational-relation requirement: if an account of what, at the most basic level, determines legal facts is true in any possible legal system, it is true in all possible legal systems. For example, if a Hartian account of legal facts is true in any possible legal system, it is true in all possible legal systems. I use this all-or-nothing result in my critique of a Hartian account, but the result is of interest in its own right.


A common view among ancient historians about Roman attentiveness to children's psychological development needs reconsideration. The view holds that Romans ignored children's cognitive ontogeny, perceiving early childhood as a largely undifferentiated life stage. A separate but related issue is the problematic claim that Roman childhood was entirely a matter of social construction. I present evidence from over four hundred years of Roman writing to make three points against Roman neglect of children and radical social construction. First, a consensus (granted our limited number of sources) about "developmental psychology" prevailed from the late republic to late antiquity. Second, this consensus is consistent with modern findings and theories. In particular, the Roman material maps onto a developmental timeline featuring a "2-month revolution," when the infant engages in dyadic protoconversations with adults, and a "9-month revolution," when the infant shares attention triadically with adults toward third objects. In the Roman consensus, both dyadic protoconversations and triadic joint attention were central to cultural learning. Third, when the Roman consensus about children's minds did change, it was because of the Christian doctrine of original sin, according to which even newborns were psychologically corrupt. Nonetheless, I argue, this rupture in the Roman consensus does not entail that we should suppose childhood to have been entirely a social construction or merely a projection of a religious or other ideology. Rather, any construction of childhood-even the late-antique Christian one-will necessarily rest upon a foundation of, and thus be constrained by, certain inescapable biological and psychological "givens." (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The current set of meta-analyses elucidates the long-term psychiatric, psychosocial, and physical consequences of the Holocaust for survivors. In 71 samples with 12,746 participants Holocaust survivors were compared with their counterparts (with no Holocaust background) on physical health, psychological well-being, posttraumatic stress symptoms, psychopathological symptomatology, cognitive functioning, and stress-related physiology. Holocaust survivors were less well adjusted, as apparent from studies on nonselected samples (trimmed combined effect size d = 0.22, 95% CI [0.13, 0.31], N = 9,803) and from studies on selected samples (d = 0.45, 95% CI [0.32, 0.59], N = 2,943). In particular, they showed substantially more posttraumatic stress symptoms (nonselect studies: d = 0.72, 95% CI [0.46, 0.98], N = 1,763). They did not lag, however, much behind their comparisons in several other domains of functioning (i.e., physical health, stress-related physical measures, and cognitive functioning) and showed remarkable resilience. The coexistence of stress-related symptoms and good adaptation in some other areas of functioning may be explained by the unique characteristics of the symptoms of Holocaust survivors, who combine resilience with the use of defensive mechanisms. In most domains of functioning no differences were found between Israeli samples and samples from other countries. The exception was psychological well-being: For this domain it was found that living in Israel rather than elsewhere can serve as a protective factor. A biopsychological stress-diathesis model is used to interpret the findings, and future directions for research and social policy are discussed.

http://depts.washington.edu/bcpt/docs/Barel et al, Surviving the Holocaust Psych Bull 2010  136 5 677 698.pdf


Several studies have demonstrated the impact that the quality of teacher education has on teaching and student performance. The assessment of the competences of higher education teachers by students is one way of assessing the quality of teachers and, therefore, the quality of public higher education itself. It is therefore pertinent to carry out empirical studies that make it possible to understand how students evaluate teachers' competences. The objective of this study was to evaluate the competences of higher education teachers in the public university of East Timor, based on the students' opinion. Using a random sample of 342 students enrolled in four of the nine faculties of the National University of East Timor (UNTL), surveys were carried out to evaluate the pedagogical, professional, social and personality traits of teachers. The results showed a positive evaluation by the students, although the objectives of the National Strategic Plan for Education 2011-2030 (METL, 2011) have not yet been fully achieved.


Cancer is a pathological condition in which the balance between cell growth and death is disordered. Various molecules have been reported to be involved in the oncogenic process of invasion, metastasis and resistance to treatment. An exponential growth in the collection of genomic and proteomic data in the past 20 years has provided major advances in understanding the molecular mechanisms of human cancer, which has been applied to diagnostic and treatment strategies. Targeted therapies have been developed and adopted, particularly for advanced, refractory or recurrent cancers, depending on individual molecular profiles. The aim of the present review is to provide a report of the current literature regarding the molecular biology of gynecological cancers.


This article traces the fascinating history of early efforts to identify defendants and their prior convictions as well as the evolving use of prior convictions in aggravating punishment; examines how contemporary repeat offender penalties fall short of punishment goals and contribute to the racially lopsided profile of punishment today; and critiques potential justifications for the prior conviction exception to the rule in Apprendi v. New Jersey, arguing that the exception should be abandoned. The article summarizes empirical research testing the relationship between prior convictions and examining the efficacy of repeat offender sentences in reducing recidivism; collects commentary on the use of risk prediction in sentencing; surveys state-by-state eighteenth century authority that belies the claim that denying element status to prior convictions that raise the range of punishment is a longstanding tradition; evaluates the weaknesses of the case law underlying the Court's decision in Almendarez-Torres; argues that defendants need not be prejudiced when prior convictions are treated as elements; and observes that the original reason that a very small number of states in the nineteenth century stopped requiring prior convictions to be treated as elements – namely, that an offender's criminal history was often unknown unless or until a warden recognized him – no longer exists. An earlier version of the article was delivered as the Barrock Lecture on Criminal Law at the Marquette University Law School.


Current USDA forecasts indicate that US farms are entering a period of lower net farm income, following historical highs in 2012 and 2013. A sustained period of lower net farm income may lead to lower farmland values as returns to farmland decline, raising questions about whether specific sectors of the U.S. farm economy will become financially stressed in this environment. Using USDA's 2013 Agricultural Resource Management Survey data (ARMS) with new imputed farm debt data we assess financial stress for both borrowers and lenders under scenarios of lower net farm income and land values. To accomplish this, we use both financial ratio analysis and a synthetic credit rating model. We then examine scenarios of a 25% drop in net farm income, and a 35% drop in land values. Our results suggest that the overall financial health of the U.S. farm economy is relatively strong, however some sectors remain vulnerable. We find that a drop of 35% in farmland values will negatively impact specific sectors, including: peanut, tobacco, and poultry farms; highly leveraged farms, farms with gross sales over 1 million dollars, and farmers who rent a majority of their farmland.


Semantically related mediators form a hierarchical structure based on the definition of views in each mediator, since a view in a mediator is defined by views in other mediators or base tables in several local information servers. A global query is transformed into a set of its sub-queries; and, each sub-query is the unit of evaluation in an information server or a child mediator. Therefore, it is possible to speed up the execution of a global query if the previous results of frequently requested sub-queries are materialized in a mediator. However, the integrating schema in a mediator can be incrementally modified; and, the evaluation frequency of a global query can also be continuously varied. In order to select the optimized set of materialized sub-queries, with respect to their current evaluation frequencies, the proposed method applies a decay factor for modeling the recent access behavior of each sub-query. As a result, it is possible to adjust the optimized set of materialized sub-queries adaptively according to the recent changes in the evaluation frequencies of sub-queries. Consequently, this paper proposes an algorithm for selecting the optimized set of sub-queries to be materialized in each mediator of a hierarchical mediator system adaptively such that the overall query evaluation cost of the hierarchical mediator system can be minimized at all times.


The object of this work was to study the effect of N-nitrosomethylurea (NMU), N-nitrosoethylurea (NEU) and N-nitrosodimethylurea (NDMU) taken at different concentrations on the ability of Mycobacterium rubrum to synthesize carotenoids. In contrast to NEU and NDMU, NMU modified the morphology of the organism and intensified the rate of carotene synthesis. The method of stepwise selection with NMU was used to obtain a mutant producing 7050 micrograms/g of carotenoids and capable of synthesizing pigments which were not typical of the wild strain (auroxanthine, cryptoxanthine, lycopine, leprotine and neoxanthine).


We have numerically simulated dynamic ruptures along a "slip‐weakening" megathrust fault with a subducted seamount of realistic geometry, demonstrating that seamounts can act as a barrier to earthquake ruptures. Such barrier effect is calculated to be stronger for increased seamount normal stress relative to the ambient level, for larger seamount height‐to‐width ratio, and for shorter seamount‐to‐nucleation distance. As the seamount height increases from 0 to 40% of its basal width, the required increase in the effective normal stress on the seamount to stop ruptures drops by as much as ~20%. We further demonstrate that when a seamount is subducted adjacent to the earthquake nucleation zone, coseismic ruptures can be stopped even if the seamount has a lower effective normal stress than the ambient level. These results indicate that subducted seamounts may stop earthquake ruptures for a wide range of seamount normal stress conditions, including the case of the thrust fault being lubricated by seamount‐top fluid‐rich sediments, as suggested from observations in the Japan and Sunda Trenches.


One of the most pressing problems of current constitutional law in the aftermath of September 11 is how to balance constitutional rights and national security interests. No one however seems to pause and ask should we balance individual rights and national security interests and if so when. One of the reasons for this is the widespread acceptance of what I shall term in this Article, the balancing consciousness: the view that every problem can and should be solved through balancing conflicting considerations. This Article demonstrates that the balancing consciousness is misleading. Not every problem can and should be solved through balancing conflicting considerations. Instead of the balancing consciousness, this Article argues for a dual model, which envisions two logical forms of decision-making - balancing and non-balancing. This model has far-reaching implication for constitutional adjudication. The dual model is based on a distinction between two levels, or orders, of considerations: first-order considerations, and second-order considerations. The Article argues that constitutional rights can be divided between these two types of considerations, and that balancing between a constitutional right and a governmental interest is appropriate only when the constitutional right is of the first order, not when it is of the second order. Interestingly this insight, concerning the limited scope of balancing, was once acknowledged in constitutional jurisprudence, but has since been abandoned. This Article is therefore also a call for reinstalling the original scope of balancing as it was once installed in American constitutional law.


Background Oral cancer survival rates increase significantly when it is detected and treated early. Unfortunately, clinicians now lack tests which easily and reliably distinguish pre-malignant oral lesions from those already transitioned to malignancy. A test for proteins, ones found in non-invasively-collected whole saliva and whose abundances distinguish these lesion types, would meet this critical need. Methodology/Principal Findings To discover such proteins, in a first-of-its-kind study we used advanced mass spectrometry-based quantitative proteomics analysis of the pooled soluble fraction of whole saliva from four subjects with pre-malignant lesions and four with malignant lesions. We prioritized candidate biomarkers via bioinformatics and validated selected proteins by western blotting. Bioinformatic analysis of differentially abundant proteins and initial western blotting revealed increased abundance of myosin and actin in patients with malignant lesions. We validated those results by additional western blotting of individual whole saliva samples from twelve other subjects with pre-malignant oral lesions and twelve with malignant oral lesions. Sensitivity/specificity values for distinguishing between different lesion types were 100%/75% (p = 0.002) for actin, and 67%/83% (p<0.00001) for myosin in soluble saliva. Exfoliated epithelial cells from subjects' saliva also showed increased myosin and actin abundance in those with malignant lesions, linking our observations in soluble saliva to abundance differences between pre-malignant and malignant cells. Conclusions/Significance Salivary actin and myosin abundances distinguish oral lesion types with sensitivity and specificity rivaling other non-invasive oral cancer tests. Our findings provide a promising starting point for the development of non-invasive and inexpensive salivary tests to reliably detect oral cancer early.


Abstract : One-quarter of the population in Miami-Dade County, Florida, lacks health insurance, a fraction well above the national average (about one-sixth of the nation's population is without health insurance). To address the problem of financing health care for the uninsured in Miami-Dade and elsewhere, the state of Florida in 1991 passed legislation allowing local jurisdictions to impose a surtax on sales. The legislation restricted the use of the proceeds of any Miami-Dade County surtax to support the activities of the county's sole public health-care facility, Jackson Memorial Hospital (JMH). Miami-Dade County voters approved the surtax, which has helped stabilize the financially troubled hospital. In the past ten years, JMH has grown and improved financially and is a leader in treating eye disorders and pediatric patients. Recently, advocates for better access to health care by the poor, along with representatives from other not-for-profit hospitals, have suggested that surtax revenues be distributed across a wider range of institutions. But do hospitals other than JMH provide uncompensated care, and at what level? And might the greater access to surtax-funded care at JMH be causing patients to pass up facilities much nearer to their homes and travel long distances for care?


American industrial enterprises long organized their production processes in rigid hierarchies in which production-level employees had little discretion or decision making authority. Recently, however, many firms have adopted participatory management programs purporting to give workers a substantially greater degree of input into corporate decisions. Quality circles, self-directed work teams, and employee representation on the board of directors are probably the best-known examples of this phenomenon. These forms of workplace organization have garnered considerable attention from labor lawyers and economists, but relatively little from corporate law academics. This is unfortunate, both because the tools routinely used by corporate law academics have considerable application to the problem and because employee participation is ultimately a question of corporate governance. According to conventional academic wisdom, perceptions of procedural justice are important to corporate efficiency. Employee voice promotes a sense of justice, increasing trust and commitment within the enterprise and thus productivity. Workers having a voice in decisions view their tasks as being part of a collaborative effort, rather than as just a job. In turn, this leads to enhanced job satisfaction, which, along with the more flexible work rules often associated with work teams, results in a greater intensity of effort from the firms workers and thus leads to a more efficient firm. Although this view of participatory management has become nearly hegemonic, the academic literature nevertheless remains somewhat vague when it comes to explaining just why employee involvement should have these beneficial results. In contrast, my article presents a clear explanation of why some firms find employee involvement enhances productivity and, perhaps even more important, why it fails to do so in some firms. Despite the democratic rhetoric of employee involvement, participatory management in fact has done little to disturb the basic hierarchial structure of large corporations. Instead, it is simply an adaptive response to three significant problems created by the tendency in large firms towards excessive levels of hierarchy. First, large branching hierarchies themselves create informational inefficiencies. Second, informational asymmetries persist even under efficient hierarchial structures. Finally, excessive hierarchy impedes effective monitoring of employees. Participatory management facilitates the flow of information from the production level to senior management by creating a mechanism for by-passing mid-level managers, while also bringing to bear a variety of new pressures designed to deter shirking.


New, accurately located and well‐preserved agnostid trilobite material has been collected from the type locality of the Drumian (middle Cambrian, Miaolingian) Manuels River Formation, Newfoundland, Canada. The well‐exposed grey to black shales containing the fauna were deposited on the former microcontinent Avalonia. Four interval zones for the succession are proposed, namely, the Tomagnostus fissus, Hypagnostus parvifrons, Ptychagnostus atavus and Ptychagnostus punctuosus zones. The Tomagnostus fissus and Ptychagnostus atavus zones are distinct from each other, which leads to a significantly shorter and stratigraphically higher Ptychagnostus atavus Zone compared with other sections (Scandinavia, South China, Utah and Nevada, Greenland). Specimens of Ptychagnostus atavus, however, occur abundantly, with 107 specimens identified in a short interval of the succession. The Ptychagnostus punctuosus Zone can be correlated globally. The faunal assemblage is comparable to that of Scandinavia, Greenland and England. Ptychagnostus affinis is recorded for the first time from Avalonia. The 1408 collected specimens were assigned to the suborders Agnostina and Eodiscina and to the families Peronopsidae and Ptychagnostidae, and Condylopygidae and Eodiscidae, respectively, with the following species: Peronopsis fallax (Linnarsson), Peronopsis scutalis (Hicks), Hypagnostus parvifrons (Linnarsson), Ptychagnostus punctuosus (Angelin), Ptychagnostus affinis (Brøgger), Ptychagnostus atavus (Tullberg), Tomagnostus fissus (Lundgren), Tomagnostus perrugatus (Grönwall), Pleuroctenium granulatum (Barrande) and Eodiscus punctatus (Salter).


As a first step in the development of a gene therapy approach to epilepsy, we evaluated the ability of adenovirus vectors to direct the transfer into and expression of a marker gene in human brain slices obtained from patients undergoing surgery for medically intractable epilepsy. Following injection of adenovirus vectors containing the Escherichia coli lacZ gene into hippocampal and cortical brain slices, lacZ mRNA, beta-galactosidase protein, and enzymatic activity were detected, confirming successful gene transfer, transcription, and translation into a functional protein. Transfected cells were predominantly glial, with some neurons expressing beta-galactosidase as well. These results support the potential of adenovirus vectors to transfer genetic information into human epileptogenic brain, resulting in expression of the gene into a functional protein. These findings also have implications for the development of gene therapy approaches to certain seizure disorders. A number of potential therapeutic approaches are discussed, including the elevation of inhibitory neurotransmitter or neuropeptide levels, expression or modulation of postsynaptic receptors, and manipulation of signal transduction systems.


Through much of the earlier part of the Middle Cenomanian the sea-levels in western Asia, northern Europe and the Western Interior of the U.S.A. were lower than during the later Early Cenomanian and most of the later Middle Cenomanian. In north-west Europe the first sign of this Mid-Cenomanian Eustatic Low was just before the end of the Zone of Cunningtoniceras inerme . There was then an abrupt and strong fall of sea-level at the base of Milankovitch couplet C 1, early in the Subzone of Turrilites costatus . Sea-level continued to be low through couplets C 1 to C 3 for some 60,000 years: this is the Mid-Cenomanian Regressive Trough. In western Germany it has been distinguished as the Primus Event. In north Texas and the Western Interior of the U.S.A. the Trough occurred in the Zone of Conlinoceras tarrantense which can be dated as 95.78 [plus-minus] 0.61 Ma.A later regressive trough occurred at the start of the Subzone of Turrilites acutus , which is marked by the Mid-Cenomanian Event in Germany. The overall lower sea-level from late in the Zone of C. inerme to early in the Subzone of T. acutus is the Mid-Cenomanian Eustatic Low. It lasted some 300,000 years.


This paper analyses the performance of Indonesia's economy since the early 1980s using Thirlwall's balance-of-payments-constrained (BoPC) growth model, estimated in state-space form to take account of the varying nature of the income elasticities of demand for exports and imports. Results indicate that after peaking in the mid 1980s at above 10 percent, Indonesia's BoPC growth rate has declined significantly, to about 3 percent in recent years. This is the result of changes in the three components of this growth rate: the income elasticities of demand for exports and imports, and the growth rate of world income, all three significantly lower. Especially worrisome for Indonesia's future is the decline in the income elasticity of demand for exports, a variable that summarizes the non-price competitiveness of its exports. This is the consequence of the lack of progress in upgrading the export basket and increasing its sophistication, with natural resources and low value-added manufacturing still dominating the country's exports. Focusing on the two income elasticities, the analysis shows that their determinants are variables that proxy the economy's structural changes (for example, the manufacturing employment share) and within-sector productivity growth (for example, complexity of the economy, gross fixed capital formation as a share of GDP).


Background: The Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study offers an important opportunity to advance cancer research by extending the original WHI studies to examine survivorship in women diagnosed with cancer during their participation in WHI. Methods: The goals of LILAC are to (i) obtain cancer treatment information and long-term cancer outcomes for women diagnosed with one of eight selected cancers (breast, endometrial, ovarian, lung, and colorectal cancers, and melanoma, lymphoma, and leukemia); (ii) augment the existing WHI biorepository with fixed tumor tissue from the solid tumor sites for cancers diagnosed since 2002; and (iii) develop, refine, and validate methods to use administrative data to capture treatment and recurrence data. Methods for accomplishing these goals are described, as are results from the initial LILAC participant survey. Results: A total of 9,934 WHI participants living with cancer were eligible for LILAC participation, of which 78% (N = 7,760) agreed to participate. Among the three most prevalent cancer types, 54% are breast cancer survivors, 11% are melanoma survivors, and 10% are survivors of colorectal cancer. Conclusions: In addition to describing this resource, we present pertinent lessons that may assist other investigators interested in embedding survivorship research into existing large epidemiologic cohorts. Impact: The LILAC resource offers a valuable opportunity for researchers to study cancer survivorship and issues pertinent to cancer survivors in future studies. Cancer Epidemiol Biomarkers Prev; 27(2); 125–37. ©2017 AACR.


Purpose We present salvage intracranial stenting after recanalization failure with retrievable stent in acute cerebral artery occlusion patients. Methods Fourteen consecutive patients who have recanalization failure with clot retrievable stent in acute cerebral artery occlusion were underwent salvage intracranial stenting for prevention of reocclusion with deployment of same retrievable stent. Results At baseline, mean age was 71.9 years and mean initial NIHSS score was 15.5. A recanalization to TICI 2 or 3 was achieved in 7 patients (50%) after salvage stenting and 4 of this 7 patients had a good outcome (mRS ≤2). But, another seven patients had recanalization failure, 3 of this 7 patients expired due to aggravation of cerebral infarction. Conclusions The initial result of salvage stenting for recanalization failure patients makes it an attractive strategy for selected patients. But, large studies are needed to validate for this trial. Disclosures K. Jang: None. S. Park: None. D. Jang: None. B. Moon: None. Y. Han: None. Y. Park: None.


Blends of wool and moisture management fibres such as Coolmax and Finecool have been prepared to produce innovative yarns with specific functionalities. These yarns have been used to produce knitted fabrics and their performance was evaluated, including vertical and horizontal wicking. The influence of wool fibre proportion on the performance of each blend is analyzed. It is observed that the Coolmax based fabrics show the best capillarity performance, and the wool fibre based fabrics show lower water absorption performance.


Australia's Office of the Gene Technology Regulator (OGTR) is pushing to change the definition of genetically modified organisms (GMOs). The proposed changes would remove from regulation some GMOs that are presently subject to regulation by the OGTR. At present GMOs are subject to risk analysis, to safety evaluations, and to GM labelling if used in food. The proposed regulations, if they are not disallowed by the Australian Parliament, will water down the definition of GMOs in Australia, will have Australia applying definitions of GMOs that are different from major trading partners, and they risk damaging the clean and green export reputation of Australia's food and agriculture sectors. The GM proposed deregulation would be bad science and bad deregulation. Australia is a minnow in the world of GMOs, accounting for just 0.4% of the global GMO agricultural hectares (Australian organic agriculture accounts for 51% of global organic agriculture). GMOs account for just 0.2% of Australia's agricultural hectares (organic accounts for 8.8%). Food shoppers of the world reject GM food, led by Chinese consumers of whom 60% reject GM food. OGTR figures reveal that only 10% of Australians agree with the proposition that GMOs are "safe". GMOs require labelling in Australia, and a direct consequence is that there are no GM food products on Australian supermarket shelves. The global GMO industry is founded on the lie of "substantial equivalence" where GM proponents insist to regulators that their GMO is the "same" as the organism from which it is derived, but to the Patent Office that their GMO is "novel, unique, different, and a real invention" and that it thereby warrants patent protection. Recent failures of deregulation, including London's Grenfell Tower, Melbourne's Lacrosse Apartments, and Sydney's Opal Tower, highlight the follies of deregulation, and the reality that deregulation privatises profits and socialises costs. The case has not been made for deregulating of GMO in Australia, and there are substantial uncalibrated costs, risks and downsides for Australia's food and agriculture exports industry. The proposed regulations ought to be disallowed.


Supplemental digital content is available in the text. Abstract Pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS) is infrequent, but children might present as a life-threatening disease. In a systematic quantitative review, we analyzed 11 studies of PIMS-TS, including 468 children reported before July 1, 2020. We found a myriad of clinical features, but we were able to describe common characteristics: previously healthy school-aged children, persistent fever and gastrointestinal symptoms, lymphopenia, and high inflammatory markers. Clinical syndromes such as myocarditis and Kawasaki disease were present in only one third of cases each one. Pediatric intensive care unit admission was frequent, although length of stay was less than 1 week, and mortality was low. Most patients received immunoglobulin or steroids, although the level of evidence for that treatment is low. The PIMS-ST was recently described, and the detailed quantitative pooled data will increase clinicians' awareness, improve diagnosis, and promptly start treatment. This analysis also highlights the necessity of future collaborative studies, given the heterogeneous nature of the PIMS-TS.


Explosive forming is one of the effective metal forming methods using underwater shock wave generated by the detonation of an explosive. We have done the experiment of eccentric spherical free metal forming by this method. This free metal forming process does not use require expensive metal die. We used simple metal die with only circular edges and considered the metal plate formed to required shape using this method. It was possible to change the pressure distribution applied on the metal plate by changing the set-up position of explosive and the shape of the device. We have considered this method to cause lessen cost in the small production by various types of metal forming process. In this paper, we introduce the method of eccentric spherical free metal forming using underwater shock wave and present the experimental results.


Peptides represent a promising format for the development of therapeutics since they combine the advantages of proteins and small molecules. Several techniques based on rational design or in vitro evolution can be used to develop peptides as therapeutics. A limitation of peptides is a rapid clearance from the blood circulation when applied intravenously, preventing their application in therapies that require prolonged drug exposure. Several methods have been tested to extend the in vivo half-life of peptides, including fusion to long-lived serum proteins, PEGylation and conjugation to non-covalent albumin-binding ligands. A particularly attractive approach is a "piggy back" strategy in which peptides bind via a ligand to albumin without increasing significantly their small size. Acylation with fatty acids is the most successful strategy for delaying peptide clearance. The attachment of either myristic or palmitic acid to insulin and GLP-1 led to the approval of three acylated peptide drugs as daily injectable. Nevertheless, acylated conjugates generally present low solubility and weak affinity for albumin. Peptides have been explored as an alternative, as their format offers multiple approaches for affinity maturation as well as an easier synthesis of the conjugates. However, the albumin-binding peptides developed so far do not overcome the disadvantages faced with fatty acids. The first aim of my project was the development of an albumin-binding tag that combines the favorable properties of both fatty acids and peptides, and overcomes at the same time their limitations. This tag was engineered in order to have i) a high affinity for human albumin, ii) a high solubility in physiological solutions, and iii) an efficient synthesis in conjunction with therapeutic peptides. Towards this goal, I created a chimeric format consisting of a fatty acid combined with a short linear peptide. After iterative rounds of affinity screening, an evolved peptide-fatty acid tag able to bind human, rat and rabbit albumin with Kd values of 39, 220 and 320 nM, respectively, was obtained. This makes it the best albumin-binding tag among all of the peptide- or fatty acid-based ligands that have been developed. This tag can be easily synthesized in conjugation with peptides on standard automated synthesizers. Finally, it exhibits a high solubility due to four negatively charged amino acids in the peptide sequence, despite the presence of a 16-carbon palmitic hydrophobic tail. The second aim of my project was the application of this tag to three bioactive bicyclic peptides, previously developed in the laboratory, in order to improve their in vivo half-lives. I demonstrated that the conjugation has, overall, a mild impact on peptides' binding affinity towards their targets and human albumin, and increases their proteolytic stability. Pharmacokinetic experiments showed that the tag extends the elimination half-life of bicyclic peptides in rats and rabbits approximately 25-fold to over seven and five hours, respectively. Tag conjugation to a bicyclic peptide targeting coagulation factor XII led to an efficient inhibition of coagulation in rabbits up to eight hours, suggesting a potential application in humans as anti-thrombotic drug. These results indicated that the tag will efficiently prolong the exposure of target proteins to bioactive peptides in humans due to its higher affinity for human albumin than that of rat and rabbit.


The effect of bisamidinium type dications as tectons on the crystal formation of hydroxyapatite was investigated. Evidence of the structural interactions between three tectons with different numbers and locations of H-bond donor sites and hydroxyapatite crystals has been shown. Some correlations between the molecular structure of the organic tectons and the morphology of hydroxyapatite crystals were observed. These results may be of interest in the control of hydroxyapatite morphogenesis as well as its surface properties.