Scaling Behavior and Strain Dependence of In-Plane Elastic Properties of Graphene.

We show by atomistic simulations that, in the thermodynamic limit, the in-plane elastic moduli of graphene at finite temperature vanish with system size L as a power law L(-η(u)) with η(u)≃0.325, in agreement with the membrane theory. We provide explicit expressions for the size and strain dependence of graphene's elastic moduli, allowing comparison to experimental data. Our results explain the recently experimentally observed increase of the Young modulus by more than a factor of 2 for a tensile strain of only a few per mill. The difference of a factor of 2 between the measured asymptotic value of the Young modulus for tensilely strained systems and the value from ab initio calculations remains, however, unsolved. We also discuss the asymptotic behavior of the Poisson ratio, for which our simulations disagree with the predictions of the self-consistent screening approximation.

Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome.

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.

Specific detection of Salmonella enterica and Escherichia coli strains by using ELISA with bacteriophages as recognition agents.

The use of bacteriophages, instead of antibodies, in the ELISA-based detection of bacterial strains was tested. This procedure appeared to be efficient, and specific strains of Salmonella enterica and Escherichia coli could be detected. The sensitivity of the assay was about 10(5) bacterial cells/well (10(6)/ml), which is comparable with or outperforms other ELISA tests detecting intact bacterial cells without an enrichment step. The specificity of the assay depends on the kind of bacteriophage used. We conclude that the use of bacteriophages in the detection and identification of bacteria by an ELISA-based method can be an alternative to the use of specific antibodies. The advantages of the use of bacteriophages are their environmental abundance (and, thus, a possibility to isolate various phages with different specificities) and the availability of methods for obtaining large amounts of phage lysates, which are simple, rapid, cheap, and easy.

Theoretical study of the nucleation/growth process of carbon clusters under pressure.

We used molecular dynamics and the empirical potential for carbon LCBOPII to simulate the nucleation/growth process of carbon clusters both in vacuum and under pressure. In vacuum, our results show that the growth process is homogeneous and yields mainly sp(2) structures such as fullerenes. We used an argon gas and Lennard-Jones potentials to mimic the high pressures and temperatures reached during the detonation of carbon-rich explosives. We found that these extreme thermodynamic conditions do not affect substantially the topologies of the clusters formed in the process. However, our estimation of the growth rates under pressure are in much better agreement with the values estimated experimentally than our vacuum simulations. The formation of sp(3) carbon was negligible both in vacuum and under pressure which suggests that larger simulation times and cluster sizes are needed to allow the nucleation of nanodiamonds.

Solubility of molecular crystals: polymorphism in the light of solubility theory.

The thermodynamic theory of solubility of molecular crystals in solvents is reviewed with an emphasis on solutes showing polymorphism as in case of many pharmaceuticals. The relation between solubility and binary phase diagrams of the solute solvent system is treated. The astonishing variety of possible solubility curves as a function of temperature is explained using simple models for the solution thermodynamics assuming no mixing between the solvent and solute in the solid phase, though including the case of solvates or pseudo polymorphs. In passing a new method is introduced that allows to estimate the transition temperature of enantiotropically related polymorphs from melting temperatures and enthalpies of the polymorphs.

Role of the bacteriophage lambda exo-xis region in the virus development.

Various processes of bacteriophage lambda development in Escherichia coli cells bearing either the whole lambda exo-xis region (with truncated, thus nonfunctional, exo and xis genes) or particular genes from this region were investigated. The presence of either the exo-xis region or the ea8.5 gene on a plasmid resulted in formation of fuzzy plaques by infecting phage. Both efficiency of plating and efficiency of lysogenization were decreased in such hosts. On the other hand, neither the efficiency of adsorption nor intracellular lytic development of the infecting phage (measured in one-step-growth experiments) was affected while significantly more host cells survived the infection, when containing the exo-xis region. Although no effects of the exo-xis region on the activity of the p (L) promoter was detected, this region contributed to a decreased transcription from the cII-stimulated promoters p (I), p (aQ) and p (E). These results, together with the results of measurement of efficiency of plating of phages bearing mutations in cI, cII and cIII genes on hosts containing the exo-xis region, strongly suggest that genes from this region (especially ea8.5) are involved in the regulation of bacteriophage lambda development at the stage of the lysis-vs.-lysogenization decision.

On the definition of a Monte Carlo model for binary crystal growth.

We show that consistency of the transition probabilities in a lattice Monte Carlo (MC) model for binary crystal growth with the thermodynamic properties of a system does not guarantee the MC simulations near equilibrium to be in agreement with the thermodynamic equilibrium phase diagram for that system. The deviations remain small for systems with small bond energies, but they can increase significantly for systems with large melting entropy, typical for molecular systems. These deviations are attributed to the surface kinetics, which is responsible for a metastable zone below the liquidus line where no growth occurs, even in the absence of a 2D nucleation barrier. Here we propose an extension of the MC model that introduces a freedom of choice in the transition probabilities while staying within the thermodynamic constraints. This freedom can be used to eliminate the discrepancy between the MC simulations and the thermodynamic equilibrium phase diagram. Agreement is achieved for that choice of the transition probabilities yielding the fastest decrease of the free energy (i.e., largest growth rate) of the system at a temperature slightly below the equilibrium temperature. An analytical model is developed, which reproduces quite well the MC results, enabling a straightforward determination of the optimal set of transition probabilities. Application of both the MC and analytical model to conditions well away from equilibrium, giving rise to kinetic phase diagrams, shows that the effect of kinetics on segregation is even stronger than that predicted by previous models.

Photon counting with photon number resolution through superconducting nanowires coupled to a multi-channel TDC in FPGA.

The paper presents a system for measuring photon statistics and photon timing in the few-photon regime down to the single-photon level. The measurement system is based on superconducting nanowire single photon detectors and a time-to-digital converter implemented into a programmable device. The combination of these devices gives high performance to the system in terms of resolution and adaptability to the actual experimental conditions. As a case of application, we present the measurement of photon statistics for coherent light states. In this measurement, we make use of 8th order single photon correlations to reconstruct with high fidelity the statistics of a coherent state with average photon number up to 4. The processing is performed by means of a tapped-delay-line time-to-digital converter architecture that also hosts an asynchronous-correlated-digital-counter implemented in a field programmable gate array device and specifically designed for performance optimization in multi-channel usage.

Immunohistochemical localization of carbamoyl-phosphate synthetase (ammonia) in adult rat liver; evidence for a heterogeneous distribution.

Different fixation media have been compared in order to find one that preserves the histological structure of rat liver and allows unambiguous immunohistochemical detection of carbamoyl-phosphate synthetase (ammonia). Fixation of rat liver in a mixture of methanol, acetone, and water yields the most intense immunohistochemical staining. Using a specific antiserum raised against rat liver carbamoyl-phosphate synthetase, less than 1% of the enzyme protein is extractable after this fixation procedure, and the histological structure is similar to that after fixation in Bouin's fixative. Specific immunohistochemical staining is localized exclusively in the cytoplasm of the parenchymal cells; its granular distribution is in accordance with the mitochondrial localization of carbamoyl-phosphate synthetase. Immunohistochemical staining shows a heterogeneous distribution within the liver acinus. Staining is most intense around the portal venules, decreases slowly toward the hepatic venules and is, after an abrupt decrease, virtually absent in a limited area surrounding these venules. The possible significance of the heterogeneous distribution of carbamoyl-phosphate synthetase for ammonia metabolism is discussed.

The local expression of adult chicken heart myosins during development. I. The three days embryonic chicken heart.

Immunofluorescence studies were performed on serial sections of three days embryonic chicken hearts using antibodies specific for adult atrial and ventricular myosin heavy chains respectively. The anti-ventricular myosin serum reacted with the entire myocardium showing a decreasing intensity going from the truncus arteriosus to the atrial part; however, the antiatrial myosin serum reacted weakly with the myocardium of the atrial part. Two other interesting observations were made, i) the anti-atrial myosin serum reacted with non-myocardial cells in the cardiac jelly, ii) both antisera reacted with a thin myocardial layer, extending from the ventral wall of the atrial part via the medio-dorsal wall of the atrio-ventricular canal to the dorsal wall of the ventricular part.

The position of the left and right ventricular outlets during septation. A comparison of chicken and rat development.

A comparative study was made of the relative position of the outflow tracts of chicken and rat hearts with respect to the ventricles during septation. For this purpose the position of the left and right ventricular outlet including the aortic and pulmonary valve primordia and the left and right ventricle were established with respect to the midsagittal plane of the embryo, using reconstructions of serial sections of chicken (stage 28-30) and rat (stage 28-30) embryos. In the chicken embryo no rotation of the outflow tract occurs, i.e. the position of the aortic and pulmonary valve primordia with respect to the left and right ventricle remains the same. In the rat embryo a clockwise rotation of the aortic and pulmonary valve primordia with respect to the ventricles does occur. This is in fact a detorsion. The left and right ventricle and the left ventricular outlet do not show change in position with regard to the midsagittal plane. The left ventricular outlet always straddles the interventricular septum, both lying in the midsagittal plane. These interspecies differences in the degree of detorsion of the outflow channels before septation may explain the differences in the extent of the region of contact between the endocardial outflow tract ridges.

Isomyosin expression patterns in tubular stages of chicken heart development: a 3-D immunohistochemical analysis.

The 3-D distribution of atrial and ventricular isomyosins is analysed in tubular chicken hearts (stage 12+ to 17 (H/H)) using antibodies specific for adult chicken atrial and ventricular myosin heavy chains, respectively. At stage 12+ (H/H) all myocytes express the atrial isomyosin; furthermore, all myocytes except those originally situated in the dorsolateral wall of the sinu-atrium coexpress the ventricular isomyosin as well. Moreover, it appears that recently incorporated myocardial cells at both ends of the heart tube start with a coexpression of both isomyosins. From stage 14 (H/H) onwards a regional loss of expression of one of either isomyosins is observed in the atrial and ventricular compartment. In this way the single isomyosin expression types that are characteristic for the adult working myocardium of the atria and ventricles arise. So, the isomyosin expression patterns are, unexpectedly, hardly useful to discriminate the different heart parts of the tubular heart. The ventricle, defined by its adult type of isomyosin expression, is even not detectable before stage 14 (H/H). Interestingly, interconnected coexpression areas, which may be precursor conductive tissues, are still present at stage 17 (H/H) in the outflow tract, the ventricular trabeculae, the atrio-ventricular transitional zone and in the sinu-atrium. The pattern of isomyosin coexpression was found to correlate with a peristaltoid contraction and a slow conduction velocity, whereas single expression areas correlate with a synchronous contraction and a relatively fast conduction velocity. The possible implications of the changing isomyosin pattern for the differentiation of the tubular myocardium, in particular in relation to the development of the conductive tissues, will be discussed.

The conducting tissue in the adult chicken atria. A histological and immunohistochemical analysis.

A three-dimensional reconstruction from serial sections of adult chicken heart was made to verify whether Purkinje cells, that can be recognized by a number of well-known histological criteria, form specialized tracts in the adult chicken atria. This reconstruction revealed a loosely arranged network of Purkinje cells connecting the two atria. This network has not been described before. No tracts could be detected between the sinoatrial and the atrioventricular nodes. These atrial Purkinje cells express the atrial and ventricular myosin isoform, as determined by the use of monoclonal antibodies that were prepared against atrial and ventricular myosin isoform, respectively. Some atrial myocytes that are topographically closely related to the Purkinje cells and that cannot be distinguished from the surrounding myocytes with conventional histological criteria, express, apart from the atrial myosin isoform, also the ventricular myosin isoform. The similar expression pattern of these two cell types and their close topographical relationship suggest the presence of a more elaborate system specialized in conduction than the well-known conductive system found with conventional histological techniques.

Isomyosin expression in developing chicken atria: a marker for the development of conductive tissue?

Isomyosin expression patterns in embryonic chicken atria during the first two weeks of development were analyzed immunohistochemically. In the 3-days embryonic chicken heart (HH19-20), strong coexpression of both isomyosins can be found as band-like zones at the lateral sides of the sinoatrial junction. The zones converge on the bottom of the atrium and continue as a band around the atrioventricular canal. In the 5-days heart (HH27-28) the coexpression area encompasses the entire sinoatrial junction and extends into parts of the sinus venosus and into the dorsocaudal atrial wall. In the 7-days heart (HH 32-33) the relative extension of coexpression areas reaches its maximum. Coexpression is also found in a ring-like band in the ventral (bottom) wall of the atria peripheral to the ring-like band in the atrioventricular junction. The latter band has now become continuous with the coexpression area in the bottom of the interatrial septum. Caudally coexpression extends behind the atrioventricular cushions towards the interventricular septum and cranially coexpression of the atrioventricular junction has become continuous with that of the ring around the outflow tract (cf Sanders et al. 1986). In the second week of incubation a decrease of coexpression is observed. The isomyosin expression pattern described in this study has put forward additional arguments that the conductive tissue originates from areas that continue to express both isomyosins relatively late in development.

The local expression of adult chicken heart myosins during development. II. Ventricular conducting tissue.

The development of the ventricular conducting tissue of the embryonic chicken heart has been studied using a previous finding that morphologically recognizable atrial conducting tissue coexpresses the atrial and the ventricular myosin isoforms. It is found that, by these criteria, at 9 days part of the ventricular conduction system consists of a myocardial ring located around the infundibula of the aorta and truncus pulmonalis. Part of this ring is formed by the retro-aortic root branch. The ring continues via the septal branch into the atrioventricular bundle and its branches, that all express both myosin isoforms. The retro-aortic root branch could be traced back as a part of the myocardial wall of the truncus arteriosus at the 4 days embryonic stage. At the 16th day of development, the septal branch, atrioventricular bundle and left and right bundle branches no longer express the atrial isomyosin, but two bundles originating from the septal branch still express both isomyosins, one being the retro-aortic root branch, the other being only immunologically recognizable and directed to the ventral side of the truncus pulmonalis; this latter we call the pulmonary root branch. Both bundles are remnants of the myocardial ring.

The Multicenter Morphometric Mammary Carcinoma Project (MMMCP). A nationwide prospective study on reproducibility and prognostic power of routine quantitative assessments in The Netherlands.

The Multicenter Morphometric Mammary Carcinoma Project (MMMCP) has been set up to investigate prospectively the prognostic value and reproducibility of routine assessments of the morphometric Multivariate Prognostic Index (MPI) and other quantitative parameters in comparison with classical prognosticators and steroid receptors in breast cancer patients. In this project, 34 hospitals participate, divided over six geographically different regions. Of each patient entering in the study, multiple clinical and classical pathological parameters (including tumor size and lymph node status) as well as several quantitative parameters such as mean nuclear area, DNA index and mitotic activity index will be evaluated. Of all patients, the MPI will be assessed with tumour size, lymph node status and mitotic activity index. The quantitative assessments are performed in all consecutive breast cancers which enter the participating pathology laboratories, and all measurements are controlled in Amsterdam. The patient intake time will be from January 1, 1988 until January 1, 1990. It is expected that 3000 patients will enter in this study. Follow up data will be gathered up to 10 years. However, two to five years after the initiation of the Project, a first evaluation of the reproducibility and prognostic significance of routine MPI and other assessments in breast cancer patients will be possible. A detailed description of this project is given.

Sirenomelia ('mermaid').

A case of sireniform malformation in a 17-wk-old fetus is described. In addition to the characteristic fusion of the lower limbs, there were also severe malformations of the urogenital system and lower intestinal tract. The essential features and various theories of genesis are discussed. The cases so far described in literature are reviewed. Ultrasound can be very useful in early detection of this deformity, because defective movements of the single lower limb and the typical medial position of the fibulae can be seen.

ARM: axillary reverse mapping - the need for selection of patients.

BACKGROUND: Axillary reverse mapping (ARM) is a technique that discerns axillary lymphatic drainage of the arm from the breast. This study was performed to evaluate both the feasibility of this technique and the proportion of metastatic involvement of ARM-nodes. PATIENTS AND METHODS: Patients with invasive breast cancer and an indication for axillary lymph node dissection (ALND) were enrolled in the study: patients with a tumor-positive sentinel lymph node (SLN(+)-group) and patients who had axillary metastases proven by preoperative cytology (CP-N(+)-group) were distinguished. ARM was performed in all patients by injecting blue dye. During surgery ARM-nodes were identified and removed first, followed by ALND. RESULTS: Between October 2009 and June 2011 93 patients underwent ARM. There were 43 patients in the SLN(+)-group and 50 patients in the CP-N(+)-group. No significant differences in visualization rate of ARM-nodes between the groups (86 vs 94% respectively, P = 0.196) were identified. In the SLN(+)-group none of the ARM-nodes contained metastases versus 11 patients (22%) in the CP-N(+)-group (P = 0.001). Patients receiving neoadjuvant systemic therapy had a significantly lower risk of additional axillary lymph node metastases (24.6 vs 44.4%, P = 0.046). DISCUSSION: The ARM procedure is technically feasible with a high visualization rate. The proportion of patients with metastases in the ARM-nodes was significantly higher in patients with proven axillary metastases than in patients with a positive SLN. Patients with SLN metastases appear to be good candidates for the ARM technique and possibly also patients with proven axillary metastases receiving neoadjuvant chemotherapy.

Melting of graphene: from two to one dimension.

The high temperature behaviour of graphene is studied by atomistic simulations based on an accurate interatomic potential for carbon. We find that clustering of Stone-Wales defects and formation of octagons are the first steps in the process of melting which proceeds via the formation of carbon chains. The molten state forms a three-dimensional network of entangled chains rather than a simple liquid. The melting temperature estimated from the two-dimensional Lindemann criterion and from extrapolation of our simulation for different heating rates is about 4900 K.