High-precision confocal reflection measurement for two dimensional refractive index mapping of optical fibers

We introduce a new fiber-optical approach for reflection based refractive index mapping. Our approach leads to improved stability and reliability over existing free-space confocal instruments and significantly cuts alignment efforts and reduces the number of components needed. Other than properly cleaved fiber end-faces, this setup requires no additional sample preparation. The instrument is calibrated by means of a set of samples with known refractive indices. The index steps of commercially available fibers are measured accurately down to < 10⁻³. The precision limit of the instrument is currently of the order of 10⁻⁴.

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Investigation of the molecular mechanisms of endometrial hyperplasia

While there is considerable information on the molecular aberrations associated with the development of endometrial cancer, very little is known of changes in gene expression associated with its antecedent premalignant condition, endometrial hyperplasia. In order to address this, we have compared the level of expression of components of the IGF-I signaling pathway in human endometrial hyperplasia to their level of expression in both the normal pre-menopausal endometrium and endometrial carcinoma. We have also characterized the molecular characteristics of endometrial hyperplasia as it occurs in a murine model of hormone-dependent tumorigenesis of the female reproductive tract. ^ There was a significant and selective increase in the expression of the IGF-I Receptor (IGF-IR) in both human hyperplasia and carcinoma as compared to the normal endometrium. The receptor was also activated, as judged by increased tyrosine phosphorylation. In addition, in hyperplasia and carcinoma there is activation of the downstream component Akt. The expression of the PTEN tumor suppressor is decreased in a subset of subjects with hyperplasia and in all of the carcinomas. The simultaneous loss of PTEN expression and increased IGF-IR activation in the hyperplastic endometrium was associated with an increased incidence of endometrial carcinoma elsewhere within the uterus. In the rodent hyperplasia, there was a significant increase in the expression and activation of Akt that appears to be attributable to a marked increase in the expression of IGF-II. ^ Our studies have demonstrated the pathologic proliferation of both the human and rodent endometrium is linked to a marked activation of the Akt pathway. However the cause of this dysregulation is different in the human disease and the animal model. In rodents, hyperplasia is linked to increased expression of one of the ligands of the IGF-IR, IGF-II. In humans the IGF-I receptor itself is upregulated and activated. Additional activation of the Akt pathway via the suppression of PTEN activity, results in conditions that are associated with the marked increase in the probability of developing endometrial cancer. Our data suggests that increased activity of the IGF-I pathway plays the key role in the hyperproliferative state characteristic of endometrial hyperplasia and cancer.^

Evaluation of obesity interventions targeting adults in the occupational setting

The study of obesity and its causes has evolved into one of the most important public health issues in the United States (Office of Disease Prevention and Health Promotion, 2007). Obesity is linked to several chronic conditions, such as cardiovascular disease, diabetes and some cancers (National Center for Chronic Disease Prevention and Health Promotion, 2008b) and the public health concern resides in the present morbidity and mortality associated with obesity and related conditions (National Heart, Lung and Blood Institute, 1998). Furthermore, obesity and its related conditions present economic challenges to employers in terms of medical health care, sick leave, short-term disability and long-term disability benefits utilized by employees (Østbye, Dement, and Krause, 2007). Recently, articles covering intervention programs targeting obesity in the occupational setting have surfaced in the body of scientific literature. The increased interest in this area stems from the fact that employees in the United States spend more time in the work environment than many industrialized nations, including Japan and most of Western Europe (Organisation for Economic Co-operation and Development, 2006). Moreover, scientific literature supports the idea of investing in healthy human capital to promote productivity and output from employees (Berger, Howell, Nicholson, & Sharda, 2003). The time spent in the work environment, the business need for healthy employees, and the public health concern create an opportunity for planning, implementation and analysis of interventions for effectiveness. This paper aims to identify those intervention programs that focus on the occupational setting related to obesity, to analyze the overall effect of diet, physical fitness and behavioral change interventions targeting overweight and obesity in the occupational setting, and to evaluate the details and effectiveness of components, such as, intervention setting, target participant group, content, industry and length of follow up. Once strengths and weaknesses of the interventions are evaluated, ideas will be suggested for implementation in the future.^

Ligand-stimulated internalization of a Dictyostelium discoideum G protein-coupled cAMP receptor

The social amoeba, Dictyostelium discoideum, undergoes a remarkable starvation-induced program of development that transforms a population of unicellular amoebae into a fruiting body composed of resistant spores suspended on a stalk. During this development, secreted cAMP drives chemotaxis of the amoebae, leading to their aggregation, and subsequent differentiation and morphogenesis. Four sequentially expressed G protein-coupled receptors (GPCRs) for cAMP play critical roles in this process. The first of these, cAR1, is essential for aggregation as it mediates chemotaxis as well as the propagation of secreted cAMP waves throughout aggregating populations. Ligand-induced internalization has been shown to regulate a variety of GPCRs. However, little was known at the outset of this study about the role of internalization in the regulation of cAR1 function or, for that matter, in developmental systems in general. For this study, cAMP-induced cAR1 internalization was assessed by measuring (1) the reduction of cell surface binding sites for [ 3H]cAMP and (2) the redistribution of YFP-tagged receptors to the cell's interior, cAMP was found to induce little or no loss of ligand binding (LLB) in vegetative cells. However, the ability to induce LLB increased progressively over the initial 6 hrs of development, reaching ∼70% in cells undergoing aggregation. Despite these reductions in surface binding, detectable cAR1-YFP redistribution could be induced by cAMP only after the cells reached the mound stage (10 hrs) and was found to occur naturally by the ensuing slug stage (18 hrs). Site-directed substitution of a cluster of 5 serines in the receptor's cytoplasmic tail that was previously shown to be the principal site of cAMP-induced cAR1 phosphorylation impaired both LLB and receptor redistribution and furthermore resulted in mound-stage developmental arrest, suggesting that phosphorylation of cAR1 is a prerequisite for its internalization and that cAR1 internalization is required for post-aggregative development. To assess the involvement of clathrin mediated endocytosis, Dictyostelium cells lacking the clathrin light chain gene (clc-) or either of two dynamin genes were examined and found to be defective in LLB and, in the case of clc- cells, also cAR1 redistribution and turnover. Furthermore, cAR1 overexpression in clc- cells (like the serine mutant in wild-type cells) promoted developmental arrest in mounds. The mound-arrest phenotype was also recapitulated in a wild-type background by the specific expression of cAR1 in prestalk cells (but not prespore cells), suggesting that development depends critically on internalization and clearance of cAR1 from these cells. Persistent cAR1 expression following aggregation was found to be associated with aberrant expression of prestalk and prespore genes, which may adversely affect development in the prestalk cell lineage. The PI3 kinase-TORC2 signal transduction pathway, known to be important for Dictyostelium chemotaxis and internalization of yeast pheromone receptors, was examined using chemical inhibitors and null cells and found to be necessary for cAR1 internalization. In conclusion, cAR1 was shown to be similar to other GPCRs in that its internalization depends on phosphorylation of cytoplasmic domain serines, utilizes clathrin and dynamin, and involves the TORC2 complex. In addition, the findings presented here that cAR1 internalization is both developmentally regulated and required for normal development represent a novel regulatory paradigm that might pertain to other GPCRs known to play important roles in the development of humans and other metazoans. ^

Identification of a conserved cluster in the RH domain of GRK critical for activation by GPCRs

One of the most critical aspects of G Protein Coupled Receptors (GPCRs) regulation is their rapid and acute desensitization following agonist stimulation. Phosphorylation of these receptors by GPCR kinases (GRK) is a major mechanism of desensitization. Considerable evidence from studies of rhodopsin kinase and GRK2 suggests there is an allosteric docking site for the receptor distinct from the GRK catalytic site. While the agonist-activated GPCR appears crucial for GRK activation, the molecular details of this interaction remain unclear. Recent studies suggested an important role for the N- and C-termini and domains in the small lobe of the kinase domain in allosteric activation; however, neither the mechanism of action of that site nor the RH domain contributions have been elucidated. To search for the allosteric site, we first indentified evolutionarily conserved sites within the RH and kinase domains presumably deterministic of protein function employing evolutionary trace (ET) methodology and crystal structures of GRK6. Focusing on a conserved cluster centered on helices 3, 9, and 10 in the RH domain, key residues of GRK5 and 6 were targeted for mutagenesis and functional assays. We found that a number of double mutations within helices 3, 9, and 10 and the N-terminus markedly reduced (50–90%) the constitutive phosphorylation of the β-2 Adrenergic Receptor (β2AR) in intact cells and phosphorylation of light-activated rhodopsin (Rho*) in vitro as compared to wild type (WT) GRK5 or 6. Based on these results, we designed peptide mimetics of GRK5 helix 9 both computationally and through chemical modifications with the goal of both confirming the importance of helix 9 and developing a useful inhibitor to disrupt the GPCR-GRK interaction. Several peptides were found to block Rho* phosphorylation by GRK5 including the native helix 9 sequence, Peptide Builder designed-peptide preserving only the key ET residues, and chemically locked helices. Most peptidomimetics showed inhibition of GRK5 activity greater than 80 % with an IC50 of ∼ 30 µM. Alanine scanning of helix 9 has further revealed both essential and non-essential residues for inhibition. Importantly, substitution of Arg 169 by an alanine in the native helix 9-based peptide gave an almost complete inhibition at 30 µM with an IC50 of ∼ 10 µM. In summary we report a previously unrecognized crucial role for the RH domain of GRK5 and 6, and the subsequent identification of a lead peptide inhibitor of protein-protein interaction with potential for specific blockade of GPCR desensitization. ^

Description and chemical and mineral composition of iron oxide samples from two Finnish lakes

Fifteen iron oxide accumulations from the bottoms of two Finnish lakes ("lake ores") were found to contain as much as 50% Fe. Differential X-ray powder diffraction and selective dissolution by oxalate showed that the samples consisted of poorly crystallized goethite and ferrihydrite. The crust ores of one lake had higher ferrihydrite to goethite ratios than the nodular ores of the other lake. The higher ferrihydrite proportion was attributed to a higher rate of Fe2+ supply from the ground water and/or a higher rate of oxidation as a function of water depth and bottom-sediment permeability. Values of Al-for-Fe substitution of the goethites determined from unit-cell dimensions agreed with those obtained from chemical extraction if the unit-cell volume rather than the c dimension was used. In very small goethite crystals a slight expansion of the a unit-cell dimension is probaby compensated by a corresponding contraction of the c dimension, so that a contraction of the c dimension need not necessarily be caused by Al substitution. The goethites of the two lakes differed significantly in their Al-for-Fe substitutions and hence in their unit-cell sizes, OH-bending characteristics, dehydroxylation temperatures, dissolution kinetics, and Mössbauer parameters. The difference in Al substitution (0 vs. 7 mole %) is attributed to the Al-supplying power of the bottom sediments: the silty-clayey sediments in one lake appear to have supplied A1 during goethite formation, whereas the gravelly-sandy sediments in the other lake did not. The compositions of the goethites thus reflect their environments of formation.

Analysis of biogenic magnetite nanoparticles

Cobalt doped magnetite (CoxFe3-xO4) nanoparticles have been produced through the microbial reduction of cobalt-iron oxyhydroxide by the bacterium Geobacter sulfurreducens. The materials produced, as measured by SQUID, x-ray magnetic circular dichroism, Mössbauer spectroscopy, etc., show dramatic increases in coercivity with increasing cobalt content without a major decrease in overall saturation magnetization. Structural and magnetization analyses reveal a reduction in particle size to <4 nm at the highest Co content, combined with an increase in the effective anisotropy of the magnetic nanoparticles. The potential use of these biogenic nanoparticles in aqueous suspensions for magnetic hyperthermia applications is demonstrated. Further analysis of the distribution of cations within the ferrite spinel indicates that the cobalt is predominantly incorporated in octahedral coordination, achieved by the substitution of Fe2+ site with Co2+, with up to 17 per cent Co substituted into tetrahedral sites.

Achievements of the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences in South-Southeast Asia.

Since 2008, the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences has contributed to ensuring the substitution of sharp curettage by manual vacuum aspiration (MVA) and medical abortion in selected hospitals in participating countries of South-Southeast Asia. This initiative facilitated the registration of misoprostol in Pakistan and Bangladesh, and the approval of mifepristone for "menstrual regulation" in Bangladesh. The Pakistan Nursing Council agreed to include MVA and medical abortion in the midwifery curriculum. The Bangladesh Government has approved the training of nurses and paramedics in the use of MVA to treat incomplete abortion in selected cases. The Sri Lanka College of Obstetricians and Gynaecologists, in collaboration with partners, has presented a draft petition to the relevant authorities appealing for them to liberalize the abortion law in cases of rape and incest or when lethal congenital abnormalities are present. Significantly, the initiative has introduced or strengthened the provision of postabortion contraception.

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

La sociología frente a los nuevos ataques cientificistas

En 2011 Marradi llamó la atención sobre la expansión semántica que han sufrido algunos de los términos más utilizados en las ciencias sociales debido a un complejo de inferioridad respecto a las ciencias físicas. La cascada de los componentes conceptuales de las llamadas ciencias "duras" a la "blandas" es, sin duda, impresionante. Obviamente, el problema no es el mestizaje de las ciencias humanas, sino la substitución del pensamiento mismo con eslóganes, sin reflexionar sobre sus presupuestos epistemológicos y ontológicos. En mi presentación quiero extender el análisis de las consecuencias del complejo de inferioridad en tres direcciones: i. ampliando los referentes (los términos importados), incluyendo a otro término clave de parte de las ciencias sociales: el término indicador; ii. analizando la importancia que tuvo la cuantificación en el desarrollo de la disciplina sociológica, en competición con la disciplina económica para obtener un reconocimiento público; iii. marcando la importancia del éxito de una imagen de ciencia entre el mundo de los que toman decisiones políticas y económicas, que limita las posibilidades de la investigación social

Chemical and isotopical analsyes of DSDP Hole 34-321 basalts

A blue-green smectite (iron-rich saponite) and green mica (celadonite) are the dominant sheet silicates in veins within the 10.5 m of basalt cored during DSDP Leg 34, Site 32l, in the Nazca plate. Oxygen isotopic analyses of these clays, and associated calcite, indicate a formation temperature of <25°C. Celadonite contains appreciable Fe2O3, K2O and SiO2, intermediate MgO, and very little Al2O3. Celadonite is commonly associated with goethite and hematite, which suggests that this phase formed by precipitation within a dominantly oxygenated environment of components leached from basalt and provided by seawater. A mass balance estimate indicates that celadonite formation can remove no more than 15% of the K annually transported to the oceans by rivers. In contrast, iron-rich saponite containing significant Al2O3 appears to have precipitated from a nonoxidizing, distinctly alkaline fluid containing a high Na/K ratio relative to unmodified seawater. Seawater-basalt interaction at low temperatures, resulting in the formation of celadonite and smectite may explain chemical gradients observed in interstitial waters of sediments overlying basalts.

Chemical composition of interstitial solutions from sediments of DSDP Legs 6-8, 11, 12, 14, 15, and 22

Through the Deep Sea Drilling Project samples of interstitial solutions of deeply buried marine sediments throughout the World Ocean have been obtained and analyzed. The studies have shown that in all but the most slowly deposited sediments pore fluids exhibit changes in composition upon burial. These changes can be grouped into a few consistent patterns that facilitate identification of the diagenetic reactions occurring in the sediments. Pelagic clays and slowly deposited (<1 cm/1000 yr) biogenic sediments are the only types that exhibit little evidence of reaction in the pore waters. In most biogenic sediments sea water undergoes considerable alteration. In sediments deposited at rates up to a few cm/1000 yr the changes chiefly involve gains of Ca(2+) and Sr(2+) and losses of Mg(2+) which balance the Ca(2+) enrichment. The Ca-Mg substitution may often reach 30 mM/kg while Sr(2+) may be enriched 15-fold over sea water. These changes reflect recrystallization of biogenic calcite and the substitution of Mg(2+) for Ca(2+) during this reaction. The Ca-Mg-carbonate formed is most likely a dolomitic phase. A related but more complex pattern is found in carbonate sediments deposited at somewhat greater rates. Ca(2+) and Sr(2+) enrichment is again characteristic, but Mg(2+) losses exceed Ca(2+) gains with the excess being balanced by SO4(post staggered 2-) losses. The data indicate that the reactions are similar to those noted above, except that the Ca(2+) released is not kept in solution but is precipitated by the HCO3(post staggered -) produced in SO4(post staggered 2-) reduction. In both these types of pore waters Na(+) is usually conservative, but K(+) depletions are frequent. In several partly consolidated sediment sections approaching igneous basement contact, very marked interstitial calcium enrichment has been found (to 5.5 g/kg). These phenomena are marked by pronounced depletion in Na(+), Si and CO2, and slight enhancement in Cl(-). The changes are attributed to exchange of Na(+) for Ca(2+) in silicate minerals forming from submarine weathering of igneous rocks such as basalts. Water is also consumed in these reactions, accounting for minor increases in total interstitial salinity. Terrigenous, organic-rich sediments deposited rapidly along continental margins also exhibit significant evidences of alteration. Microbial reactions involving organic matter lead to complete removal of SO4(post staggered 2-), strong HCO3(post staggered -) enrichment, formation of NH4(post staggered +), and methane synthesis from H2 and CO2 once SO4(post staggered 2-) is eliminated. K+ and often Na+ (slightly) are depleted in the interstitial waters. Ca(2+) depletion may occur owing to precipitation of CaCO3. In most cases interstitial Cl- remains relatively constant, but increases are noted over evaporitic strata, and decreases in interstitial Cl- are observed in some sediments adjacent to continents.

AMS 14C ages and isotopic compositions of samples from the Derugin Basin, Sea of Okhotsk

An area of massive barite precipitations was studied at a tectonic horst in 1500 m water depth in the Derugin Basin, Sea of Okhotsk. Seafloor observations and dredge samples showed irregular, block- to column-shaped barite build-ups up to 10 m high which were scattered over the seafloor along an observation track 3.5 km long. High methane concentrations in the water column show that methane expulsion and probably carbonate precipitation is a recently active process. Small fields of chemoautotrophic clams (Calyptogena sp., Acharax sp.) at the seafloor provide additional evidence for active fluid venting. The white to yellow barites show a very porous and often layered internal fabric, and are typically covered by dark-brown Mn-rich sediment; electron microprobe spectroscopy measurements of barite sub-samples show a Ba substitution of up to 10.5 mol% of Sr. Rare idiomorphic pyrite crystals (~1%) in the barite fabric imply the presence of H2S. This was confirmed by clusters of living chemoautotrophic tube worms (1 mm in diameter) found in pores and channels within the barite. Microscopic examination showed that micritic aragonite and Mg-calcite aggregates or crusts are common authigenic precipitations within the barite fabric. Equivalent micritic carbonates and barite carbonate cemented worm tubes were recovered from sediment cores taken in the vicinity of the barite build-up area. Negative d13C values of these carbonates (>-43.5 per mill PDB) indicate methane as major carbon source; d18O values between 4.04 and 5.88 per mill PDB correspond to formation temperatures, which are certainly below 5°C. One core also contained shells of Calyptogena sp. at different core depths with 14C-ages ranging from 20 680 to >49 080 yr. Pore water analyses revealed that fluids also contain high amounts of Ba; they also show decreasing SO4**2- concentrations and a parallel increase of H2S with depth. Additionally, S and O isotope data of barite sulfate (d34S: 21.0-38.6 per mill CDT; d18O: 9.0-17.6 per mill SMOW) strongly point to biological sulfate reduction processes. The isotope ranges of both S and O can be exclusively explained as the result of a mixture of residual sulfate after a biological sulfate reduction and isotopic fractionation with 'normal' seawater sulfate. While massive barite deposits are commonly assumed to be of hydrothermal origin, the assemblage of cheomautotrophic clams, methane-derived carbonates, and non-thermally equilibrated barite sulfate strongly implies that these barites have formed at ambient bottom water temperatures and form the features of a Giant Cold Seep setting that has been active for at least 49 000 yr.