Search

Byline: Priyanka. Misale, Anjali. Lepcha, Philip. Thomas, Swapna. Sebastian, Tunny. Sebastian Objective: The objective of the study is to establish normative values of cortical evoked response audiometry (CERA) in a [...]

Nearly one-third of the world's population has hypertension. The human and societal impact of hypertension is enormous. Primary hypertension accounts for 95 % of cases of hypertension in adults. The pathogenesis of primary hypertension is complex. The kidney and the sympathetic nervous system play important roles in the development and maintenance of hypertension. This review discusses their respective roles, the interaction between the two, implications of sympathetic overactivity in kidney disease and therapeutic interventions that have been developed on the basis of this knowledge, especially modulation of the sympathetic nervous system. Keywords Hypertension * Kidney * CKD * Sympathetic nervous system * Renal denervation * Pathogenesis, Introduction Hypertension is one of the most preventable causes of premature morbidity and mortality in the world. The global prevalence of hypertension in adults was 26 % in 2000 and [...]

Fluid and [HCO.sub.3.sup.-] secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and [HCO.sub.3.sup.-]in secretory glands is fueled by [Na.sup.+]/[HCO.sub.3.sup.-]cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by [Cl.sup.-]/[HCO.sub.3.sup.-]exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate ([IP.sub.3]) receptor-binding protein released with [IP.sub.3] (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and [HCO.sub.3.sup.-]secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis., Introduction Transepithelial ion and [HCO.sub.3.sup.-]transport is the fundamental function of all epithelia and determines, among other things, bodily fluid volume and ionic composition, systemic and tissue acid-base balance and secretion, [...]

Byline: Thomas Philip Shakespeare, MBBS, MPH, FRANZCR, FAMS, GradDipMed ClinEpi (North Coast Cancer Institute, Coffs Harbour Health Campus, New South Wales, Australia, thomasshakespeare@gmail.com., PRIMER Collaboration, New South Wales, Australia); Val [...]

The intention of this study is to provide a holistic approach to interpretation of Berio's Sequenza IV, illuminating some of the complexities and ambiguities of the score and offering possibilities for performance. Comparison of the original with the revised version of the score is shown to offer considerable insight upon performance decisions. Analytical observations are applied to the practical issues of interpretation and projection, such as the articulation of melody, phrasing, clusters and grace-notes. Consideration is given to stylistic issues, such as the appropriation of tonality and its implications for performance, and the use of time and rubato. Keywords: Analysis; Berio; Interpretation; Performing Tradition; Piano; Style

Taking classic works of the American experimental movement as the primary focus for discussion, this article examines the nature of interpretative decisions both before and during a performance. The issues which inform a performer's decisions as to when, how, and what to play are placed within the context both of what is known of the composer's intentions and of the performing traditions which have subsequently developed. Keywords: Indeterminacy; Interpretation; Notation; Performers; Performing Traditions

The SLC26 transporters are a family of mostly luminal [Cl.sup.-] and HC[O.sub.3] transporters. The transport mechanism and the [Cl.sup.-]/HC[O.sub.3.sup.-] stoichiometry are not known for any member of the family. To address these questions, we simultaneously measured the HC[Osub.3] and [Cl.sup.-] fluxes and the current or membrane potential of slc26a3 and slc26a6 expressed in Xenopus laevis oocytes and the current of the transporters expressed in human embryonic kidney 293 cells, slc26a3 mediates a coupled 2[Cl.sup-]/1HC[O.sub.3.sup.-] exchanger. The membrane potential modulated the apparent affinity for extracellular [Cl.sup.-] of [Cl.sup.-]/HC[O.sub.3] exchange by slc26a3. Interestingly, the replacement of [Cl.sup.-] with N[O.sub.3.sup.-] or SC[N.sup.-] uncoupled the transport, with large N[O.sub.3.sup.-] and SC[N.sub.-] currents and low HC[O.sub.3.sup.-] transport. An apparent uncoupled current was also developed during the incubation of slc26a3-expressing oocytes in HC[O.sub.3.sup.-]-buffered [Cl.sup.-]-free media. These findings were used to develop a turnover cycle for [Cl.sup.-] and HC[O.sub.3.sup.-] transport by slc26a3. [Cl.sup.-] and HC[O.sub.3.sup.-] flux measurements revealed that slc26a6 mediates a 1[Cl.sup.-]/2HC[O.sub.3.sup.-] exchange. Accordingly, holding the membrane potential at 40 and -100 mV accelerated and inhibited, respectively, [Cl.sup.-]-mediated HC[O.sub.3.sup.-] influx, and holding the membrane potential at -100 mV increased HC[O.sub.3.sup.-]-mediated [Cl.sup.-] influx. These findings indicate that slc26a6 functions as a coupled 1[Cl.sup.-]/2HC[O.sub.3.sup.-] exchanger. The significance of isoform-specific [Cl.sup.-] and HC[O.sub.3.sup.-] transport stoichiometry by slc26a3 and slc26a6 is discussed in the context of diseases of epithelial [Cl.sup.-] absorption and HC[O.sub.3.sup.-] secretion.

[gamma]-Aminobutyric acid type A receptors ([GABA.sub.A]RS) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of [GABA.sub.A]R cell surface stability. Here. we have examined the regulation of [GABA.sub.A]R endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of [GABA.sub.A]RS was evident. Internalized receptors were then either rapidly recycled back to the cell surface, or on a slower time scale, targeted for lysosomal degradation. This sorting decision was regulated by a direct interaction of [GABA.sub.A]RS with Huntingtin-associated protein 1 (HAP1), HAP1 modulated synaptic [GABA.sub.A]R number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating [GABA.sub.A]R sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses.

We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, folic acid deficiency and riboflavin deficiency, independently or interactively, are important determinants of genomic stability, cell death, cell proliferation and homocysteine (Hcy) concentration in 9-d human lymphocyte cultures. Lymphocytes of seven wild-type (CC) and seven mutant (TT) homozygotes were cultured under the four possible combinations of deficiency and sufficiency of riboflavin (0 and 500 nmol/L) and folic acid (20 and 100 nmol/L) at a constant L-methionine concentration of 50 [micro]mol/L. Viable cell growth was 25% greater in TT than in CC cells (P < 0.05) and 32% greater at 100 nmol/L folic acid than at 20 nmol/L folic acid (P = 0.002). The comprehensive cytokinesis-block micronucleus assay was used to measure micronuclei (MNi; a marker for chromosome breakage and loss), nucleoplasmic bridges (NPB; a marker of chromosome rearrangement) and nuclear buds (NBUD, a marker of gene amplification). The MNi levels were 21% higher in Fl cells than in CC cells (P < 0.05) and 42% lower in the high folic acid medium than in the low folic acid medium (P < 0.0001). The NBUD levels were 27% lower in TT cells than in CC cells (P < 0.05) and 45% lower in the high folic acid medium than in the low folic acid medium (P < 0.0001). High riboflavin concentration (500 nmol/L) increased NBUD levels by 25% (compared with 0 nmol/L riboflavin) in folate-deficient conditions (20 nmol/L folic acid medium; P < 0.05), and there was an interaction between folic acid and riboflavin that affected NBUD levels (P = 0.042). This preliminary investigation suggests that MTHFR C677T polymorphism and riboflavin affect genome instability; however, the effect is relatively small compared with that of folic acid.

The proteasome plays a central role in the degradation of regulatory and misfolded proteins. Current models suggest that substrates access the internal catalytic sites by processively threading their termini through the gated substrate channel Here, we found that latent (dosed) and activated (open) proteasomes degraded two natively disordered substrates at internal peptide bonds even when they lacked accessible termini, suggesting that these substrates themselves promoted gating of the proteasome. This endoproteolysis provides a molecular mechanism for regulated release of transcription factors from inactive precursors as well as a means of accessing internal folding defects of misfolded multidomain proteins., The proteasome degrades the majority of cellular proteins in eukaryotes. Its activity allows for surveillance by the immune system, controls the levels of various regulatory proteins, and prevents the accumulation [...]

In this article, I analyze how ideas of attachment to place and the experience of political and economic marginality combine to produce a particular moral geography for people of the Manambondro region of southeast Madagascar. Though the elements of this moral geography comprise an archive of sorts of the colonial encounter, they also speak of people's consciousness of their marginality within the postcolonial present. I argue that moral geography represents a structure of feeling, a form of social consciousness that captures something profound about people's senses of place and also, regarding their ambivalence toward modernity, their sense of who they are and who they might become. [colonialism, modernity, moral geography, place, postcolonialism, structure of feeling, Madagascar]

Author(s): Joo Young Choi [1]; Daniella Muallem [1]; Kirill Kiselyov [1]; Min Goo Lee [2]; Philip J. Thomas [1]; Shmuel Muallem (corresponding author) [1] Cystic fibrosis (CF) is a disease [...]

Byline: Mohammad Ghaziuddin (1), Philip Thomas (2), Elizabeth Napier (3), Gaby Kearney (3), Luke Tsai (4), Kathleen Welch (4), William Fraser (3) Author Affiliation: (1) University of Michigan, Ann Arbor, Michigan (2) University of Bradford, Bradford, United Kingdom (3) University of Wales, Candiff, United Kingdom (4) University of Michigan, Ann Arbor, Michigan Article History: Registration Date: 09/10/2004

This article examines consumption practices in a region of rural southeast Madagascar, focusing in particular on the building of houses with materials produced outside the local economy. Whilst recognizing that processes of delocalization in vernacular architecture are taking place through the consumption of non-locally produced materials, it is argued that this process exists alongside others of relocalization. One form of relocalization is a process by which non-locally produced materials are incorporated into local cultural schemas through spatial and ritual practices. Another form of relocalization involves the intentional projects of migrants, who build houses in their natal villages partly as a means by which to forge continuing and meaningful ties with their ancestral homeland during periods of residence in other parts of Madagascar. The article thus suggests that people may not only localize goods from the global economy through the work of appropriation, but may also employ them in the production of locality., Introduction Walking among the houses of Manambondro village in coastal southeast Madagascar during the early 1990s I found a mixture of architectural styles and materials. Locally gathered materials predominated in [...]

A study was conducted on the biophysical characterization of six peptides (m1-m6) representing the predicted amino-terminal membrane-spanning domain of cystic fibrosis transmembrane conductance regulator. The results indicate that the peptides exhibit an increase in Beta-sheet in trifluoroethanol, an inducer of alpha-helices. The findings also show that the possible functional role of m6 is manifested through a shift in secondary structure.

Experiment was conducted to study the regulation of Cl- channels in rat submandibular, pancreatic acinar and duct cells. Monoclonal and polyclonal antibodies recognizing COOH-terminal epitopes of cystic fibrosis transmembrane conductance regulator (CFTR) gene product show that duct and acinar cells from the two glands express CFTR in the luminal membrane. Combined immunologic, functional and pharmacological evidence lead to the conclusion that acinar cells of the submandibular gland and pancreas express functional CFTR-dependent Cl- channels.

The synthesis, physical characterization and theoretical aspects of a new series of nonlinear optical molecules were investigated using nuclear magnetic resonance spectroscopy and quantum-chemical calculations. The molecules which were synthesized via the reaction of tertiary amines with tetracyano-p-quinodimethane, were found to exhibit a charge-separated ground state structure. The polarization properties of the molecules were also found to evolve with increasing solvent polarity.

The ability of a polypeptide to fold into a unique, functional, three-dimensional structure in vivo is dependent upon its amino acid sequence and the function of molecular chaperone proteins and enzymes that catalyse folding. Intense study of the physical chemistry and cell biology of folding have greatly aided our understanding of the mechanisms normally employed. Evidence is accumulating that many disease-causing mutations and modifications exert their effects by altering protein folding. Here we discuss the pathobiology of these processes.