Rat mesangial cell hypertrophy in response to transforming growth factor-β1

Rat mesangial cell hypertrophy in response to transforming growth factor-β1. Central features of progressive glomerular sclerosis are initial glomerular hypertrophy and subsequent accumulation of extracellular matrix proteins. Since TGF-β1 may play a key role in this glomerular response to injury, the present study sought to explore further TGF-β1 actions and regulated expression of its receptor in rat mesangial cells. The rat TGF-β type II receptor (TGF-βRII) homolog was cloned by screening a rat kidney cDNA library with a human TGF-βRII cDNA probe, and sequenced. Expression of this receptor subtype in rat mesangial cells was then demonstrated by RNase protection assay, and by Northern blot analysis of poly (A)+ RNA, TGF-βRII expression was down-regulated in cells treated with exogenous TGF-β1. Affinity cross linking studies demonstrated presence of this receptor on cell surface. Rat mesangial cells also expressed TGF-β1 and autoinduction by TGF-β1 was observed in the same cells, suggesting that this polypeptide may act in an autocrine fashion on mesangial cells, and that it may stimulate a positive autoamplification loop. TGF-β1 inhibited mesangial cell proliferation and stimulated significant overall protein and collagen production. Furthermore, mesangial cell size increased in response to chronic TGF-β1 treatment. These findings demonstrate that rat mesangial cells express key components of the TGF-β system and raise the intriguing possibility that in the glomerular mesangium, TGF-β1 may not only induce extracellular matrix synthesis, but may also participate in the process of glomerular hypertrophy in response to injury

Another Short and Elementary Proof of Strong Subadditivity of Quantum Entropy

A short and elementary proof of the joint convexity of relative entropy is presented, using nothing beyond linear algebra. The key ingredients are an easily verified integral representation and the strategy used to prove the Cauchy-Schwarz inequality in elementary courses. Several consequences are proved in a way which allow an elementary proof of strong subadditivity in a few more lines. Some expository material on Schwarz inequalities for operators and the Holevo bound for partial measurements is also included.Comment: The proof given here is short and more elementary that in either quant-ph/0404126 or quant-ph/0408130. The style is intended to be suitable to classroom presentation. For a Much More Complicated approach, see Section 6 of quant-ph/050619

Kahler Stabilized, Modular Invariant Heterotic String Models

We review the theory and phenomenology of effective supergravity theories based on orbifold compactifications of the weakly-coupled heterotic string. In particular, we consider theories in which the four-dimensional theory displays target space modular invariance and where the dilatonic mode undergoes Kahler stabilization. A self-contained exposition of effective Lagrangian approaches to gaugino condensation and heterotic string theory is presented, leading to the development of the models of Binetruy, Gaillard and Wu. Various aspects of the phenomenology of this class of models are considered. These include issues of supersymmetry breaking and superpartner spectra, the role of anomalous U(1) factors, issues of flavor and R-parity conservation, collider signatures, axion physics, and early universe cosmology. For the vast majority of phenomenological considerations the theories reviewed here compare quite favorably to other string-derived models in the literature. Theoretical objections to the framework and directions for further research are identified and discussed.Comment: Invited review article for International Journal of Modern Physic

TGF-β receptor expression and binding in rat mesangial cells: Modulation by glucose and cyclic mechanical strain

TGF-β receptor expression and binding in rat mesangial cells: Modulation by glucose and cyclic mechanical strain.BackgroundTransforming growth factor-β (TGF-β) is a causal factor in experimental glomerulosclerosis, and it mediates the increased extracellular matrix (ECM) accumulation that occurs in cultured mesangial cells (MCs) exposed to high glucose concentrations and cyclic mechanical strain. This change is associated with increased levels of TGF-β, but may also involve alterations in receptor expression and binding.MethodsRat MCs cultured in media containing either 8 or 35 mM glucose were seeded into culture plates with elastin-coated flexible bottoms. Thereafter, they were subjected to cyclic stretch or static conditions and then examined for125I-TGF-β1 binding and expression of TGF-β receptors at the gene and protein levels.ResultsKinetic studies showed that MCs bound TGF-β1 in a time- and concentration-dependent manner, expressing 6800 high-affinity receptors per cell, with an apparent dissociation constant (Kd) of 15.4 pM, while cross-linking analysis identified three TGF-β receptors (βR) corresponding to βRI, βRII, and βRIII of 54, 73, and 200 kDa, respectively. Immunocytochemical studies of βRI and βRII protein revealed MC expression in a homogeneous, punctate distribution, whereas Northern analysis demonstrated the presence of the corresponding mRNAs. Exposure to cyclic stretching significantly increased (10%) the overall number of TGF-β receptors, whereas ligands associated with βRs I, II, and III also increased (25 to 50%). The finding of increased (30 to 40%) βRI and βRII transcript levels and immunoreactive protein (163 and 59%, respectively) in the absence of significant changes in the apparent Kd indicated that stretch-induced binding was the result of increased receptor synthesis and expression and not due to a change in binding affinity. In a similar, but more dramatic fashion, exposure to high glucose also elevated (50%) the receptor number, as well as the amount of ligands associated with βRs I, II, and III (100 to 250%). This same treatment also increased the levels of βRI and βRII mRNA (30 to 40%) and the immunoreactive protein (82 and 82%, respectively), without significantly altering the binding affinity of the receptor. A concerted or synergistic effect of both stimuli was not evidenced.ConclusionThese results suggest that the modulation of TGF-β receptors may be an additional control point in mediating the glucose- and mechanical force-induced increase in ECM deposition by MCs

U.S. adult perceptions of the harmfulness of tobacco products: descriptive T findings from the 2013–14 baseline wave 1 of the path study

Introduction: This study is the first nationally representative survey of U.S. adults (18+) to examine perceptions of the relative harms of eight non-cigarette tobacco products. Methods: Data are from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study Adult Questionnaire, a nationally representative study of 32,320 adults in the United States conducted from September 2013 to December 2014. Results: 40.7% of adults believed that electronic cigarettes were less harmful than cigarettes, and 17.8% of adults believed that hookah was less harmful than cigarettes. Those less knowledgeable about the health risks of smoking were more likely to believe that the non-cigarette products were less harmful than cigarettes. Current non-cigarette tobacco product users were more likely to perceive that product to be less harmful than cigarettes (except filtered cigars). There was a significant positive correlation between beliefs that cigarettes were harmful and the likelihood of using hookah; perceptions of the harmfulness of cigarettes was not associated with the likelihood of using any other product. Conclusions: Perceptions of harmfulness varied widely across non-cigarette tobacco products. E-cigarettes and hookah in particular are seen as less harmful compared to cigarettes

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture

Epithelia within tubular organs form and expand lumens. Failure of these processes can result in serious developmental anomalies. Although tight junction assembly is crucial to epithelial polarization, the contribution of specific tight junction proteins to lumenogenesis is undefined. Here, we show that ZO-1 (also known as TJP1) is necessary for the formation of single lumens. Epithelia lacking this tight junction scaffolding protein form cysts with multiple lumens and are defective in the earliest phases of polarization, both in two and three dimensions. Expression of ZO-1 domain-deletion mutants demonstrated that the actin-binding region and U5-GuK domain are crucial to single lumen development. For actin-binding region, but not U5-GuK domain, mutants, this could be overcome by strong polarization cues from the extracellular matrix. Analysis of the U5-GuK binding partners shroom2, α-catenin and occludin showed that only occludin deletion led to multi-lumen cysts. Like ZO-1-deficiency, occludin deletion led to mitotic spindle orientation defects. Single lumen formation required the occludin OCEL domain, which binds to ZO-1. We conclude that ZO-1–occludin interactions regulate multiple phases of epithelial polarization by providing cell-intrinsic signals that are required for single lumen formation

Multiplicativity of completely bounded p-norms implies a new additivity result

We prove additivity of the minimal conditional entropy associated with a quantum channel Phi, represented by a completely positive (CP), trace-preserving map, when the infimum of S(gamma_{12}) - S(gamma_1) is restricted to states of the form gamma_{12} = (I \ot Phi)(| psi >< psi |). We show that this follows from multiplicativity of the completely bounded norm of Phi considered as a map from L_1 -> L_p for L_p spaces defined by the Schatten p-norm on matrices; we also give an independent proof based on entropy inequalities. Several related multiplicativity results are discussed and proved. In particular, we show that both the usual L_1 -> L_p norm of a CP map and the corresponding completely bounded norm are achieved for positive semi-definite matrices. Physical interpretations are considered, and a new proof of strong subadditivity is presented.Comment: Final version for Commun. Math. Physics. Section 5.2 of previous version deleted in view of the results in quant-ph/0601071 Other changes mino

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators