In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low-Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity

Intravital imaging has revealed that T cells change their migratory behavior during physiological activation inside lymphoid tissue. Yet, it remains less well investigated how the intrinsic migratory capacity of activated T cells is regulated by chemokine receptor levels or other regulatory elements. Here, we used an adjuvant-driven inflammation model to examine how motility patterns corresponded with CCR7, CXCR4, and CXCR5 expression levels on ovalbumin-specific DO11.10 CD4(+) T cells in draining lymph nodes. We found that while CCR7 and CXCR4 surface levels remained essentially unaltered during the first 48-72 h after activation of CD4(+) T cells, their in vitro chemokinetic and directed migratory capacity to the respective ligands, CCL19, CCL21, and CXCL12, was substantially reduced during this time window. Activated T cells recovered from this temporary decrease in motility on day 6 post immunization, coinciding with increased migration to the CXCR5 ligand CXCL13. The transiently impaired CD4(+) T cell motility pattern correlated with increased LFA-1 expression and augmented phosphorylation of the microtubule regulator Stathmin on day 3 post immunization, yet neither microtubule destabilization nor integrin blocking could reverse TCR-imprinted unresponsiveness. Furthermore, protein kinase C (PKC) inhibition did not restore chemotactic activity, ruling out PKC-mediated receptor desensitization as mechanism for reduced migration in activated T cells. Thus, we identify a cell-intrinsic, chemokine receptor level-uncoupled decrease in motility in CD4(+) T cells shortly after activation, coinciding with clonal expansion. The transiently reduced ability to react to chemokinetic and chemotactic stimuli may contribute to the sequestering of activated CD4(+) T cells in reactive peripheral lymph nodes, allowing for integration of costimulatory signals required for full activation.

Standardized pelvic floor exercises improve stress urinary incontinence in women with intrinsic sphincter deficiency.

OBJECTIVES Pelvic floor rehabilitation is the conservative therapy of choice for women with stress urinary incontinence (SUI). The success rate of surgical procedures in SUI patients with intrinsic sphincter deficiency (ISD) is low. The aim of this study was to analyse the effect of a standardized physiotherapy on patients with SUI and normotonic urethra and ISD. METHODS In this study, 64 patients with ISD and 69 patients with normotonic urethra were enrolled. Maximum urethral pressure (MUCP) >20 cm H2 O was considered as normotonic urethral pressure. Before and after physiotherapy MUCP was measured and cough testing was performed. Additionally, patient reported outcome was assessed using the King's Health Questionnaire (KHQ). For statistical analyses Excel 2010 (Microsoft Inc; Redmond, Washington) and SPSS 20 (SPSS Inc; Chicago, Illinois) for Windows were used. Power calculation was based on the primary endpoint incontinence impact and general health. For power calculation, GraphPad Statmate version 2.00 for Windows was used. RESULTS Sixty-four patients with ISD and 69 patients with normotonic urethra were included in the study. In SUI patients with normotonic and hypotonic urethra KHQ-scores regarding the primary endpoins "general health" and "incontinence impact" significantly improved following standardized physiotherapy. In both groups MUCP increased after physiotherapy. In SUI patients with ISD standardized physiotherapy resulted in a decreased incidence of a positive cough test. CONCLUSIONS Standardized physiotherapy should be offered to patients with SUI and ISD. Long-term results are subject to future studies. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

A Synthetic Factor XIIa Inhibitor Blocks Selectively Intrinsic Coagulation Initiation.

Coagulation factor XII (FXII) inhibitors are of interest for the study of the protease in the intrinsic coagulation pathway, for the suppression of contact activation in blood coagulation assays, and they have potential application in antithrombotic therapy. However, synthetic FXII inhibitors developed to date have weak binding affinity and/or poor selectivity. Herein, we developed a peptide macrocycle that inhibits activated FXII (FXIIa) with an inhibitory constant Ki of 22 nM and a selectivity of >2000-fold over other proteases. Sequence and structure analysis revealed that one of the two macrocyclic rings of the in vitro evolved peptide mimics the combining loop of corn trypsin inhibitor, a natural protein-based inhibitor of FXIIa. The synthetic inhibitor blocked intrinsic coagulation initiation without affecting extrinsic coagulation. Furthermore, the peptide macrocycle efficiently suppressed plasma coagulation triggered by contact of blood with sample tubes and allowed specific investigation of tissue factor initiated coagulation.

Why Do Economies Enter into Preferential Agreements on Trade in Services? Assessing the Potential for Negotiated Regulatory Convergence in Asian Services Markets

More than one-third of the World Trade Organization-notified services trade agreements that were in effect between January 2008 and August 2015 involved at least one South or Southeast Asian trading partner. Drawing on Baier and Bergstrand’s (2004) determinants of preferential trade agreements and using the World Bank’s database on the restrictiveness of domestic services regimes (Borchert, Gootiiz, and Mattoo 2012), we examine the potential for negotiated regulatory convergence in Asian services markets. Our results suggest that Asian economies with high levels of preexisting bilateral merchandise trade and wide differences in services regulatory frameworks are more likely candidates for services trade agreement formation. Such results lend support to the hypothesis that the heightened “servicification” of production generates demand for the lowered services input costs resulting from negotiated market openings.

Why do Countries Enter into Preferential Agreements on Trade in Services? Assessing the Potential for Negotiated Regulatory Convergence in Asian Services Markets

More than a third of the World Trade Organization (WTO)-notified services trade agreements (STAs) in effect over January 2008 - August 2015 have involved at least one (South or Southeast) Asian trading partner. Drawing on Baier and Bergstrand's (2004) determinants of preferential trade agreements and using the World Bank's database on the restrictiveness of domestic services regimes (Borchert et.al. 2012), we examine the potential for negotiated regulatory convergence in Asian services markets. Our results suggest that countries within Asia with high levels of pre-existing bilateral merchandise trade and wide differences in services regulatory frameworks are more likely candidates for STA formation. Such results lend support to the hypothesis that the heightened "servicification" of production generates a demand for the lowered service input costs resulting from negotiated market opening.

Why do countries enter into preferential agreements on trade in Services? assessing the potential for negotiated regulatory convergence in asian Services markets

Presentation made by Pierre Sauvé and Anirudh Shingal at the Asian International Economists Network (AIEN) Workshop, Asian Development Bank, Manila.

Growth, convergence and trade: The services sector in India’s states

India’s success story in services is well documented at the national level, but similar literature does not exist for India’s states. In this paper, we bridge this gap in research by looking at India’s services growth at the sub-national level and in doing so, also challenge existing literature by arguing that this growth has positive implications for income distribution. We find that even as per capita income is not converging across India’s states, per capita services are; evidence is provided both in terms of traditional measures of sigma- and beta-convergence and more recent panel unit root tests. A more disaggregated analysis of services sectors reveals convergence in railways, public administration and financial services. Finally, a Jensen & Kletzer (2005) approach to determining tradability provides evidence of most services being “traded” across India’s states, suggesting the role of such trade in the services growth and convergence story.

Lung Structure and the Intrinsic Challenges of Gas Exchange

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. © 2016 American Physiological Society. Compr Physiol 6:827-895, 2016.

Services growth and convergence: Getting India’s states together

India’s success story in services is well documented at the national level, but similar literature does not exist for India’s states. In this paper, we bridge this gap in research by looking at India’s services growth at the sub-national level and in doing so, also challenge existing literature by arguing that this growth has positive implications for income distribution. The first interesting finding is that even as per capita income is not converging across India’s states, per capita services are and we provide evidence for this both in terms of traditional measures of sigma- and beta-convergence and more recent panel unit root tests. Secondly, not only is external demand an important determinant of services value added at the state level, but this demand also emanates from all over the country rather than being concentrated in the neighbouring or richer states. This suggests that the benefits from services growth are being distributed more widely than may be perceived.