Do anionic phospholipids serve as cofactors or second messengers for the regulation of activity of cloned ATP-sensitive K+ channels?

The regulation of ion channels by anionic phospholipids is currently very topical. An outstanding issue is whether phosphatidylinositol 4,5-diphosphate and related species act as true second messengers in signaling or behave in a manner analogous to an enzymatic cofactor. This question is especially pertinent regarding ATP-sensitive K+ channels in smooth muscle, for which there is substantial literature supporting inhibitory regulation by hormones. In this study, we have examined regulation of the potential cloned equivalents of the smooth muscle ATP-sensitive K+ channel (SUR2B/Kir6.1 and SUR2B/Kir6.2). We find that both can be inhibited via the G(q/11)-coupled muscarinic M3 receptor but that the pathways by which this occurs are different. Our data show that SUR2B/Kir6.1 is inhibited by protein kinase C and binds anionic phospholipids with high affinity, such that potential physiological fluctuations in their levels do not influence channel activity. In contrast, Kir6.2 is not regulated by protein kinase C but binds anionic phospholipids with low affinity. In this case, phosphatidylinositol 4,5-diphosphate and related species have the potential to act as second messengers in signaling. Thus, Kir6.1 and Kir6.2 are regulated by distinct inhibitory mechanisms

NDE of Thick Composites in the Aerospace Industry — An Overview

Designers are turning to thick fiber reinforced composites, with increasing success, in order to meet the unique structural requirements which arise within the aerospace industry. These composites offer many superior properties, especially in the design of solid rocket motor cases, where there is a tremendous potential for advantage in strength-to-weight and stiffness-to-weight ratios over conventional materials [1,2]. The increased use of thick fiber reinforced composites presents quite a challenge to the NonDestructive Evaluation (NDE) community. To inspect these materials, conventional NDE techniques must be modified and/or new techniques must be developed to permit interrogation of the full material thickness and adjacent bondlines. Thick fiber reinforced composites exhibit a degree of anisotropy that is orders of magnitude above that of previously employed structural materials (i.e., metals). This anisotropy stems not only from the basic construction of the composite (oriented fibers imbedded within a matrix), but also from what are currently considered “acceptable flaws” within the material (varying degrees of delamination, matrix cracking, porosity, etc.). Successful NDE requires that one be able to distinguish the signals from these “acceptable flaws” from those deemed unacceptable. For the detection of some types of flaws, conventional techniques can be applied to composites with only slight modification, whereas for others, new techniques must be developed. For instance, recently, a large (expensive) solid rocket motor segment sustained an accidental impact. Standard ultrasonic inspection techniques successfully revealed delaminations between a number of layers in the composite case beneath the point of contact. Structural analysis, however, indicated that additional information regarding the degree of fiber breakage was needed. Unfortunately, since no NDE technique was available to assess the degree of fiber breakage, the contractor had to assume the worst and, consequently, scrap the motor

Nodal-Stage Classification in Invasive Lobular Breast Carcinoma: Influence of Different Interpretations of the pTNM Classification

Purpose Application of current nodal status classification is complicated in lobular breast carcinoma metastases. The aim of this study was to define the optimal interpretation of the pTNM classification in sentinel node (SN) -positive patients to select patients with limited or with a high risk of non-SN involvement. Patients and Methods SN metastases of 392 patients with lobular breast carcinoma were reclassified according to interpretations of the European Working Group for Breast Screening Pathology (EWGBSP) and guidelines by Turner et al, and the predictive power for non-SN involvement was assessed. Results Reclassification according to definitions of EWGBSP and Turner et al resulted in different pN classification in 73 patients (19%). The rate of non-SN involvement in the 40 patients with isolated tumor cells according to Turner et al and with micrometastases according to EWGBSP was 20%, which is comparable to the established rate for micrometastases. The rate of non-SN involvement in the 29 patients with micrometastases according to Turner et al and with macrometastases according to EWGBSP was 48%, which is comparable to the established rate for macrometastases. Therefore, the EWGBSP method to classify SN tumor load better reflected the risk of non-SN involvement than the Turner et al system. Conclusion Compared with the guidelines by Turner et al, the EWGBSP definitions better reflect SN metastatic tumor load and allow better differentiation between patients with lobular breast carcinoma who have a limited or a high risk of non-SN metastases. Therefore, we suggest using the EWGBSP definitions in these patients to select high-risk patients who may benefit from additional local and/or systemic therapy

Perceived stressors of climate vulnerability across scales in the Savannah zone of Ghana: a participatory approach

Smallholder farmers in sub-Saharan Africa are confronted with climatic and non-climatic stressors. Research attention has focused on climatic stressors, such as rainfall variability, with few empirical studies exploring non-climatic stressors and how these interact with climatic stressors at multiple scales to affect food security and livelihoods. This focus on climatic factors restricts understanding of the combinations of stressors that exacerbate the vulnerability of farming households and hampers the development of holistic climate change adaptation policies. This study addresses this particular research gap by adopting a multi-scale approach to understand how climatic and non-climatic stressors vary, and interact, across three spatial scales (household, community and district levels) to influence livelihood vulnerability of smallholder farming households in the Savannah zone of northern Ghana. This study across three case study villages utilises a series of participatory tools including semi-structured interviews, key informant interviews and focus group discussions. The incidence, importance, severity and overall risk indices for stressors are calculated at the household, community, and district levels. Results show that climatic and non-climatic stressors were perceived differently; yet, there were a number of common stressors including lack of money, high cost of farm inputs, erratic rainfall, cattle destruction of crops, limited access to markets and lack of agricultural equipment that crossed all scales. Results indicate that the gender of respondents influenced the perception and severity assessment of stressors on rural livelihoods at the community level. Findings suggest a mismatch between local and district level priorities that have implications for policy and development of agricultural and related livelihoods in rural communities. Ghana’s climate change adaptation policies need to take a more holistic approach that integrates both climatic and non-climatic factors to ensure policy coherence between national climate adaptation plans and District development plans

Hyperon Photoproduction in the Nucleon Resonance Region

Cross-sections and recoil polarizations for the reactions gamma + p --> K^+ + Lambda and gamma + p --> K^+ + Sigma^0 have been measured with high statistics and with good angular coverage for center-of-mass energies between 1.6 and 2.3 GeV. In the K^+Lambda channel we confirm a structure near W=1.9 GeV at backward kaon angles, but our data shows a more complex s- and u- channel resonance structure than previously seen. This structure is present at forward and backward angles but not central angles, and its position and width change with angle, indicating that more than one resonance is playing a role. Rising back-angle cross sections at higher energies and large positive polarization at backward angles are consistent with sizable s- or u-channel contributions. None of the model calculations we present can consistently explain these aspects of the data.Comment: 5 pages, 3 figures, submitted to Physical Review Letter

First Measurement of Beam-Recoil Observables Cx and Cz in Hyperon Photoproduction

Spin transfer from circularly polarized real photons to recoiling hyperons has been measured for the reactions $\vec\gamma + p \to K^+ + \vec\Lambda$ and $\vec\gamma + p \to K^+ + \vec\Sigma^0$. The data were obtained using the CLAS detector at Jefferson Lab for center-of-mass energies $W$ between 1.6 and 2.53 GeV, and for $-0.85<\cos\theta_{K^+}^{c.m.}< +0.95$. For the $\Lambda$, the polarization transfer coefficient along the photon momentum axis, $C_z$, was found to be near unity for a wide range of energy and kaon production angles. The associated transverse polarization coefficient, $C_x$, is smaller than $C_z$ by a roughly constant difference of unity. Most significantly, the {\it total} $\Lambda$ polarization vector, including the induced polarization $P$, has magnitude consistent with unity at all measured energies and production angles when the beam is fully polarized. For the $\Sigma^0$ this simple phenomenology does not hold. All existing hadrodynamic models are in poor agreement with these results.Comment: 28 pages, 18 figures, Submitted to Physical Review

Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats

<p>Abstract</p> <p>Background</p> <p>CXCR4 is the receptor for chemokine CXCL12 and reportedly plays an important role in systemic vascular repair and remodeling, but the role of CXCR4 in development of pulmonary hypertension and vascular remodeling has not been fully understood.</p> <p>Methods</p> <p>In this study we investigated the role of CXCR4 in the development of pulmonary hypertension and vascular remodeling by using a CXCR4 inhibitor AMD3100 and by electroporation of CXCR4 shRNA into bone marrow cells and then transplantation of the bone marrow cells into rats.</p> <p>Results</p> <p>We found that the CXCR4 inhibitor significantly decreased chronic hypoxia-induced pulmonary hypertension and vascular remodeling in rats and, most importantly, we found that the rats that were transplanted with the bone marrow cells electroporated with CXCR4 shRNA had significantly lower mean pulmonary pressure (mPAP), ratio of right ventricular weight to left ventricular plus septal weight (RV/(LV+S)) and wall thickness of pulmonary artery induced by chronic hypoxia as compared with control rats.</p> <p>Conclusions</p> <p>The hypothesis that CXCR4 is critical in hypoxic pulmonary hypertension in rats has been demonstrated. The present study not only has shown an inhibitory effect caused by systemic inhibition of CXCR4 activity on pulmonary hypertension, but more importantly also has revealed that specific inhibition of the CXCR4 in bone marrow cells can reduce pulmonary hypertension and vascular remodeling via decreasing bone marrow derived cell recruitment to the lung in hypoxia. This study suggests a novel therapeutic approach for pulmonary hypertension by inhibiting bone marrow derived cell recruitment.</p

High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma

The objective of this paper is to investigate the mesothelin expression level to the clinicopathological features, chemoresponse, and to the outcome of patients with epithelial ovarian carcinoma (EOC). Mesothelin mRNA was detected by real-time quantitative reverse-transcription PCR in 139 EOC patients. Clinical characteristics, histopathological items, responses to chemotherapy, progression-free survival (PFS), and overall survival (OS) were recorded. Tumours with advanced stages had higher mesothelin than those with early stages. The chemoresistant patients showed significantly higher mesothelin than did chemosensitive patients (2.81 vs 0.43, P<0.001), irrespective of optimal or suboptimal surgery in those with advanced stages. Highly expressed levels of mesothelin were an independent but poor prognostic factor in the PFS (2.03 (1.23–3.37) P=0.006) and OS (3.72 (1.64–8.45), P=0.002) of the 139 EOC patients in multivariate analysis. In addition, patients in advanced stages with highly expressed mesothelin also had significantly worse OS, regardless of whether they had undergone optimal (13.85 (1.76–125.60), P=0.013) or suboptimal (4.47 (1.83–10.88), P=0.001) debulking surgery in multivariate analysis. Out results provide new evidence that mesothelin expression is associated with chemoresistance and with shorter disease-free survival and worse OS of patients with EOC