Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF‐κB pathway

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF‐receptors‐1 and ‐2 (FGFR‐1/‐2), inducible nitric oxide synthase (iNOS) and MMP‐9 expression. Our data revealed increased expression of bFGF and FGFR‐1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP‐9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up‐regulation of both iNOS and MMP‐9 that was specifically mediated by nuclear factor‐κB (NF‐κB) activation. Collectively, our data demonstrate a novel NF‐κB‐mediated pathway linking bFGF with iNOS and MMP‐9 expression that is associated with carotid plaque vulnerability.     

Complete 1H, 15N and 13C resonance assignments of Bacillus cereus metallo-β-lactamase and its complex with the inhibitor R-thiomandelic acid

β-Lactamases inactivate β-lactam antibiotics by hydrolysis of their endocyclic β-lactam bond and are a major cause of antibiotic resistance in pathogenic bacteria. The zinc dependent metallo-β-lactamase enzymes are of particular concern since they are located on highly transmissible plasmids and have a broad spectrum of activity against almost all β-lactam antibiotics. We present here essentially complete (>96 %) backbone and sidechain sequence-specific NMR resonance assignments for the Bacillus cereus subclass B1 metallo-β-lactamase, BcII, and for its complex with R-thiomandelic acid, a broad spectrum inhibitor of metallo-β-lactamases. These assignments have been used as the basis for determination of the solution structures of the enzyme and its inhibitor complex and can also be used in a rapid screen for other metallo-β-lactamase inhibitors.     

Inhibin/activin-betaE subunit in normal and malignant human cervical tissue and cervical cancer cell lines

Inhibins are dimeric glycoproteins, composed of an alpha-subunit and one of two possible beta-subunits (betaA or betaB), with substantial roles in human reproduction and in endocrine-responsive tumours. Recently a novel beta subunit named betaE was described, although it is still unclear if normal or cancerous cervical epithelial cells as well as cervical cancer cell lines can synthesise the novel inhibin-betaE subunit. About 4 normal cervical tissue samples together with 10 specimens of well-differentiated squamous cervical cancer and adenocarcinoma of the cervix were immunohistochemical analyzed. Additionally, two cervical carcinoma cell lines (HeLa and CaSki) were analyzed by immunofluorescence and RT–PCR for the expression of this novel subunit. We demonstrated for the first time an immunolabelling of the inhibin-betaE subunit in normal and malignant cervical tissue, as well as cervical cancer cells. Although the physiological role is still quite unclear in cervical tissue, inhibin-βE might play important roles in carcinogenesis. Moreover, the synthesis of this subunit in cervical carcinoma cell lines of squamous and glandular epithelial origins also allows the use of these cell lines in elucidating its functions in cervical cancer pathogenesis. However, since the expression of the inhibin-βE is minimal in HeLa cells as assessed by immunofluorescence and RT–PCR, the CaSki cell line might be a better model for further functional experiments regarding cervical cancer pathogenesis.     

Synergy Management Services Companies: A New Business Model for Industrial Park Operators

The concept of industrial symbiosis (IS) was introduced decades ago and its environmental and economic benefits are well established, but the broad acceptance of IS still faces significant barriers. This article provides a new approach to capture synergies within industrial parks by suggesting a new business model. Building on findings from a survey conducted by the authors and on literature, we first identify potential barriers to low‐carbon synergistic projects. Economic concerns of technically feasible synergies and financial issues turn out to be the largest barriers, because of long payback periods and fluctuating raw material and by‐product market prices. Existing business models do not offer easy ways to overcome or relax these barriers. We therefore introduce the concept of a synergy management services company (SMSCO), a synergy contractor and third‐party financing model, to overcome these barriers. This model shifts the financial risk of the synergistic project from collaborating firms to the SMSCO. We posit that this attribute of the SMSCO model makes it attractive for industrial park operators who seek long‐term solutions to secure future viability of their park.     

Improved reliability of the urine lactate concentration under controlled hydration after maximal exercise

Context: Urine lactate may be a novel biomarker of lactate production capacity but its reliability has been unsatisfactory so far.

Objective: To compare the reliability of urine lactate between controlled hydration and no hydration after maximal exercise.

Material and methods: Athletes performed swimming exercise four times: two followed by consumption of 1?L of water and two followed by no water intake. Blood and urine lactate was measured.

Results: The reliability of urine lactate was good and similar to that in blood only after controlled hydration. Blood and urine lactate were correlated under both hydration conditions.

Discussion and conclusion: Controlled hydration after exercise provides satisfactory reliability of urine lactate.     

Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

Brain iron deposition is a feature of Parkinson’s disease pathology, but how this contributes to neurodegeneration is unclear. This study show that Parkinson’s disease-linked mutations in LRRK2 cause aberrant brain iron accumulation in vivo and iron dyshomeostasis in vitro, supporting a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.     

Non Linear Programming (NLP) Formulation for Quantitative Modeling of Protein Signal Transduction Pathways

Modeling of signal transduction pathways plays a major role in understanding cells'' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.     

A rare case of a 39 year old male with a parasite called Dioctophyma renale mimicking renal cancer at the computed tomography of the right kidney. A case report

We present a very rare case of a 39 year old patient with Dioctophyma renale depicted as a Bosniak cyst IV of the right kidney who was finally subjected to a robotic assisted radical nephrectomy.