Conformational Changes of Calpain from Human Erythrocytes in the Presence of Ca2

Small angle x-ray scattering has been used to monitor calpain structural transitions during the activation process triggered by Ca(2+) binding. The scattering pattern of the unliganded enzyme in solution does not display any significant difference with that calculated from the crystal structure. The addition of Ca(2+) promotes the formation of large aggregates, indicating the exposure of hydrophobic patches on the surface of the protease. In contrast, Ca(2+) addition in the presence of the thiol proteinase inhibitor E64 or of the inhibitor leupeptin causes a small conformational change with no dissociation of the heterodimer. The resulting conformation appears to be slightly more extended than the unliganded form. From the comparison between ab initio models derived from our data with the crystal structure, the major observable conformational change appears to be localized at level of the L-subunit and in particular seems to confirm the mutual movement already observed by the crystallographic analysis of the dII (dIIb) and the dI (dIIa) domains creating a functional active site. This work not only provides another piece of supporting evidence for the calpain conformational change in the presence of Ca(2+), but actually constitutes the first experimental observation of this change for intact heterodimeric calpain in solution

Early Detection and Investigation of Extracellular Vesicles Biomarkers in Breast Cancer

Breast cancer (BC) is the most commonly diagnosed malignant tumor in women worldwide, and the leading cause of cancer death in the female population. The percentage of patients experiencing poor prognosis along with the risk of developing metastasis remains high, also affecting the resistance to current main therapies. Cancer progression and metastatic development are no longer due entirely to their intrinsic characteristics, but also regulated by signals derived from cells of the tumor microenvironment. Extracellular vesicles (EVs) packed with DNA, RNA, and proteins, are the most attractive targets for both diagnostic and therapeutic applications, and represent a decisive challenge as liquid biopsy-based markers. Here we performed a study based on a multiplexed phenotyping flow cytometric approach to characterize BC-derived EVs from BC patients and cell lines, through the detection of multiple antigens. Our data reveal the expression of EVs-related biomarkers derived from BC patient plasma and cell line supernatants, suggesting that EVs could be exploited for characterizing and monitoring disease progression

Synchronisation in networks of delay-coupled type-I excitable systems

We use a generic model for type-I excitability (known as the SNIPER or SNIC model) to describe the local dynamics of nodes within a network in the presence of non-zero coupling delays. Utilising the method of the Master Stability Function, we investigate the stability of the zero-lag synchronised dynamics of the network nodes and its dependence on the two coupling parameters, namely the coupling strength and delay time. Unlike in the FitzHugh-Nagumo model (a model for type-II excitability), there are parameter ranges where the stability of synchronisation depends on the coupling strength and delay time. One important implication of these results is that there exist complex networks for which the adding of inhibitory links in a small-world fashion may not only lead to a loss of stable synchronisation, but may also restabilise synchronisation or introduce multiple transitions between synchronisation and desynchronisation. To underline the scope of our results, we show using the Stuart-Landau model that such multiple transitions do not only occur in excitable systems, but also in oscillatory ones.Comment: 10 pages, 9 figure

Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease.

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Methods: Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. Results: The lowest levels of TRAIL at baseline were significantly (p<0.05) associated with the appearance, after 24 months of follow-up, of at least two new atheromatous plaques in all territories and of one new plaque in the carotid artery, even after adjusting for CV risk factors. In addition, the patients with low levels of TRAIL at baseline were characterized by the presence of at least one hypoechoic plaque in the carotid artery. This association was significant (p<0.05) even after adjusting for CKD stage. Conclusions: Overall, the results of our study suggest TRAIL as an assertable independent prognostic biomarker for atheromatosis plaque formation in CKD patients. This observation further supports the potential role of TRAIL for the prevention/treatment of CV disease.The NEFRONA study was funded by a research grant from Abbvie and the Spanish government RETIC (RD16/0009/0011) and FISPI16/01354. MVA is the recipient of the Italian Ministry of Health grant No. GR-2013-0 2358192. SG is the recipient of the "Associazione Italiana per la Ricerca sul Cancro, AIRC" fellowship, No. 18055. Moreover, the authors would like to thank Fondazione Dott. Carlo Fornasini (Poggio Renatico, Ferrara, Italy). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Temperature and wavelength drift tolerant WDM transmission and routing in on-chip silicon photonic interconnects

We demonstrate a temperature and wavelength shift resilient silicon transmission and routing interconnect system suitable for multi-socket interconnects, utilizing a dual-strategy CLIPP feedback circuitry that safeguards the operating point of the constituent photonic building blocks along the entire on-chip transmission-multiplexing-routing chain. The control circuit leverages a novel control power-independent and calibration-free locking strategy that exploits the 2nd derivative of ring resonator modulators (RMs) transfer function to lock them close to the point of minimum transmission penalty. The system performance was evaluated on an integrated Silicon Photonics 2-socket demonstrator, enforcing control over a chain of RM-MUX-AWGR resonant structures and stressed against thermal and wavelength shift perturbations. The thermal and wavelength stress tests ranged from 27 degrees C to 36 degrees C and 1309.90 nm to 1310.85 nm and revealed average eye diagrams Q-factor values of 5.8 and 5.9 respectively, validating the system robustness to unstable environments and fabrication variations. (C) 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreemen

Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window?

Background: To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments. Methodology/Principal Findings: MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged,42 % of area at risk, or,24 % of left ventricle, and was reduced by more than 50 % (p,0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size

An unusual cause of haemoptysis in a young male

Inflammatory myofibroblastic tumours are reported to occur in a variety of sites, including the head and neck, abdominal organs, central nervous system and urinary tract. They only rarely occur in the lung. We report a case of a 25-year-old male admitted with haemoptysis. His chest radiograph showed a peripheral right lung opacity and computed tomography revealed a right lower lobe soft tissue density mass. Bronchoscopy and fine needle aspiration were unhelpful. a diagnosis of pulmonary carcinoma was made, and the patient underwent a right lower lobectomy. On pathology, the tumor was found to be an inflammatory pseudotumor. These lesion are extremely rare, constituting less than 1% of pulmonary malignancies, but are known to occur in young patients. We believe clinicians need to retain an index of suspicion for the presence of this disease in young patients, which can masquerade as more common malignancies

Surgery for recurrent inflammatory pseudotumor of the lung

<p>Abstract</p> <p>Background</p> <p>Cases of recurrent inflammatory pseudotumor have only rarely been reported. The treatment for recurrent pseudotumor is surgery. Patients not eligible for surgery require different treatment, and the optimal type of the treatment is controversial.</p> <p>Case Presentation</p> <p>A 54-year-old woman was noted to have an abnormal shadow in the right middle lung field on chest X-ray. Computed tomography of the chest revealed an infiltrative lesion in the right segment 4 and a nodule in the right segment 8. She underwent right middle lobectomy and partial resection of the right segment 8. Histopathology revealed non-atypical lymphocytes and plasma cells infiltrates, leading to the diagnosis of the lymphoplasmacytic type of inflammatory pseudotumor. During postoperative follow-up, chest computed tomography revealed a nodular lesion in the left segment 3 and an infiltrative lesion in the right segment 2. Left segment 3 segmentectomy and right segment 2 wedge resection were performed. The histopathological findings were similar to those of the first surgical specimen, leading to the diagnosis of recurrent lymphoplasmacytic type of inflammatory pseudotumor.</p> <p>Conclusion</p> <p>Surgical cases of recurrent inflammatory pseudotumor of the lung have been reported only very rarely. We believe that surgery is the best treatment for recurrent inflammatory pseudotumor of the lung when patients are eligible.</p