Structural and biochemical insights of CypA and AIF interaction

The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370-394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed. We show that AIF(370-394) interacts with CypA on the same surface recognized by AIF(Δ1-121) protein and that the region is very close to the CypA catalytic pocket. Such region partially overlaps with the binding site of cyclosporin A (CsA), the strongest catalytic inhibitor of CypA. Our data point toward distinct CypA structural determinants governing the inhibitor selectivity and the differential biological effects of AIF and CsA, and provide new structural insights for designing CypA/AIF selective inhibitors with therapeutic relevance in neurodegenerative diseases

Design, Optimization, and Structural Characterization of an Apoptosis-Inducing Factor Peptide Targeting Human Cyclophilin A to Inhibit Apoptosis Inducing Factor-Mediated Cell Death

Blocking the interaction between the apoptosis-inducing factor (AIF) and cyclophilin A (CypA) by the AIF fragment AIF(370-394) is protective against glutamate-induced neuronal cell death and brain injury in mice. Starting from AIF(370-394), we report the generation of the disulfide-bridged and shorter variant AIF(381-389) and its structural characterization by nuclear magnetic resonance (NMR) in the free and CypA-bound state. AIF(381-389) in both the free and bound states assumes a β-hairpin conformation similar to that of the fragment in the AIF protein and shows a highly reduced conformational flexibility. This peptide displays a similar in vitro affinity for CypA, an improved antiapoptotic activity in cells and an enhanced proteolytic stability compared to the parent peptide. The NMR-based 3D model of the AIF(381-389)/CypA complex provides a better understanding of the binding hot spots on both the peptide and the protein and can be exploited to design AIF/CypA inhibitors with improved pharmacokinetic and pharmacodynamics features

Acquisition Parameters Influence Diffusion Metrics Effectiveness in Probing Prostate Tumor and Age-Related Microstructure

: This study aimed to investigate the Diffusion-Tensor-Imaging (DTI) potential in the detection of microstructural changes in prostate cancer (PCa) in relation to the diffusion weight (b-value) and the associated diffusion length lD. Thirty-two patients (age range = 50-87 years) with biopsy-proven PCa underwent Diffusion-Weighted-Imaging (DWI) at 3T, using single non-zero b-value or groups of b-values up to b = 2500 s/mm2. The DTI maps (mean-diffusivity, MD; fractional-anisotropy, FA; axial and radial diffusivity, D// and D┴), visual quality, and the association between DTI-metrics and Gleason Score (GS) and DTI-metrics and age were discussed in relation to diffusion compartments probed by water molecules at different b-values. DTI-metrics differentiated benign from PCa tissue (p ≤ 0.0005), with the best discriminative power versus GS at b-values ≥ 1500 s/mm2, and for b-values range 0-2000 s/mm2, when the lD is comparable to the size of the epithelial compartment. The strongest linear correlations between MD, D//, D┴, and GS were found at b = 2000 s/mm2 and for the range 0-2000 s/mm2. A positive correlation between DTI parameters and age was found in benign tissue. In conclusion, the use of the b-value range 0-2000 s/mm2 and b-value = 2000 s/mm2 improves the contrast and discriminative power of DTI with respect to PCa. The sensitivity of DTI parameters to age-related microstructural changes is worth consideration

Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 2

In this contribution, new data concerning red algae, lichens and bryophytes of the Italian flora are presented. It includes new records and confirmations for the algal genus Grateloupia, the bryophyte genus Didymodon, and the lichen genera Buellia, Cladonia, Letharia, Pertusaria, and Pyrenula

Optimal control to reduce emissions in gasoline engines: An iterative learning control approach for ECU calibration maps improvement

Control of emissions in gasoline engines has become more stringent in the last decades, especially in Europe, posing new and important problems in the control of complex nonlinear systems. In this work a preliminary investigation is conducted on the idea of exploiting Iterative Learning Control to optimize calibration maps that are commonly used in the Engine Control Unit of gasoline engines. In this spirit, starting from existing maps, we show how to refine them using a gradient-descent iterative learning control algorithm, considering additional constraints in the optimization problem. The outcome of this procedure is a control signal which can be integrated in a modified map. The performance of the proposed technique is validated on the provided training signal and cross-validated on different reference signals. Simulation results show the effectiveness of the approach

Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 3

In this contribution, new data concerning bryophytes, fungi and lichens and of the Italian flora are presented. It includes new records and confirmations for the bryophyte genera Dicranodontium, Fontinalis, Lophocoleaand Riccia, the fungal genus Diplolaeviopsis, the lichen genera Agonimia, Cladonia, Protoparmelia, Rhizocarpon, and Scytinium

er.autopilot 1.0: The Full Autonomous Stack for Oval Racing at High Speeds

The Indy Autonomous Challenge (IAC) brought together for the first time in history nine autonomous racing teams competing at unprecedented speed and in head-to-head scenario, using independently developed software on open-wheel racecars. This paper presents the complete software architecture used by team TII EuroRacing (TII-ER), covering all the modules needed to avoid static obstacles, perform active overtakes and reach speeds above 75 m/s (270 km/h). In addition to the most common modules related to perception, planning, and control, we discuss the approaches used for vehicle dynamics modelling, simulation, telemetry, and safety. Overall results and the performance of each module are described, as well as the lessons learned during the first two events of the competition on oval tracks, where the team placed respectively second and third.Comment: Preprint: Accepted to Field Robotics "Opportunities and Challenges with Autonomous Racing" Special Issu

Care of patients with ST-elevation myocardial infarction: an international analysis of quality indicators in the acute coronary syndrome STEMI Registry of the EURObservational Research Programme and ACVC and EAPCI Associations of the European Society of Cardiology in 11 462 patients

Aims To use quality indicators to study the management of ST-segment elevation myocardial infarction (STEMI) in different regions. Methods and results Prospective cohort study of STEM I within 24 h of symptom onset (11 462 patients, 196 centres, 26 European Society of Cardiology members, and 3 affiliated countries). The median delay between arrival at a percutaneous cardiovascular intervention (PCI) centre and primary PCI was 40 min (interquartile range 20-74) with 65.8% receiving PCI within guideline recommendation of 60 min. A third of patients (33.2%) required transfer from their initial hospital to one that could perform emergency PCI for whom only 27.2% were treated within the quality indicator recommendation of 120 min. Radial access was used in 56.6% of all primary PCI, but with large geographic variation, from 76.4 to 9.1%. Statins were prescribed at discharge to 98.7% of patients, with little geographic variation. Of patients with a history of heart failure or a documented left ventricular ejection fraction <= 40%, 84.0% were discharged on an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and 88.7% were discharged on beta-blockers. Conclusion Care for STEMI shows wide geographic variation in the receipt of timely primary PCI, and is in contrast with the more uniform delivery of guideline-recommended pharmacotherapies at time of hospital discharge. [GRAPHICS]

Location of primary tumor and benefit from anti-epidermal growth factorreceptor monoclonalantibodies in patients with RAS and BRAF wild-typemetastatic colorectal cancer

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p 5 .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p, .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97;95%confidence interval: 2.09–7.53; p,.0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti- EGFRs