Wake response to an ocean-feedback mechanism: Madeira Island case study

This discussion focused on the numerical study of a wake episode. The Weather Research and Forecasting model was used in a downscale mode. The current literature focuses the discussion on the adiabatic dynamics of atmospheric wakes. Changes in mountain height and consequently on its relation to the atmospheric inversion layer should explain the shift in wake regimes: from a 'strong-wake' to a 'weak-wake' scenario. Nevertheless, changes in SST variability can also induce similar regime shifts. Increase in evaporation, contributes to increase convection and thus to an uplift of the stratified atmospheric layer, above the critical height, with subsequent internal gravity wave activity.Comment: Under review proces

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.

Purpose Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and methods Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL

Monitoring phagocytic uptake of amyloid beta into glial cell lysosomes in real time

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ_{1-42} analogue (Aβ^{pH}) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of Aβ^{pH} in real time in live animals. We find that microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. Aβ^{pH} can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD

Systemic Risk and the Ripple Effect in the Supply Chain

Supply chains are highly complex systems, and disruptions may ripple through these systems in unexpected ways, but they may also start in unexpected ways. We investigate the causes of ripple effect through the lens of systemic risk. We derive supply chain systemic risk from the finance discipline where sources of risk are found in systemic risk-taking, contagion, and amplification mechanisms. In a supply chain context, we identify three dimensions that influence systemic risk, the nature of a disruption, the structure, and dependency of the supply chain, and the decision-making. Within these three dimensions, there are several factors including correlation of risk, compounding effects, cyclical linkages, counterparty risk, herding behavior, and misaligned incentives. These factors are often invisible to decision makers, and they may operate in tandem to exacerbate ripple effect. We highlight these systemic risks, and we encourage further research to understand their nature and to mitigate their effect

Relationship between nano-architectured Ti1−xCux thin film and electrical resistivity for resistance temperature detectors

Ti1−xCux thin films were produced by the glancing angle deposition technique (GLAD) for resistance temperature measurements. The deposition angle was fixed at α = 0° to growth columnar structures and α = 45° to growth zigzag structures. The Ti-to-Cu atomic concentration was tuned from 0 to 100 at.% of Cu in order to optimize the temperature coefficient of resistance (TCR) value. Increasing the amount of Cu in the Ti1−xCux thin films, the electrical conductivity was gradually changed from 4.35 to 7.87 × 105 Ω−1 m−1. After thermal “stabilization,” the zigzag structures of Ti1−xCux films induce strong variation of the thermosensitive response of the materials and exhibited a reversible resistivity versus temperature between 35 and 200 °C. The results reveal that the microstructure has an evident influence on the overall response of the films, leading to values of TCR of 8.73 × 10−3 °C−1 for pure copper films and of 4.38 × 10−3 °C−1 for a films of composition Ti0.49Cu0.51. These values are very close to the ones reported for the bulk platinum (3.93 × 10−3 °C−1), which is known to be one of the best material available for these kind of temperature-related applications. The non-existence of hysteresis in the electrical response of consecutive heating and cooling steps indicates the viability of these nanostructured zigzag materials to be used as thermosensitive sensors.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013 and Project PTDC/EEI-SII/5582/2014. A. Ferreira and C. Lopes thanks the FCT for Grant SFRH/BPD/102402/2014 and SFRH/BD/103373/2014. The authors thank financial support from the Basque Government Industry Department under the ELKARTEK Programinfo:eu-repo/semantics/publishedVersio

Using European travellers as an early alert to detect emerging pathogens in countries with limited laboratory resources

BACKGROUND: The volume, extent and speed of travel have dramatically increased in the past decades, providing the potential for an infectious disease to spread through the transportation network. By collecting information on the suspected place of infection, existing surveillance systems in industrialized countries may provide timely information for areas of the world without adequate surveillance currently in place. We present the results of a case study using reported cases of Shigella dysenteriae serotype 1 (Sd1) in European travellers to detect "events" of Sd1, related to either epidemic cases or endemic cases in developing countries. METHODS: We identified papers from a Medline search for reported events of Sd1 from 1940 to 2002. We requested data on shigella infections reported to the responsible surveillance entities in 17 European countries. Reports of Sd1 from the published literature were then compared with Sd1 notified cases among European travellers from 1990 to 2002. RESULTS: Prior to a large epidemic in 1999–2000, no cases of Sd1 had been identified in West Africa. However, if travellers had been used as an early warning, Sd1 could have been identified in this region as earlier as 1992. CONCLUSION: This project demonstrates that tracking diseases in European travellers could be used to detect emerging disease in developing countries. This approach should be further tested with a view to the continuous improvement of national health surveillance systems and existing European networks, and may play a significant role in aiding the international public health community to improve infectious disease control

Comparative Genomics Study of Multi-Drug-Resistance Mechanisms in the Antibiotic-Resistant Streptococcus suis R61 Strain

BACKGROUND: Streptococcus suis infections are a serious problem for both humans and pigs worldwide. The emergence and increasing prevalence of antibiotic-resistant S. suis strains pose significant clinical and societal challenges. RESULTS: In our study, we sequenced one multi-drug-resistant S. suis strain, R61, and one S. suis strain, A7, which is fully sensitive to all tested antibiotics. Comparative genomic analysis revealed that the R61 strain is phylogenetically distinct from other S. suis strains, and the genome of R61 exhibits extreme levels of evolutionary plasticity with high levels of gene gain and loss. Our results indicate that the multi-drug-resistant strain R61 has evolved three main categories of resistance. CONCLUSIONS: Comparative genomic analysis of S. suis strains with diverse drug-resistant phenotypes provided evidence that horizontal gene transfer is an important evolutionary force in shaping the genome of multi-drug-resistant strain R61. In this study, we discovered novel and previously unexamined mutations that are strong candidates for conferring drug resistance. We believe that these mutations will provide crucial clues for designing new drugs against this pathogen. In addition, our work provides a clear demonstration that the use of drugs has driven the emergence of the multi-drug-resistant strain R61

Triadin/Junctin Double Null Mouse Reveals a Differential Role for Triadin and Junctin in Anchoring CASQ to the jSR and Regulating Ca2+ Homeostasis

Triadin (Tdn) and Junctin (Jct) are structurally related transmembrane proteins thought to be key mediators of structural and functional interactions between calsequestrin (CASQ) and ryanodine receptor (RyRs) at the junctional sarcoplasmic reticulum (jSR). However, the specific contribution of each protein to the jSR architecture and to excitation-contraction (e-c) coupling has not been fully established. Here, using mouse models lacking either Tdn (Tdn-null), Jct (Jct-null) or both (Tdn/Jct-null), we identify Tdn as the main component of periodically located anchors connecting CASQ to the RyR-bearing jSR membrane. Both proteins proved to be important for the structural organization of jSR cisternae and retention of CASQ within them, but with different degrees of impact. Our results also suggest that the presence of CASQ is responsible for the wide lumen of the jSR cisternae. Using Ca2+ imaging and Ca2+ selective microelectrodes we found that changes in e-c coupling, SR Ca2+content and resting [Ca2+] in Jct, Tdn and Tdn/Jct-null muscles are directly correlated to the effect of each deletion on CASQ content and its organization within the jSR. These data suggest that in skeletal muscle the disruption of Tdn/CASQ link has a more profound effect on jSR architecture and myoplasmic Ca2+ regulation than Jct/CASQ association