Long-term <i>hm</i>F2 trends in the Eurasian longitudinal sector from the ground-based ionosonde observations

International audienceThe method earlier used for the foF2 long-term trends analysis is applied to reveal hmF2 long-term trends at 27 ionosonde stations in the European and Asian longitudinal sectors. Observed M(3000)F2 data for the last 3 solar cycles are used to derive hmF2 trends. The majority of the studied stations show significant hmF2 linear trends with a confidence level of at least 95% for the period after 1965, with most of these trends being positive. No systematic variation of the trend magnitude with latitude is revealed, but some longitudinal effect does take place. The proposed geomagnetic storm concept to explain hmF2 long-term trends proceeds from a natural origin of the trends rather than an artificial one related to the thermosphere cooling due to the greenhouse effect

Effect of in-cylinder swirl on engine efficiency and heat rejection in a light-duty diesel engine

[EN] During the last years, the growing awareness about the impacts of climate change lead to an increase in the importance of the efficiency over other criteria in the design of internal combustion engines. In this framework, the heat transfer to the combustion chamber walls can be considered as one of the main sources of indicated efficiency diminution. Hence, the main objective of this research is to thoroughly assess the effect of the swirl ratio on the heat rejection to the chamber walls, and thus on the efficiency, of a fully instrumented four-cylinder direct-injection diesel engine with variable swirl ratio (covering the range from 1.4 to 3). The analysis, based on the engine global energy balance, includes a combination of theoretical and experimental tools such as thermal flow measurement and dedicated thermocouples in the cylinder head and liner. Considering the results, it is shown that an increase in swirl ratio leads to a heat transfer enhancement, along with important changes on the combustion development. As a result of the combination of these two effects, it is shown that intermediate swirl ratios can slightly improve engine efficiency at low load, while increasing swirl worsens the combustion process and efficiency at high load. However, convective heat transfer increases about 3% of the fuel energy in the chamber when swirl ratio increases from 1.4 to 3. The heat rejection characterization is completed with the analysis of the wall temperatures. Despite the observed trends, heat transfer does not seem to be the only key issue for explaining the indicated and brake efficiencies, thus the pumping work plays an important role due to the effect of reducing the intake section to generate the swirl motion.This work was supported by GM Global R&D and the Spanish Ministry of Economy and Competitiveness (TRA2013-41348-R).Olmeda, P.; Martín, J.; Blanco-Cavero, D.; Warey, A.; Domenech, V. (2017). Effect of in-cylinder swirl on engine efficiency and heat rejection in a light-duty diesel engine. International Journal of Engine Research. 18(1-2):81-92. https://doi.org/10.1177/1468087417693078S8192181-

State-Dependent Allosteric Inhibition of the Human SLC13A5 Citrate Transporter by Hydroxysuccinic Acids, PF-06649298 and PF-06761281 s

ABSTRACT In the liver, citrate is a key metabolic intermediate involved in the regulation of glycolysis and lipid synthesis and reduced expression of the hepatic citrate SLC13A5 transporter has been shown to improve metabolic outcomes in various animal models. Although inhibition of hepatic extracellular citrate uptake through SLC13A5 has been suggested as a potential therapeutic approach for Type-2 diabetes and/or fatty liver disease, so far, only a few SLC13A5 inhibitors have been identified. Moreover, their mechanism of action still remains unclear, potentially limiting their utility for in vivo proof-of-concept studies. In this study, we characterized the pharmacology of the recently identified hydroxysuccinic acid SLC13A5 inhibitors, PF-06649298 and PF-06761281, using a combination of 14 C-citrate uptake, a membrane potential assay and electrophysiology. In contrast to their previously proposed mechanism of action, our data suggest that both PF-06649298 and PF-06761281 are allosteric, state-dependent SLC13A5 inhibitors, with low-affinity substrate activity in the absence of citrate. As allosteric state-dependent modulators, the inhibitory potency of both compounds is highly dependent on the ambient citrate concentration and our detailed mechanism of action studies therefore, may be of value in interpreting the in vivo effects of these compounds

Males, but Not Females, Demonstrate Mitochondrial Dysfunction in the C26 Model of Cancer Cachexia

Cancer cachexia is characterized by progressive muscle wasting that can lead to symptoms such as anemia, severe weight loss, and fatigue. These symptoms can lead to limitations in activities of daily living and can cause resistance to chemotherapy treatments in cancer patients. There are no current treatments available to treat cancer cachexia and a critical need remains to identify mechanisms of cancer cachexia. Recently, our group identified mitochondrial disfunction precedes muscle atrophy in males but not females in a model of lung cancer induced atrophy. However, it is unknown whether this finding is replicated when studying a different type of cancer. PURPOSE: This study set out to determine if mitochondrial respiration is impaired in the plantaris muscle in a well-established colon cancer model of cachexia. METHODS: The time-course study consisted of male and female mice in four groups per sex: An age-matched control (PBS), and three groups implanted with C26 tumors. Tumor growth for 10-15 days, 20 days, and 25 days. Tumors were implanted bilaterally into the hind flank for a total of 1X106 cells PBS (one-half per each hindflank). The plantaris was weighed for wet mass then teased into small fiber bundles and permeabilized for the quantification of mitochondrial function. Mitochondrial dysfunction was classified by a decrease in the respiratory control ratio (RCR), which is the ratio of state 3 (maximal ADP stimulated respiration) to state 4 (oligomycin-induced leak respiration). Male and Female data were analyzed separately using a one-way ANOVA. RESULTS: The tumor burden increased as the number of days increased. Male RCR showed a mean difference in RCR at the early timepoint (10-15 day, p=0.058) and demonstrated significantly lower RCR at the 20 day timepoint compared to PBS control (20d= 1.170± 0.094, PBS= 2.41 ± 0.13, p=0.031). Interestingly, RCR was not significantly different between male PBS and 25 days (1.864± 0.21, p=0.084). RCR in the plantaris from females was not different among any of the groups (p=0.401). CONCLUSION: Along with our previously published data in a lung cancer model, these data indicate that the mechanisms of muscle atrophy are sex dependent. Specifically, mitochondrial dysfunction appears to play an important role in cancer-induced atrophy in male, but not female, mice

Prevalence and follow-up of occult HCV infection in an Italian population free of clinically detectable infectious liver disease.

BACKGROUND: Occult hepatitis C virus infection (OCI) is a recently described phenomenon characterized by undetectable levels of HCV-RNA in serum/plasma by current laboratory assays, with identifiable levels in peripheral blood mononuclear cells (PBMCs) and/or liver tissue by molecular tests with enhanced sensitivity. Previous results from our group showed an OCI prevalence of 3.3% in a population unselected for hepatic disease. The present study aimed to evaluate OCI prevalence in a larger cohort of infectious liver disease-free (ILDF) subjects. Clinical follow-up of OCI subjects was performed to investigate the natural history of the infection. METHODS AND FINDINGS: 439 subjects referred to a Turin Blood Bank for phlebotomy therapy were recruited. They included 314 ILDF subjects, 40 HCV-positive subjects and 85 HBV-positive subjects, of whom 7 were active HBV carriers. Six subjects (4/314 ILDF subjects [1.27%] and 2/7 active HBV carriers [28%]) were positive for HCV-RNA in PBMCs, but negative for serological and virological markers of HCV, indicating OCI. HCV genotypes were determined in the PBMCs of 3/6 OCI subjects two had type 1b; the other had type 2a/2c. OCI subjects were followed up for at least 2 years. After 12 months only one OCI persisted, showing a low HCV viral load (3.73×10(1) UI/ml). By the end of follow-up all OCI subjects were negative for HCV. No seroconversion, alteration of liver enzyme levels, or reduction of liver synthesis occurred during follow-up. CONCLUSIONS: This study demonstrated the existence of OCI in ILDF subjects, and suggested a high OCI prevalence among active HBV carriers. Follow-up suggested that OCI could be transient, with a trend toward the decrease of HCV viral load to levels undetectable by conventional methods after 12-18 months. Confirmation studies with a longer follow-up period are needed for identification of the OCI clearance or recurrence rates, and to characterize the viruses involved

Risk factors associated with bacteremia in COVID-19 patients admitted to intensive care unit: a retrospective multicenter cohort study

Purpose: This&nbsp;multicenter observational study was done to evaluate risk factors related to the development of BSI in patients admitted to ICU for COVID-19. Methods: All patients with COVID-19 admitted&nbsp;in two COVID-19 dedicated ICUs in two different hospital&nbsp;between 02–2020 and 02–2021 were recruited. Result: 537 patients were included of whom 265 (49.3%) experienced at least one BSI. Patients who developed bacteremia had a higher SOFA score [10 (8–12) vs 9 (7–10), p &lt; 0.001], had been intubated more frequently [95.8% vs 75%, p &lt; 0.001] and for a median longer time [16&nbsp;days (9–25) vs 8&nbsp;days (5–14), p &lt; 0.001]. Patients with BSI had a median longer ICU stay [18&nbsp;days (12–31.5) vs 9&nbsp;days (5–15), p &lt; 0.001] and higher mortality [54% vs 42.3%, p &lt; 0.001] than those who did not develop it. Development of BSI resulted in a higher SOFA score [aHR&nbsp;1.08 (95% CI 1.03–1.12)] and a higher Charlson score [csAHR 1.15&nbsp;(95% CI 1.05–1.25)]. Conclusion: A high SOFA score and a high Charlson score resulted associated with BSI’s development. Conversely, immunosuppressive therapy like steroids and tocilizumab, has no role in increasing the risk of bacteremia

The synaptic ribbon is critical for sound encoding at high rates and with temporal precision.

We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each synaptic contact. Spontaneous and sound-evoked firing rates of SGNs and their compound action potential were reduced, indicating impaired transmission at ribbonless IHC-SGN synapses. The temporal precision of sound encoding was impaired and the recovery of SGN-firing from adaptation indicated slowed synaptic vesicle (SV) replenishment. Activation of Ca2+-channels was shifted to more depolarized potentials and exocytosis was reduced for weak depolarizations. Presynaptic Ca2+-signals showed a broader spread, compatible with the altered Ca2+-channel clustering observed by super-resolution immunofluorescence microscopy. We postulate that RIBEYE disruption is partially compensated by multi-AZ organization. The remaining synaptic deficit indicates ribbon function in SV-replenishment and Ca2+-channel regulation

Evaluation of the preclinical efficacy of lurbinectedin in malignant pleural mesothelioma

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients