Eastern Mediterranean water outflow during the Younger Dryas was twice that of the present day

Eastern Mediterranean deep-intermediate convection was highly sensitive to varying inputs of fresh water fluxes associated with increased rainfall during the African Humid period (15-6 kyr Before Present). Here we investigate changes in the water-outflow from the Eastern Mediterranean Sea since the last deglaciation using neodymium isotope ratios. Our results indicate enhanced outflow during the Younger Dryas, two times higher than present-day outflow and about three times higher than during the last Sapropel. We propose that the increased outflow into the western Mediterranean over the Younger Dryas was the result of the combined effect of 1) enhanced climate-driven convection in the Aegean Sea and 2) reduced convection of western deep water during this period. Our results provide solid evidence for an enhanced Younger Dryas westward flow of Eastern Mediterranean sourced waters in consonance with an intensification of Mediterranean water-outflow during a weakened state of the Atlantic circulatio

Exceptional eruptive CO2 emissions from intra-plate alkaline magmatism in the Canary volcanic archipelago

Alkaline mafic magmas forming intra-plate oceanic islands are believed to be strongly enriched in CO2 due to low-degree partial melting of enriched mantle sources. However, until now, such CO2 enhancement has not been verified by measuring CO2 degassing during a subaerial eruption. Here, we provide evidence of highly CO2-rich gas emissions during the 86-day 2021 Tajogaite eruption of Cumbre Vieja volcano on La Palma Island, in the Canary archipelago. Our results reveal sustained high plume CO2/SO2 ratios, which, when combined with SO2 fluxes, melt inclusion volatile contents and magma production rates at explosive and effusive vents, imply a magmatic CO2 content of 4.5 ± 1.5 wt%. The amount of CO2 released during the 2021 eruptive activity was 28 ± 14 Mt CO2. Extrapolating to the volume of alkaline mafic magmas forming La Palma alone (estimated as 4000 km3 erupted over 11 Ma), we infer a maximum CO2 emission into the ocean and atmosphere of 1016 moles of CO2, equivalent to 20% of the eruptive CO2 emissions from a large igneous province eruption, suggesting that the formation of the Canary volcanic archipelago produced a CO2 emission of similar magnitude as a large igneous province

PhoP: A Missing Piece in the Intricate Puzzle of Mycobacterium tuberculosis Virulence

Inactivation of the transcriptional regulator PhoP results in Mycobacterium tuberculosis attenuation. Preclinical testing has shown that attenuated M. tuberculosis phoP mutants hold promise as safe and effective live vaccine candidates. We focused this study to decipher the virulence networks regulated by PhoP. A combined transcriptomic and proteomic analysis revealed that PhoP controls a variety of functions including: hypoxia response through DosR crosstalking, respiratory metabolism, secretion of the major T-cell antigen ESAT-6, stress response, synthesis of pathogenic lipids and the M. tuberculosis persistence through transcriptional regulation of the enzyme isocitrate lyase. We also demonstrate that the M. tuberculosis phoP mutant SO2 exhibits an antigenic capacity similar to that of the BCG vaccine. Finally, we provide evidence that the SO2 mutant persists better in mouse organs than BCG. Altogether, these findings indicate that PhoP orchestrates a variety of functions implicated in M. tuberculosis virulence and persistence, making phoP mutants promising vaccine candidates

Contrasting Transcriptional Responses of a Virulent and an Attenuated Strain of Mycobacterium tuberculosis Infecting Macrophages

Along with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra

Prokayrotic Ubiquitin-Like Protein (Pup) Proteome of Mycobacterium tuberculosis

Prokaryotic ubiquitin-like protein (Pup) in Mycobacterium tuberculosis (Mtb) is the first known post-translational small protein modifier in prokaryotes, and targets several proteins for degradation by a bacterial proteasome in a manner akin to ubiquitin (Ub) mediated proteolysis in eukaryotes. To determine the extent of pupylation in Mtb, we used tandem affinity purification to identify its “pupylome”. Mass spectrometry identified 55 out of 604 purified proteins with confirmed pupylation sites. Forty-four proteins, including those with and without identified pupylation sites, were tested as substrates of proteolysis in Mtb. Under steady state conditions, the majority of the test proteins did not accumulate in degradation mutants, suggesting not all targets of pupylation are necessarily substrates of the proteasome under steady state conditions. Four proteins implicated in Mtb pathogenesis, Icl (isocitrate lyase), Ino1 (inositol-1-phosphate synthase), MtrA (Mtb response regulator A) and PhoP (phosphate response regulator P), showed altered levels in degradation defective Mtb. Icl, Ino1 and MtrA accumulated in Mtb degradation mutants, suggesting these proteins are targeted to the proteasome. Unexpectedly, PhoP was present in wild type Mtb but undetectable in the degradation mutants. Taken together, these data demonstrate that pupylation regulates numerous proteins in Mtb and may not always lead to degradation

Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages

BACKGROUND: Macrophage cell death following infection with Mycobacterium tuberculosis plays a central role in tuberculosis disease pathogenesis. Certain attenuated strains induce extrinsic apoptosis of infected macrophages but virulent strains of M. tuberculosis suppress this host response. We previously reported that virulent M. tuberculosis induces cell death when bacillary load exceeds approximately 20 per macrophage but the precise nature of this demise has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the characteristics of cell death in primary murine macrophages challenged with virulent or attenuated M. tuberculosis complex strains. We report that high intracellular bacillary burden causes rapid and primarily necrotic death via lysosomal permeabilization, releasing hydrolases that promote Bax/Bak-independent mitochondrial damage and necrosis. Cell death was independent of cathepsins B or L and notable for ultrastructural evidence of damage to lipid bilayers throughout host cells with depletion of several host phospholipid species. These events require viable bacteria that can respond to intracellular cues via the PhoPR sensor kinase system but are independent of the ESX1 system. CONCLUSIONS/SIGNIFICANCE: Cell death caused by virulent M. tuberculosis is distinct from classical apoptosis, pyroptosis or pyronecrosis. Mycobacterial genes essential for cytotoxicity are regulated by the PhoPR two-component system. This atypical death mode provides a mechanism for viable bacilli to exit host macrophages for spreading infection and the eventual transition to extracellular persistence that characterizes advanced pulmonary tuberculosis

Isotemporal substitution of inactive time with physical activity and time in bed: cross-sectional associations with cardiometabolic health in the PREDIMEDPlus study

Background: This study explored the association between inactive time and measures of adiposity, clinical parameters, obesity, type 2 diabetes and metabolic syndrome components. It further examined the impact of reallocating inactive time to time in bed, light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) on cardio-metabolic risk factors, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Methods: This is a cross-sectional analysis of baseline data from 2189 Caucasian men and women (age 55-75 years, BMI 27-40 Kg/m2) from the PREDIMED-Plus study (http://www.predimedplus.com/). All participants had ≥3 components of the metabolic syndrome. Inactive time, physical activity and time in bed were objectively determined using triaxial accelerometers GENEActiv during 7 days (ActivInsights Ltd., Kimbolton, United Kingdom). Multiple adjusted linear and logistic regression models were used. Isotemporal substitution regression modelling was performed to assess the relationship of replacing the amount of time spent in one activity for another, on each outcome, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Results: Inactive time was associated with indicators of obesity and the metabolic syndrome. Reallocating 30 min per day of inactive time to 30 min per day of time in bed was associated with lower BMI, waist circumference and glycated hemoglobin (HbA1c) (all p-values < 0.05). Reallocating 30 min per day of inactive time with 30 min per day of LPA or MVPA was associated with lower BMI, waist circumference, total fat, visceral adipose tissue, HbA1c, glucose, triglycerides, and higher body muscle mass and HDL cholesterol (all p-values < 0.05). Conclusions: Inactive time was associated with a poor cardio-metabolic profile. Isotemporal substitution of inactive time with MVPA and LPA or time in bed could have beneficial impact on cardio-metabolic health

A search for Very High Energy gamma-ray emission from Scorpius X-1 with the MAGIC telescopes

The acceleration of particles up to GeV or higher energies in microquasars has been the subject of considerable theoretical and observational efforts in the past few years. Sco X-1 is a microquasar from which evidence of highly energetic particles in the jet has been found when it is in the so-called Horizontal Branch (HB), a state when the radio and hard X-ray fluxes are higher and a powerful relativistic jet is present. Here we present the first very high energy gamma-ray observations of Sco X-1 obtained with the MAGIC telescopes. An analysis of the whole dataset does not yield a significant signal, with 95% CL flux upper limits above 300 GeV at the level of 2.4x10^{-12} ph/cm^2/s. Simultaneous RXTE observations were conducted to search for TeV emission during particular X-ray states of the source. A selection of the gamma-ray data obtained during the HB based on the X-ray colors did not yield a signal either, with an upper limit of 3.4x10^{-12} ph/cm^2/s. These upper limits place a constraint on the maximum TeV luminosity to non-thermal X-ray luminosity of L_{VHE}/L_{ntX}<0.02, that can be related to a maximum TeV luminosity to jet power ratio of L_{VHE}/L_{j}<10^{-3}. Our upper limits indicate that the underlying high-energy emission physics in Sco X-1 must be inherently different from that of the hitherto detected gamma-ray binaries.Comment: 5 pages, 2 figures, 2 tables. Version as published in ApJ

Balancing the immune response in the brain: IL-10 and its regulation

Background: The inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology. Main body: The production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders. Conclusion: The regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.We acknowledge the Portuguese Foundation for Science and Technology (FCT) for providing a PhD grant to DLS (SFRH/BD/88081/2012) and a post-doctoral fellowship to SR (SFRH/BPD/72710/2010). DS, AGC and SR were funded by FEDER through the Competitiveness Factors Operational Programme (COMPETE) and National Funds through FCT under the scope of the project POCI-01-0145-FEDER007038; and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The MS lab was financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT in the framework of the project “Institute for Research and Innovation in Health Sciences ” (POCI-01-0145-FEDER-007274). MS is a FCT Associate Investigator. The funding body had no role in the design of the study and collection, analysis, and interpretation of the data and in writing the manuscript

PG 1553+113: five years of observations with MAGIC

We present the results of five years (2005-2009) of MAGIC observations of the BL Lac object PG 1553+113 at very high energies (VHEs, E > 100 GeV). Power law fits of the individual years are compatible with a steady mean photon index \Gamma = 4.27 $\pm$ 0.14. In the last three years of data, the flux level above 150 GeV shows a clear variability (probability of constant flux < 0.001%). The flux variations are modest, lying in the range from 4% to 11% of the Crab Nebula flux. Simultaneous optical data also show only modest variability that seems to be correlated with VHE gamma ray variability. We also performed a temporal analysis of (all available) simultaneous Fermi/LAT data of PG 1553+113 above 1 GeV, which reveals hints of variability in the 2008-2009 sample. Finally, we present a combination of the mean spectrum measured at very high energies with archival data available for other wavelengths. The mean spectral energy distribution can be modeled with a one-zone Synchrotron Self Compton (SSC) model, which gives the main physical parameters governing the VHE emission in the blazar jet.Comment: 11 pages, 6 figures, accepted for publication in Ap