Atmospheric deposition represents a significant source of nutrients at the Mediterranean basin scale. We apply aerosol deposition fields simulated from atmospheric models into the high resolution ...oceanic biogeochemical model NEMOMED12/PISCES with nutrient ratios used for plankton growth set to Redfield ratio. We perform 3 simulations to determine the impact of nutrients on productivity over the period 1997–2012: (i) without atmospheric deposition, (ii) with nitrogen deposition from anthropogenic and natural sources, and (iii) with deposition of both nitrogen (from anthropogenic and natural sources) and phosphate from desert dust. Time series of modeled deposition fluxes are compared to available measurements. This comparison with measurements shows that both variability and intensity ranges are realistic enough for our main purpose of estimating the atmospheric deposition impact on Mediterranean biogeochemical tracers such as surface nutrient concentrations, chlorophyll a and plankton concentrations. Our results show that atmospheric deposition is one of the major sources of nitrogen and phosphorus for some regions of the oligotrophic Mediterranean Sea. More than 18·109gNmonth−1 are deposited to the whole Mediterranean Sea. This deposition is responsible for an average increase of 30–50% in primary production over vast regions. Natural dust-derived deposition of phosphorus is sparser in space and time (0.5·109gmonth−1 on average over the entire basin). However, dust deposition events can significantly affect biological production. We calculate fertilizing effects of phosphate from dust to be low on average (6–10%) but up to 30% increase in primary productivity can be observed during the months when surface water stratification occurs. Finally, these fertilizing effects are shown to be transmitted along the biological chain (primary production, Chl a, phytoplankton, zooplankton, grazing). We also perform a preliminary study on the maximal biological response of the Mediterranean by simulating extreme deposition events throughout the basin over a full year period. We show that nitrogen deposition effects observed in our long-term simulations (1997–2012) are close to maximal effects (i.e. those produced by high intensity deposition events) whereas dust-derived phosphate effects are substantially weaker than the effect on productivity reached when an extreme deposition event occurs.
We describe the daily evolution of the three-dimensional (3D) structure of a major dust outbreak initiated by an extratropical cyclone over East Asia in early March 2008, using new aerosol retrievals ...derived from satellite observations of IASI (Infrared Atmospheric Sounding Interferometer). A novel auto-adaptive Tikhonov-Phillips-type approach called AEROIASI is used to retrieve vertical profiles of dust extinction coefficient at 10 microns for most cloud-free IASI pixels, both over land and ocean. The dust vertical distribution derived from AEROIASI is shown to agree remarkably well with along-track transects of Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) spaceborne lidar vertical profiles (mean biases less than 110 meters, correlation of 0.95, and precision of 260 meters for mean altitudes of the dust layers). AEROIASI allows the daily characterization of the 3D transport pathways across East Asia of two dust plumes originating from the Gobi and North Chinese deserts. From AEROIASI retrievals, we provide evidence that (i) both dust plumes are transported over the Beijing region and the Yellow Sea as elevated layers above a shallow boundary layer, (ii) as they progress eastward, the dust layers are lifted up by the ascending motions near the core of the extratropical cyclone, and (iii) when being transported over the warm waters of the Japan Sea, turbulent mixing in the deep marine boundary layer leads to high dust concentrations down to the surface. AEROIASI observations and model simulations also show that the progression of the dust plumes across East Asia is tightly related to the advancing cold front of the extratropical cyclone.
BackgroundTargeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor ...receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet.MethodWe developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD.ResultsUsing experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation.ConclusionsThese results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the
...gene coding for the apolipoprotein E protein (apoE). Humans have three versions of
gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.
Gfi-1B is a transcriptional repressor that is crucial for erythroid differentiation: inactivation of the GFI1B gene in mice leads to embryonic death due to failure to produce differentiated red ...cells. Accordingly, GFI1B expression is tightly regulated during erythropoiesis, but the mechanisms involved in such regulation remain partially understood. We here identify HMGB2, a high-mobility group HMG protein, as a key regulator of GFI1B transcription. HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. HMGB2 expression increases during erythroid differentiation concomitantly to the increase of GfI1B transcription. Importantly, knockdown of HMGB2 in immature hematopoietic progenitor cells leads to decreased Gfi-1B expression and impairs their erythroid differentiation. We propose that HMGB2 potentiates GATA-1–dependent transcription of GFI1B by Oct-1 and thereby controls erythroid differentiation.
The multiple depot vehicle scheduling problem (MDVSP) is a well-known and important problem arising in public transport. Although many solution approaches have been published in the literature, ...algorithms using metaheuristics appeared only very recently (large neighborhood search and Tabu search). In this paper, we introduce an iterated local search algorithm for the MDVSP, incorporating a neighborhood schema called “block moves”, based on the notion of ejection chains. Using a set of benchmark instances, we show empirically that the proposed algorithm performs better than the best metaheuristics implemented so far and obtains high quality results within short computational times.
Gfi-1B is a transcriptional repressor essential for the regulation of erythropoiesis and megakaryopoiesis. Here we identify Gfi-1B p32, a Gfi-1B isoform, as essential for erythroid differentiation. ...Gfi-1B p32 is generated by alternative splicing and lacks the two first zinc finger domains of the protein. Selective knock down of Gfi-1B p32 compromises erythroid differentiation, whereas its ectopic expression induces erythropoiesis in the absence of erythropoietin. Gfi-1B p32 isoform binds to Gfi-1B target gene promoters and associates with the LSD1-CoREST repressor complex more efficiently than the major Gfi-1B p37 isoform. Furthermore, we show that Gfi-1B includes a KSKK motif in its SNAG domain, which recruits the repressor complex only when dimethylated on lysine 8. Mutation of lysine 8 prevents Gfi-1B p32-induced erythroid development. Our results thus highlight a key role for the alternatively spliced Gfi-1B p32 isoform in erythroid development.
To better study and manage chestnut trees and species, we identified nuclear single nucleotide polymorphism (SNP) markers using restriction-associated DNA sequencing. Out of 343 loci tested, 68 SNP ...markers were selected that withhold stringent quality criteria such as quasi-systematic amplification across species and Mendelian segregation in both purebred and hybrid individuals. They provide sufficient power for species, hybrids and backcross characterization as well as for clonal identification, as shown by a comparison with single sequenced repeat (SSR) loci.
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