Lack of Adiponectin Drives Hyperosteoclastogenesis in Lipoatrophic Mice.

Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlighted the dual bone phenotype of PPARγ null mice: one the one hand, the increased bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explored the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibited mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent ten-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted in chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and DLI (n=30), or isolated reinfusion of donor lymphocytes (DLI) (n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy = 385 d, second allograft = 391d, chemotherapy = 174d, DLI alone = 140d, palliative care = 43d. A second SCT or a combination of chemotherapy and donor lymphocytes infusion yielded similar outcome (HR=0.85, p=0.53) unlike chemotherapy alone (HR 1.43 p=0.04), palliative care (HR=4.24, p<0.0001) or isolated DLI (HR=1,94, p<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML

Roles of hydrophilin-like protein in the filamentous fungi Alternaria brassicicola

During their life cycle, fungi face adverse environmental conditions associated with alterations in water status. Phytopathogenic fungi are faced with this type of stress during the infection process, especially when they colonize seeds. Although these organisms are particularly effective to adapt to these water potential decreases, these coping mechanisms are so far very poorly described, particularly in filamentous fungi. Alternaria brassicicola is a seed-borne fungal pathogen responsible for the black spot disease on Brassicaceae plants. Alteration of Brassicaceae seed quality is one of the most damaging effects of the black spot. Beyond contribution to pathogen dissemination, the presence of the fungus on the seeds compromises seedling germination and survival. To better understand the determinism of fungus transmission to seeds, we previously established a reliable Arabidopsis-based pathosystem allowing investigations of A. brassicicola transmission to seeds. In particular, we showed that two mutants strain ∆abhog and ∆abnik exhibiting higher susceptibility to osmotic and water stress were highly impaired in seed transmission ability. Transcriptomic analyzes, carried out under different experimental in vitro conditions inducing these types of stress (addition of sorbitol or Poly Ethylene Glycol (PEG) or by incubation under low relative humidity (1% RH)), allowed us to identify additional mechanisms potentially involved in the fungal adaptive responses. In particular, these analyzes revealed a pool of over-expressed genes encoding putative proteins which share physiochemical features typical of hydrophilin-like proteins. We initiated studies of some of these hydrophilins by generating respective Knock-Out mutants. Functional studies has been carried out to determine whether these mutants were impaired in their adaptive response to water stress and other types of stress (such as oxidative stress) and whether hydrophilins are involved in pathogenicity. Additional transcriptomic assays conducted on ∆abhog and ∆abnik strain growth under sorbitol exposure revealed that numerous hydrophilins are regulated by these two genes

Is the dark matter interpretation of the EGRET gamma excess compatible with antiproton measurements?

We investigate the internal consistency of the halo dark matter model which has been proposed by de Boer et al. to explain the excess of diffuse galactic gamma rays observed by the EGRET experiment. Any model based on dark matter annihilation into quark jets, such as the supersymmetric model proposed by de Boer et al., inevitably also predicts a primary flux of antiprotons from the same jets. Since propagation of the antiprotons in the unconventional, disk-dominated type of halo model used by de Boer et al. is strongly constrained by the measured ratio of boron to carbon nuclei in cosmic rays, we investigate the viability of the model using the DarkSUSY package to compute the gamma-ray and antiproton fluxes. We are able to show that their model is excluded by a wide margin from the measured flux of antiprotons. We therefore find that a model of the type suggested by Moskalenko et al., where the intensities of protons and electrons in the cosmic rays vary with galactic position, is far more plausible to explain the gamma excess.Comment: 14 pages, 5 figures. Matches published versio

Correction: Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman–Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT)

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Low Prevalence of Lactase Persistence in Bronze Age Europe Indicates Ongoing Strong Selection over the Last 3,000 Years

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years in multiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235-A [1], only rose to appreciable frequencies during the Bronze and Iron Ages [2, 3], long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of people from the Pontic-Caspian steppe that began around 5,000 years ago [4, 5]. We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany (∼3,200 before present, BP), the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population. We complemented these data with genotypes of 18 individuals from the Bronze Age site Mokrin in Serbia (∼4,100 to ∼3,700 BP) and 37 individuals from Eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites (∼5,980 to ∼3,980 BP). We infer low LP in all three regions, i.e., in northern Germany and South-eastern and Eastern Europe, suggesting that the surge of rs4988235 in Central and Northern Europe was unlikely caused by Steppe expansions. We estimate a selection coefficient of 0.06 and conclude that the selection was ongoing in various parts of Europe over the last 3,000 years

Cell wall integrity and high osmolarity glycerol pathways are required for adaptation of Alternaria brassicicola to cell wall stress caused by brassicaceous indolic phytoalexins

Camalexin, the characteristic phytoalexin of Arabidopsis thaliana, inhibits growth of the fungal necrotroph Alternaria brassicicola. This plant metabolite probably exerts its antifungal toxicity by causing cell membrane damage. Here we observed that activation of a cellular response to this damage requires cell wall integrity (CWI) and the high osmolarity glycerol (HOG) pathways. Camalexin was found to activate both AbHog1 and AbSlt2 MAP kinases, and activation of the latter was abrogated in a AbHog1 deficient strain. Mutant strains lacking functional MAP kinases showed hypersensitivity to camalexin and brassinin, a structurally related phytoalexin produced by several cultivated Brassica species. Enhanced susceptibility to the membrane permeabilization activity of camalexin was observed for MAP kinase deficient mutants. These results suggest that the two signalling pathways have a pivotal role in regulating a cellular compensatory response to preserve cell integrity during exposure to camalexin. AbHog1 and AbSlt2 deficient mutants had reduced virulence on host plants that may, at least for the latter mutants, partially result from their inability to cope with defence metabolites such as indolic phytoalexins. This constitutes the first evidence that a phytoalexin activates fungal MAP kinases and that outputs of activated cascades contribute to protecting the fungus against antimicrobial plant metabolites