Characterization of developmental role and mechanistic function of Kremen proteins

The Wnt/beta-catenin signaling pathway plays pivotal roles during embryonic development and adult tissue homeostasis; these include the regulation of cell fate decisions during germ layer induction, axial patterning and organogenesis, as well as cell proliferation and stem cell maintenance. Wnt signaling is antagonized by Dickkopf (Dkk) proteins, which play an important role in antero-posterior patterning of the central nervous system. Dkks function by inhibiting the Wnt receptor LRP5/6. They act in conjunction with transmembrane proteins of the Kremen family (Krm1 and 2, collectively termed Krms). Dkk binds to both LRP5/6 and Krm and induces formation of a ternary complex, which is cleared from the cell surface by endocytosis, leading to shut down of Wnt signal transduction. This study was initiated by several open questions: How do Krms function to mediate LRP6 clearance from the cell surface? Are there other proteins involved in this process? Do Krms have Dkk-independent roles during Xenopus development? Towards a mechanistic analysis of Krm/Dkk mediated Wnt inhibition, several screens for Krm interaction/binding partners were undertaken which led to the identification and characterization of Erlectin, a novel secreted protein which (i) binds to N-glycans linked to Krm2; (ii) is a member of the endoplasmic reticulum (ER) synexpression group in Xenopus; (iii) is localized in the ER lumen; and (iv) is essential for normal Xenopus development. As a second major result of this study, I observed and established that Krm2 plays a Dkk1-independent role during Xenopus neural crest formation. The experimental data revealed that Krm2 (i) is co-expressed with Wnts and regulated by zygotic Wnt signaling; (ii) shows differential expression in the neural crest and can induce neural crest tissue when overexpressed; (iii) is required for neural crest formation; and (iv) promotes cell surface localization of LRP6, as well as LRP6-mediated Wnt signaling in cultured cells. Based on these findings I developed a model in which Krms may be considered as context-dependent inhibitors or activators of Wnt/LRP6 signaling, which are regulated by the presence or absence of Dkk, respectively

Association between Body Mass Index and depression: the "fat and jolly" hypothesis for adolescents girls

International audienceABSTRACT: BACKGROUND: Results concerning the association between Body Mass Index (BMI) and depression in adolescence are conflicting, some describing a linear association (increase in BMI with level of depression), some a U-shaped association (both underweight and obesity are associated with high levels of depression), and they mostly concern small samples. The purpose of this study was to describe the association between BMI and depression in a large representative sample of French adolescents. METHODS: The association between BMI and depression, measured on the Adolescent Depression Rating Scale (ADRS), was tested in a French national representative sample of 39542 adolescents aged 17. Self-report data is derived from the 2008 ESCAPAD study, an epidemiological study based on a questionnaire focused on health and drug consumption.We used spline function analysis to describe the association between BMI and depression. RESULTS: The association between BMI and depression is significant (p<0.001) and non-linear for both genders, with no effect of parental working and marital status. For boys, there is U-shaped association. For girls the shape of the association is complex and shows inverted convexity for high levels of BMI. The spline shows higher scores for depression among overweight girls than among obese girls. CONCLUSION: There is evidence for a gender difference in the association between BMI and depression in adolescents, supporting the need to study boys and girls separately. Overweight adolescent girls are more likely to be depressed than obese adolescent girls, giving support for "fat and jolly" hypothesis not only among older women but also among adolescent girls

B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4. The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

Diagnostic value of kappa free light chain index in patients with primary progressive multiple sclerosis – a multicentre study

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS

Global disparities in SARS-CoV-2 genomic surveillance

Genomic sequencing is essential to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments, vaccines, and guide public health responses. To investigate the global SARS-CoV-2 genomic surveillance, we used sequences shared via GISAID to estimate the impact of sequencing intensity and turnaround times on variant detection in 189 countries. In the first two years of the pandemic, 78% of high-income countries sequenced >0.5% of their COVID-19 cases, while 42% of low- and middle-income countries reached that mark. Around 25% of the genomes from high income countries were submitted within 21 days, a pattern observed in 5% of the genomes from low- and middle-income countries. We found that sequencing around 0.5% of the cases, with a turnaround time <21 days, could provide a benchmark for SARS-CoV-2 genomic surveillance. Socioeconomic inequalities undermine the global pandemic preparedness, and efforts must be made to support low- and middle-income countries improve their local sequencing capacity

Global disparities in SARS-CoV-2 genomic surveillance

Genomic sequencing is essential to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments, vaccines, and guide public health responses. To investigate the global SARS-CoV-2 genomic surveillance, we used sequences shared via GISAID to estimate the impact of sequencing intensity and turnaround times on variant detection in 189 countries. In the first two years of the pandemic, 78% of high-income countries sequenced >0.5% of their COVID-19 cases, while 42% of low- and middle-income countries reached that mark. Around 25% of the genomes from high income countries were submitted within 21 days, a pattern observed in 5% of the genomes from low- and middle-income countries. We found that sequencing around 0.5% of the cases, with a turnaround time <21 days, could provide a benchmark for SARS-CoV-2 genomic surveillance. Socioeconomic inequalities undermine the global pandemic preparedness, and efforts must be made to support low- and middle-income countries improve their local sequencing capacity