Hypoxia-Inducible Factor-1α Restricts the Anabolic Actions of Parathyroid Hormone

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH

Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study

International audienceInflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio-demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94-0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55-11.07), higher body mass index (OR = 1.16, 95% CI = 1.06-1.28), higher Fagerstrom score (OR = 1.22, 95% CI = 1.01-1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia

Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition

The canonical Wnt signaling pathway is critical for skeletal development and maintenance, but the precise roles of the individual Wnt co-receptors, Lrp5 and Lrp6, that enable Wnt signals to be transmitted in osteoblasts remain controversial. In these studies, we used Cre-loxP recombination, in which Cre-expression is driven by the human osteocalcin promoter, to determine the individual contributions of Lrp5 and Lrp6 in postnatal bone acquisition and osteoblast function. Mice selectively lacking either Lrp5 or Lrp6 in mature osteoblasts were born at the expected Mendelian frequency but demonstrated significant reductions in whole-body bone mineral density. Bone architecture measured by microCT revealed that Lrp6 mutant mice failed to accumulate normal amounts of trabecular bone. By contrast, Lrp5 mutants had normal trabecular bone volume at 8 weeks of age, but with age, these mice also exhibited trabecular bone loss. Both mutants also exhibited significant alterations in cortical bone structure. In vitro differentiation was impaired in both Lrp5 and Lrp6 null osteoblasts as indexed by alkaline phosphatase and Alizarin red staining, but the defect was more pronounced in Lrp6 mutant cells. Mice lacking both Wnt co-receptors developed severe osteopenia similar to that observed previously in mice lacking β-catenin in osteoblasts. Likewise, calvarial cells doubly deficient for Lrp5 and Lrp6 failed to form osteoblasts when cultured in osteogenic media, but instead attained a chondrocyte-like phenotype. These results indicate that expression of both Lrp5 and Lrp6 are required within mature osteoblasts for normal postnatal bone development

Activin Receptor Type 2A (ACVR2A) Functions Directly in Osteoblasts as a Negative Regulator of Bone Mass

Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 upon exposure to activin ligands. Osteoblasts lacking ACVR2B did not show significant changes in vitro. However, osteoblasts deficient in ACVR2A exhibited enhanced differentiation indicated by alkaline phosphatase activity, mineral deposition, and transcriptional expression of osterix, osteocalcin, and dentin matrix acidic phosphoprotein 1. To investigate activin signaling in osteoblasts in vivo, we analyzed the skeletal phenotypes of mice lacking these receptors in osteoblasts and osteocytes (osteocalcin-Cre). Similar to the lack of effect in vitro, ACVR2B-deficient mice demonstrated no significant change in any bone parameter. By contrast, mice lacking ACVR2A had significantly increased femoral trabecular bone volume at 6 weeks of age. Moreover, mutant mice lacking both ACVR2A and ACVR2B demonstrated sustained increases in trabecular bone volume, similar to those in ACVR2A single mutants, at 6 and 12 weeks of age. Taken together, these results indicate that activin receptor signaling, predominantly through ACVR2A, directly and negatively regulates bone mass in osteoblasts

Ideal Interpolation, H-Bases and Symmetry

International audienceMultivariate Lagrange and Hermite interpolation are examples ofideal interpolation. More generally an ideal interpolation problemis defined by a set of linear forms, on the polynomial ring, whosekernels intersect into an ideal.For an ideal interpolation problem with symmetry, we addressthe simultaneous computation of a symmetry adapted basis of theleast interpolation space and the symmetry adapted H-basis ofthe ideal. Beside its manifest presence in the output, symmetry isexploited computationally at all stages of the algorithm

Secure Key Encapsulation Mechanism with Compact Ciphertext and Public Key from Generalized Srivastava code

Code-based public key cryptosystems have been found to be an interesting option in the area of Post-Quantum Cryptography. In this work, we present a key encapsulation mechanism (KEM) using a parity check matrix of the Generalized Srivastava code as the public key matrix. Generalized Srivastava codes are privileged with the decoding technique of Alternant codes as they belong to the family of Alternant codes. We exploit the dyadic structure of the parity check matrix to reduce the storage of the public key. Our encapsulation leads to a shorter ciphertext as compared to DAGS proposed by Banegas et al. in Journal of Mathematical Cryptology which also uses Generalized Srivastava code. Our KEM provides IND-CCA security in the random oracle model. Also, our scheme can be shown to achieve post-quantum security in the quantum random oracle model

Solving geoinformatics parametric polynomial systems using the improved Dixon resultant

Improvements in computational and observational technologies in geoinformatics, e.g., the use of laser scanners that produce huge point cloud data sets, or the proliferation of global navigation satellite systems (GNSS) and unmanned aircraft vehicles (UAVs), have brought with them the challenges of handling and processing this “big data”. These call for improvement or development of better processing algorithms. One way to do that is integration of symbolically presolved sub-algorithms to speed up computations. Using examples of interest from real geoinformatic problems, we will discuss the Dixon-EDF resultant as an improved resultant method for the symbolic solution of parametric polynomial systems. We will briefly describe the method itself, then discuss geoinformatics problems arising in minimum distance mapping (MDM), parameter transformations, and pose estimation essential for resection. Dixon-EDF is then compared to older notions of “Dixon resultant”, and to several respected implementations of Gröbner bases algorithms on several systems. The improved algorithm, Dixon-EDF, is found to be greatly superior, usually by orders of magnitude, in both CPU usage and RAM usage. It can solve geoinformatics problems on which the other methods fail, making symbolic solution of parametric systems feasible for many problems

Algebraic Cryptanalysis of STARK-Friendly Designs:Application to MARVELlous and MiMC

The block cipher Jarvis and the hash function Friday, both members of the MARVELlous family of cryptographic primitives, are among the first proposed solutions to the problem of designing symmetric-key algorithms suitable for transparent, post-quantum secure zero-knowledge proof systems such as ZK-STARKs. In this paper we describe an algebraic cryptanalysis of Jarvis and Friday and show that the proposed number of rounds is not sufficient to provide adequate security. In Jarvis, the round function is obtained by combining a finite field inversion, a full-degree affine permutation polynomial and a key addition. Yet we show that even though the high degree of the affine polynomial may prevent some algebraic attacks (as claimed by the designers), the particular algebraic properties of the round function make both Jarvis and Friday vulnerable to Gröbner basis attacks. We also consider MiMC, a block cipher similar in structure to Jarvis. However, this cipher proves to be resistant against our proposed attack strategy. Still, our successful cryptanalysis of Jarvis and Friday does illustrate that block cipher designs for “algebraic platforms” such as STARKs, FHE or MPC may be particularly vulnerable to algebraic attacks

STC1 interference on calcitonin family of receptors signaling during osteoblastogenesis via adenylate cyclase inhibition

Stanniocalcin 1 (STC1) and calcitonin gene-related peptide (CGRP) are involved in bone formation/remodeling. Here we investigate the effects of STC1 on functional heterodimer complex CALCRL/RAMP1, expression and activity during osteoblastogenesis. STC1 did not modify CALCRL and ramp 1 gene expression during osteoblastogenesis when compared to controls. However, plasma membrane spatial distribution of CALCRL/RAMP1 was modified in 7-day pre-osteoblasts exposed to either CGRP or STC1, and both peptides induced CALCRL and RAMP1 assembly. CGRP, but not STC1 stimulated cAMP accumulation in 7-day osteoblasts and in CALCRL/RAMP1 transfected HEK293 cells. Furthermore, STC1 inhibited forskolin stimulated cAMP accumulation of HEK293 cells, but not in CALCRL/RAMP1 transfected HEK293 cells. However, STC1 inhibited cAMP accumulation in calcitonin receptor (CTR) HEK293 transfected cells stimulated by calcitonin. In conclusion, STC1 signals through inhibitory G-protein modulates CGRP receptor spatial localization during osteoblastogenesis and may function as a regulatory factor interacting with calcitonin peptide members during bone formation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.CAPES/CNPq (VS PNPD fellowship program); FAPERGS/CNPq [008/2009 (FCRG)]; Portuguese Foundation for Science and Technology (FCT) [PTDC/MAR/121279/2010, PEst-C/MAR/LA0015/2013, SFRH/BPD/89811/2012]; CNPq (SRT PhD fellowship program); CNPq (LAMM PhD fellowship program); CNPq (FCRG research productivity fellowship program); INCT Exitotoxicity and Neuroprotection (DOGS

Precision-medicine findings from the FACE-SZ cohort to develop motivation-enhancing programs in real-world schizophrenia

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes. Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life. Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits. Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p = 0.021), severe nicotine dependence (aOR = 2.906, p < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p = 0.001), positive symptoms (aOR = 1.052, p = 0.006), current major depressive episode (aOR = 2.627, p < 0.001), sleep disorders (aOR = 1.474, p = 0.024) and lower medication adherence (aOR = 0.836, p = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder. Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia. © 2022 Informa UK Limited, trading as Taylor & Francis Group.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte