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

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

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

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

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

Cryptanalysis of Rational Multivariate Public Key Cryptosystems

In 1989, Tsujii, Fujioka, and Hirayama proposed a family of multivariate public key cryptosystems, where the public key is given as a set of multivariate rational functions of degree 4[5]. These cryptosystems are constructed via composition of two quadratic rational maps. In this paper, we present the cryptanalysis of this family of cryptosystems. The key point of our attack is to transform a problem of decomposition of two rational maps into a problem of decomposition of two polynomial maps. We develop a new improved 2R decomposition method and other new techniques, which allows us to find an equivalent decomposition of the rational maps to break the system completely. For the example suggested for practical applications, it is extremely fast to perform the computation to derive an equivalent private key, and it requires only a few seconds on a standard PC. Key Words: multivariate public key cryptosystems, rational polynomials, map decomposition

Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation.

Insulin-like growth factor binding protein 4 (IGFBP-4) is abundantly expressed in bone and is generally believed to function as an inhibitor of IGF action. To investigate the function of locally produced IGFBP-4 in bone in vivo, we targeted expression of IGFBP-4 to osteoblasts using a human osteocalcin promoter to direct transgene expression. IGFBP-4 protein levels in calvaria of transgenic (OC-BP4) mice as measured by Western ligand blot were increased 25-fold over the endogenous level. Interestingly, levels of IGFBP-5 were decreased in the OC-BP4 mice, possibly because of a compensatory alteration in IGF-1 action. Morphometric measurements showed a decrease in femoral length and total bone volume in transgenic animals compared with the controls. Quantitative histomorphometry at the distal femur disclosed a striking reduction in bone turnover in the OC-BP4 mice. Osteoblast number/bone length and bone formation rate/bone surface in OC-BP4 mice were approximately one-half that seen in control mice. At birth, OC-BP4 mice were of normal size and weight but exhibited striking postnatal growth retardation. Organ allometry (mg/g body weight) analysis revealed that, whereas most organs exhibited a proportional reduction in weight, calvarial and femoral wet weights were disproportionally small (approximately 70% and 80% of control, respectively). In conclusion, paracrine overexpression of IGFBP-4 in the bone microenvironment markedly reduced cancellous bone formation and turnover and severely impaired overall postnatal skeletal and somatic growth. We attribute these effects to the sequestration of IGF-1 by IGFBP-4 and consequent impairment of IGF-1 action in skeletal tissue