Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Disease

Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr−/− high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr−/− high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis

Response of different PTH assays to therapy with sevelamer or CaCO3 and active vitamin D sterols

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO3) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO3 therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO3 and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 ± 75 and 932 ± 89 pg/ml, and levels declined to 491 ± 55 and 543 ± 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO3. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels

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

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

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

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

LLANO DE LOS JUNCOS. TEJEDA [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

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

Altimetry for the future: building on 25 years of progress

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion

First report of apple bitter rot caused by colletotrichum fioriniae in brittany, France

France is the third largest European producer of apples (Malus domestica), after Poland and Italy, with 2.1 million tons yearly (Eurostat 2015), and the largest producer of European cider apples, with 8,500 ha and 250,000 tons of fruit. Cider apples from Brittany represent over a quarter of the national tonnage (Anonymous 2012). Apple bitter rot symptoms have been observed on ‘Galeuse’ apples (a local variety in Brittany) for nearly 5 to 7 years and again in September 2015, during harvest at one apple orchard near Brest, France. Lesions were round, 1 to 4 cm in diameter, brown and dry with acervuli, producing orange spore masses in concentric rings. Fungal isolates were obtained from symptomatic apples by culturing necrotic tissue pieces on potato dextrose agar at 25°C in the dark. Cultures were light gray, with cottony aerial mycelium becoming darker with age and with reverse colors ranging from brownish pink to dark gray with black spots. Cultures had dark melanized structures similar to acervuli that oozed orange-colored conidia. Conidia were cylindrical to fusiform, pointed at one or both ends, and 10.0 to 14.0 μm × 3.0 to 3.5 μm. Both cultural and morphological characteristics were similar to those described for Colletotrichum acutatum sensu lato (Damm et al. 2012). Total genomic DNA was extracted and the ITS region of rDNA was amplified using the universal primers ITS4 and ITS5, then sequenced. The resulting sequence was 100% identical to C. acutatum species complex sequences obtained by a BLAST search in GenBank. Based on Damm et al. (2012), five other loci were used to further characterize the isolate: partial GAPDH, CHS-1, HIS3, ACT, and TUB2 genes sequences were amplified and sequenced. Sequences were deposited in GenBank (Accession Nos. KT887552 for ITS, KT887551 for TUB, KT887555 for CHS, KT887553 for HIS3, KT887556 for ACT, and KT887554 for GAPDH). The multilocus phylogenetic analysis carried out with the obtained sequences and reference sequences (Damm et al. 2012) revealed that the isolate clustered within C. fioriniae, as also suggested by the BLAST results, and consistent with the initial identification as C. acutatum. Koch’s postulates were performed on 10 ‘Golden Delicious’ apples. Surface sterilized fruits were wound-inoculated with 20 μl of a conidial suspension (105 conidia/ml). After 10 days incubating at 20°C, symptoms identical to those initially observed developed around the inoculation point, while controls inoculated with water remained symptomless. Fungal colonies reisolated from the lesions were morphologically similar to the original isolate. Previous studies have demonstrated that this pathogen is present worldwide on Malus spp., and apple bitter rot is considered one of the most important diseases in the United States (Ivic et al. 2013). In Europe, there are increasing numbers of reports ofColletotrichum species on apples (Ivic et al. 2013; Baroncelli et al. 2014), but to our knowledge, this is the first report in France of anthracnose on apples caused by C. fioriniae. In Europe, bitter rot caused by C. acutatum species may become a major problem and require additional investigation