Biological sulfation reactions require 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as the universal sulfate donor. While the biosynthetic pathway of PAPS has been well characterized, the phosphatase degrading PAPS remains unidentified. Here, we discover MESH1 as a PAPS phosphatase that hydrolyzes PAPS into adenosine-5'-phosphosulfate and phosphate. Our crystallographic analysis of the MESH1-PAPS complex confirms PAPS as a bona fide substrate of MESH1. We further show that MESH1 localizes to Golgi, where sulfotransferases consume PAPS to produce sulfated glycosaminoglycan (sGAG). We show that MESH1 (also known as HDDC3) knockdown enhances sGAG production in a chondrogenic cell line. Furthermore, in brachymorphic mice, Mesh1 knockout significantly elevates sGAG levels in joint cartilage and improves bone density. In Caenorhabditis elegans lacking bpnt-1, neurotoxic PAP accumulation is alleviated by MESH1 overexpression, reducing upstream PAPS levels. Our biochemical, structural and functional findings establish MESH1 as a key PAPS phosphatase and highlights its potential as a therapeutic target in disorders characterized by sulfation deficiency.

R-peak time (RPT) is an electrocardiographic parameter that represents the time taken for electrical activation to spread from the endocardium to the epicardium. In human medicine, right ventricular RPT is measured from lead V1 to lead V2, and left ventricular RPT from lead V5 to lead V6. The aim of the present study was to define RPT duration in a group of clinically healthy dogs with different thoracic conformations. Sixty clinically healthy dogs underwent a 12-lead electrocardiogram recorded using a previously described precordial system. The dogs were allocated into three morphologic groups. In the brachymorphic group, the median and 25th-75th percentiles for RPT in V1 were 10.5 ms (10-12 ms); V2, 18 ms (16.5-20 ms); V3, 19 ms (18-22 ms); V4, 20 ms (17-23.5 ms); V5, 21 ms (18.5-24 ms); and V6: 22 ms (18.5-25.5 ms). In the mesomorphic group, RPT in V1 was 16 ms (14-18 ms); V2, 22 ms (20-24 ms); V3, 23 ms (21-25 ms); V4, 23 ms (22-25 ms); V5, 25 ms (23-27 ms); and V6, 28 ms (25-30 ms). In the dolichomorphic group, RPT in V1 was 15 ms (13-17 ms); V2, 29 ms (26-32.5 ms); V3, 30 ms (27-33.5 ms); V4, 29.5 ms (26-35 ms); V5, 30 ms (28-34 ms); and V6, 31.5 ms (28-35 ms). RPT in V1 was significantly shorter than RPT in V2 to V6 in all morphotypes (P < 0.05). In all precordial leads, RPT was significantly different between morphotypes (P < 0.05). These results are in agreement with previous findings in humans and with the observation that V1 reads the right ventricle and V2 to V6 read the left ventricle. These preliminary data provide RPT ranges in clinically healthy dogs of different morphotypes.

The aim of the research was to the study morphological features of the maxilla in people of different ages according to the results of craniometric researches. A craniometric study was performed on 50 bone preparations of the skull with the calculation of the main indices of the skull, including cranial, facial, high-longitudinal, high-latitude, transverse-zygomatic and frontal-zygomatic indices, as well as the main linear parameters of the maxilla - length, width and height. In the studied material, three main morphological types of the structure of the skull are presented: brachycrania (people with round head), mesocrania (people with middle head) and dolichocrania (people with long head). More often than others there was a brachycranial form, in which a decrease in the height-longitudinal parameters of the skull was observed, at the same time in dolichocracy there was an increase in the height-longitudinal and height-latitude parameters, in mesocracy - their intermediate indicators. The variability of the skull indices determines the variability of the main parameters of the maxilla. In people with a brachymorphic skull, a wider type of the facial section and, accordingly, of the maxilla is observed, in skulls with a meso- and dolichomorphic form of structure, on the contrary, the middle and narrow type of the maxilla is more common.

Myostatin (MSTN) is a negative modulator of muscle mass. We characterized the horse (Equus caballus) MSTN gene and identified and analysed single nucleotide polymorphisms (SNPs) in breeds of different morphological types. Sequencing of coding, untranslated, intronic, and regulatory regions of MSTN gene in 12 horses from 10 breeds revealed seven SNPs: two in the promoter, four in intron 1, and one in intron 2. The SNPs of the promoter (GQ183900:g.26T>C and GQ183900:g.156T>C, the latter located within a conserved TATA-box like motif) were screened in 396 horses from 16 breeds. The g.26C and the g.156C alleles presented higher frequency in heavy (brachymorphic type) than in light breeds (dolichomorphic type such as Italian Trotter breed). The significant difference of allele frequencies for the SNPs at the promoter and analysis of molecular variance (AMOVA) on haplotypes indicates that these polymorphisms could be associated with variability of morphology traits in horse breeds.

We used the egg avidin gold complex as a polycationic probe for the localization of negatively charged sites in the secretory granules of mouse mast cells. We compared the binding of this reagent to mast cell granules in wild-type mice and in congenic brachymorphic mice in which mast cell secretory granules contained undersulfated proteoglycans. We localized anionic sites by post-embedding labeling of thin sections of mouse skin and tongue tissues fixed in Karnovsky's fixative and OsO(4) and embedded in Araldite. Transmission electron microscopy revealed that the mast cell granules of bm/bm mice had a lower optical density than those of wild-type mice (P<0.001) and a lower avidin gold binding density (by approximately 50%, P<0.001). The latter result provided additional evidence that the contents of mast cell granules in bm/bm mice were less highly sulfated than in those of wild-type mice. In both wild-type and bm/bm mast cells, the distribution of granule equivalent volumes was multimodal, but the unit granule volume was approximately 19% lower in bm/bm cells than in wild-type cells (P<0.05). Thus, bm/bm mast cells develop secretory granules that differ from those of wild-type mice in exhibiting a lower optical density and slightly smaller unit granules, however the processes that contribute to granule maturation and granule-granule fusion in mast cells are operative in bm/bm cells.

In contrast to the functional role of heparan sulfate proteoglycans (HSPGs), the importance of chondroitin sulfate proteoglycans (CSPGs) in modulating signaling pathways involving hedgehog proteins, wingless-related proteins and fibroblast growth factors remains unclear. To elucidate the importance of sulfated CSPGs in signaling paradigms required for endochondral bone formation, the brachymorphic (bm) mouse was used as a model for undersulfated CSPGs. The bm mouse exhibits a postnatal chondrodysplasia caused by a mutation in the phosphoadenosine phosphosulfate (PAPS) synthetase (Papss2) gene, leading to reduced levels of PAPS and undersulfated proteoglycans. Biochemical analysis of the glycosaminoglycan (GAG) content in bm cartilage via sulfate labeling and fluorophore-assisted carbohydrate electrophoresis revealed preferential undersulfation of chondroitin chains (CS) and normal sulfation of heparan sulfate chains. In situ hybridization and immunohistochemical analysis of bm limb growth plates showed diminished Indian hedgehog (Ihh) signaling and abnormal Ihh protein distribution in the extracellular matrix. Consistent with the decrease in hedgehog signaling, BrdU incorporation exhibited a significant reduction in chondrocyte proliferation. Direct measurements of Ihh binding to defined GAG chains demonstrated that Ihh interacts with CS, particularly chondroitin-4-sulfate. Furthermore, co-immunoprecipitation experiments showed that Ihh binds to the major cartilage CSPG aggrecan via its CS chains. Overall, this study demonstrates an important function for CSPGs in modulating Ihh signaling in the developing growth plate, and highlights the importance of carbohydrate sulfation in regulating growth factor signaling.

The goal of the study was to determine what correlations exist between anthropometric and psychodynamic indexes among various constitutional types of Georgian women (20-55 years of age). For this reason we have investigated 175 women. For the study of temperament and character we have used questionnaire by Aizenk and temperament scale by Sheldon. Determination of mood types and intellect was also conducted. We have found that correlation among subspecies of temperament and anthropometrical signs among women is increasing with the age or remains the same and is in the limits of 0,3-0,4; as for the relations between character forms and anthropometrical signs they also increase with age, (0,4-0,5) also correlations are growing among anthropometrical results and various types of intellect in 0,5-0,6 limits. Relations with the mood types increase as well in 0,3-0,4 limits. It was shown that Georgian women in young age with dolichomorphic figure, extraverts, sanguine by temperament, with distinctly expressed middle logic intellect, according to the type plastic- dynamic, constant -- stabile, with middle excitability; i.e. are harmonic-dynamic constitutional types. Women in higher age with brachymorphic figure, introverts, basically phlegmatic, with middle logic and verbal intellect; according to the type constant -- stabile, strongly dynamic, with middle excitability, express self control, high level of mental activity; they are conflict-static constitutional types.