Short stature caused by SHOX gene haploinsufficiency: from diagnosis to treatment

Estudos realizados em pacientes portadores de deleções parciais dos cromossomos sexuais permitiram a caracterização do SHOX, gene localizado na região pseudoautossômica no braço curto dos cromossomos sexuais, fundamental na determinação da altura normal. A perda de uma cópia deste gene na síndrome de Turner (ST) explica dois terços da baixa estatura observada nesta síndrome. A haploinsuficiência do SHOX é detectada em 77% dos pacientes com discondrosteose de Leri-Weill, uma forma comum de displasia esquelética de herança autossômica dominante e em 3% das crianças com baixa estatura idiopática (BEI), tornando os defeitos neste gene a principal causa monogênica de baixa estatura. A medida da altura sentada em relação à altura total (Z da AS/AT para idade e sexo) é uma forma simples de identificar a desproporção corpórea e, associada ao exame cuidadoso do paciente e de outros membros da família, auxilia na seleção de pacientes para o estudo molecular do SHOX. O uso de hormônio de crescimento (GH) está bem estabelecido na ST e em razão da causa comum da baixa estatura com o de crianças com defeitos isolados do SHOX o tratamento destes pacientes com GH é também proposto. Neste artigo será revisado os aspectos clínicos, moleculares e terapêuticos da haploinsuficiência do SHOX.Studies involving patients with short stature and partial deletion of sex chromosomes identified SHOX gene in the pseudoautosomal region of the X and Y chromosomes. SHOX haploinsufficiency is an important cause of short stature in a diversity of clinical conditions. It explains 2/3 of short stature observed in Turner syndrome (TS) patients. Heterozygous mutations in SHOX are observed in 77% of patients with Leri-Weill dyschondrosteosis, a common dominant inherited skeletal dysplasia and in 3% of children with idiopathic short stature, indicating that SHOX defects are the most frequent monogenetic cause of short stature. The sitting height/height ratio (SH/H) standard deviation score is a simple way to assess body proportions and together with a careful exam of other family members, effectively selected a group of patients that presented a high frequency of SHOX mutations. Growth hormone treatment of short stature due to TS is well established and considering the common etiology of short stature in patients with isolated defects of SHOX gene, this treatment is also proposed for these patients. Here, we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

A TWO-STEP APPROACH FOR THE SEISMIC ASSESSMENT OF MASONRY STRUCTURES ACCOUNTING FOR THE ACTUAL MASONRY PATTERN

Seismic assessment of masonry structures is a pressing concern in the scientific community. Over the last few decades, significant progress has been made in developing numerical modelling strategies for masonry. However, due to the unique mechanics of masonry, which exhibit a quasi-brittle and anisotropic behaviour, there is no trade-off between accuracy and computational efficiency when conducting numerical simulations of masonry structures. This study proposes a new approach to conduct in-plane numerical simulations of masonry structures, which couple limit and pushover analyses considering the actual masonry pattern. The first step of the procedure involves a block-based limit analysis, which considers the actual masonry pattern. Macroblocks, i.e., the portions which compose the collapse mechanism, are then identified using an ad-hoc algorithm that searches for the pivot point of the obtained failure mechanisms. In the second step, a pushover analysis is conducted on the simplified structure composed of macroblocks, considered as continuum bodies, interacting via frictional interfaces. The proposed approach is preliminary tested on two structural-scale benchmarks made of dry-stack masonry, showing promising results

Effects of pollen collection on colony development and in the bromatological composition Apis mellifera L. pupae

Africanized bees (Apis mellifera L.) were studied in the Botucatu region (São Paulo State), Brazil, from August to November, 1996, with the objective of quantifying pollen trapping and its effects on colony development and composition of worker bee pupae. Mean trapped pollen yield was 1.47 kg/beehive. Trapping had little effect on brood production, causing only a 9.7% reduction in total worker brood area and a 4.0% reduction in drone brood area, as compared to the treatment without pollen types. Pollen harvest did not affect the bromatological composition of worker pupae (white bodies and slightly pigmented eyes), mean values obtained for both treatments being 18.87% dry matter, 48.07% crude protein, 18.52% ether extract and 3.72% ash

Integrated management of ash from industrial and domestic combustion : a new sustainable approach for reducing greenhouse gas emissions from energy conversion

This work supports, for the first time, the integrated management of waste materials arising from industrial processes (fly ash from municipal solid waste incineration and coal fly ash), agriculture (rice husk ash), and domestic activities (ash from wood biomass burning in domestic stoves). The main novelty of the paper is the reuse of wood pellet ash, an underestimated environmental problem, by the application of a new technology (COSMOS-RICE) that already involves the reuse of fly ashes from industrial and agricultural origins. The reaction mechanism involves carbonation: this occurs at room temperature and promotes permanent carbon dioxide sequestration. The obtained samples were characterized using XRD and TGA (coupled with mass spectroscopy). This allowed quantification of the mass loss attributed to different calcium carbonate phases. In particular, samples stabilized using wood pellet ash show a weight loss, attributed to the decomposition of carbonates greater than 20%. In view of these results, it is possible to conclude that there are several environmental benefits from wood pellet ash reuse in this way. In particular, using this technology, it is shown that for wood pellet biomass the carbon dioxide conversion can be considered negative

Competitiveness of Computational Modelling Strategies: a Framework to Implement Efficient Digital Twins of Historical Masonry Structures

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Bromatological and mineral compositions of collected pollen for africanized honeybees (Apis mellifera L.) in Botucatu, São Paulo State

The bromatological and mineral compositions of pollen collected by Africanized honeybees (Apis mellifera L.) in the Botucatu region, São Paulo State, Brazil, from August to November, 1966, were investigated. The pollen collections from six beehives, at weekly intervals, lasted for seven consecutive days. Mean fresh pollen composition was: 75.9% dry matter, 26.2% crude protein (CP), 5.1% ether extract (EE), 2.6% ash, 1.1% crude fiber, 3.58% nitrogen, 0.43% phosphorus, 0.67% potassium, 0.26% calcium, 0.08% magnesium, 0.21% sulfur, 114.2 ppm iron, 88.4 ppm zinc, 15.0 ppm copper, 32.4 ppm manganese, and 9.9 ppm boron. Statistical analysis showed that pollen collected in October had the highest contents of CP, and of the elements P, S and Mn compared to the other months. According to cluster and principal components analyses for bromatological composition, the variables with most and least discriminatory power were the percentages of CP and EE, respectively. As to mineral composition, the most discriminatory variables were S, Mn, and N, while the least discriminatory were Mg, B, and K

Photonic band gaps in materials with triply periodic surfaces and related tubular structures

We calculate the photonic band gap of triply periodic bicontinuous cubic structures and of tubular structures constructed from the skeletal graphs of triply periodic minimal surfaces. The effect of the symmetry and topology of the periodic dielectric structures on the existence and the characteristics of the gaps is discussed. We find that the C(I2-Y**) structure with Ia3d symmetry, a symmetry which is often seen in experimentally realized bicontinuous structures, has a photonic band gap with interesting characteristics. For a dielectric contrast of 11.9 the largest gap is approximately 20% for a volume fraction of the high dielectric material of 25%. The midgap frequency is a factor of 1.5 higher than the one for the (tubular) D and G structures

Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature

Objective: Most children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS.Design and methods: We selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools.Results: We identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n  = 4), SHOX (n  = 3), FGFR3 (n  = 2), NPR2 (n  = 2), ACAN(n  = 2), and COL2A1 (n  = 1) or involved in the RAS/MAPK pathway: NF1 (n  = 2), PTPN11(n  = 1), CBL (n  = 1), and BRAF (n  = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS ≤ or > −3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children.Conclusion: A multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification

Disease Gene Characterization through Large-Scale Co-Expression Analysis

In the post genome era, a major goal of biology is the identification of specific roles for individual genes. We report a new genomic tool for gene characterization, the UCLA Gene Expression Tool (UGET).Celsius, the largest co-normalized microarray dataset of Affymetrix based gene expression, was used to calculate the correlation between all possible gene pairs on all platforms, and generate stored indexes in a web searchable format. The size of Celsius makes UGET a powerful gene characterization tool. Using a small seed list of known cartilage-selective genes, UGET extended the list of known genes by identifying 32 new highly cartilage-selective genes. Of these, 7 of 10 tested were validated by qPCR including the novel cartilage-specific genes SDK2 and FLJ41170. In addition, we retrospectively tested UGET and other gene expression based prioritization tools to identify disease-causing genes within known linkage intervals. We first demonstrated this utility with UGET using genetically heterogeneous disorders such as Joubert syndrome, microcephaly, neuropsychiatric disorders and type 2 limb girdle muscular dystrophy (LGMD2) and then compared UGET to other gene expression based prioritization programs which use small but discrete and well annotated datasets. Finally, we observed a significantly higher gene correlation shared between genes in disease networks associated with similar complex or Mendelian disorders.UGET is an invaluable resource for a geneticist that permits the rapid inclusion of expression criteria from one to hundreds of genes in genomic intervals linked to disease. By using thousands of arrays UGET annotates and prioritizes genes better than other tools especially with rare tissue disorders or complex multi-tissue biological processes. This information can be critical in prioritization of candidate genes for sequence analysis