12 research outputs found
The concept of creating a form-based code of Zelenodolsk
The purpose of the study is to identify and compare territorial zones, volumetric-spatial characteristics of buildings and the peculiarities of the formation of open public spaces in Zelenodolsk. The main results of the study are that a comprehensive urban planning analysis was carried out, on the basis of which the features of the formation of territorial zones in the city were revealed, the boundaries of spatial-environmental morphotypes, their environmental features were identified, and the specificity of the formation of a design code for different areas of the city was determined. The significance of the results obtained for architecture and urban planning lies in the fact that the concept of the form-based code developed in the study for Zelenodolsk can become the basis for updating (or updating) urban planning documents (Local standards for urban planning, General plan, urban planning regulations, City beautification rules). The method of identifying and forming spatial-environmental morphotypes in the city is also of great importance, as the basis for creating a form-based code for Russian small and medium-sized industrial cities
Empirical study of the mental representation of the image of the city (on the example of Kazan and Naberezhnye Chelny)
The purpose of the study is to identify the formed image of the territory in the perception of its inhabitants, using empirical research data for this. The main results of the study are that a comprehensive analysis of the mental representation of the urban space was carried out, on the basis of which the key elements of the image of the territory, the boundaries of the vernacular districts of the city, their urbanonymy were identified, as well as the significant role of urban open public spaces in the formation of the image of the territory. The authors come to the conclusion about the peculiarities of building images of cities, centered on symbolically significant elements and spaces that act as anchors for forming the image of a city in the perception of residents, attaching the population to the territory and constructing local identity
Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome
Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood.
Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies.
Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation.
Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation
The concept of creating a form-based code of Zelenodolsk
The purpose of the study is to identify and compare territorial zones, volumetric-spatial characteristics of buildings and the peculiarities of the formation of open public spaces in Zelenodolsk. The main results of the study are that a comprehensive urban planning analysis was carried out, on the basis of which the features of the formation of territorial zones in the city were revealed, the boundaries of spatial-environmental morphotypes, their environmental features were identified, and the specificity of the formation of a design code for different areas of the city was determined. The significance of the results obtained for architecture and urban planning lies in the fact that the concept of the form-based code developed in the study for Zelenodolsk can become the basis for updating (or updating) urban planning documents (Local standards for urban planning, General plan, urban planning regulations, City beautification rules). The method of identifying and forming spatial-environmental morphotypes in the city is also of great importance, as the basis for creating a form-based code for Russian small and medium-sized industrial cities
Empirical study of the mental representation of the image of the city (on the example of Kazan and Naberezhnye Chelny)
The purpose of the study is to identify the formed image of the territory in the perception of its inhabitants, using empirical research data for this. The main results of the study are that a comprehensive analysis of the mental representation of the urban space was carried out, on the basis of which the key elements of the image of the territory, the boundaries of the vernacular districts of the city, their urbanonymy were identified, as well as the significant role of urban open public spaces in the formation of the image of the territory. The authors come to the conclusion about the peculiarities of building images of cities, centered on symbolically significant elements and spaces that act as anchors for forming the image of a city in the perception of residents, attaching the population to the territory and constructing local identity
Características y significado de los factores de riesgo en el desarrollo de síndromes hematológicos en niños
In order to identify the causes of the development of diseases of the blood system and hematopoietic apparatus in children at the early stages of their formation, the risk factors for the development of hematological abnormalities in children of 1378 children living in Russia were studied. For this, the results of anamnesis and laboratory diagnostic methods of research were used. The data of peripheral blood, iron metabolism, biochemical analysis and bone marrow hematopoiesis were taken into account. The results of the study made it possible to identify risk factors for the development of hematological abnormalities in children. It was determined that persistent hematological abnormalities in children can form against the background of congenital inferiority or intrauterine damage to the hematopoietic system, caused by the influence of unfavorable factors at the ante and postnatal stages of development, alimentary disorders, immaturity and failure of the immunohematological system. Hematological deviations arising in response to the action of endo - and exogenous factors can be considered as adaptive transformations of peripheral blood parameters, reflecting the general reaction of the hematopoietic system. Taking into account risk factors makes it possible to form children into risk groups for the occurrence of hematological syndromes in the early stages of development, to timely diagnose and treat them.Para identificar las causas del desarrollo de enfermedades del sistema sanguíneo y del aparato hematopoyético en niños en las primeras etapas de su formación, se estudiaron los factores de riesgo para el desarrollo de anomalías hematológicas en niños de 1378 niños que viven en Rusia. Para esto, se utilizaron los resultados de la anamnesis y los métodos de investigación de diagnóstico de laboratorio. Se tuvieron en cuenta los datos de sangre periférica, metabolismo del hierro, análisis bioquímico y hematopoyesis de la médula ósea. Los resultados del estudio permitieron identificar factores de riesgo para el desarrollo de anomalías hematológicas en los niños. Se determinó que las anomalías hematológicas persistentes en los niños pueden formarse en el contexto de inferioridad congénita o daño intrauterino al sistema hematopoyético, causado por la influencia de factores desfavorables en las etapas ante y posnatal del desarrollo, trastornos alimentarios, inmadurez y falla del sistema inmunohematológico. sistema. Las desviaciones hematológicas que surgen en respuesta a la acción de factores endógenos y exógenos se pueden considerar como transformaciones adaptativas de los parámetros sanguíneos periféricos, lo que refleja la reacción general del sistema hematopoyético. Tener en cuenta los factores de riesgo permite agrupar a los niños en grupos de riesgo para la aparición de síndromes hematológicos en las primeras etapas del desarrollo, para diagnosticarlos y tratarlos a tiempo
Antimicrobial Effects of Sulfonyl Derivative of 2(5H)-Furanone against Planktonic and Biofilm Associated Methicillin-Resistant and -Susceptible Staphylococcus aureus
The gram-positive opportunistic bacterium Staphylococcus aureus is one of the most common causatives of a variety of diseases including skin and skin structure infection or nosocomial catheter-associated infections. The biofilm formation that is an important virulence factor of this microorganism renders the antibiotic therapy ineffective, because biofilm-embedded bacteria exhibit strongly increased tolerance to antimicrobials. Here, we describe a novel 3-chloro-5(S)-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy]-4-[4-methylphenylsulfonyl]-2(5H)-furanone (F105), possessing a sulfonyl group and l-menthol moiety. Minimal inhibitory and bactericidal concentration values (MIC and MBC) of F105 were 10 and 40 mg/L, respectively, suggesting F105 biocidal properties. F105 exhibits pronounced activity against biofilm-embedded S. aureus and increases the efficacy of aminoglycosides (amikacin, gentamicin, and kanamycin) and benzalkonium chloride with fractional inhibitory concentration index values of 0.33–0.44 and 0.29, respectively, suggesting an alternative external treatment option, e.g., for wound infections. Moreover, low concentrations (0.5–1.3 mg/L) of F105 reduced the MICs of these antimicrobials twofold. By using confocal laser scanning microscopy and CFU counting, we show explicitly that F105 also restores the antimicrobial activity of gentamicin and ampicillin against S. aureus biofilms by several orders of magnitude. Biofilm structures were not destroyed but sterilized, with embedded cells being almost completely killed at twofold MBC. While F105 is quite toxic (CC50/MBC ratio 0.2), our data suggest that the F105 chemotype might be a promising starting point for the development of complex topical agents for combined anti-staphylococcal biofilm-therapies restoring the efficacy of some antibiotics against difficult to treat S. aureus biofilm
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
International audienc
Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia
ROR alpha, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, mis sense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome