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1.
J Bone Miner Res ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32176830

RESUMO

OBJECTIVES: Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB) but little is known about the clinical characteristics of those with early disease. METHODS: Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. RESULTS: We studied 222 individuals of whom 54.9% were female with average (± sem) age of 50.1± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu which was present in 141/222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%) of which 9 (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 vs. 49.8 ± 8.9, p=0.07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years vs. 59 years, p=0.25). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalised to the upper limit of normal in each centre were higher in those with lesions (0.75 ± 0.69 vs 0.42 ± 0.29; p<0.0001). Similar findings were observed for other biochemical markers of bone turnover but the sensitivity of ALP and other markers in detecting lesions was poor. CONCLUSIONS: Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow up of this cohort will provide important information on the natural history of early PDB and its response to treatment. This article is protected by copyright. All rights reserved.

2.
PLoS One ; 15(3): e0229820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160208

RESUMO

Teriparatide is a bone-forming therapy for osteoporosis that increases bone quantity and texture, with uncertain action on bone geometry. No data are available regarding its influence on bone strain. To investigate teriparatide action on parameters of bone quantity and quality and on Bone Strain Index (BSI), also derived from DXA lumbar scan, based on the mathematical model finite element method. Forty osteoporotic patients with fractures were studied before and after two years of daily subcutaneous 20 mcg of teriparatide with dual X-ray photon absorptiometry to assess bone mineral density (BMD), hip structural analysis (HSA), trabecular bone score (TBS), BSI. Spine deformity index (SDI) was calculated from spine X-ray. Shapiro-Wilks, Wilcoxon and Student's t test were used for classical statistical analysis. Auto Contractive Map was used for Artificial Neural Network Analysis (ANNs). In the entire population, the ameliorations after therapy regarded BSI (-13.9%), TBS (5.08%), BMD (8.36%). HSA parameters of femoral shaft showed a worsening. Dividing patients into responders (BMD increase >10%) and non-responders, the first presented TBS and BSI ameliorations (11.87% and -25.46%, respectively). Non-responders presented an amelioration of BSI only, but less than in the other subgroup (-6.57%). ANNs maps reflect the mentioned bone quality improvements. Teriparatide appears to ameliorate not only BMD and TBS, but also BSI, suggesting an increase of bone strength that may explain the known reduction in fracture risk, not simply justified by BMD increase. BSI appears to be a sensitive index of TPD effect. ANNs appears to be a valid tool to investigate complex clinical systems.

3.
Nucleic Acids Res ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32083658

RESUMO

The rapid development of Chromosome Conformation Capture (3C-based techniques), as well as imaging together with bioinformatics analyses, has been fundamental for unveiling that chromosomes are organized into the so-called topologically associating domains or TADs. While TADs appear as nested patterns in the 3C-based interaction matrices, the vast majority of available TAD callers are based on the hypothesis that TADs are individual and unrelated chromatin structures. Here we introduce TADpole, a computational tool designed to identify and analyze the entire hierarchy of TADs in intra-chromosomal interaction matrices. TADpole combines principal component analysis and constrained hierarchical clustering to provide a set of significant hierarchical chromatin levels in a genomic region of interest. TADpole is robust to data resolution, normalization strategy and sequencing depth. Domain borders defined by TADpole are enriched in main architectural proteins (CTCF and cohesin complex subunits) and in the histone mark H3K4me3, while their domain bodies, depending on their activation-state, are enriched in either H3K36me3 or H3K27me3, highlighting that TADpole is able to distinguish functional TAD units. Additionally, we demonstrate that TADpole's hierarchical annotation, together with the new DiffT score, allows for detecting significant topological differences on Capture Hi-C maps between wild-type and genetically engineered mouse.

4.
Genetics ; 214(3): 651-667, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31907200

RESUMO

The three-dimensional (3D) organization of chromosomes can influence transcription. However, the frequency and magnitude of these effects remain debated. To determine how changes in chromosome positioning affect transcription across thousands of genes with minimal perturbation, we characterized nuclear organization and global gene expression in budding yeast containing chromosome fusions. We used computational modeling and single-cell imaging to determine chromosome positions, and integrated these data with genome-wide transcriptional profiles from RNA sequencing. We find that chromosome fusions dramatically alter 3D nuclear organization without leading to strong genome-wide changes in transcription. However, we observe a mild but significant and reproducible increase in the expression of genes displaced away from the periphery. The increase in transcription is inversely proportional to the propensity of a given locus to be at the nuclear periphery; for example, a 10% decrease in the propensity of a gene to reside at the nuclear envelope is accompanied by a 10% increase in gene expression. Modeling suggests that this is due to both deletion of telomeres and to displacement of genes relative to the nuclear periphery. These data suggest that basal transcriptional activity is sensitive to radial changes in gene position, and provide insight into the functional relevance of budding yeast chromosome-level 3D organization in gene expression.

5.
Neurobiol Aging ; 85: 154.e1-154.e3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31530427

RESUMO

Paget's disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. A strong genetic component has been shown in PDB, and variants in several genes, such as SQSTM1, VCP, and OPTN, have been associated with the disease. Mutations in the same genes have also been reported in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Hexanucleotide repeat expansions in the C9ORF72 gene have been shown to be responsible for both familial and sporadic frontotemporal dementia/amyotrophic lateral sclerosis. Thence, we evaluated the frequency of the C9ORF72 hexanucleotide repeat expansions in a cohort of 191 Italian PDB patients and in 106 controls. The pathogenic repeat expansion was detected in 2 PDB patients (1.0%). During the follow-up period, both PDB patients did not develop any sign of mental decline and/or motor neuron disease. Our study suggests that repeat expansions in the C9ORF72 gene are rare in patients with PDB.

7.
BMJ Open ; 9(9): e030689, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488492

RESUMO

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

8.
Calcif Tissue Int ; 105(4): 412-422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31236621

RESUMO

Adequate vitamin D status is essential for skeletal health. Paget's disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case-control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy-safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8 weeks until 25OHD levels reaches 70 nmol/L as primary therapy and 50.000 UI of cholecalciferol administered every 2 weeks for 52 weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50 nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70 nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70 nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

9.
J Morphol ; 279(12): 1753-1763, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397929

RESUMO

Flight is an energetically costly form of transport imparting biomechanical stress that acts upon the wing bones. Previous studies have suggested that the cross-sectional and microstructural features of wing bones may be adapted to resist biomechanical loads. During flight, however, each wing bone potentially experiences a unique loading regime. To assess possible differences among wing bones, we analyzed the microstructural features of the humerus, radius, ulna, and carpometacarpus (CMC) in eight griffon vultures (Gyps fulvus). Vascular canal orientation was evaluated in the diaphysis of the wing bones. Laminarity index (LI) was significantly different in the humerus versus CMC and ulna versus CMC. Results showed a lower proportion of circular vascular canals, due to resistance to torsional loads, in CMC than in humerus and ulna. The midshaft cross-section revealed an elliptical shape in the CMC compared to the circular shape observed in the other wing bones, with a maximum second moment of inertia (Imax ) orientation which suggests a capacity to withstand bending loads in a dorsoventral direction. The volumetric bone mineral density in the diaphysis was statistically different in CMC compared to the other bones analyzed. Its lower mineral density may reflect an adaptation to a different type and load of stresses in CMC compared to the proximal wing bones. No significant difference was found in the relative cortical area (CA/TA) among the four elements, while the polar moment of area J (Length-standardized) revealed a higher resistance to torsional load in the humerus than in the other bones. Our results would seem to indicate that griffon wing bones are structured as an adaptation, represented by two segments that respond to force in two ways: the proximal segment is specially adapted to resist torsional loads, whereas the distal one is adapted to resist bending loads.


Assuntos
Osso e Ossos/anatomia & histologia , Falconiformes/anatomia & histologia , Falconiformes/fisiologia , Voo Animal/fisiologia , Asas de Animais/anatomia & histologia , Adaptação Fisiológica , Animais , Densidade Óssea/fisiologia , Osso e Ossos/fisiologia , Estudos Transversais , Processamento de Imagem Assistida por Computador
10.
BMC Endocr Disord ; 18(1): 55, 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089481

RESUMO

BACKGROUND: Here we study the effect of type 2 diabetes (T2DM) on bone cell precursors, turnover and cytokines involved in the control of bone cell formation and activity. METHODS: We enrolled in the study 21 T2DM women and 21 non diabetic controls matched for age and body mass index (BMI). In each subject we measured bone cell precursors, Receptor Activator of Nuclear Factor κB (RANKL), Osteoprotegerin (OPG), Sclerostin (SCL) and Dickoppf-1 (DKK-1) as cytokines involved in the control of osteoblast and osteoclast formation and activity, bone density (BMD) and quality trough trabecular bone score (TBS) and bone turnover. T2DM patients and controls were compared for the analyzed variables by one way ANOVA for Gaussian ones and by Mann-Whitney or Kruskal-Wallis test for non-Gaussian variables. RESULTS: RANKL was decreased and DKK-1 increased in T2DM. Accordingly, patients with T2DM have lower bone turnover compared to controls. BMD and TBS were not significantly different from healthy controls. Bone precursor cells were more immature in T2DM. However the number of osteoclast precursors was increased and that of osteoblasts decreased. CONCLUSIONS: Patients with T2DM have more immature bone cells precursors, with increased number of osteoclasts and decreased osteoblasts, confirming low bone turnover and reduced cytokines such as RANKL and DKK-1. BMD and TBS are not significantly altered in T2DM although, in contrast with other studies, this may be due to the match of patients and controls for BMI rather than age.


Assuntos
Remodelação Óssea/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Ligante RANK/sangue
11.
Nat Commun ; 8(1): 1753, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29170434

RESUMO

At the kilo- to megabase pair scales, eukaryotic genomes are partitioned into self-interacting modules or topologically associated domains (TADs) that associate to form nuclear compartments. Here, we combine high-content super-resolution microscopies with state-of-the-art DNA-labeling methods to reveal the variability in the multiscale organization of the Drosophila genome. We find that association frequencies within TADs and between TAD borders are below ~10%, independently of TAD size, epigenetic state, or cell type. Critically, despite this large heterogeneity, we are able to visualize nanometer-sized epigenetic domains at the single-cell level. In addition, absolute contact frequencies within and between TADs are to a large extent defined by genomic distance, higher-order chromosome architecture, and epigenetic identity. We propose that TADs and compartments are organized by multiple, small-frequency, yet specific interactions that are regulated by epigenetics and transcriptional state.


Assuntos
Cromossomos/genética , Drosophila/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Cromossomos/química , Cromossomos/metabolismo , Drosophila/química , Drosophila/metabolismo , Epigênese Genética , Genoma , Análise de Célula Única
12.
Sci Rep ; 6: 35985, 2016 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-27786255

RESUMO

Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling.


Assuntos
Cromossomos Humanos/genética , Genoma Humano , Modelos Genéticos , Linhagem Celular , Segregação de Cromossomos/genética , Cromossomos Humanos/ultraestrutura , Bases de Dados Genéticas , Diploide , Fibroblastos/ultraestrutura , Células-Tronco Embrionárias Humanas/ultraestrutura , Humanos , Imagem Tridimensional
13.
RNA Biol ; 13(2): 134-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26828280

RESUMO

Physical entanglement, and particularly knots arise spontaneously in equilibrated polymers that are sufficiently long and densely packed. Biopolymers are no exceptions: knots have long been known to occur in proteins as well as in encapsidated viral DNA. The rapidly growing number of RNA structures has recently made it possible to investigate the incidence of physical knots in this type of biomolecule, too. Strikingly, no knots have been found to date in the known RNA structures. In this Point of View Article we discuss the absence of knots in currently available RNAs and consider the reasons why knots in RNA have not yet been found, despite the expectation that they should exist in Nature. We conclude by singling out a number of RNA sequences that, based on the properties of their predicted secondary structures, are good candidates for knotted RNAs.


Assuntos
Conformação de Ácido Nucleico , RNA/química , DNA Viral/química , DNA Viral/genética , Modelos Moleculares , Proteínas/química , RNA/genética
14.
FEBS Lett ; 589(20 Pt A): 2987-95, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-25980604

RESUMO

Chromosomes are large polymer molecules composed of nucleotides. In some species, such as humans, this polymer can sum up to meters long and still be properly folded within the nuclear space of few microns in size. The exact mechanisms of how the meters long DNA is folded into the nucleus, as well as how the regulatory machinery can access it, is to a large extend still a mystery. However, and thanks to newly developed molecular, genomic and computational approaches based on the Chromosome Conformation Capture (3C) technology, we are now obtaining insight on how genomes are spatially organized. Here we review a new family of computational approaches that aim at using 3C-based data to obtain spatial restraints for modeling genomes and genomic domains.


Assuntos
Cromossomos/ultraestrutura , Genoma , Modelos Genéticos , Animais , Cromossomos/genética , Simulação por Computador , Regulação da Expressão Gênica , Humanos , Conformação de Ácido Nucleico
15.
Radiol Med ; 120(7): 674-82, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25652156

RESUMO

PURPOSE: The aim of this study was to investigate whether the population differences in osteoporosis observed nowadays is a reflection of the times and modern lifestyle factors, or whether they were also present in the past. MATERIALS AND METHODS: The study was performed on the skeletal remains of medieval and post-medieval populations from a burial ground in the North-West of Italy. Some individuals had been buried inside the church (privileged subjects), others outside in the parvis (members of rural population), and others still to the north of the church. X-ray, computed tomography and dual-energy X-ray absorptiometry studies were carried out on the lumbar spines and/or femurs of 27 male and 28 female individuals to determine any associations between cortical index, bone mineral density (BMD), gender, age and social status. RESULTS: No statistically significant differences were observed in cortical index values according to gender, age or place of burial. Conversely, statistically significant differences in average BMD values were observed according to place of burial; in particular, among those buried inside the church, a lower BMD was observed compared to the parvis group (1.09 vs. 1.42, p < 0.001) and the north group (1.09 vs. 1.49, p < 0.001). CONCLUSIONS: The differences observed in the BMD values may be related to the different lifestyle of the rural population, i.e. more dietary calcium intake, more sun exposure and vigorous physical activity, compared to that of the privileged individuals.


Assuntos
Osteoporose/história , Absorciometria de Fóton , Cadáver , Feminino , História Medieval , Humanos , Itália , Masculino , Osteoporose/diagnóstico por imagem , Tomografia Computadorizada por Raios X
16.
Proc Natl Acad Sci U S A ; 112(7): 2052-7, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25646433

RESUMO

The ongoing effort to detect and characterize physical entanglement in biopolymers has so far established that knots are present in many globular proteins and also, abound in viral DNA packaged inside bacteriophages. RNA molecules, however, have not yet been systematically screened for the occurrence of physical knots. We have accordingly undertaken the systematic profiling of the several thousand RNA structures present in the Protein Data Bank (PDB). The search identified no more than three deeply knotted RNA molecules. These entries are rRNAs of about 3,000 nt solved by cryo-EM. Their genuine knotted state is, however, doubtful based on the detailed structural comparison with homologs of higher resolution, which are all unknotted. Compared with the case of proteins and viral DNA, the observed incidence of knots in available RNA structures is, therefore, practically negligible. This fact suggests that either evolutionary selection or thermodynamic and kinetic folding mechanisms act toward minimizing the entanglement of RNA to an extent that is unparalleled by other types of biomolecules. A possible general strategy for designing synthetic RNA sequences capable of self-tying in a twist-knot fold is finally proposed.


Assuntos
Conformação de Ácido Nucleico , RNA/química , Bases de Dados de Proteínas , Modelos Moleculares
17.
ScientificWorldJournal ; 2014: 173082, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25379519

RESUMO

Atypical or silent celiac disease may go undiagnosed for many years and can frequently lead to loss of bone mineral density, with evolution to osteopenia or osteoporosis. The prevalence of the latter conditions, in case of new diagnosis of celiac disease, has been evaluated in many studies but, due to the variability of epidemiologic data and patient features, the results are contradictory. The aim of this study was to evaluate bone mineral density by dual-energy X-ray absorptiometry in 175 consecutive celiac patients at time of diagnosis (169 per-protocol, 23 males, 146 females; average age 38.9 years). Dual-energy X-ray absorptiometry was repeated after 1 year of gluten-free diet in those with T-score value <-1 at diagnosis. Stratification of patients according to sex and age showed a higher prevalence of low bone mineral density in men older than 30 years and in women of all ages. A 1-year gluten-free diet led to a significant improvement in lumbar spine and femoral neck mean T-score value. We propose that dual-energy X-ray absorptiometry should be performed at diagnosis of celiac disease in all women and in male aged >30 years, taking into account each risk factor in single patients.


Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/prevenção & controle , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Osteoporose/prevenção & controle , Absorciometria de Fóton , Adulto , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/patologia , Doença Celíaca/complicações , Doença Celíaca/diagnóstico por imagem , Doença Celíaca/patologia , Feminino , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/patologia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/etiologia , Osteoporose/patologia , Fatores de Risco
18.
Soft Matter ; 10(34): 6491-8, 2014 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-25048107

RESUMO

The dynamical properties of entangled polyelectrolytes are investigated theoretically and computationally for a proposed novel micromanipulation setup. Specifically, we investigate the effects of DC and AC electric fields acting longitudinally on knotted DNA chains, modelled as semiflexible chains of charged beads, under mechanical tension. We consider various experimentally accessible values of the field amplitude and frequency as well as several of the simplest knot types. In particular, we consider both torus and twist knots because they are respectively known to be able or unable to slide along macroscopic threads and ropes. Strikingly, this qualitative distinction disappears in this microscopic context because all the considered knot types acquire a systematic drift in the direction of the electric force. Notably, the knot drift velocity and diffusion coefficient in zero field (both measurable also experimentally) can be used to define a characteristic "frictional" lengthscale for the various knot types. This previously unexplored length provides valuable information on the extent of self-interactions in the nominal knotted region. It is finally observed that the motion of a knot can effectively follow the AC field only if the driving period is larger than the knot relaxation time (for which the self-diffusion time provides an upper bound). These results suggest that salient aspects of the intrinsic dynamics of knots in DNA chains could be probed experimentally by means of external, time-dependent electric fields.


Assuntos
DNA/química , Modelos Moleculares , Estimulação Elétrica , Eletricidade , Polímeros/química
19.
J Bone Miner Res ; 28(11): 2338-46, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23658060

RESUMO

Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM-positive individuals were included, with an effect size approximately one-third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Progressão da Doença , Predisposição Genética para Doença , Mutação/genética , Osteíte Deformante/genética , Osteíte Deformante/patologia , Idoso , Biomarcadores/metabolismo , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Internacionalidade , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fatores de Risco , Proteína Sequestossoma-1 , Resultado do Tratamento
20.
PLoS Comput Biol ; 9(3): e1003019, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23555238

RESUMO

The connection between chromatin nuclear organization and gene activity is vividly illustrated by the observation that transcriptional coregulation of certain genes appears to be directly influenced by their spatial proximity. This fact poses the more general question of whether it is at all feasible that the numerous genes that are coregulated on a given chromosome, especially those at large genomic distances, might become proximate inside the nucleus. This problem is studied here using steered molecular dynamics simulations in order to enforce the colocalization of thousands of knowledge-based gene sequences on a model for the gene-rich human chromosome 19. Remarkably, it is found that most (≈ 88%) gene pairs can be brought simultaneously into contact. This is made possible by the low degree of intra-chromosome entanglement and the large number of cliques in the gene coregulatory network. A clique is a set of genes coregulated all together as a group. The constrained conformations for the model chromosome 19 are further shown to be organized in spatial macrodomains that are similar to those inferred from recent HiC measurements. The findings indicate that gene coregulation and colocalization are largely compatible and that this relationship can be exploited to draft the overall spatial organization of the chromosome in vivo. The more general validity and implications of these findings could be investigated by applying to other eukaryotic chromosomes the general and transferable computational strategy introduced here.


Assuntos
Cromossomos Humanos Par 19/química , Genes , Simulação de Dinâmica Molecular , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 19/metabolismo , Cromossomos Humanos Par 19/ultraestrutura , Análise por Conglomerados , Biologia Computacional , Redes Reguladoras de Genes , Humanos , Interfase/genética , Mitose/genética , Transcrição Genética
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