From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions

©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein

Cyclic Force Applied to FAs Induces Actin Recruitment Depending on the Dynamic Loading Pattern

Mechanical forces acting on focal adhesions (FAs) are believed to be an important determinant for cytoskeletal reorganization. However, the effect of the temporal pattern of forces on cellular responses has not been elucidated. In the present study, we examined the responses of FAs to locally-applied cyclic forces. Magnetic micro beads coated with fibronectin were attached to the apical surface of endothelial cells and continuous or cyclic forces at frequencies of 0.1-10 Hz with duty cycles of 0-100% were applied to the beads using a newly developed electromagnetic tweezer. A significant increase in actin recruitment around the beads was observed when cyclic forces at 1-2 Hz and 25-50% duty cycles were applied. This tendency disappeared upon modification of myosin activity. These results indicate that the sensitivity to temporal patterns of forces is detemined by the viscoelastic properes of FAs and depends on myosin activity

Effects of Age of Onset of Tonic-Clonic Seizures on Neuropsychological Performance in Children

Forty-eight children (aged 9 to 15 years) with tonic-clonic seizures were administered a neuropsychological test battery. The children with seizures of early onset (before age 5) were significantly impaired relative to the children with later onset on 8 of the 14 measures in the battery. The deficits were seen on tasks whose requirements included the repetition of a simple motor act, attention and concentration, memory, and complex problem solving. These findings emphasize the need for further research to determine the causal factors of the greater dysfunction seen in the early onset group. RÉSUMÉ Quarante huit enfants ÁgÉs de 9 À 15 ans souffrant de crises Épileptiques tonico-cloniques ont ÉtÉÉtudiÉs avec une batterie de tests neuropsychologiques. Pour huit des quatorze mesures de cette batterie de tests les enfants dont les cirses avaient dÉbutÉ prÉcocÉment (avant cinq ans) se sont avÉrÉs Étre signiflcativement dÉtÉriorÉs par rapport À ceux dont les crises avaient dÉbutÉ plus tardivement. Les dÉficits se sont manifestÉs pour des tÁches nÉcessitant la rÉpÉtition d'un acte moteur simple, attention et concentration, mÉmoire et capacitÉÀ rÉsoudre des problÈmes complexes. Ces rÉsultats mettent l'accent sur la nÉcessitÉ de poursuivre les recherches afin de dÉterminer les facteurs responsables de la plus grande dysfonction observÉe chez les enfants dont l'Épilepsie a dÉbutÉ tÔt dans la vie. RESUMEN Se ha aplicado una bateria de tests neuro-psicolÓgicos a 48 niÑos de 9 a 15 aÑos de edad que padecÍan ataques tonico-clÓnicos. Los niÑos con ataques de comienzo precoz (antes de los 5 aÑos) mostraron incapacidades significativas compareÁndolos con niÑos con comienzos mÁs tardios en 8 de los 14 tests de la bateria. Los defectos fueron detectados en las pruebas cuyos requisitos incluÍan la repeticiÓn de un acto motor simple, atenciÓn y concentraciÓn, memoria y resoluciÓn de problemas complejos. Estos hallazgos indican la necesidad de continuar la inves-tigaciÓn para determinar los factores causales de la mayor disfunciÓn observada en el grupo de comienzo precoz. ZUSAMMENFASSUNG 48 Kinder (9 bis 15 Jahre alt) mit tonisch-klonischen KrÄmpfen wurden mit einer neuropsychologischen Testbatterie untersucht. Die Kinder mit einem FrÜhbeginn der AnfÄlle (vor dem Alter von 5 Jahren) zeigten sich bei 8 von 14 Tests der Serie deutlich beeintrÄchtigt im VerhÄltnis zu Kindern mit spÄterem Anfallsbeginn. Die Defekte traten bei Aufgaben auf, die folgende AnsprÜche stellten: Wiederholung einer einfachen motorischen Handlung, Aufmerksamkeit und Konzentration, GedÄchtnis und komplexes ProblemlÖsen. Diese Befunde deuten auf die Notwendigkeit weiterer Untersuchungen, um die ursÄchlichen Faktoren der grÖßeren Funktionseinbuße zu bestimmen, die bei Patienten mit frÜhem Anfallsbeginn beobachtet wird.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65238/1/j.1528-1157.1981.tb04102.x.pd

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL

The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia

BACKGROUND: Manipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this. METHODS: Ten healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals. RESULTS: Following oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo) CONCLUSIONS: This study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress

Focal Cerebral Magnetic Resonance Changes Associated with Partial Status Epilepticus

We report 2 patients with transient abnormalities on magnetic resonance imaging (MRI) associated with partial status epilepticus (SE). A man with a 4-month history of partial seizures had complex partial SE for 9 days, with left temporal maximum on ictal EEG. Left temporal lobe T 2 signal was increased on MRI during SE, but cerebral MRI was normal 9 weeks later. A woman with “cryptogenic” temporal lobe epilepsy for 16 years had complex partial SE for 1 week, with right temporal maximum on ictal EEG. T 2 Signal was increased over the entire right temporal lobe, extending into the insula, without mass effect, on MRI 1 month after SE ended. Repeat MRI 1 month later showed marked decrease in volume of increased T 2 intensity, without gadolinium enhancement, but with mild mass effect over the right anteroinferomesial temporal areas. A gemistocytic astrocytoma was resected. Focal cerebral MRI abnormalities consistent with cerebral edema may be due to partial SE but also may indicate underlying glioma, even in long-standing partial epilepsy. Focal structural imaging changes consistent with neoplasm should be followed to full resolution after partial SE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65221/1/j.1528-1157.1994.tb02909.x.pd

'Correction:' Serum transforming growth factor beta-1 (TGF-beta-1) levels in diabetic patients are not associated with pre-existent coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM). The association between TGF-β1 levels and long-term major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) is controversial. No study specifically addressed patients with CAD and diabetes mellitus (DM).</p> <p>Methods</p> <p>Patients (n = 135, 30–80 years) referred for coronary angiography were submitted to clinical and laboratory evaluation, and the coronary angiograms were evaluated by two operators blinded to clinical characteristics. CAD was defined as the presence of a 70% stenosis in one major coronary artery, and DM was characterized as a fasting glycemia > 126 mg/dl or known diabetics (personal history of diabetes or previous use of anti-hyperglycemic drugs or insulin). Based on these criteria, study patients were classified into four groups: no DM and no CAD (controls, C n = 61), DM without CAD (D n = 23), CAD without DM (C-CAD n = 28), and CAD with DM (D-CAD n = 23). Baseline differences between the 4 groups were evaluated by the χ²test for trend (categorical variables) and by ANOVA (continuous variables, post-hoc Tukey). Patients were then followed-up during two years for the occurrence of MACE (cardiac death, stroke, myocardial infarction or myocardial revascularization). The association of candidate variables with the occurrence of 2-year MACE was assessed by univariate analysis.</p> <p>Results</p> <p>The mean age was 58.2 ± 0.9 years, and 51% were men. Patients with CAD had a higher mean age (p = 0.011) and a higher percentage were male (p = 0.040). There were no significant baseline differences between the 4 groups regarding hypertension, smoking status, blood pressure levels, lipid levels or inflammatory markers. TGF-β1 was similar between patients with or without CAD or DM (35.1 ×/÷ 1.3, 33.6 ×/÷ 1.6, 33.9 ×/÷ 1.4 and 31.8 ×/÷ 1.4 ng/ml in C, D, C-CAD and D-CAD, respectively, p = 0.547). In the 2-year follow-ip, independent predictors of 2-year MACE were age (p = 0.007), C-reactive protein (p = 0.048) and systolic blood pressure (p = 0.008), but not TGF-β1.</p> <p>Conclusion</p> <p>Serum TGF-β1 was not associated with CAD or MACE occurrence in patients with or without DM.</p

People and Things on the Move: Domestic Material Culture, Poverty and Mobility in Victorian London

© 2016, The Author(s). The development of what Mayne and Lawrence (Urban History 26: 325–48, 1999) termed “ethnographic” approaches to studying nineteenth-century households and urban communities has gathered momentum in recent years. As such research agendas have taken hold and been applied to new contexts, so critiques, methodological developments, and new intellectual and theoretical currents, have provided opportunities to enhance and develop approaches. This article contributes to this on-going process. Drawing upon household archaeological research on Limehouse, a poor neighborhood in Victorian London, and inspired by the theoretical insights provided by the “new mobilities paradigm,” it aims to place “mobility” as a central and enabling intellectual framework for understanding the relationships between people, place, and poverty. Poor communities in nineteenth-century cities were undeniably mobile and transient. Historians and archaeologists have often regarded this mobility as an obstacle to studying everyday life in such contexts. However, examining temporal routines and geographical movements across a variety of time frames and geographical scales, this article argues that mobility is actually key to understanding urban life and an important mechanism for interpreting the fragmented material and documentary traces left by poor households in the nineteenth-century metropolis.We are grateful to the UK’s Arts and Humanities Research Council who funded the research upon which this paper is based (Grant Reference AH/E002285/1): ‘Living in Victorian London: Towards a Material History of Everyday Domestic Life in the Nineteenth-Century Metropolis