Spatially restricted loading of BRD2 at DNA double-strand breaks protects H4 acetylation domains and promotes DNA repair

The n-terminal tail of histone H4 recruits repair proteins, including 53BP1, to DNA double-strand breaks (DSB) and undergoes dynamic acetylation during DSB repair. However, how H4 acetylation (H4Ac) recruits repair proteins and reorganizes chromatin during DNA repair is unclear. Here, we show that the bromodomain protein BRD2 is recruited to DSBs. This recruitment requires binding of BRD2’s tandem bromodomains to H4Ac, which is generated at DSBs by the Tip60/KAT5 acetyltransferase. Binding of BRD2 to H4Ac protects the underlying acetylated chromatin from attack by histone deacetylases and allows acetylation to spread along the flanking chromatin. However, BRD2 recruitment is spatially restricted to a chromatin domain extending only 2 kb either side of the DSB, and BRD2 does not spread into the chromatin domains flanking the break. Instead, BRD2 facilitates recruitment of a second bromodomain protein, ZMYND8, which spreads along the flanking chromatin, but is excluded from the DSB region. This creates a spatially restricted H4Ac/BRD2 domain which reorganizes chromatin at DSBs, limits binding of the L3MBTL1 repressor and promotes 53BP1 binding, while limiting end-resection of DSBs. BRD2 therefore creates a restricted chromatin environment surrounding DSBs which facilitates DSB repair and which is framed by extensive ZMYND8 domains on the flanking chromatin.

Susceptibility to downy mildew (Plasmopara viticola) and powdery mildew (Erysiphe necator) of differentVitiscultivars and genotypes

Turkey has a very old history of viticulture and also homeland of the grapevine (Vitis spp.). Vitis cultivars belonging to different species are grown in almost every region in the country. However, particularly downy mildew and powdery mildew diseases affect the cultivars belonging to Vitis vinifera . In northern of Turkey Vitis labrusca and hybrids between V.vinifera and V.labrusca are rather common. V.labrusca cultivars or genotypes exhibit generally higher degree of resistance than V. vinifera cultivars. However, resistance level can vary from cultivar to cultivar and even from clone to clone within one cultivar. In this study, different Vitis hybrids and genotypes which exhibit different downy and powdery mildew susceptibility are compared for two years. Especially some V.labrusca hybrids and genotypes appeared resistance for both diseases. On the other hand, interspecific crosses and V.vinifera cultivars were found to be more susceptible. Using resistant lines as parent in later breeding activities, it could be possible grow high quality table cultivars with much fewer pesticide applications or possibly without them.

Comparison of 3DCRT,VMAT and IMRT techniques in metastatic vertebra radiotherapy: A phantom Study

Vertebra metastases can be seen during the prognosis of cancer patients. Treatment ways of the metastasis are radiotherapy, chemotherapy and surgery. Three-dimensional conformal therapy (3D-CRT) is widely used in the treatment of vertebra metastases. Also, Intensity Modulated Radiotherapy (IMRT) and Volumetric Arc Therapy (VMAT) are used too. The aim of this study is to examine the advantages and disadvantages of the different radiotherapy techniques. In the aspect of this goal, it is studied with a randophantom in Uludag University Medicine Faculty, Radiation Oncology Department. By using a computerized tomography image of the phantom, one 3DCRT plan, two VMAT and three IMRT plans for servical vertebra and three different 3DCRT plans, two VMAT and two IMRT plans for lomber vertebra are calculated. To calculate 3DCRT plans, CMS XiO Treatment System is used and to calculate VMAT and IMRT plans Monaco Treatment Planning System is used in the department. The study concludes with the dosimetric comparison of the treatment plans in the spect of critical organ doses, homogeneity and conformity index. As a result of this study, all critical organ doses are suitable for QUANTEC Dose Limit Report and critical organ doses depend on the techniques which used in radiotherapy. According to homogeneity and conformity indices, VMAT and IMRT plans are better than one in 3DCRT plans in servical and lomber vertebra radiotherapy plans

The relationship of cutting force with hole quality in drilling process of AISI H13 steel

The harmony of the drilling machine-cutting tool-work piece is very important for producing the machine part with the ideal dimensions. For this purpose in this study, the effect of cutting forces on hole quality (surface roughness, diameter deviation and circular deviation) was investigated by 14 mm diameter uncoated and (AlCrN monolayer) coated carbide drills for drilling AISI H13 hot work tool steel on vertical machining center. Four different cutting speeds (60, 75, 90 and 108 m / min) and three different feed rates (0.15, 0.20 and 0.25 mm / rev) were used in the experiments. Cutting forces have been found to be effective in improving hole quality. Better hole quality has obtained with coated drills than uncoated drills in experiments. It has been observed that coated drills have the effect of improving the hole quality due to the operation with less cutting force and better chip evacuation

The relationship between quality of life and social support among adolescents

Social support plays an important role in quality of life. The social support given to adolescents is thought to positively affect identity development and life quality as well as physical and psychosocial health. In this context, this study aims to examine the relationship between adolescents’ quality of life and social support levels. Designed as a relational screening model, the study was conducted at 5 secondary schools with 436 voluntarily participating students in Dulkadiroğlu, Kahraman Maraş during the 2016-2017 academic year. Within the study, the “Life Quality Scale for Children” and the “Social Relationship Principles Scale for Adolescents” was implemented. In the data analysis process, descriptive statistics, multiple regression analysis and Pearson Product-Moment Correlation analysis tests were used. According to the study results, a positive relationship was found between friends and family support and physical health, psychosocial health and quality of life

Partial spleen embolization reduces the risk of portal hypertension-induced upper gastrointestinal bleeding in patients not eligible for TIPS implantation

Triple Coronary Artery Thrombosis Presenting as Acute Anterior ST-Segment Elevation Myocardial Infarction

Simultaneous multivessel epicardial coronary artery thrombosis is an uncommon finding in acute ST-segment elevation myocardial infarction (STEMI). It generally leads to cardiogenic shock and sudden cardiac death in the hospital. We report a 42-year-old male patient presenting with acute anterior STEMI with triple coronary artery thrombosis. An emergency coronary angiogram showed total occlusion of the left anterior descending artery (LAD) with thrombus formation. At the same time, thrombus formations were also seen in the circumflex artery (CXA), the second obtuse marginal (OM2) branch, and the distal right coronary artery (RCA). We unsuccessfully attempted thrombus aspiration of the LAD. Subsequently, we decided to stent the LAD, and a successful percutaneous coronary intervention (PCI) was performed for the LAD. In a second procedure, RCA thrombosis regressed with 24-hour tirofiban (glycoprotein IIb/IIIa receptor inhibitor) perfusion, although CXA thrombosis and OM thrombosis did not regress. Therefore, we performed stenting of the CXA and OM with a newer provisional technique called the flower petal technique. Thrombolysis in myocardial infarction (TIMI) flow grade III was seen after stenting. The patient was discharged from the hospital 5 days after PCI without any symptoms.

Importance of Static Correction and Damping in the Analysis of a Cable-Stayed Bridge Subjected to Displacement Loading

Cable-stayed bridges with long spans are excited by different support vibrations on both sides of the main span. Therefore, a realistic seismic structural analysis of the bridge must involve multiple-support excitation. The dynamic equation of motion, in which all degrees of freedom are solved at once, can be solved directly. A modal analysis might also be possible, but care must be taken with the number of modes used in the analysis. If the ground motion is described in terms of displacement and velocity, which is referred to as displacement loading, then a static correction that will account for the unconsidered higher modes must be performed. In this study, the procedure of multiple-support excitation through the use of modal transformation is explained in detail. The effects of changes in damping levels that affect the analysis results are investigated by using the static correction method in displacement loading. An example is given to illustrate the mentioned problem by using a finite-element model of the cable-stayed Bill Emerson Memorial Bridge. DOI: 10.1061/(ASCE)BE.1943-5592.0001041. © 2017 American Society of Civil Engineers. Author keywords: Multiple-support excitation; Static correction method; Damping effect; Modal analysis; Displacement loading. Introduction The seismic analysis of structures that have long spans, such as cable-stayed or suspension bridges, pipelines, and domes, need further consideration when modal superposition in conjunction with ground displacement is to be used. As it is known from the literature, if the supports of the structure are far apart, a traveling wave results in different support excitations (Su et al. 2007; Zhang et al. 2009). Displacement loading excites high-frequency modes (Wilson 2002), and errors are likely to occur if these high-frequency modes are omitted in the modal analysis. To circumvent this problem, several studies have established an analysis procedure to minimize the computational model errors in the case of displacement loading. Tsai (1998) proposed the static correction method to provide convergence between the solutions obtained by displacement-loading and conventional acceleration-loading analyses. Tsai (1998) gave examples to illustrate the effect of the static correction method on the results of convergence analysis obtained by displacement and acceleration loadings for uniform excitation. Wilson (2002) described the general characteristics of displacement loading and probable numerical errors that emerge in the closed-form solution. Wilson (2002) highlighted the effect of damping on the consistency of analysis. Furthermore, the author noted that as the damping ratio increased, the analysis results were increasingly inconsistent. Li and Yang (2008) analyzed the seismic response of a long continuous rigid-frame bridge subjected to multiple-support excitation by displacement loading. They used the direct integration method, which provides a closed-form solution without modal analysis by neglecting the damping effect. Tian and Yang (2009) compared acceleration and displacement loading by using the direct integration solution and focused on the numerical errors caused by the integration time step and their effect on the convergence analysis by neglecting the damping effects. Yau and Frýba investigated the response of suspension bridges with moving loads against multisupport displacement motion (Yau and Frýba 2007; Frýba and Yau 2009; Yau 2009). In their studies, these authors modeled the center span of a suspension bridge as an equivalent Euler–Bernoulli beam that includes the stiffness of the cables for dynamic analysis. Du et al. (2012) analyzed a coupled bridge–train system that was subjected to displacement ground motion. In their study, a modal analysis was performed to obtain the dynamic response of the bridge–train system. However, the effect of static correction was overlooked. Multisupport-excitation analysis is well known and widely used by engineers, and acceleration loading is generally used in such applications (Soyluk 2004; Abdel Raheem et al. 2011; Ye et al. 2012; Jiao et al. 2013; Wang and Kiureghian 2014; Surh et al. 2015). Cui and Gao (2011) investigated the traveling-wave effect in long-span cable-stayed bridges, and they concluded that research on long-span cable-stayed bridges needs to not only account for the traveling wave effect but also include wave refraction, reflection, and scattering in different media. Li et al. (2014) investigated the effect of support flexibility on seismic responses of a reticulated dome under multiple-support excitation with spatially correlated and coherent excitations. The properties of spatial correlation and coherency of multiple-support excitations were highlighted, and the study revealed that coherency affected the seismic response. Wang et al. (2015) investigated the apparent wave-velocity effect on the seismic performance of the Taizhou suspension bridge. They presented a review of the critical issues in analyzing the traveling-wave effect and proposed characteristics of the shear force and bending moment distributions of the towers and the traveling-wave effect on those force distributions. In this study, the modal analysis procedure for long-span structures subjected to displacement loading is analyzed by using a finite-element model of the cable-stayed Bill Emerson Memorial Bridge, which has been studied by many researchers (Dyke et al. 2003; Caicedo et al. 2003; Koh and Dyke 2007; Domaneschi and Research Assistant, Ph.D. Candidate, Civil Engineering Dept., Izmir Institute of Technology, Urla, Izmir 35430, Turkey (corresponding author). E-mail: [email protected] Assistant Professor, Ph.D., Civil Engineering Dept., Izmir Institute of Technology, Urla, Izmir 35430, Turkey. E-mail: [email protected] Note. This manuscript was submitted on August 30, 2016; approved on December 8, 2016; published online on February 22, 2017. Discussion period open until July 22, 2017; separate discussions must be submitted for individual papers. This paper is part of the Journal of Bridge Engineering, © ASCE, ISSN 1084-0702. © ASCE 04017009-1 J. Bridge Eng. J. Bridge Eng., 2017, 22(6): 04017009 D ow nl oa de d fr om a sc el ib ra ry .o rg b y IZ M IR Y U K SE K T E K N O L O JI E N ST IT U SU o n 10 /2 6/ 17 . C op yr ig ht A SC E . F or p er so na l u se o nl y; a ll ri gh ts r es er ve d. Martinelli 2014; De Mari et al. 2015). The static correction method, applied for consistency of the displacement and the base shear response, is investigated. The pseudostatic effects of the support reactions are also studied. The compatibility of mass, stiffness, and static-load participation ratios with the exact modal variation of displacement and base shear force response are investigated. In addition, the effect of damping in the modal analysis is evaluated. To the knowledge of the authors, neither a comprehensive investigation of modal contributions on analysis results nor a study on damping in multiple-support displacement loading has been performed so far. Formulation of Multiple-Support Excitation Two different methods are used to solve the equation of motion of long-span bridges subjected to support excitation, the displacementloading and acceleration-loading methods. They are classified according to the construction of the external load function. In conventional acceleration loading, the external load function is obtained by multiplying the mass matrix of unconstrained degrees of freedom (DOF), the ground acceleration, and its expansion vector (Chopra 2013). Because the mass matrix is associated with this procedure, this loading type can be consideredmass proportional. In displacement loading, the external load function is constructed by multiplying the stiffness matrix and the displacement vector of the constrained (support) DOF. Therefore, this type of loading can be considered stiffness proportional. The equation of motion of a long-span structure subjected to support excitation can be written as M Mg MT g Mgg þ €y tðtÞ €ygðtÞ þ C Cg CT g Cgg _ ytðtÞ _ ygðtÞ þ K Kg KT g Kgg ytðtÞ ygðtÞ 1⁄4 0 FgðtÞ (1) where M, C, and K = mass, damping, and stiffness matrices of unconstrained DOF, respectively;Mgg, Cgg, and Kgg = mass, damping, and stiffness matrices of constrained DOF, respectively; and Mg, Cg, and Kg = coupling mass, damping, and stiffness matrices of constrained and unconstrained DOF, respectively. y(t) and yg(t) denote the absolute displacement vector of unconstrained and constrained DOF, respectively. Fg(t) denotes the total force acting on the support DOF. The equation of motion given in Eq. (1) can be separated into two parts as follows: M€ytðtÞ þ C _ ytðtÞ þ KytðtÞ 1⁄4 KgygðtÞ Cg _ ygðtÞ Mg€ygðtÞ (2) M g€y tðtÞ þMgg€ygðtÞ n o þ C g _ ytðtÞ þ Cgg _ ygðtÞ n o þ K g ytðtÞ þ KggygðtÞ n o 1⁄4 FgðtÞ (3) Eqs. (2) and (3) denote the equation of motion of the unconstrained and constrained DOF, respectively. In common practice, the third term on the right-hand side of Eq. (2) is much smaller than the first and second terms. Thus, the third term is neglected [Eq. (4)]. M€ytðtÞ þ C _ ytðtÞ þ KytðtÞ 1⁄4 KgygðtÞ Cg _ ygðtÞ (4) Because the right side of Eq. (4) includes both ground displacement and velocity input, the external load can be referred to as displacement and velocity loading. For low damping values, the second term of the right side of Eq. (4) is negligible. In this case, the external dynamic loading is referred to as displacement loading in the literature. Then, the equation of motion of unconstrained DOF takes the following form: M€ytðtÞ þ C _ ytðtÞ þ KytðtÞ 1⁄4 KgygðtÞ (5) In dynamic analysis, the relative displacement vectors of unconstrained DOF are used in general, and therefore, the external load function consists of the mass matrix multiplied by the ground-acceleration vector. As a result, this type of loading is called mass proportional and/or acceleration loading. If the equation

Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome

The 26S proteasome is the macromolecular machine responsible for ATP/ubiquitin dependent degradation. As aberration in proteasomal degradation has been implicated in many human diseases, structural analysis of the human 26S proteasome complex is essential to advance our understanding of its action and regulation mechanisms. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for elucidating structural topologies of large protein assemblies, with its unique capability of studying protein complexes in cells. To facilitate the identification of cross-linked peptides, we have previously developed a robust amine reactive sulfoxide-containing MS-cleavable cross-linker, disuccinimidyl sulfoxide (DSSO). To better understand the structure and regulation of the human 26S proteasome, we have established new DSSO-based in vivo and in vitro XL-MS workflows by coupling with HB-tag based affinity purification to comprehensively examine protein-protein interactions within the 26S proteasome. In total, we have identified 447 unique lysine-to-lysine linkages delineating 67 interprotein and 26 intraprotein interactions, representing the largest cross-link dataset for proteasome complexes. In combination with EM maps and computational modeling, the architecture of the 26S proteasome was determined to infer its structural dynamics. In particular, three proteasome subunits Rpn1, Rpn6, and Rpt6 displayed multiple conformations that have not been previously reported. Additionally, cross-links between proteasome subunits and 15 proteasome interacting proteins including 9 known and 6 novel ones have been determined to demonstrate their physical interactions at the amino acid level. Our results have provided new insights on the dynamics of the 26S human proteasome and the methodologies presented here can be applied to study other protein complexes.

Hypoxia enhances secretion of matrix metalloproteinases in bovine dermal fibroblasts: an in vitro approach to bovine digital dermatitis