Structural basis for allosteric PARP-1 retention on DNA breaks Zandarashvili, Levani; Langelier, Marie-France; Velagapudi, Uday Kiran ...
Science (American Association for the Advancement of Science),
04/2020, Letnik:
368, Številka:
6486
Journal Article
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The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all ...target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.
Selective Laser Sintered food exhibits anisotropic mechanical properties that are characteristic for its layer-by-layer manufacturing process. A constitutive model that is capable of describing the ...anisotropic elasto-viscoplastic-damaging behavior of the material, which was experimentally characterized by compression testing in two distinct principal orientations, is presented. Damage is modeled by applying the effective stress concept in combination with a viscoplastic flow rule that effectively regularizes damage localization. The model allows for quantitative predictions of the mechanical response of the printed food and is a valuable tool for assessing texture properties of food with Selective Laser Sintering.
•The anisotropic mechanical behavior of Selective Laser Sintered food was studied.•An orthotropic constitutive model is formulated.•The effective stress concept was used for modeling anisotropic damage.•The model parameter identification was demonstrated for 3D printed food.
Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a ...complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. This choice between these opposing outcomes integrates many inputs primarily through a number of key cross-road proteins, including ATM, p53, and p21. Evidence of re-entry into the cell-cycle by neurons can be seen in aging and diseases such as Alzheimer's disease. This aberrant cell-cycle re-entry is lethal and can lead to the apoptotic death of the neuron. Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. Recently developed interventions targeting the DDR and/or the senescent phenotype in a range of non-neuronal tissues are being reviewed as they might become of therapeutic interest in neurodegenerative diseases.
Radiation damage induced by X‐ray beams during macromolecular diffraction experiments remains an issue of concern in structural biology. While advances in our understanding of this phenomenon, driven ...in part by a series of workshops in this area, undoubtedly have been and are still being made, there are still questions to be answered. Eight papers in this volume give a flavour of ongoing investigations, addressing various issues. These range over: a proposed new metric derived from atomic B‐factors for identifying potentially damaged amino acid residues, a study of the relative damage susceptibility of protein and DNA in a DNA/protein complex, a report of an indication of specific radiation damage to a protein determined from data collected using an X‐ray free‐electron laser (FEL), an account of the challenges in FEL raw diffraction data analysis, an exploration of the possibilities of using radiation damage induced phasing to solve structures using FELs, simulations of radiation damage as a function of FEL temporal pulse profiles, results on the influence of radiation damage during scanning X‐ray diffraction measurements and, lastly, consideration of strategies for minimizing radiation damage during SAXS experiments. In this short introduction, these contributions are briefly placed in the context of other current work on radiation damage in the field.
•A new type of vibration shapes called a free response shape (FRS) is introduced.•FRSs can be obtained using a continuously scanning laser Doppler vibrometer system.•An analytical expression of FRSs ...of a damped beam structure is derived.•A damage identification methodology using FRSs is proposed and investigated.•The methodology has been numerically and experimentally validated.
Spatially dense operating deflection shapes and mode shapes can be rapidly obtained by use of a continuously scanning laser Doppler vibrometer (CSLDV) system, which sweeps its laser spot over a vibrating structure surface. This paper introduces a new type of vibration shapes called a free response shape (FRS) that can be obtained by use of a CSLDV system, and a new damage identification methodology using FRSs is developed for beam structures. An analytical expression of FRSs of a damped beam structure is derived, and FRSs from the analytical expression compare well with those from a finite element model. In the damage identification methodology, a free-response damage index (FRDI) is proposed, and damage regions can be identified near neighborhoods with consistently high values of FRDIs associated with different modes; an auxiliary FRDI is defined to assist identification of the neighborhoods. A FRDI associated with a mode consists of differences between curvatures of FRSs associated with the mode in a number of half-scan periods of a CSLDV system and those from polynomials that fit the FRSs with properly determined orders. A convergence index is proposed to determine the proper order of a polynomial fit. One advantage of the methodology is that the FRDI does not require any baseline information of an undamaged beam structure, if it is geometrically smooth and made of materials that have no stiffness and mass discontinuities. Another advantage is that FRDIs associated with multiple modes can be obtained using free response of a beam structure measured by a CSLDV system in one scan. The number of half-scan periods for calculation of the FRDI associated with a mode can be determined by use of the short-time Fourier transform. The proposed methodology was numerically and experimentally applied to identify damage in beam structures; effects of the scan frequency of a CSLDV system on qualities of obtained FRSs were experimentally investigated.
Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription ...factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.
Fires usually occur in homes because of carelessness and changes in environmental conditions. They cause threats to the residential community and may result in human death and property damage. ...Consequently, house fires must be detected early to prevent these types of threats. The immediate notification of a fire is the most critical issue in domestic fire detection systems. Fire detection systems using wireless sensor networks sometimes do not detect a fire as a consequence of sensor failure. Wireless sensor networks (WSN) consist of tiny, cheap, and low-power sensor devices that have the ability to sense the environment and can provide real-time fire detection with high accuracy. In this paper, we designed and evaluated a wireless sensor network using multiple sensors for early detection of house fires. In addition, we used the Global System for Mobile Communications (GSM) to avoid false alarms. To test the results of our fire detection system, we simulated a fire in a smart home using the Fire Dynamics Simulator and a language program. The simulation results showed that our system is able to detect early fire, even when a sensor is not working, while keeping the energy consumption of the sensors at an acceptable level.
AbstractDamage state (DS) assessment of reinforced masonry shear wall (RMSW) building systems is key for developing simulation tools for pre- and post-earthquake risk-assessment frameworks. However, ...the majority of available RMSW damage models are generated based on DSs that are identified from component testing and/or modeling. Recent system-level studies showed that individual wall (component-level) responses might vary significantly from those observed when similar components are tested within an RMSW building (i.e., at the system level). Subsequently, in working toward more representative damage models for the next generation of seismic risk assessment standards, the current study focuses on developing a system-level-based damage state (SDS) assessment methodology as an alternative to the currently adopted component-level-based damage state (CDS) assessment approaches. Within this focus, and based on the available building response knowledge levels and expected component damage sequence, four SDS assessment methods, linked to different system-level damage indicators, are proposed. To demonstrate the application of the proposed methodology, the experimental results of a two-story RMSW building tested under simulated seismic loading are adopted in the current study. The results show that response predictions based on the CDS might be unconservative due to possible unexpected system-level failure modes and load-resisting mechanisms. The study shows that some RMSW system-level mechanisms (e.g., wall–diaphragm coupling), and the subsequent damage, cannot be evaluated through component-level testing.
In this paper, the ideas of deep auto‐encoder (DAE) and manifold learning are adopted to solve the problem of structural condition diagnosis. A scalable decentralized end‐to‐end unsupervised ...structural condition diagnostic framework is proposed. Three damage diagnosis mechanisms are clarified. The structural damage diagnosis approaches are presented from the latent coding domain and the time domain, respectively. In the latent coding domain, an undercomplete DAE is established to extract the distribution of the low‐dimensional manifold of the signal. On the contrary, in the time domain, an overcomplete DAE is adopted to extract the reconstruction error of the signal. Subsequently, normalized damage quantitative indicators are developed in the two domains. The damage localization method is also clarified. The proposed method can extract features directly from original vibration data without the need for additional signal preprocessing techniques. More importantly, the algorithm relies only on the output signals and does not require a numerical or scale model. This framework can be used to identify, locate, and quantify structural damages. The validity of the diagnostic framework is verified using a well‐designed laboratory benchmark structure. A large‐scale grandstand structure is further used to prove the ability of the proposed method for identifying slight structural damage caused by the loosening of joint bolts. The results clearly demonstrate an elegant performance of the proposed damage detection algorithm in structural condition assessment and damage localization.
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