With more and more transportation tunnels have been and will be constructed in loess areas in Northwest China with high earthquake potential, the overall stability of portal section under earthquakes actions and the related aseismic countermeasures attracted the attentions from both the scholars and engineers, especially the tunnels in the upper slope connecting the high bridges crossing rivers or valleys. In order to study the dynamic response characteristics and damage evolution of steep loess slope with a tunnel under the earthquake actions, a large-scale shaking table tests were performed on steep loess slope with a tunnel. Wenchuan-tangyu (WT) wave and El Centro (El) wave records were applied on the model to investigate the displacement response and acceleration response of loess slope with a tunnel under the horizontal (X) and the combined action of horizontal and vertical (X-Z) seismic loads, respectively. In particular, three-dimensional non-contact optical measurement techniques were used to obtain the slope surface displacements. The results showed that the main deformation pattern of the slope was horizontal movement and settlement when the seismic wave input was in the X and X-Z directions, respectively. However, the X direction seismic wave had a greater impact on the deformation of the slope, and the tunnel portal slope was destroyed under the action of a large horizontal seismic acceleration finally. Slope failure ahead of a tunnel could be divided into four stages, i.e. elastic deformation stage, plastic deformation accumulation stage, local failure stage, and overall failure stage. The peak ground displacement of X direction (PGDX) and peak ground displacement of Z direction (PGDZ) of the slope surface increased with the increasing of the input peak ground acceleration (PGA) when the input wave was same waveform and same direction. The existence of the tunnel had a great influence on the PGA and the PGA amplification factor (PGAAF) of the soil mass surrounding it. This was because the seismic waves encounter a tunnel surface with clear differences in the physical properties of the medium during their propagation in the slope, thereby forming a strong reflection and refraction effect, and the amplitude changed significantly. Numerical simulation results were basically consistent with the experimental results.

Enhanced oil recovery using nanoparticles is a promising method. However, when injected into a reservoir, nanoparticles can block pores and cause permeability damage. Therefore, enhancing their performance to lower the permeability damage effect is crucial. This study investigated the effect of pH alteration through carbon dioxide (CO2) injection on the permeability damage of limestone caused by the aluminum oxide (α-Al2O3) nanofluid. The methodology involved nanofluid alternating CO2 core flooding experiments by using nanofluids with pH of 4.5 and 2.8. After core flooding, permeability damage was calculated as a percentage of the reduction of the original permeability. The results revealed that the permeability damage in the case of nanofluid alternating CO2 injection was 23.23%. In only nanofluid with a pH of 4.5 injection case, permeability damage was 47.53%. In the 2.8 pH nanofluid injection case, permeability damage was 31.01%. The retention of nanoparticles was confirmed through scanning electron microscopy and energy dispersive X-ray analysis. Permeability damage could be attributed to a large nanoparticles’ agglomeration size, roughness of pore surfaces, and nanoparticle sedimentation. The results of the study revealed that altering pH through the α-Al2O3 nanofluid alternating CO2 injection can effectively reduce the permeability damage of limestone.

In this paper, we present the investigation results of radiation-induced effects in metal-oxide-semiconductor (MOS) doped with moderate amounts of Zinc Oxide (ZnO) as a potential candidate for space-borne application. The samples were fabricated via the sputtering method at a working pressure of 3mTorr and a deposition temperature of 300oC. The ZnO samples were exposed to 1.25-MeV gamma-ray utilizing Co60 source, and their electronic response was measured at ionizing doses ranging from 10 kGy to 300 kGy. A comparative work was performed through finite element method to simulate the electronic response of the PN junction diode due to ionizing radiation. The results indicate that the ideality factor of the MOS diode increases as the ionizing dose increases, rendering it unsuitable for use as a diode. The degradation of the electrical parameters was also simulated, showing the increase in hole concentration. These findings suggest that the ejection of electrons occurred, which agrees with the gamma radiation effects trend. Furthermore, as the intensity of radiation increases, the spatial charge that arises from the separation of hole-electron pairs results in a substantial reduction of the electric field in the central portion of the n-type region. These findings provide insights into the degradation of electrical parameters in MOS devices under gamma radiation and have implications for their use in space-borne applications.

Fatigue in any material is a result of continuous irreversible degradation process. Traditionally, fatigue life is predicted by extrapolating experimentally curve fitted empirical models. In the current study, unified mechanics theory is used to predict fatigue life of Ti-6Al-4V under monotonic tensile, compressive and cyclic load conditions. The unified mechanics theory is used to derive constitutive model for fatigue life prediction using a three-dimensional computational model. The proposed analytical and computational models have been used to predict the low cycle fatigue life of Ti-6Al-4V alloys. It is shown that the unified mechanics theory can be used to predict fatigue life of Ti-6Al-4V alloys by using simple predictive models that are based on fundamental equation of the material, which is based on thermodynamics associated with degradation of materials.

Background: Increased DNA damage and the propension to cancer development, depend on the modulation of the mechanisms to control and maintain genomic integrity. Poly(ADP-Ribose)Polymerase activation and automodification are early responses to genotoxic stress. Upon binding to DNA strand breaks, the enzyme, a molecular DNA nick sensor, is hyperactivated: this is the first step in a series of events leading to either DNA repair or apoptosis. Enzyme hyperactivation and automodification can be easily measured and are widely used to look at DNA damage extent in the cell. We investigated whether these two markers (increased catalytic activity and auto modification), could help to monitor DNA damage in lymphocytes of flower growers from Southern Italy, occupationally exposed to pesticides. Methods: Peripheral lymphocyte lysates were analysed for Poly(ADP-Ribose) Polymerase activity, and by SDS-PAGE and anti-Poly(ADP-Ribose)Polymerase 1-antibody to measure automodified anti-Poly(ADP-Ribose) Polymerase levels by densitometry. Results: Poly(ADP-Ribose)Polymerase activity levels were consistent with those of enzyme auto-modification. Growers daily exposed to pesticides, showed both biomarkers very high, either in the presence or in the absence of pathologies. Conclusions: PARP activity and auto-modification in peripheral blood lymphocytes are possible,non-invasive, and routinar tools to monitor the healthy conditions of floricoltorists.

Abstract Eye health is crucial and the onset of diseases can reduce vision and affect the quality of life of patients. The main causes of progressive and irreversible vision loss include various pathologies such as cataracts, ocular atrophy, corneal opacity, age-related macular degeneration, uncorrected refractive error, posterior capsular opacification, uveitis, glaucoma, diabetic retinopathy, retinal detachment, undetermined disease and other disorders involving oxidative stress and inflammation. The eyes are constantly exposed to the external environment and, for this reason, must be protected from damage from the outside. Many drugs, including cortisonics and antinflammatory drugs have widely been used to counteract eye disorders. However, recent advances have been obtained via supplementation of patients with natural antioxidants and nutraceuticals. In particular, evidence has been accumulated that polyphenols (mostly deriving from Citrus Bergamia) represent a reliable source of antioxidants able to counteract oxidative stress accompanying early stages of eye diseases. Luteolin, in particular, has been found to protect foto-receptors thereby improving vision in many disease states. Moreover, a consistent anti-inflammatory response was found to occur when curcumin is used alone or in combination with other nutraceuticals. On the other hand, CoQ10 has been demonstrated to produce consistent effect in reducing ocular pressure thereby leding to protection in patients undergoing glaucoma. Finally, both grape seed extract rich in anthocyanosides and polynsatured fatty acids (PUFAs) seem to contribute in the prevention of retinal disorders. Thus, combination of nutraceuticals and anti-oxidants may represent the right solution for a multiaction activity in eye protection to be associated to current drug therapies, and this will be of potential interest in early stages of eye disorders.

It remains unclear in the literature what is the cause of the so-called alkali-carbonate reaction (ACR) damage to concrete yet, a consensus is reached when considering dedolimitization as non-expansive. However, expansion and cracks as distress features are often attributed to alkali-silica reaction (ASR) when evidence of a reactive mineral is found in the aggregate. Evidently, different types of aggregates may produce different types and degrees of damage. Therefore, this work aims to assess the damage to concrete generated and propagated by the so-called ACR susceptible reactive Kingston coarse aggregate through mechanical testing (i.e., direct shear test), microscopy (the damage rating index – DRI), and other techniques. Distinct induced expansion levels (i.e., 0%, 0.05%, 0.12%, and 0.20%) were selected to compare the distress caused by ACR to concrete affected by ASR. Result show that the behaviour of ACR, namely as captured through the DRI, is inconsistent with that of ASR thus attesting to ACR being a distinct distress mechanism.

The average age of in-service bridges has increased in recent years in the United States. To address this issue, structural health monitoring and damage identification approaches can be employed to prioritize maintenance/replacement of aging bridges. Among the damage identification and operational health monitoring approaches, finite element (FE) model updating methods can offer a solution to evaluate the mechanics-based characteristics of bridges. However, in a real-world setting, unidentifiability and mutual dependency between model parameters, modeling errors, especially due to boundary conditions, as well as ill-conditioning of updating algorithms can pose challenges to the application of FE model updating methods. To address these challenges, this study presents a two-step FE model updating approach. In the first step, modal-based model updating is used to estimate linear model parameters mainly related to the stiffness of boundary conditions and material properties. In the second step, in order to refine parameter estimation accounting for nonlinear response behavior of the bridge, a time-domain model updating is carried out. In this step, boundary conditions are fixed at their final estimates using modal-based model updating. To prevent the convergence of updating algorithm to local solutions, the initial estimates for nonlinear material properties are selected based on their corresponding final estimates in the modal-based model updating. To validate the applicability of the two-step FE model updating approach, a series of forced-vibration experiments are designed and carried out on a pair of decommissioned and deteriorated prestressed bridge I-girders. After carrying out the two-step FE model updating, the final estimates of concrete compressive strength are shown to provide reasonable assessment of the damage extent in the girders.

In this paper, we investigate the effects of mean stress, multiaxial loading, and residual stresses on the fatigue life of springs. We study the fatigue life of a homogeneously stressed material subjected to cyclic loading with nonzero mean stress. Traditional methods for estimating fatigue life are based on Goodman and HAIGH diagrams. The formal analytical descriptions, namely "stress-life" and "strain-life" approaches, are found to be more suitable for the numerical methods. The fatigue analysis method described above, which describes crack growth per cycle, is extended. The extensions allow consideration of the mean stress of a load cycle. Closed-form expressions for crack length versus number of cycles are derived. The complementary effects on the fatigue life of springs, which ultimately have a significant influence on the fatigue life of springs, are summarized. For the proposed unified fatigue life functions, the ranges for the stress loading factor are extended by introducing the effective stress intensity. The solution leads to the factor range for the effective stress intensity, the effective mean value of the stress intensity factor and the effective stress ratio. The developed method assumes the homogeneous stress state in the whole spring element. For the non-homogeneously loaded structural elements, the weak-link concept is applied to account for fatigue.

To achieve rapid post-earthquake repair of self-centering ribbed floor flat beam frame structures, a ductile hybrid joint consisting of dog bone weakened energy dissipating steel bars connected to the upper and lower column sections through high-strength threads based on the damage control design concept is proposed. By moving the ductile energy dissipating zone out to the locally weakened section of the energy dissipating steel bars and the locally unbonded prestressed steel bars in the core area, the residual deformation was limited and the seismic performance was improved. Based on the working principle of hybrid joints, low cycle loading tests were conducted on two joint specimens to analyze the influence of lateral prestress on the seismic performance of the hybrid joints. Numerical modeling methods were used to compare the position of the energy-consuming steel bars in the composite layer and the friction performance of joints. The research results indicated that the hybrid joint had stable load-bearing, deformation, and energy dissipation capabilities, with damage primarily concentrated on the energy-consuming steel bars. Even at an inter-story displacement angle of 5.5%, the upper and lower column segments remained elastic. After unloading, the connection seam at the joint was closed, and the self-centering performance was good. When the inter-story displacement angle reached 5.5%, the lateral prestress increased from 150 kN to 250 kN, the ultimate bearing capacity of the joint increased by 16.3%, and the cumulative energy consumption increased by 30.0%. The influence of the friction coefficient of the joint surface on the structural performance was set at a threshold of 0.7. When it was less than the threshold, the ultimate bearing capacity and initial stiffness of the joint increased with an increase in the friction coefficient. After reaching the threshold, the increase in the ultimate bearing capacity of the joint slowed down, and the rate of stiffness degradation gradually accelerated. This joint had excellent seismic performance and can also achieve post-earthquake repair of structures.

Background: One of the most astounding discoveries of recent times is the recognition that cancer embodies a transition from a higher level of metazoan cell organization to a more foundational pre-metazoic state. This shift is steered by genes housed within the ancestral genome compartment, pervasive across all metazoan genomes, encompassing humans, and governed by a pre-metazoic gene regulatory mechanism (aGRN). This work aims to highlight the emerging field of evolutionary cancer cell biology (ECCB), which points to the deep homology between cancer and protist life cycles tracing back to the common ancestor of amoebozoans, metazoans, and fungi (AMF). The ECCB analysis reveals the essence of the non-gametogenic germline of the AMF ancestor, which serves as a blueprint for all metazoan germlines and stem cell lineages and controls the life cycle of cancer. Every germ and stem cell lineage of humans and metazoans traces its lineage back to this Urgermline, transmitting crucial processes such as asymmetric cell cycling, differentiation, stemness, and phenomena like GST and SGT (aka EMT and MET) to their subsequent evolutionary descendants. Oxygen-sensitive germline and stem cells suffer DNA-DSB due to stress and oxygen ranges reminiscent of ancestral hyperoxia, leading to cell senescence. Cells that can overcome senescence can proliferate as DSCD cells with defective symmetric cell division, paving the way for malignancy and PGCC cancers. Conclusions: Understanding cancer from its evolutionary origins may help break some of the logjams in cancer prevention and open up new therapeutic pathways.

The appropriate maintenance of highway roads is critical for the safe operation of road networks and conserves maintenance costs. Multiple methods have been developed to investigate the surface of roads for various types of cracks and potholes, among other damage. Like road surface damage, the condition of expansion joints in concrete pavement is important to avoid unexpected hazardous situations. Thus, in this study, a new system is proposed for autonomous expansion joint monitoring using a vision-based system. The system consists of the following three key parts: (1) a camera-mounted vehicle, (2) indication marks on the expansion joints, and (3) a deep learning-based automatic evaluation algorithm. With paired marks indicating the expansion joints in a concrete pavement, they can be automatically detected. An inspection vehicle is equipped with an action camera that acquires images of the expansion joints in the road. You Only Look Once (YOLO) automatically detects the expansion joints with indication marks, which has a performance accuracy of 95%. The width of the detected expansion joint is calculated using an image processing algorithm. Based on the calculated width, the expansion joint is classified into the following two types: normal and dangerous. The obtained results demonstrate that the proposed system is very efficient in terms of speed and accuracy.

Coastal flooding exacerbated by climate change is recognised as a major global threat which is expected to impact more than a quarter of people currently residing in Pacific Islands countries. While most research in the last decade has focused on understanding the dynamics and impacts of future coastal flooding from extreme sea levels, relative sea level rise (RSLR) effects on tsunami hazards are not well understood. Far-field or distant-sourced tsunamis tend to have relatively lower impacts in Pacific Island states compared with locally sourced events, but there is limited understanding on how the impact of far-field tsunamis changes over time due to RSLR. Using the hydrodynamics software BG-Flood, we modelled the Tōhoku tsunami from propagation to inundation in Samoa under incremental SLR to examine the effects that RSLR has on changing the exposure of the built environment (e.g., buildings) to a far-field tsunami. Outputs of maximum tsunami inundation and flow depth intensities which incorporate incremental SLR were then combined with digital representations of buildings and depth-damage functions in the RiskScape multi-hazard risk modelling software to assess the changes in building exposure over time. Results indicate that present day buildings exposure in Samoa to a Tōhoku-oki type far-field tsunami will increase by approx. 600% with 1 m RSLR by 2080–2130, and approx. 2,350% with 2 m RSLR by 2130–2140. These findings provide a useful baseline for tsunami hazard risk assessment under changing sea level conditions in analogous island environments.

Damage in concrete structures initiates as the growth of diffuse microcracks that is followed by damage localisation and eventually leads to structural failure. Weak changes such as diffuse microcracking processes are failure precursors. Identification and characterisation of these failure precursors at an early stage of concrete degradation and application of suitable precautionary measures will considerably reduce the costs of repair and maintenance. To this end, a reduced order multiscale model for simulating microcracking-induced damage in concrete at the mesoscale levelis proposed. The model simulates the propagation of microcracks in concrete using a two-scale computational methodology. First, a realistic concrete specimen that explicitly resolves the coarse aggregates in a mortar matrix was generated at the mesoscale. Microcrack growth in the mortar matrix is modelled using a synthesis of continuum micromechanics and fracture mechanics. Model order reduction of the two-scale model is achieved using clustering technique. Model predictions are calibrated and validated using uniaxial compression tests performed in the laboratory.

The formation of high-melting-point Cu₆Sn₅ interconnections is crucial to overcome the collapse of Sn-based micro-bumps and produce reliable intermetallic interconnections in three-dimensional (3D) package. However, because of the multiple reflows in 3D package manufacturing, Cu₆Sn₅ interconnections will experience the cyclic polymorphic transitions in the solid state. The repeated and abrupt change in the Cu₆Sn₅ lattice due to the cyclic polymorphic transitions can cause extreme strain oscillations, producing damages at the surface and in the interior of the Cu₆Sn₅ matrix. Moreover, because of the polymorphic-transition-induced grain splitting and superstructure phase formation, the reliability of Cu₆Sn₅ interconnections will thus face great challenges in 3D package. In addition, the Cu₆Sn₅ polymorphic transition is structure-dependent, and the η′↔η polymorphic transition will occur at the surface while the η′↔ηs↔η polymorphic transition will occur in the deep matrix. Our results can provide in-depth understandings of structural evolution and damage mechanism of Cu₆Sn₅ interconnections in real 3D package manufacturing.

Timely detection of surface damages on wind turbine blades is imperative for minimising downtime and avoiding possible catastrophic structural failures. With recent advances in drone technology, a large number of high-resolution images of wind turbines are routinely acquired and subsequently analysed by experts to identify imminent damages. Automated analysis of these inspection images with the help of machine learning algorithms can reduce the inspection cost, thereby reducing the overall maintenance cost arising from the manual labour involved. In this work, we develop a deep learning based automated damage suggestion system for subsequent analysis of drone inspection images. Experimental results demonstrate that the proposed approach could achieve almost human level precision in terms of suggested damage location and types on wind turbine blades. We further demonstrate that for relatively small training sets advanced data augmentation during deep learning training can better generalise the trained model providing a significant gain in precision.

DNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer. Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs. Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated. This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair

Detection of early stage corrosion on slender steel members is crucial for preventing buckling failures of steel structures. An active photoacoustic fiber optic sensors (FOS) system has been reported for early stage steel corrosion detection of steel plates and rebars using surface ultrasonic waves. The objective of this paper is to investigate the surface corrosion/rust detection problem on steel rods using numerically simulated surface ultrasonic waves. The finite element method (FEM) is applied in simulating the propagation of ultrasonic waves on steel rod models. Transmission mode of damage detection is adopted, in which one source (transmitter) and one sensor (receiver) are considered. In this research, radial displacements at the receiver were simulated and analyzed by short-time Fourier transform (STFT) for detecting, locating, and quantifying a surface rust located between the transmitter and the receiver. From our time domain and frequency domain analyses, it is found that the presence, location, and dimensions (length, width, and depth) of surface rust can be estimated by ultrasonic waves propagating through the surface rust.

The evaluation of geometric defects is necessary in order to maintain the integrity of structures over time. These assessments are designed to detect damages of structures and ideally help inspectors to estimate the remaining life of structures. Current methodologies for monitoring structural systems, while providing useful information about the current state of a structure, are limited in the monitoring of defects over time and in linking them to predictive simulation. This paper presents a new approach to the predictive modeling of geometric defects. A combination of segmented from point clouds are parametrized using the convex hull algorithm to extract features from detected defects, and a stochastic dynamic model is then adapted to these features to model the evolution of the hull over time. Describing a defect in terms of its parameterized hull enables consistent temporal tracking for predictive purposes, while implicitly reducing data dimensionality and complexity as well. In this study, 2D point clouds analogous to information derived from point clouds were first generated over simulated life-cycles. The evolutions of point cloud hull parameterizations were modeled as stochastic dynamical processes via autoregressive integrated moving average (ARIMA) and vectorized autoregression (VAR) and compared against ground truth. The results indicate that this convex hull approach provides consistent and accurate representations of defect evolution across a range of defect topologies and is reasonably robust to noisy measurements, however assumptions regarding the underlying dynamical process play a significant the role in predictive accuracy. The results were then validated on experimental data from fatigue testing with high accuracy. Longer term, the results of this work will support finite element model updating for predictive analysis of structural capacity.

The past is an important lesson for facing the future with greater awareness. In this context, school plays a key role to spread knowledge on natural phenomena and to promote behavior change. Together with researchers, teachers can be strong allies to build more resilient future citizens. The Istituto Nazionale di Geofisica e Vulcanologia (INGV) school training activities provide tools to get ready for the next earthquake and/or tsunamis. About 5000 students from both Middle schools (ISCED 2) and High schools (ISCED 3) were involved in active learning activities based on a flipped-up approach during special online scientific events in the Pandemic. Online lab activities were conducted respectively during the European Researchers’ Night (“Earthquakes: history teaches us the future: researchers for a day with experimentation in didactics for ESL”) and during the World Water Day 2021 and the World Earth Day 2021 (“Tsunamis: history teaches us the future researchers for a day with experimentation in didactics for ESL”). These two Episodes of Situated Learning (ELS) experiences triggered students’ interest, favoring remote learning, developing life skills, focusing on historical seismic studies of both past earthquakes and tsunamis.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of DIPG tumors contain a specific K27M mutation in one of two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p<0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p<0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system and their interplay and therefore potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Windthrow (i.e., trees broken and uprooted by wind) is a major natural disturbance in the Amazon. Images from medium-resolution optical satellites (mostly Landsat) combined with extensive field data have allowed researchers to assess patterns of tree mortality and monitor forest recovery over decades of subsequent succession in different regions. Although satellites with high spatial-resolution have become available for the Amazon in the last decade, they have not yet been employed for the mapping and quantification of windthrow tree-mortality. Here, we address how increasing the spatial resolution of satellites affects plot-to-landscape estimates of windthrow tree-mortality. We combined forest inventory data with Landsat 8 (30 m pixel), Sentinel 2 (10 m), and WorldView 2 (2 m) imagery over an old-growth forest in the Central Amazon that was disturbed by a single windthrow event in November/2015. Remote sensing estimates of tree mortality were produced with Spectral Mixture Analysis and analyzed together with forest inventory data using Generalized Linear Models. Windthrow tree-mortality measured in 3 transects (30 subplots) crossing the entire disturbance gradient was 26.9 ± 11.1% (mean ± 95% CI). Based on this ground truth, the three satellites produced reliable and statistically similar estimates (from 26.5% to 30.3% windthrow tree-mortality, p&lt;0.001). The mean-associated uncertainties decreased systematically with increasing spatial resolution (i.e., from Landsat 8 to Sentinel 2 and WorldView 2). However, the overall quality of fit of models showed the opposite pattern, which may reflect the influence of crown damage not accounted for in our field study, and fast-growing regeneration of leaf area. Among the satellites studied, Landsat 8 most accurately captured field observations of variations in tree mortality across the disturbance gradient (i.e., lower under- and/or overestimation from undisturbed to extremely damaged forest). Although satellites with high spatial-resolution can refine estimates of windthrow severity by allowing the quantification of individual tree damage and mortality, our results validate the reliability of Landsat imagery for assessing patterns of windthrow tree-mortality in dense and heterogeneous tropical forests. Although high-resolution imagery may improve estimates of tree damage and mortality, these should be validated using field data at compatible scales.

The successive waves of the Covid-19 pandemic are driven by SARS-CoV-2 variants that reached critical detection levels in different parts of the world. But how evolved the Wuhan virus since its detection in December 2019 into the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529) variants of concern? This is a story of mice and men, of up to 1,000,000 infected cells in one person, where each cell produces between 10⁵ and 10⁶ viral RNAs, of immune-compromised patients, the digestive tract and viral recombination.

The angle of seismic excitation is a significant factor of the seismic response of RC buildings. The procedure required for the calculation of the angle for which the potential seismic damage is maximized (critical angle) contains multiple nonlinear time history analyses using in each one of them different angles of incidence. Moreover, the seismic codes recommend the application of more than one accelerograms for the evaluation of seismic response. Thus, the whole procedure becomes time consuming. Herein, a method to reduce the time required for the estimation of the critical angle based on Multilayered Feedforward Perceptron Neural Networks is proposed. The basic idea is the detection of cases in which the critical angle increases the class of seismic damage compared to the class which arises from the application of the seismic motion along the buildings’ structural axes. To this end, the problem is expressed and solved as Pattern Recognition problem. As inputs of networks the ratios of seismic parameters’ values along the two horizontal seismic records' components, as well as appropriately chosen structural parameters, were used. The results of analyses show that the neural networks can reliably detect the cases in which the calculation of the critical angle is essential.

Keywords: underground engineering; numerical simulation; excavation length effect, major principal stress; displacement; damage initiation; CPU time

Ultrasonic measurements are used in civil engineering for structural health monitoring of concrete infrastructures. The late portion of the ultrasonic wavefield, the coda, is sensitive to small changes in the elastic moduli of the material. Coda Wave Interferometry (CWI) correlates these small changes in the coda with the wavefield recorded in intact, or unperturbed, concrete specimen to reveal the amount of velocity change that occurred. CWI has the potential to detect localised damages and global velocity reductions alike. In this study, the sensitivity of CWI to different types of concrete mesostructures and their damage levels is investigated numerically. Realistic numerical concrete models of concrete specimen are generated and damage evolution is simulated using the discrete element method. In the virtual concrete lab, the simulated ultrasonic wavefield is propagated from one transducer using a realistic source signal and recorded at a second transducer. Different damage scenarios reveal a different slope in the decorrelation of waveforms with the observed reduction in velocities in the material. Finally, the impact and possible generalizations of the findings are discussed and recommendations are given for a potential application of CWI in concrete at structural scale.

Rapid Visual Screening (RVS) is a procedure that estimates structural scores for buildings and prioritize their retrofit and upgrade requirements. Despite the speed and simplicity of RVS, many of the collected parameters are non-commensurable and include subjectivity due to visual observations. It might cause uncertainties in the evaluation, which emphasizes the use of a fuzzy-based method. This study aims to propose a novel RVS methodology based on the interval type-2 fuzzy logic system (IT2FLS) to set the priority of vulnerable building to undergo detailed assessment while covering uncertainties and minimizing their effects during evaluation. The proposed method estimates the vulnerability of a building, in terms of Visual Damage Index, considering the number of stories, age of building, plan irregularity, vertical irregularity, building quality, and peak ground velocity, as inputs with a single output variable. Applicability of the proposed method has been investigated using a post-earthquake damage database of 28 reinforced concrete buildings from the Bingöl earthquake in Turkey.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions suggesting a mechanism for spontaneous HBV DNA disperse throughout hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions indicating their creation by non-homologous-end-joining (NHEJ). Their formation coincided with robust oxidative damage of hepatocyte DNA. This was associated with activation of the poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair as reflected by augmented transcription of PARP1 and XRCC1, the PARP1 binding partner, OGG1, a responder to oxidative DNA damage, and by increased activity of NAD+, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains HTJ format of the initial merges. The findings showed that HBV and WHV are immediate inducers of oxidative DNA damage, hijack dsDNA repair to integrate into hepatocyte genome and by this may initiate pro-oncogenic process. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.

Extracellular vesicles (EVs) represent a heterogeneous population of small vesicles, consisting of a phospholipidic bilayer surrounding a soluble interior cargo. Almost all cell types release EVs, thus they are naturally present in all body fluids. Among the several potential applications, EVs could be used as drug delivery vehicles in disease treatment, in immune therapy because of their immunomodulatory properties and in regenerative medicine. In addition to general markers, EVs are characterized by the presence of specific biomarkers (proteins, miRNAs) that allow the identification of their cell- or tissue-origin. For these features, they represent a potential powerful diagnostic tool to monitor state and progression of specific diseases. As regards, a large body of studies supports the idea that endothelial derived (EMPs) together with platelet-derived microparticles (PMPs) are deeply involved in the pathogenesis of diseases characterized by micro- and macrovascular damages, including diabetes. Existing literature suggests that the detection of circulating EMPs and PMPs and their specific miRNA profile may represent a very useful non-invasive signature to achieve informations about the onset of peculiar disease manifestations. In this Review, we discuss the possible utility of EVs in the early diagnosis of diabetes-associated microvascular complications, specifically related to kidney.

In this paper, quasi-static axial compression tests are performed on the nodal Moso bamboos to study the size effect on energy absorption of the bamboos and the damage pattern of the multiple bamboo columns. Experimental results show that under the same moisture content, growth age and growing environment, the specific energy absorption (SEA) of the test samples increases with the increase of the out-diameter and thickness of the bamboo columns, indicating that size effect exists for energy absorption of the Moso Bamboos. For the multiple bamboo columns, there are mainly three failure modes for the constituent single bamboo columns: splitting above the node, splitting below the node and splitting through the node. Also, the tensile tests are conducted on three kinds of dog-bone shaped bamboo samples to investigate the macroscopic tensile fracture mode in the longitudinal direction of Moso bamboos. Results show that there is no direct relationship between the fracture pattern and moisture content of the bamboos, as well as the growth age of the bamboos. However, the tensile loading rate and the shape of the dog-bone shaped bamboo sample could affect the macroscopic fracture pattern of the bamboos in some cases.

ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.

The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origin is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45-MCM2-7-GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases such as DNA polymerase α-primase (Pol α), DNA polymerase δ and ε at replication forks play pivotal roles in the mechanism of initiation reactions including the initiation of signalling unperturbed and stalled replication forks, ‘replication stress’ events, via ATR (ATM-Rad 3-related protein kinase). All these processes are essential for the accurate transfer of the cells’ genetic information to their daughters. Failures and dysfunctions in these processes gives rise to genome instability followed by genetic diseases including cancer. Thus, in their review ‘Hallmarks of Cancer: New Dimensions‘ Hanahan and Weinberg (2022) called genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels which will be discussed in the review.

Replication protein A (RPA) is a heterotrimeric protein complex and the main single-stranded DNA (ssDNA) binding protein in eukaryotes. RPA has key functions in most of the DNA-associated metabolic pathways and DNA damage signalling. Its high affinity for ssDNA helps to stabilise ssDNA structures and prevents the DNA sequence from nuclease attacks. RPA consists of multiple DNA-binding domains which are oligonucleotide/oligosaccharide-binding (OB)-folds, responsible for DNA binding, and interactions with proteins. These RPA-ssDNA and RPA-protein interactions are crucial for DNA replication, DNA repair, DNA damage signalling, and the conversation of the genetic information of cells. Proteins such as ATR use RPA to locate to regions of DNA damage for DNA damage signalling. Recruitment of nucleases and DNA exchange factors to sites of double strand breaks are also an important RPA function to ensure effective DNA recombination to correct these DNA lesions. Due to its high affinity to ssDNA, RPA’s removal from ssDNA is of central importance to allow these metabolic pathway to proceed and processes to exchange RPA against downstream factors are established in all eukaryotes. These facetted and multi-layered functions of RPA will be discussed in detail in the review. RPA is also a major player in a variety of human diseases, which will be discussed.

Ultrasonic-guided lamb wave approach is an effective non-destructive testing (NDT) method used for detecting localized mechanical damage, corrosion, and welding defects experienced in metallic pipelines. Signal processing of the guided waves is often challenged due to the complexity of operational conditions and environments in the pipelines. Machine learning approaches in recent years, including convolutional neural networks (CNN) and long short-term memory (LSTM), have exhibited their advantages to overcome these challenges for signal process and data classification of complex systems, thus great potential for damage detection of critical oil/gas pipeline structures. In this study, a CNN-LSTM hybrid model is utilized for decoding ultrasonic guided waves for damage detection of metallic pipelines, and twenty-nine features are extracted as input to classify different types of defects from metallic pipes. The prediction capacity of the CNN-LSTM model is assessed by comparing it to the CNN and LSTM. The results demonstrate that the CNN-LSTM hybrid model exhibits much higher accuracy, with 94.8%, as compared to those of CNN and LSTM. Interestingly, the results also reveal that predetermined features, including time-, frequency-, and time-frequency domains, could significantly improve the robustness of the deep learning approaches, even though the deep learning approaches are often believed they include automated feature extraction, without the hand-crafted steps as the shallow learning do. Furthermore, the CNN-LSTM model displays higher performance when the noise level is relatively low (e.g., SNR=9 or higher), as compared to the other two models, but its prediction drops gradually with the increase of the noise.

DNA double-strand breakage is the most lethal damage to chromosomal DNA. It activates a series of cellular DNA damage response pathways, including DNA damage sensing, control of cell cycle arrest and apoptosis, and DNA repair. DNA damage response pathways are regulated by complex signaling machineries. Of the intracellular signaling cascades, diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Because both DG and PA serve as second messengers, DGK activity induces a shift of signaling pathways from DG-mediated to PA-mediated cascades, thereby implicating DGK in the regulation of widely various functions. Reportedly, one member of the DGK family, DGKζ, is intimately involved in the regulation of stress responses through p53 and NF-κB. Stresses such as ischemia and infarction cause DGKζ downregulation. Experimental DGKζ depletion renders cells and mice vulnerable to various stressors such as chemotherapeutic agents and ionizing irradiation. Nevertheless, how DGKζ is involved in DNA repair, a critical event of DNA damage response for survival remains unknown. For this study, we examined how DGKζ depletion affects DNA repair mechanisms. We demonstrated that DGKζ depletion causes attenuation of Akt activation and DNA-PK protein expression upon DNA damage, which might engender downregulated BRCA1 protein synthesis and stability. Results suggest that DGKζ depletion attenuates BRCA1-mediated DNA repair machinery, thereby conferring vulnerability to DNA damage.

To study the strengthening effect on recycled concrete columns by carbon fiber composite materials (CFRP) under different levels of seismic damage, four column specimens were designed for pseudo-static tests. The four specimens were respectively non-destructive without strengthening (prototype), non-destructive strengthening, medium seismic damage strengthening and severe seismic damage strengthening, according to the replacement rate of recycled aggregates and the level of seismic damage. The characteristics of the deformation damage and seismic performance indicators of each specimen were compared and analyzed. A decrease was observed in the initial stiffness of the seismically damaged recycled concrete column specimens strengthened with CFRP, while the ductility, peak bearing capacity and energy dissipation capacity of the specimens were improved. On the other hand, with the reduction of seismic damage and the increase of recycled aggregate replacement rate, the ductility and energy dissipation capacity of the reinforced seismic damaged recycled concrete column specimens were enhanced to different levels. In particular, the cumulative energy consumption of the strengthened specimens under medium seismic damage increased most significantly by 32.5%. In general, the hysteretic curves of the strengthened specimens were full, and the average ductility coefficients were 4.1–6.8. CFRP strengthening was more effective in restoring and enhancing the performance of the recycled concrete column specimens with medium and lower seismic damage levels (displacement ratio ≤ 3%).

The dynamic response of structural elements subjected to blast loading is a problem of growing interest in the field of defense and security. In this work, a novel computational tool for the rapid evaluation of the effects of explosions, hereafter referred as SimEx, is presented and discussed. The classical correlations for the reference chemical (1 kg of TNT) and nuclear (106 kg of TNT) explosions, both spherical and hemispherical, are used together with the blast wave scaling laws and the International Standard Atmosphere (ISA) model to compute the dynamic response of Single-Degree-of-Freedom (SDOF) systems subject to blast loading. The underlying simplifications in the analysis of the structural response follow the directives established by UFC 3-340-02 and the Protective Design Center Technical Reports of the US Army Corps of Engineers, which offer useful estimates with a low computational cost, enabling in particular the computation of damage diagrams in the Charge Weight-Standoff distance (CW-S) space for the rapid screening of component (or building) damage levels. SimEx is a computer application based on Matlab and developed by the Fluid Mechanics Research Group at University Carlos III of Madrid (UC3M), which has been successfully used for both teaching and research purposes in the Degree in Security Engineering, taught to the future Guardia Civil officers at the Spanish University Center of the Civil Guard (CUGC). This dual use has allowed the development of the application well beyond its initially objective, testing on one hand the implemented capacities by undergraduate cadets with end-user profile, and implementing new functionalities and utilities by Masters and PhD students. With this experience, the application has been continuously growing since its initial inception in 2014 both at a visual and a functional level, including new effects in the propagation of the blast waves, such as clearing and confinement, and incorporating new calculation assistants, such as those for the thermochemical analysis of explosive mixtures; crater formation; fragment mass distributions, ejection speeds and ballistic trajectories; and the statistical evaluation of damage to people due to overpressure, body projection, and fragment injuries.

Recent technological improvements have made abundant changes in construction industry. In specific, some technical applications, such as Building Information Modeling (BIM) opens up many possibilities. Some studies have articulated the use of BIM and its advantages in construction, but most of them are theoretical, not practical. This study is to provide an insight to such obstacles in BIM research. By investigating a real project that could utilize BIM in planning and construction phases, the authors try to investigate a possible outline of advantages in BIM implementation. The study area was set to a railway construction site in South Korea. The site covers a multiple railway tracks, stations, telecommunication facilities, infrastructure facilities, railway structures, and so numerous. In the site, the authors have identified 12 errors in 7 projects that could be prevented if BIM was utilized before the construction. The total upfront costs required to provide a BIM for 7 projects were $116,348. On the other hand, the total costs required to fix the errors in 7 projects were $166,486. This can be regarded as the benefits of using BIM because if BIM was implemented then the associated errors are easily replaced. Therefore, the benefit-cost ratio can be estimated as 1.32 for one-month delay and 1.36 for a three-month delay.

The Siret River crosses NE Romania from the north to the south and it discharges into the Danube, near the city of Galati. During the period, 17^th June - 10^th July 2010, significant amounts of precipitations in the mountainous basin of Siret were recorded. The floods comprised two periods with four bimodal cycles and they were counted among the strongest on the Romanian territory. The exceptional floods occurred in the rivers of Siret, Suceava, Moldova, Bistrita, Trotus and so on. The most important compound flood wave was determined by the precipitations which fell within the period, 29^th June to 1^st July 2010, when significant amounts of rain were recorded, sometimes, exceeding 80 mm. The high discharges on the Bistrita River – downstream from the Bicaz Reservoir – were controlled by complex hydro technical works. The maximum discharge for the year 2010 summer floods was recorded at Dragesti hydrometric station: 2,884 m³/s (historic discharge) compared to the preceding historic discharge of the year 2008 (2,850 m³/s). The effects of floods were strongest in the counties of Suceava, Neamt, and Bacau. The floods on the main course of the Siret River were analyzed in correlation with the tributaries within the mountainous sector.

Translation is spatiotemporally regulated and ER-associated mRNAs are generally in efficient translation. It is unclear whether the ER-associated mRNAs are deadenylated or degraded on the ER surface in situ or in the cytosol. Here, we showed that ER possessed active deadenylases, particularly the poly(A)-specific ribonuclease (PARN), in common cell lines and mouse tissues. Consistently, purified recombinant PARN exhibited a strong ability to insert into the Langmuir monolayer and liposome. ER-anchored PARN was found to be able to reshape the poly(A) length profile of the ER-associated RNAs by suppressing long poly(A) tails without significantly influencing the cytosolic RNAs. The shortening of long poly(A) tails did not affect global translation efficiency, suggesting that the non-specific action of PARN towards long poly(A) tails was beyond the scope of translation regulation on the ER surface. Transcriptome sequencing analysis indicated that the ER-anchored PARN trigged the degradation of a small subset of ER-enriched transcripts. The ER-anchored PARN modulated the translation of its targets by redistributing ribosomes to heavy polysomes, suggesting that PARN may play a role in dynamic ribosome reallocation. During DNA damage response, MK2 phosphorylated PARN-Ser557 to modulate PARN translocation from the ER to cytosol. By promoting the decay of ER-associated MDM2 transcripts with low ribosome occupancy, the ER-anchored PARN modulated DNA damage response and thereby cell viability. These findings revealed that a highly regulated communication between mRNA degradation rate and translation efficiency is present on the ER surface in situ and that PARN may contribute to this communication by modulating the dynamic ribosome reallocation between transcripts with low and high ribosome occupancies.

Radiation therapy (RT) is one of the main approaches of cancer therapy, including non-small cell lung cancer (NSCLC). Radiation-induced DNA double-stranded breaks (DSBs), single-stranded DNA breaks (SSBs) and oxidized nucleobases cause replication fork stalling, chromosomal instability or point mutagenesis and can lead to cell death. Translesion DNA synthesis (TLS) is one of the DNA damage tolerance (DDT) pathways promoting replication of damaged DNA. Here, we explored the effects of the knockout of primase-polymerase PRIMPOL (PRIMPOL −/−) and TLS polymerase POLI (POLI −/−) genes in two different monoclonal lines derived from human NSCLC A549 cells. Our study aimed to investigate the impact of their absence on the susceptibility of these cells to ionizing radiation (IR)-induced stress. Without IR, cells that do not have PRIMPOL or POLI experience a considerable rise in apoptosis by day 7 of continuous cultivation and a noteworthy decline in cell migration under spatial confinement when compared to the parental wild-type cells. Despite this, we have found that PRIMPOL −/− exhibited higher clonogenic survival compared to wild-type cell lines in response to IR stress. Both of these cell lines demonstrated remarkable resilience to radiation stress, surpassing the survival rate of the original A549 cells. POLI deficiency reduces cellular γH2AX foci accumulation, while the presence of highest number of γH2AX foci in PRIMPOL−/− cells was ATM-independent. We report for the first time that increased post-irradiation clonogenic survival of PRIMPOL −/− A549 cells might be associated with the increase of CD133+ but not CD44+ populations of cancer stem-like cells.

Rapid post-earthquake damage diagnosis of bridges can guide decision-making for emergency response management and recovery. This can be facilitated using digital technologies to remove the barriers of manual post-event inspections. Prior mechanics-based Finite Element (FE) models can be used for post-event response simulation using the measured ground motions at nearby stations; however, the damage assessment outcomes would suffer from uncertainties in structural and soil material properties, input excitations, etc. For instrumented bridges, these uncertainties can be reduced by integrating sensory data with prior models through a model updating approach. This study presents a sequential Bayesian model updating technique, through which a linear/nonlinear FE model, including soil-structure interaction effects, and the foundation input motions are jointly identified from measured acceleration responses. The efficacy of the presented model updating technique is first examined through a numerical verification study. Then, seismic data recorded from the San Rogue Canyon Bridge in California are used for a real-world case study. Comparison between the free-field and the foundation input motions reveals valuable information regarding the soil-structure interaction effects at the bridge site. Moreover, the reasonable agreement between the recorded and estimated bridge responses shows the potentials of the presented model updating technique for real-world applications. The updated FE model is considered as the digital twin of the bridge and can be used to analyze the bridge and monitor the structural response at element, section, and fiber levels to diagnose the location and severity of any potential damage mechanism.

The effectiveness of a recently proposed methodology in the identification of damage in planar, multi-storey, Reinforced Concrete (RC) moment-frames, which develop a plastic-yield mechanism on their beams, is showcased here via the examining of a group of such existing multi-storey frames with three or more unequal spans. According to the methodology, the diagram of the instantaneous Eigen-Frequencies of the frame in the nonlinear regime is drawn as a function of the inelastic seismic roof displacement by performing a sequence of pushover and instantaneous modal analyses with gradually increasing target displacement. Using this key-diagram, the locations of severe seismic damage in an existing moment-frame can be evaluated if the instantaneous fundamental eigen-frequency of the damaged frame, at an analysis step within the nonlinear area, is known in advance by “the monitoring and the identification of frequencies” using a local network of uniaxial accelerometers. This is a hybrid technique because both procedures, the instrumental Monitoring of the structure and the Pushover analysis on the frame (M and P technique), are combined. Moreover, the damage image of the planar multi-storey moment-frame is illustrated, and the lateral stiffness matrix of the damaged frame is calculated with high accuracy.

In the process of use and manufacture, carbon fiber foam sandwich structures were often damaged by low-energy impact, resulting in performance degradation. Therefore, it was necessary to study the damage caused by low-speed impact of composite sandwich structures. In this paper, based on Hashin failure criterion, an equivalent finite element model of carbon fiber foam sandwich panel under low velocity impact was established. The model was used to simulate the damage of foam sandwich panel with [±45°/±45°/ (core) /±45°/±45°] ply structure under the impact energy of 10.58J, 21.17J, 31.75J and 42.34J. The simulation results of impact damage depth were compared with the experimental results. The error was less than 10%, which proved the rationality of the impact equivalent model. The model was used to predict and analyze the damage of foam sandwich panels with [±45°/ (core) /±45°], [±45°/ (0°, 90°) / (core) /±45°] and [±45°/ (0°, 90°) (core) / (0°, 90°) /±45°] ply structures under 21.17J impact energy. By comparing and analyzing the damage situation, impact force response time and impact velocity response time, the low energy impact resistance was analyzed. The results showed that increasing the number of ply structure of [±45°] can reduce the impact damage degree and improve the bearing capacity of sandwich panels.

Premature failure and degradation of layers are the main problems for transportation infrastruc-ture. Addressing these issues necessitates implementing structural health monitoring (SHM) for transportation layers. This strategic approach is instrumental in mitigating maintenance expenses, prolonging the operational lifespan, and preventing accidents resulting from abrupt layer col-lapse. To this end, this research investigated the stress/strain and damage detection capabilities of a self-sensing cementitious composite developed for potential utilization in the construction of an intelligent subgrade layer. The prepared self-sensing cementitious composite consisted of 10% cement and hybrid conductive fillers, including multiwalled carbon nanotubes (MWCNTs) and graphene nanoplatelets (GNPs) in sand. Initial findings reveal that the electrical resistivity of the composite is significantly affected by the concentration of MWCNTs/GNPs, with a minimum concentration of more than 0.5% needed to achieve a responsive cementitious composite. More-over, the piezoresistive analysis indicates that an increase in the concentration of MWCNTs/GNPs and stress levels leads to an improvement in the stress/strain sensing perfor-mance. When the self-sensing cementitious composite is subjected to equivalent stress levels, variations in the FCR exhibit an increasing trend with decreasing resilient modulus, stemming from a decrease in stiffness due to the increased concentration of MWCNTs/GNPs. Additionally, the EIS analysis demonstrates a contraction for the Nyquist curves under compressive ramp loading prior to failure, followed by the expansion of these curves postfailure. Scanning electron microscopy (SEM) images visually showcase the bridging effects of MWCNTs and the filling ef-fects of GNPs within the composite structure.

Pathological aseptic calcification is the most common form of structural valvular degeneration (SVD), leading to premature failure of heart valve bioprostheses (BHVs). The processing methods used to obtain GA-fixed pericardium-based biomaterials determine the hemodynamic characteristics and durability of BHVs. This article presents a comparative study of the effects of several processing methods on the degree of damage to the ECM of GA-fixed pericardium-based biomaterials as well as on their biostability, biocompatibility, and resistance to calcification. Based on the assumption that preservation of the native ECM structure will enable the creation of calcinosis-resistant materials, this study provides a soft biomimetic approach for the manufacture of GA-fixed biomaterials using gentle decellularization and washing methods. It has been shown that the use of soft methods for preimplantation processing of materials, ensuring maximum preservation of the intactness of the pericardial ECM, radically increases the resistance of biomaterials to calcification. The data obtained are of interest for the development of new calcinosis-resistant biomaterials for the manufacture of BHVs.

This paper focuses on parametric model order reduction (PMOR) of guided ultrasonic wave propagation and its interaction with damage in a fiber metal laminate (FML). Structural health monitoring in FML seeks to detect, localize and characterize the damage with high accuracy and minimal use of sensors. This can be achieved by the inverse problem analysis approach which employs the signal measurement data recorded by the embedded sensors in the structure. The inverse analysis requires to solve the forward simulation of the underlying system several thousand times. These simulations are often exorbitantly expensive and triggered the need for improving their computational efficiency. A PMOR approach hinged on the proper orthogonal decomposition method is presented in this paper. An adaptive parameter sampling technique is established with the aid of a surrogate model to efficiently update the reduced-order basis in a greedy fashion. A numerical experiment is conducted to illustrate the parametric training of the reduced-order model. The results show that the reduced-order solution based on the PMOR approach is accurately complying with that of the high fidelity solution.

Unavoidable exposure to radiosensitive normal tissues around cancerous tumor during the radiotherapy can cause side effects such as self-limited acute toxicities, mild chronic symptoms, or severe organ dysfunction. Nevertheless, clinical use of currently available radiation protective agents is limited because of their generic cytotoxicity. A study on radiation protective effect of delphinidin was conducted with proton-beam-exposed human colon cells (CCD-18Co). The measurement in changes of survival fractions of CCD-18Co with/without delphinidin administration at different radiation doses were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. The changes in expression of reactive oxygen species (ROS) and in activities of antioxidant enzymes were measured by colorimetric assays using pertinent assay kits. The measurement of pro-apoptosis/pro-survival protein expressions using Western blot assay and the measurement of DNA damage using comet assay were also fulfilled to evaluate the molecular level of radiation damages in CCD-18Co cells. The experimental results revealed that the pre-administration of delphinidin regulated antioxidant enzymes, reduced ROS, decreased DNA damage, regulated pro-apoptosis/pro-survival proteins, and eventually reduced apoptosis of CCD-18Co cells. In conclusion, it is claimed that delphinidin is nontoxic natural radiation protective compound, and thus delphinidin can be used to protect normal colon tissues during the proton beam therapy.

This study proposes a machine-learning-based framework for detecting mechanical damage in pipelines, utilizing physics-informed datasets collected from simulations for mechanical damage. The framework provides an effective workflow from dataset generation to damage detection and identification for three types of pipeline events: welds, clamps, and corrosion defects. While the study initially focused on optimizing the CNN structure using various advanced optimizers, it also investigated the impact of sensing systems on data classification and the effect of noise on classification performance. The study's analysis highlights the importance of selecting the appropriate sensing system for the specific application. The authors also found that the proposed framework is robust to experimentally relevant levels of noise, suggesting its applicability in real-world scenarios where noise is present. Overall, this study contributes to the development of a more reliable and effective method for detecting mechanical damage in pipelines. The proposed framework provides an effective workflow for damage detection and identification, and the findings on the impact of sensing systems and noise on classification performance add to its robustness and reliability.

The genetic pool of valuable old ornamental cultivars and their in situ maintenance may be threated by climate change. Meanwhile, the ornamental plants like roses make up an important share of both gardens and urban green spaces, where they are particularly vulnerable to multistress growth conditions. The aim of this research was to evaluate the effect of changing climatic conditions on growth and flowering of 11 historic climber roses through long-term studies (2000-2017) conducted in Central Europe. The evaluation of plants consisted of assessment of frost damage and the timing of early phenological stages (starting of bud break, leaf unfolding) as well as gathering data on beginning, fullness and end of flowering and its abundance. Frost damage was not recorded in any year only in ‘Mme Plantier’, and did not occur for any cultivar after the winter in the years 2007, 2008, and 2014. Only a little damage to one-year shoots was recorded after the winter in the years 2015-2017. Frost damage to ‘Alberic Barbier’, ‘Albertine’, ‘Chaplin's Pink Climber’, ‘Orange Triumph clg’ and ‘Venusta Pendula’ led to pruning to ground level in every year excluding those listed above. Frost damage of once blooming roses limited their flowering; however, the many-year data-sets showed a trend for decreased frost damage and improved abundance of flowering, and these results can be interpreted as a response to the increase of average air temperature. The timing of bud breaking and leaf development in all climber roses was strictly correlated with average air temperature in the dormancy period. The reactions of climber roses to weather conditions confirmed the influence of climatic changes on ornamental crop plants in Central Europe, introducing the potential possibility for the wider application of climber roses, but without certainty of flowering every year.

Fixed offshore wind turbines continue to be developed for high latitude areas where not only wind and wave loads need to be considered, but also moving sea ice. Current rules and regulations for the design of fixed offshore structures in ice-covered waters do not adequately consider effects of ice loading and its stochastic nature on fatigue life of the structure. Ice crushing on such structures results in ice-induced vibrations, which can be represented by loading the structure using a variable-amplitude loading (VAL) sequence. Typical offshore load spectra are developed for wave and wind loading. Thus, a combined VAL spectrum is developed for wind, wave, and ice action. To this goal, numerical models are used to simulate the dynamic ice-, wind-, and wave-structure interaction. The stress time-history at an exemplarily selected critical point in an offshore wind energy monopile support structure is extracted from the model and translated into a VAL sequence, which can then be used as a loading sequence for the fatigue assessment or fatigue testing of welded joints of offshore wind turbine support structures. This study presents the approach to determine combined load spectra and standardized time series for wind, wave, and ice action.

Neurodegeneration is a major problem in neuroscience and medicine as it causes and worsens many neurological and psychiatric disorders. It involves gradual loss of neurons at different levels of the brain, affecting cognition, emotion, behavior, consciousness, and attention. Understanding the causes and consequences of neurodegeneration is crucial for identifying the risk factors, biomarkers, and treatments. However, the current therapies are mostly symptomatic and ineffective. Therefore, new and innovative methods, such as noninvasive brain stimulation (NIBS), are needed to modulate brain activity and plasticity in a safe and reversible manner. This field is rapidly developing, with a focus on exploring new clinical applications, mechanisms, and combinations of NIBS and drugs. This special issue covers the latest progress and challenges in the study of neurodegeneration in cognitive impairment and mood disorders from the experimental, clinical, and translational perspectives. It addresses the complexity and diversity of these conditions, the lack of disease-modifying treatments, the ethical and practical issues of conducting research in vulnerable and diverse populations, the integration and interpretation of data from multiple sources and modalities, and the development and validation of novel methods such as NIBS, artificial intelligence, and drug repurposing. Collaborative efforts among various stakeholders are needed to improve our knowledge and treatment of neurodegeneration underlying cognitive impairment and mood disorders.

In order to study the collapse failure of shaft wall of high depth inclined ore-pass under ore impact wear behavior, 25 ore-passes in a deep mine in Yunnan, China were investigated. Considering the ore-pass structural characteristics and the impact wear effect of ore on shaft wall, the shaft wall damage model of high depth inclined ore-pass is constructed based on the contact mechanics theory. Furthermore, No. 1#, 2#, 3# and 9# ore-passes of the mine are taken as examples for analysis, and the three results of theoretical analysis, numerical simulation and engineering case are used for comparison and verification. The shaft wall damage degree is predicted, and the damage mechanism between total shaft wall damage volume Qtol and ore-pass depth H, ore-pass dip angle θ, inclined angle of chute α, shaft diameter D and ore block size P is quantitatively investigated. The results show that the rationality of the proposed model is verified by numerical analysis and field engineering situations. Moreover, the deeper ore-pass depth H, the more shaft wall damage volume Qtol with the increase of collision frequency. Qtol increases exponentially with P and increases gradually with D. With the increase of θ or α, Qtol increases generally first and then decreases. Therefore, Qtol can be effectively reduced by selecting the appropriate structure parameters of ore-pass and adopting the technology of drilling straight ore-pass. This work provides technical support for long period safe operation of high depth inclined ore-pass.

Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins that work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases resulting in abasic sites. Many DNA glycosylases are product inhibited by binding to the abasic site more avidly than the damaged base. Traditionally apurinic/apyrimidinic endonuclease, APE1, was believed to help turnover the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three-to-five-fold. Moreover, we have shown UV-DDB can assist chromatin decompaction facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER.

This study investigates the interpretability of machine learning (ML) models applied to cumulative damage prediction during a sequence of earthquakes, emphasizing the use of techniques such as SHapley Additive exPlanations (SHAP), Partial Dependence Plots (PDPs), Local Interpretable Model-agnostic Explanations (LIME), Accumulated Local Effects (ALE), Permutation and Impurity-based technique. The research explores the cumulative damage during seismic sequences, aiming to identify critical predictors and assess their influence on the cumulative damage. Moreover, the predictors contribution in respect with the range of final damage is evaluated. Nonlinear time history analyses are applied to extract the seismic response of an eight-story Reinforced Concrete (RC) frame. The regression problem’s input variables are divided into two distinct physical classes: pre-existing damage from the initial seismic event and seismic parameters representing the intensity of the subsequent earthquake, expressed by Park and Ang damage index (DIPA) and Intensity Measures (IMs), respectively. The study offers a comprehensive review of cutting-edge ML methods, hyperparameter tuning, and ML method comparisons. A LightGBM model emerges as the most efficient, among 15 different ML methods examined, with critical predictors for final damage being the initial damage caused by the first shock and the IMs of the subsequent shock: IFVF and SIH. The importance of these predictors is supported by feature importance analysis and local/global explanation methods, enhancing the interpretability and practical utility of the developed model.

Wernicke-Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated to impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, isolate or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation; TDD), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior, which appears to be dependent on TDD. Also, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

Susceptibility to photoimmune suppression and photocarcinogenesis is greater in male than in female humans and mice and is exacerbated in female estrogen receptor-beta knockout (ER-β-/-) mice. We previously reported that the active vitamin D hormone, 1,25-dihydroxyvitamin D3 (1,25(OH)2D) applied topically protects against ultraviolet radiation (UV)-induction of cutaneous cyclobutane pyrimidine dimers (CPDs) and suppression of contact hypersensitivity (CHS) in female mice. Here we compare these responses in female versus male Skh:hr1 mice, in ER-β-/- versus wild type C57BL/6 mice, and in female ER-blockaded Skh:hr1 mice. Induction of CPDs was significantly greater in male than female Skh:hr1 mice and was more effectively reduced by 1,25(OH)2D in female Skh:hr1 and C57BL/6 mice, than in male Skh:hr1 or ER-β-/- mice respectively. This correlated with reduced sunburn inflammation by 1,25(OH)2D in female but not male Skh:hr1 mice. Furthermore, although 1,25(OH)2D alone dose-dependently suppressed basal CHS responses in male Skh:hr1 and ER-β-/- mice, UV-induced immunosuppression was universally observed. In female Skh:hr1 and C57BL/6 mice, the immunosuppression was decreased by 1,25(OH)2D dose-dependently, but not in male Skh:hr1, ER-β-/- or ER-blockaded mice. These results reveal a sex bias in genetic, inflammatory and immune photoprotection by 1,25(OH)2D favoring female mice, that is dependent on the presence of ER-β.

In this paper, we investigated transducer placement strategies for detecting crack in primary aircraft structures using ultrasonic Structural Health Monitoring (SHM). The approach developed is for an expected damage location based on fracture mechanics, for example fatigue crack growth in a high stress location. To assess the performance of the developed approach, finite-element (FE) modelling of a damage tolerant aluminum fuselage has been performed by introducing an artificial crack at a rivet hole into the structural FE model and assessing its influence on the Lamb wave propagation, compared to a baseline measurement simulation. The efficient practical sensor position was determined from the largest change in area that is covered by reflected and missing wave scatter using an additive color model. Blob detection algorithms were employed in order to determine the boundaries of this area and to calculate the blob centroid. To demonstrate that the technique can be generalized, the results from different crack lengths and from tilted crack are also presented.

Synthetic fiber ropes are frequently used as mooring lines in floaters supporting Floating Offshore Wind Turbines (FOWTs) due to their various advantages. Damages in these lines can lead to the disruption of the FOWTs normal operation and thus their early detection is crucial. Currently, this damage detection problem has been investigated exclusively for FOWT chain mooring lines. This study focuses on the damage detection in FOWT synthetic mooring lines under varying environmental-operational conditions (EOCs) via two types of vibration-based Structural Health Monitoring methods: those based on Multiple Models and those based on a single Functional Model. The methods are based on multivariate AutoRegressive or on scalar Transmittance Function (TF) AutoRegressive with eXogenous input models. All methods are evaluated through a Monte Carlo study involving 390 simulations with a 10MW wind turbine mounted on the semi-submersible OO-Star wind floater and two damage scenarios (10%, 14% stiffness reduction) to a single mooring line. The results using acceleration signals from only two measuring positions on the mooring line, indicate the great potential for robust SHM in FOWTs synthetic mooring lines with the TF model-based methods successfully detecting the considered early stage damage scenarios, even for EOCs not encountered in the methods training.

Leukemia encompasses diverse blood cancers marked by the unchecked growth and developmental blockage of myeloid or lymphoid precursor cells within the bone marrow and the bloodstream. Treatment traditionally involves intensive chemotherapy or hematopoietic stem cell transplantation, albeit these approaches often yield severe side effects and encounter resistance from leukemia cells. Hence, the quest for novel therapies targeting leukemic cells selectively is paramount to enhancing leukemia outcomes. Exploring natural products is a promising avenue for pursuing effective chemotherapy and preventive measures against leukemia. These compounds serve as a crucial wellspring for drug development and offer a source of biologically active elements for potential therapeutic interventions in leukemia. The enzyme telomerase plays a vital role in stabilizing chromosomes by adding DNA sections to the end of chromosomes during the mitotic cycle. Notably, hTERT mRNA expression strongly correlates with telomerase activity, making it a potential target for therapeutic intervention without adverse systemic effects. Telomerase inhibition is a promising target in cancer therapy, especially in combination with natural ingredients, demonstrating less cytotoxicity than chemotherapies.

Carbon fiber reinforced polymer (CFRP) bending structure is widely used in the aviation field. The occurrence and propagation of delamination damage will reduce the safety of in-service bending structures. As a detection tool with high damage sensitivity, Lamb wave can effectively identify delamination damage. In this study, the signal difference coefficient (SDC) was introduced to quantify delamination damage and evaluate the sensitivity of A0 and S0 mode lamb waves to delamination damage. The simulation results show that compared with the S0 mode Lamb wave, the A0 mode Lamb wave exhibits higher delamination damage sensitivity. The delamination damage can be quantified based on the strong correlation between the SDC and the delamination damage size. The control effect of the linear array PZT phase time-delay method on Lamb wave mode was investigated by simulation. The phase time-delay method realizes the generation of a single-mode Lamb wave, which can separately excite the A0 mode and S0 mode Lamb wave to identify delamination damage of different sizes. The A0 mode Lamb wave was excited by the developed one-dimensional linear comb transducer (LCT), which was used to conduct the detection experiment on the CFRP bending plate with delamination damage sizes of Φ6.0 mm, Φ10.0 mm, and Φ15.0 mm. The experimental results verify the correctness of the simulation. According to the Hermite interpolation results of the finite-element simulation data, the relationship between the delamination damage size and the SDC was fitted by the Gaussian function, which can accurately quantify the delamination damage. The absolute error of the delamination damage quantification with fitting expression is not larger than 0.8 mm, and the percentage error is not more than 8%.

Laser Direct Writing (LDW), also known as 3D multi-photon laser lithography of resins, is a promising technique for fabricating complex free-form elements, including micro-optical functional components. Regular organic or hybrid (organic-inorganic) resins are often used, with latter exhibiting better optical characteristics, as well as having the option to be heat-treated into inorganic glass-like structures, particularly useful for resilient micro-optics. While this work is a continuation of SZ2080™ calcination development , the Laser-Induced Damage Threshold (LIDT) of such sol-gel-derived glass micro-structures, particularly those that undergo heat treatment, has not been well-characterized. In this pilot study, we investigated the LIDT using the Series-on-One (S-on-1) protocol of functional micro-lenses produced via LDW and subsequently calcinated. Our results demonstrate that the LIDT can be significantly increased, even multiple times, by this approach, thus enhancing the resilience and usefulness of these free-form micro-optics. This work represents the first investigation in terms of LIDT into the impact of calcination on LDW produced sol-gel-derived glass micro-structures, and provides important insights for the development of robust micro-optical devices.

Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in interpretation of genotype-related phenotype. To exclude these confounders, we created a Fancg-KO (KO) mouse model using CRISPR/Cas9. The entire Fancg locus was targeted and maintained on the immunological well-characterized C57BL/6J background. Intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting loss of FANCG can be embryonic lethal. KO mice displayed infertility, hypogonadism but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from Fancg-KO mice were hypersensitive to crosslinking agents-cisplatin and Mitomycin C, and Fancg-KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. Reconstitution of these MEFs with Fancg cDNA corrected for the ICL hypersensitivity. Collectively, this project provides a new, genetically and immunologically well-defined Fancg-KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.

The aggregate aftermath of persistent inflammation in patients with inflammatory bowel disease (IBD) places them at increased risk for the advancement to colitis-associated colorectal cancer (CACRC). CACRC is preceded by IBD, the highly heterogenous, pharmacologically incurable, pertinacious, reverting/worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the length/duration and stringency/severity of colon inflammation predisposed by the exogenous/free hemoglobin alpha chain (HbαC) the byproduct of infiltrating immune cells, extravasated erythrocytes, and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen-free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS) exacerbated by decreased tissue antioxidant defenses. Mitigation of Fenton reaction via pharmaceutical therapy would attenuate the ROS, promote apoptosis, DNAD repair, and subsequent prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin’s clearance rare from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Furthermore, deferoxamine’s hydrophilic structure limits its ability to cross cell membranes. Thus, it may be beneficial if administered intracellularly to avoid the higher plasma concentrations and longer incubation periods associated with extracellular administration. Finally, the effectiveness of flavonoids and natural herb antioxidants is associated with high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. These cells are then treated with haptoglobin, deferoxamine (DFO), and flavonoids in order to separate free HbαC and measure their impact on hydroxyl radical formation therapies. The molecular pathogenesis of sporadic colorectal cancer (SCRC) i.e., “inflammation-dysplasia-carcinoma” progression sequence is well described, but the immunopathogenesis of CACRC herein reviewed is broadly still in prodromal stage/phase to be validated and understood. Therefore this timely review outlines the molecular and immunological basis of disease pathogenesis and the pharmaceutical intervention as a protective measure for CACRC.

Earthquakes are one of the most catastrophic natural phenomena. After an earthquake, earthquake reconnaissance enables effective recovery by collecting building damage data and other impacts. This paper aims to identify state-of-the-art data sources for building damage assessment and provide guidance for more efficient data collection. We have reviewed 38 articles that indicate the sources used by different authors to collect data related to damage and post-disaster recovery progress after earthquakes between 2014 and 2021. The current data collection methods have been grouped into seven categories: fieldwork or ground surveys, omnidirectional imagery (OD), terrestrial laser scanning (TLS), remote sensing (RS), crowdsourcing platforms, social media (SM) and closed-circuit television videos (CCTV). The selection of a particular data source or collection technique for earthquake reconnaissance includes different criteria depending on what questions are to be answered by this data. We conclude that modern reconnaissance missions can not rely on a single data source and that different data sources should complement each other, validate collected data, or systematically quantify the damage. The recent increase in the number of crowdsourcing and SM platforms used to source earthquake reconnaissance data demonstrates that this is likely to become an increasingly important source of data.

Formulating a novel concept about the origin of human aging has been constrained by the dominance of a “classic theory” that was proposed nearly 70 years ago. Despite concern over the validity of some of its assumptions, the theory remained basic to our understanding of aging’s relationship with natural selection (NS). However, the logic upon which it rests was tested and subsequently challenged. The present theory describes the single cause of human aging consistent with Darwin’s evolutionary requirement for selection of adaptive traits. It describes an emergent property of the developmental program (DP), that is expressed upon completion of ontogenesis. It involves redundant expression of regulatory processes from the last stage of the DP. That mechanism subsequently preserves a non-aging, stable interval of unchanging NS during which reproductive fitness is achieved. Thereafter, loss of DP regulatory redundancy due to reliability limits, stochastic mutation accumulation, reproductive and a specific type of DNA damage, initiates aging which causes an inexorable decline in strength of NS to begin. It starts approximately a decade later than proposed in the classic theory. Since reproduction and aging are inextricably linked by the same emergent property, selection of that regulatory mechanism makes both traits products of NS.

The World Health Organization identifies alcohol as a cause in several neoplasias of the oro-pharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. This study re-views ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that en-compasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals that interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells responsible for building and repairing tissues are reviewed. Cancer stem cells suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underlie and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological interven-tion. Specifically, research should pay attention to reestablish metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

Abstract5′,8-Cyclo-2′-deoxyadenosine (cdA), in the 5′R and 5′Sdiastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA. So far, it was unknown whether the diastereomeric cdA lesions could induce specific PARP1 binding. Here we provide the first evidence of PARP1 to selectively recognize the diastereomeric lesions 5′S-cdA and 5′R-cdA in vitro as compared to deoxyadenosine in model DNA substrates (23-mers) by using circular dichroism,fluorescence spectroscopy, immunoblotting analysis and gel mobility shift assay. Several features of the recognition of the damaged and undamaged oligonucleotides by PARP1were characterized. Remarkably, PARP1 efficiently binds to both cdA lesions in the double stranded (ds)-oligonucleotides. In particular, PARP1 proved to bind 5′S-cdAwith a higher affinity constant for the 5'S lesion in a model of ds DNA than 5′R-cdA, showing different recognition patterns, also compared with undamaged dA. This new finding highlights the ability of PARP1 to recognize and differentiate the distorted DNA backbone in a biomimetic system caused by different diastereomeric forms of a cdA lesion.

Increased screen time during the COVID-19 pandemic and the accelerated incorporation of technology into daily practices have directly contributed to the increased prevalence of eye disease. The human eye is not built for continual technological use and must adjust to exposure to digital screens. Overexposure to technology can result in eye strain and an increased risk of eye diseases such as myopia with complications later in life, including retinal tears, cataracts, and macular degeneration. As vision and ocular diseases become more prevalent, the study of eye diseases, including their causes and treatments, is especially relevant. There is a need to prevent ocular diseases before they become a burden to individuals, their families, and their communities by better understanding the pathophysiology of ocular diseases. Several ocular diseases are thought to be caused by imbalances in reactive oxygen species (ROS) and autophagy. ROS refers to a class of highly reactive oxygen-containing molecules that can undergo damaging reactions with other molecules in the cell. Autophagy is a cellular process of self-eating whereby damaged, harmful, or dead material in cells is broken down to maintain cellular homeostasis. This paper discusses the role of ROS and autophagy in the pathogenesis of computer vision syndrome (CVS), digital eye strain (DES), myopia, cataracts, glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), optic nerve crush injury (OCN), optic nerve gliomas, and retinoblastoma. Lifestyle changes such as limiting screen time, ensuring adequate exposure to evening sunlight, and using blue light protection measures or protective eyewear are important in the prevention of eye disease. Nutrition also contributes significantly to eye health. A balanced diet rich in vitamins and antioxidants may help to prevent ROS and autophagy imbalance-induced eye disease. Medical and surgical treatments become necessary when preventative measures fail. This paper also addresses how government measures to decrease the onset of eye disease, including targeted programs to increase access to fresh vegetables and fruits in food deserts, are a critical macro-level avenue to reduce eye disease prevalence in the US, which according to the National Eye Institute, costs $139 billion yearly.

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities in de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have changed the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road towards a personalized treatment for de novo mHSPC is still long considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as predictive biomarker requires further validation, as well as it remains to ascertain how the genomic alterations detected in mHSPC, that are considered predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

The current SARS- CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS- CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.