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.

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.

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

In the current manuscript, a novel software application for Rapid Damage Assessment of RC buildings subjected to earthquake excitation is presented based on Artificial Neural Networks. The software integrates the use of a novel deep learning methodology for Rapid Damage Assessment into modern software development platforms, while the developed graphical user interface promotes the ease of use even from non-experts. The aim is to foster actions both in the pre- and post- earthquake phase. The structure of the source code permits the usage of the application either autonomously as a software tool for Rapid Visual Inspections of buildings prior to or after a strong seismic event or as a component of Building Information Modelling systems in the framework of digitizing building data and properties. The methodology implemented for the estimation of the RC buildings’ damage states is based on the theory and algorithms of Pattern Recognition problems. The effectiveness of the developed software is successfully tested using an extended, numerically generated database of RC buildings subjected to recorded seismic events

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.

Current bridge inspection practices rely on paper-based data acquisition, digitization, and multiple conversions in between incompatible formats to facilitate data exchange. This practice is time-consuming, error-prone, cumbersome, and leads to information loss. One aim for future inspection procedures is to have a fully digitized workflow that achieves loss-free data exchange, which lowers costs and offers higher efficiency. On the one hand, existing studies proposed methods to automatize data acquisition and visualization for inspections. These studies lack an open standard to make the gathered data available for other processes. On the other hand, several studies discuss data structures for exchanging damage information through out different stakeholders. However, those studies do not cover the process of automatic data acquisition and transfer. This study focused on a framework that incorporates automatic damage data acquisition, transfer, and a damage information model for data exchange. This enables inspectors to use damage data for subsequent analyses and simulations. The proposed framework shows the potentials for a comprehensive damage information model and related (semi-)automatic data acquisition and processing.

Long-haul COVID-19 illness first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is mysterious as it affects COVID-19 survivors at all levels of disease severity, even younger adults and children. While the precise definition may be lacking, the defining symptoms are fatigue, dyspnea, and headache that last for months after hospital discharge. The less typical symptoms may include cognitive impairments, chest and joint pains, myalgia, smell and taste dysfunctions, cough, mood changes, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long-haul COVID-19, which the current review aims to address. In brief, long-haul COVID-19 may be driven by long-term lung and brain damage and unresolved inflammation from multiple sources. The associated risk factors may include female sex, more than five early symptoms, early dyspnea, and specific biomarkers like D-dimer. While only rehabilitation training has been useful for long-haul COVID-19, therapeutics repurposed from mast cell activation syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, and pulmonary fibrosis also hold potential. In sum, this review hopes to provide the current understanding of what is known about long-haul COVID-19.

Macromolecular crystallography at cryogenic temperatures has so far provided the majority of the experimental evidence that underpins the determination of the atomic structures of proteins and other biomolecular assemblies by means of single crystal X-ray diffraction experiments. One of the core limitations of the current methods is that crystal samples degrade as they are subject to X-rays, and two broad groups of effects are observed: global and specific damage. While the currently successful approach is to operate outside the range where global damage is observed, specific damage is not well understood and may lead to poor interpretation of the chemistry and biology of the system under study. In this work, we present a phenomenological model in which specific damage is understood as the result of a single process, the steady excitation of crystal electrons caused by X-ray absorption, which acts as a trigger for the bulk effects that manifest themselves in the form of global damage and obscure the interpretation of chemical information from XFEL and synchrotron structural research.

Internal and mesoscopic variables differ from each other fundamentally: both are state space variables, but mesoscopic variables are additional equipped with a distribution function introducing a statistical item into consideration which is missing in connection with internal variables. Thus, the alignment tensor of liquid crystal theory can be introduced as an internal variable or as one generated by a mesoscopic background using the microscopic director as mesoscopic variable. Because the mesoscopic variable is part of the state space, the corresponding balance equations change into mesoscopic balances, and additionally an evolution equation of the mesoscopic distribution function appears. The flexibility of the mesoscopic concept is not only demonstrated for liquid crystals, but is also discussed for dipolar media and flexible fibers.

This case study investigates the effects of ventilation intervention on measured and perceived indoor air quality (IAQ) in a repaired school where occupants reported IAQ problems. Occupants´ symptoms were suspected to be related to the impurities leaked indoors through the building envelope. The study’s aim was to determine whether a positive pressure of 5-7 Pa prevents the infiltration of harmful chemical and microbiological agents from structures, thus decreasing symptoms and discomfort. Ventilation intervention was conducted in a building section comprising 12 classrooms and was completed with IAQ measurements and occupants´ questionnaires. After intervention, the concentration of total volatile organic compounds (TVOC) and fine particulate matter (PM_2.5) decreased, and occupants´ negative perceptions became more moderate compared to those for other parts of the building. The indoor mycobiota differed in species composition from the outdoor mycobiota, and changed remarkably with the intervention, indicating that some species may have emanated from an indoor source before the intervention.

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<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.

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.

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.

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.

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.

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.

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.

Damage detection based on modal parameter changes becomes popular in the last decades. Nowadays are available robust and reliable mathematical relations to predict the natural frequency changes if damage parameters are known. Using these relations, it is possible to create databases containing a large variety of damage scenarios. Damage can be thus assessed by applying an inverse method. The problem is the complexity of the database, especially for structures with more cracks. In this paper, we propose two machine learning methods, namely the random forest (RF) and the artificial neural network (ANN) as search tools. The databases we developed contain damage scenarios for a prismatic cantilever beam with one crack and ideal and non-ideal boundary conditions. The crack assessment is made in two steps. First, a coarse damage location is found from the networks trained for scenarios comprising the whole beam. Afterward, the assessment is made involving a particular network trained for the segment of the beam on which the crack is previously found. Using the two machine learning methods, we succeed to estimate the crack location and severity with high accuracy for both simulation and laboratory experiments. Regarding the location of the crack, which is the main goal of the practitioners, the errors are less than 0.6%. Based on these achievements, we concluded that the damage assessment we propose, in conjunction with the machine learning methods, is robust and reliable.

The paper presents the identification and classification of steel cord failures in the conveyor belt core based on an analysis of a two-dimensional image of magnetic field changes recorded using the Diagbelt system around scanned failures in the test belt. The obtained set of identified changes in images obtained for numerous devices parameters settings were the base for statistical analysis. It makes it possible to determine the Pearson’s linear correlation coefficient between the parameters being changed and the image of the failures. In the second stage of the research, artificial intelligence methods were applied to construct a multilayer neural network (MLP) and to teach its appropriate identification of damage. In both methods were used the same data sets, which made it possible to compare methods.

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.

Nonlinear properties of zinc germanium diphosphide (ZGP) crystals enable their ap-plications in powerful mid-IR optical parametric oscillators and second-harmonic generators. This paper summarizes mechanisms of the laser induced damage (LID) in high-purity ZGP crystals under periodically pulsed nanosecond irradiation by a Ho3+:YAG laser at 2.1 μm. The ZGP samples were manufactured by “LOC” Ent., Tomsk, Russia, or Harbin Institute of Technology, China. The impact of processing techniques and the post-growing methods for polishing and anti-reflection coating on the LID threshold are discussed. The importance of the defect structure of the crystal lattice and the parameters of transparent coatings for increasing the LID threshold is discussed. The impact of the test laser parameters on the LID threshold is analyzed. The transient area near the LID threshold obtained using digital holography is ana-lyzed. Influence of the pre-damage processes on the optical parametric oscillations is reported. Prospects for improving ZGP crystals to further increase the LID threshold are discussed.

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.

Alzheimer’s disease (AD) and vascular dementia (VaD) together contribute to almost 90% of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in Alzheimer’s disease, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. We thus highlight here the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress, inflammation and demyelination and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from the oxidative damage and the coexistence of different sources of energy production, such as mitochondrial and glycolytic ATP, allows faster adaptative mechanisms to situations of high energy demand and may help in the maintenance of neuronal function in stress situations. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of Multiple Sclerosis. This work has been performed in a model of oxidative damage on neuronal cell cultures exposed to menadione, in presence or absence of fingolimod phosphate. We have studied the mitochondrial function and several pathways related with glucose metabolism, including oxidative, glycolytic and pentose phosphate in neuronal cells cultures. Our results showed a beneficial effect on neuronal survival probably based in the recovery of all, oxidative balance, glycolysis and pentose phosphate, promoted by fingolimod phosphate. These effects are mediated, at least in part by the interaction with its specific receptor. These actions would make this drug a potential tool to the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

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.

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.

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.

Background: The hypothesis is that a hypoxic-hyperoxic preconditioning (HHP) is associated with a protective effect on myocardial function by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: Patients (n=120) were randomly assigned to an HHP and a control group. A safe inhaled oxygen fraction for the hypoxic preconditioning phase (10-14% oxygen for 10 minutes) was determined by measuring the anaerobic threshold. At hyperoxic phase, 75-80% oxygen fraction was used during 30 minutes. Results: The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs 23 (41.1%), p=0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low more than 24 h in control group. The endothelial damage markers appeared to be predictors of postoperative complications. Conclusion: The HHP with individual parameters based on the anaerobic threshold is a safe procedure, it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications.

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.

Damage to crops from wildlife interference is a common threat to food security among rural communities in or near Game Management Areas (GMAs) in Zambia. This study uses a two-stage econometric model and cross-sectional data from a survey of 2,769 households to determine the impact of land use planning on the probability and extent of wildlife-inflicted crop damage. The results show that crop damage is higher in GMAs as compared to non-GMAs, and that land use planning could be an effective tool to significantly reduce the likelihood of such damage. These findings suggest that there is merit in the current drive to develop and implement land use plans as means to minimize human-wildlife conflict such as crop damage. This is especially critical as Zambian conservation policies do not have an explicit provision for compensation in the event of damage from wildlife.

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.

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.

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.

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.

Forest damage has become more frequent in Europe in the last decades, and remote sensing offers a powerful tool for monitoring them rapidly and cost-effectively. A novel approach was developed to utilize high-resolution ESA Sentinel-2 satellite imagery and Google Earth Engine cloud computing. The processing, analysing, and visualization of vegetation and water index (NDVI, NDVIch, Z NDVI, EVI, NDWI) maps and charts derived from satellite images took place in the cloud to ensure the detection of forest disturbances in the Hungarian study site for the period 2017-2020. The index maps were classified to reveal forest disturbances, and the cloud-based method successfully showed drought and frost damage in the oak-dominated Nagyerdő forest of Debrecen. Differences in the reaction to damage between tree species were visible in the index values, therefore a Random Forest Machine Learning classifier was applied to show the spatial distribution of dominant species. Accuracy assessment was accomplished with confusion matrices that compared classified index maps to field-surveyed data, demonstrating 71% Total Accuracy for forest damage and 76% for tree species. Based on the results of this study and the resilience of Google Earth Engine, the presented method has the potential to be extended to monitor the entire Hungary.

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.

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.

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.

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.

Changes in extreme weather patterns are expected under climate change. In this study, a risk assessment was conducted using 4 building damage history datasets and 33 weather datasets (precipitation, wind speed, snow, and temperature) from 230 regions in South Korea to quantitatively analyze and predict building damage caused by potential future natural disasters. Decision tree analysis was used to evaluate building damage risk in 230 regions. The decision tree model to determine the risk of flood, gale, and typhoon was generated, which excluded gales, with less damage. The weight (variable importance) and limit value (damage limit) of the weather variables ware derived using the decision tree model. Using these two factors, we assessed the building damage risk in 230 regions in South Korea until 2100. The number of regions at risk of flood damage increased by more than 30% in average. Conversely, regions at risk of snowfall damage decreased by more than 90%. The regions at risk of typhoons decreased by 57.5% on average, and the number of regions at high risk of typhoon damage increased by up to 62.5% in RCP 8.5. These results can be used as objective data to minimize future building damage throughout South Korea, representing the first step towards sustainable development in the region with respect to disaster response.

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.

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 review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, PDIP46 and PDIP38, both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the splicesosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, Mdm2 alternative splicing and the regulation of the Nox4 NADPH oxidase.

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.

Epithelial-mesenchymal transition (EMT) networks are essential in acquiring the drug resistance and cancer malignant features in cancer stem cells (CSCs). In this regard, gene expression profiles in diffuse- and intestinal-type gastric cancer (GC) have been analyzed to reveal the network pathways in EMT and CSCs, since the diffuse-type GC has much more mesenchymal features than intestinal-type GC that has the intestinal features. The study results revealed that the activation state of several canonical pathways related to cell cycle regulation was altered. The canonical pathway on Cell cycle: G1/S checkpoint regulation was activated in diffuse-type GC, and canonical pathways on Cell cycle control of chromosomal replication and Cyclins and cell cycle regulation were activated in intestinal-type GC. Canonical pathway related to Role of BRCA1 in DNA damage response was activated in intestinal-type GC, where BRCA1, which is related to G1/S phase transition was up-regulated in intestinal-type GC. Several microRNAs (miRNAs), including mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451, and mir-605, were identified to have direct relationships of RNA-RNA interaction in Cell cycle: G1/S checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in EMT conditions. The alterations in activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC would indicate the significance of cell cycle regulation in EMT.

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.

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.

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.

The fatty acid elongase ELOngation of Very-Long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, do-cosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn6) in-vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondial-dehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with high voltage-dependent anion channel (VDAC) and adenine nucleotide trans-locase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission elec-tron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.

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.

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.

Clinical and analytical differences between adult patients monoinfected with Borrelia burgdorferi sensu lato (s.l.) and patients infected with B. burgdorferi s.l. who also had IgG antibodies against Babesia divergens have not been reported so far. Both Lyme disease caused by B. burgdorferi and babesiosis caused by B. divergens, endemic in Asturias, Northwestern Spain, are transmitted by Ixodes tick bites. Clinical, laboratory and other diagnostic tests characteristics (imaging, electro-cardiographic-ECG) of 120 residents of Asturias with confirmed B. burgdorferi s.l. infection, di-agnosed during 2015-2017, of whom 47 (39.2%) had B. divergens IgG antibodies, were retrospec-tively compared. Cardiorespiratory symptoms were reported in 9/47 (19.2%) patients with Lyme disease and B. divergens IgG antibodies compared to 4/73 (5.5%) patients with B. burgdorferi s.l. monoinfection (P=0.02). Dyspnea was recorded in 4/47 (8.5%) patients with Lyme disease and B. divergens IgG antibodies compared to 1/73 (1.4%) monoinfected (P=0.07). In addition ECG atri-oventricular (AV) block, mostly 1st degree, was detected in 5/47 (15.6%) patients with Lyme dis-ease and B. divergens IgG antibodies compared to 1/73 (2.6%) B. burgdorferi s.l. monoinfected (P=0.09). No other clinical, laboratory or other tests differences were observed between B. burgdorferi and B. divergens IgG antibodies carriers and B. burgdorferi monoinfected. We con-cluded that patients with Lyme disease and B. divergens IgG antibodies had more frequent car-diorespiratory symptoms, mainly dyspnea, compared to B. burgdorferi monoinfected patients. These symptoms were unrelated to anemia. ECG AV block, perhaps induced by summative myo-cardial damage due to either infections or B. divergens induced lung microcirculation slow-ing-down, might play a role in the cardiorespiratory dysfunction.

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.

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.

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.

To understand lung damage caused by COVID-19, we deduced two-phase lung damage mechanisms. After the lungs are infected with SARS-CoV-2 virus, the affected lung tissue swells and surface properties of pulmonary capillaries change, resulting in an increased flow resistance of affected capillaries. If a sufficient number of capillaries are affected by the infection, the swelling and increased cell wall adhesion collectively raise pulmonary vascular resistance. The increased vascular resistance further increases the dwell times of WBCs in affected capillaries and nearly capillaries. When pulmonary pressure is sufficiently higher, WBCs are forced to squeeze into interstitial spaces or alveolar spaces when local pressures are higher than what the capillaries can withstand. When more and more WBCs are dynamically retained, the flow resistance of more capillaries rises, pulmonary vascular resistance rises, and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When capillary pressures around the alveoli are sufficiently high, they cause interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alveolar space and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and alveolar spaces further reduce compressible volume, and thus cause further rise in the pulmonary vascular resistance and pulmonary pressure. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. The available free volume in the thorax cage, organ usable capacities, temperature and humid are expected to have great impacts on degree of lung damages. The free volume in the thorax cage, lung usable surplus capacity, and other organ usable capacities determine the arrival time of last-phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain leukecytes are recruited and migrated into inflamed tissues by increasing their dwell times caused by increased local flow resistance.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.