Levels Of Damage Research Articles

MiR-195-5p inhibits cisplatin resistance in lung adenocarcinoma by regulating DNA damage via targeting E2F7.

Lung adenocarcinoma (LUAD) emerges as one of the most lethal malignant tumors worldwide. Platinum-based combination chemotherapy remains one of the main methods for patients with advanced LUAD. Due to the resistance, the effect of this chemotherapy was not satisfactory. Therefore, studying the mechanism of cisplatin (DDP) resistance is essential for promoting the effect of this therapeutic strategy. Therefore, this work sought to probe the impact of E2F Transcription Factor 7 (E2F7) on LUAD resistance and the molecular regulatory mechanism. The mRNA expression level of the target gene E2F7 in LUAD was predicted by bioinformatics analysis, and regulatory miRNA upstream of the target gene was identified. The mRNA and protein expression of E2F7 in LUAD cells was detected through quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot, respectively. The expression of miR-195-5p in LUAD cells was measured via qRT-PCR. E2F7 high and low expression groups underwent enrichment analysis by utilizing Gene Set Enrichment Analysis software. The targeting relationship of miR-195-5p and E2F7 was validated by conducting a dual-luciferase reporter assay. The cell viability was tested through cell counting kit-8. The cell cycle was examined by flow cytometry. DNA damage level was determined via Comet assay and Western blot assay. The findings indicated that the mRNA and protein levels of E2F7 were high in LUAD. MiR-195-5p was the regulatory miRNA upstream of E2F7, and lowly expressed in LUAD. The cell experiments suggested that E2F7 advanced the DDP resistance of LUAD cells by repressing DNA damage. Finally, the rescue assay manifested that miR-195-5p overexpression could abate inhibition of E2F7 overexpression on the DNA damage and the DDP sensitivity of LUAD cells. MiR-195-5p raised the DDP sensitivity of LUAD cells by advancing the DNA damage in LUAD cells via inhibition of E2F7.

Deep learning approaches for image restoration in invasive coronary angiography

Abstract Background Despite being the gold standard for diagnosing coronary artery disease and guiding percutaneous coronary interventions (PCI), image restoration during invasive coronary angiography (ICA) has rarely been explored. Generative adversarial network (GAN), a deep learning model, has demonstrated its effectiveness in image restoration. Our hypothesis was that we could restore ICA images, damaged or deleted to varying degrees, using the inpainting GAN method, and we undertook efforts to test this hypothesis. Methods We extracted 22,659 ICA patch images (128 × 128 size) from 60 patients, focusing on sparse vessels for model training. To assess our inpainting GAN model, we degraded the extracted images to varying degrees: minimal, mild, moderate, severe, and completely blocked. The performance was quantitatively analyzed using metrics such as the peak signal-to-noise ratio (PSNR), structured similarity indexing methods (SSIM), and mean squared error (MSE). Results The inpainting GAN method significantly improved the image quality in all degraded images. For the blocked images, PSNR and SSIM were enhanced by 161.9% and 14.3%, respectively, with a 98% MSE reduction. In severely, moderately, mildly, and minimally damaged images, PSNR and SSIM increased by 14.9% and 14.8%, 15.7% and 14.7%, 19.3% and 15.6%, and 12.7% and 5.3%, respectively, with MSE reductions of 61.5%, 64.1%, 72.7%, and 33.9%, respectively. Conclusions Inpainting GAN can restore ICA images with varying damage levels, including deletions. Our deep-learning model can instantaneously improve ICA image quality, potentially aiding in emergency or chronic total occlusion PCI.Table 2.Quantitative Analysis of ImageFigure 1.Sample Cases Pre and Post-Rest

The impacts of contact explosions on ultra-high performance reinforced concrete slabs: experimental study and dimensional analysis

Ultra-high performance concrete (UHPC) is becoming a prevailing construction material in protective engineering. However, an insufficient research basis causes difficulty in the anti-explosion structural design of UHPC. To investigate the blast resistance of the UHPC slab (UHPCS), contact explosion tests were carried out. UHPCS exhibited superior blast resistance and a lower threshold range of failure modes than the normal reinforced concrete slab (NRCS). Compared with the NRCS, the UHPCS reached a lower damage level under the same scaled distance and had smaller craters and spalls, fewer cracks, and an absence of cross-shaped cracks. For NRCS, failure modes of medium spall, severe spall, and perforation were reached under charges of 1.0, 1.6, and 2.2 kg. In contrast, UHPCS reached medium spall, severe spall, and perforation under charges of 1.6, 3.3, and 5.0 kg. The scaled slab thicknesses (T/W1/3) of the medium spall, severe spall, and perforation of the NRCSs were 1.17, 1.27, and 1.32 times larger than those of the UHPCSs, respectively. The formulae for predicting the spall and perforation thresholds of the UHPCSs were proposed. The reduction factors were used to evaluate the mitigation effect of the blast damage on the UHPC compared to that on the NRC. The reduction factors of the crater diameter (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\gamma _\\Phi }_{C}$$\\end{document}) and the spall diameter (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\gamma _{\\Phi s}}$$\\end{document}) were determined to be 0.507 and 0.721, respectively. For quantitative analysis of the anti-explosion performance of UHPC, a simple estimation method for predicting the dimensions of the crater and spall of the UHPCS was proposed and verified based on the dimensional analysis method.

Exploration on flutter mechanism of a damaged transonic rotor blade using high-fidelity fluid–solid coupling method

Structural damage in turbomachinery is a primary origin of aeronautic accidents, which is receiving increased attention. This study is thus focused on the aeroelastic analysis of damaged blades, including the onset of flutter and underlying mechanisms. First, a high-fidelity fluid–solid coupling system is established with computational fluid dynamics (CFD) and computational structural dynamics (CSD) technologies, via which the dynamic aeroelastic analysis is conducted based on static aeroelastic deformation. Second, a damaged rotor blade is parametrically modelled with variable damage levels, extents, and positions. Finally, the modal identification method of spectral proper orthogonal decomposition (SPOD) is applied to observe flow details and provide physical insight into the flutter mechanism for damaged blades. Numerical analysis finds that there is a critical damage level below which the aeroelastic stability is positively improved with increasing damage level; otherwise, a significant loss of stability is induced. The damage location and extent further affect this critical damage level and the change rate crossing the threshold. The simulation with CFD/CSD finds that the high pressure near the trailing edge induced from boundary layer separation suppresses vibrations in stable conditions, but motivates vibrations during flutter, which is because of the high-pressure spread to nearing blades. SPOD modes reveal that high-frequency disturbances with large scale are primary factors inducing flutter, which is further stimulated by the high-order disturbances with small scale. This study provides a crucial foundation for the fatigue prediction for rotor blades in service and the optimisation design for high-performance turbomachinery in the near future.

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors.

Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

Antioxidant hydrogels for the treatment of osteoarthritis: mechanisms and recent advances

Articular cartilage has limited self-healing ability, resulting in injuries often evolving into osteoarthritis (OA), which poses a significant challenge in the medical field. Although some treatments exist to reduce pain and damage, there is a lack of effective means to promote cartilage regeneration. Reactive Oxygen Species (ROS) have been found to increase significantly in the OA micro-environment. They play a key role in biological systems by participating in cell signaling and maintaining cellular homeostasis. Abnormal ROS expression, caused by internal and external stimuli and tissue damage, leads to elevated levels of oxidative stress, inflammatory responses, cell damage, and impaired tissue repair. To prevent excessive ROS accumulation at injury sites, biological materials can be engineered to respond to the damaged microenvironment, release active components in an orderly manner, regulate ROS levels, reduce oxidative stress, and promote tissue regeneration. Hydrogels have garnered significant attention due to their excellent biocompatibility, tunable physicochemical properties, and drug delivery capabilities. Numerous antioxidant hydrogels have been developed and proven effective in alleviating oxidative stress. This paper discusses a comprehensive treatment strategy that combines antioxidant hydrogels with existing treatments for OA and explores the potential applications of antioxidant hydrogels in cartilage tissue engineering.

Noradrenaline Protects Human Microglial Cells (HMC3) Against Apoptosis and DNA Damage Induced by LPS and Aβ1-42 Aggregates In Vitro

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) plaques and neuroinflammation. This study investigates the protective effects of noradrenaline (NA) on human microglial cells exposed to lipopolysaccharides (LPS) and Aβ aggregates—major contributors to inflammation and cellular damage in AD. The reduced Aβ aggregation in the HMC3 human microglial cells co-treated with Aβ and NA was confirmed by thioflavin T (ThT) assay, fluorescent ThT staining, and immunocytochemistry (ICC). The significantly increased viability of HMC3 cells after 48 h of incubation with NA at 50 µM, 25 µM, and 10 µM, exposed to IC50 LPS and IC50 Aβ, was confirmed by XTT and LDH assays. Moreover, we found that NA treatment at 25 μM and 50 μM concentrations in HMC3 cells exposed to IC50 LPS or IC50 Aβ results in an increased proliferation of HMC3 cells, their return to normal morphology, decreased levels of DNA damage, reduced caspase-3 activity, decreased expression of pro-apoptotic DDIT3 and BAX, and increased expression of anti-apoptotic BCL-2 genes and proteins, leading to enhanced cell survival, when compared to that of the HMC3 cells treated only with IC50 LPS or IC50 Aβ. Furthermore, we showed that NA induces the degradation of both extracellular and intracellular Aβ deposits and downregulates hypoxia-inducible factor 1α (HIF-1α), which is linked to impaired Aβ clearance and AD progression. These findings indicate that NA holds promise as a therapeutic target to address microglial dysfunction and potentially slow the progression of AD. Its neuroprotective effects, particularly in reducing inflammation and regulating microglial activity, warrant further investigation into its broader role in mitigating neuroinflammation and preserving microglial function in AD.

Quantitative Study of Thermal Response of Timber–Concrete Composite Structures Under Traveling Fire Using Energy Equivalence Method

ABSTRACTThe time equivalent method can be used to quantify the fire intensity of a traveling fire into the time of action of the standard fire, which in turn can be used to assess the extent of damage to a structure under a traveling fire. However, an effective time equivalence method for timber structures has not been developed yet. Therefore, this paper proposed an energy‐based time equivalent method, referred to as the “energy equivalence method (EEM)”, for evaluating the fire resistance of timber structures under traveling fire, and validates its effectiveness through a series of fire tests. The results demonstrate that the EEM effectively quantifies the fire intensity endured by glulam under traveling fire as the equivalent exposure time under the standard fire. Furthermore, the EEM was utilized to investigate the damage behavior of a single‐layer Timber‐Concrete Composite (TCC) frame under traveling fire. The results reveal variations in the fire intensity experienced by the structure at different locations under the same traveling fire scenario, with the most severe damage occurring at a position 40% relative to the ignition end. The fire scale determines the non‐uniformity of the fire intensity and the extent of structural damage, as smaller‐scale fires (fire sizes between 10% and 40%) not only result in significant variations in damage levels at different locations but also have a more adverse impact on the structure. In fire safety design, the selection of standard and traveling fire design methods should be based on the fire scale.

Synergistic effects of combined hyperthermia and electric fields treatment in non-small cell lung-cancer (NSCLC) cell lines.

Lung cancer remains a leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) being particularly challenging due to poor survival rates, emphasizing the need for new treatments. This study examined the therapeutic effects of combining hyperthermia (HT) with tumor-treating electric fields (TTF) in NSCLC. Cells were exposed to four different conditions: hyperthermia at 42°C for 30min, electric fields at 150kHz and 0.8V/cm for 24h, a combination of both treatments, or no treatment (control). Cell proliferation was measured using WST and colony-formation assays, while apoptosis, DNA damage, and repair protein levels were analyzed via Western blotting. Metastatic potential was evaluated with a transwell assay, and cell migration was assessed using the wound-healing assay. The combination therapy significantly inhibited colony formation and reduced cell migration and invasion more effectively than individual treatments. The combined treatment also enhanced apoptosis, as indicated by increased cleaved-PARP and Annexin V levels. In addition, the DNA-damage marker γ-H2AX was elevated, while BRCA1, a protein involved in DNA repair, was significantly downregulated compared to the individual treatments. These results suggest that the enhanced anticancer effects of HT and TTF are due to increased DNA damage and suppression of DNA-repair mechanisms, highlighting the potential of this combination therapy for NSCLC treatment.

Anisotropy of radiation-induced defects in Yb-implanted β-Ga2O3

RE-doped β-Ga2O3 seems attractive for future high-power LEDs operating in high irradiation environments. In this work, we pay special attention to the issue of radiation-induced defect anisotropy in β-Ga2O3, which is crucial for device manufacturing. Using the RBS/c technique, we have carefully studied the structural changes caused by implantation and post-implantation annealing in two of the most commonly used crystallographic orientations of β-Ga2O3, namely the (-201) and (010). The analysis was supported by advanced computer simulations using the McChasy code. Our studies reveal a strong dependence of the structural damage induced by Yb-ion implantation on the crystal orientation, with a significantly higher level of extended defects observed in the (-201) direction than for the (010). In contrast, the concentration and behavior of simple defects seem similar for both oriented crystals, although their evolution suggests the co-existence of two different types of defects in the implanted zone with their different sensitivity to both, radiation and annealing. It has also been found that Yb ions mostly occupy the interstitial positions in β-Ga2O3 crystals that remain unchanged after annealing. The location is independent of the crystal orientations. We believe that these studies noticeably extend the knowledge of the radiation-induced defect structure, because they dispel doubts about the differences in the damage level depending on crystal orientation, and are important for further practical applications.

The Impact of Genetic Polymorphisms for Detecting Genotoxicity in Workers Occupationally Exposed to Metals: A Systematic Review.

The present study aims to provide a systematic review of studies on the essential and nonessential metal exposure at occupational level, genotoxicity, and polymorphisms and to answer the following questions: Are genetic polymorphisms involved in metal-induced genotoxicity? In this study, 14 publications were carefully analyzed in this setting. Our results pointed out an association between polymorphism and genotoxicity in individuals exposed to metals, because 13 studies (out of 14) revealed positive relations between genotoxicity and polymorphisms in xenobiotics metabolizing and DNA repair genes. Regarding the quality of these findings, they can be considered reliable, as the vast majority of the studies (12 out of 14) were categorized as strong or moderate in the quality assessment. Taken as a whole, occupational exposure to metals (essentials or not) induces genotoxicity in peripheral blood or oral mucosa cells. Additionally, professional individuals with certain genotypes may present higher or lower DNA damage as well as DNA repair potential, which will certainly impact the level of DNA damage in the occupational environment.

Maize plants can recover from fall armyworm damage under optimum crop production conditions in humid tropical agro-ecologies.

Farmers in Africa perceive the impact of fall armyworm (FAW) on maize to be significant, but field assessments have shown that yield losses are not significant enough to warrant pesticide interventions. This suggests that relationships between the crop stages, time, and duration of attack can affect the yield. Therefore, assessing the plant's recovery from damage using individual plants based on defoliation levels could guide whether and when pesticides should be applied. To study this, we selected 120 labeled maize plants corresponding to six levels of FAW defoliation, replicated 20 times, based on an initial damage rating. The rating scale ranged from 1 (no defoliation) to 5 (>75% defoliation) during four planting seasons. Plants with a rating scale of 1 were replicated and treated with a chemical insecticide to keep them undefoliated, and that served as a control. Damage severity was recorded weekly on all plants, starting from emergence until maturity, using the same damage rating scale. Results showed that damage severity varied significantly among different defoliation levels during all seasons. Higher levels of defoliation during dry seasons resulted in significant yield loss only for plants with damage levels 4 and 5, with damage severity ranging from 38.7% to 57.5%. These results indicate that FAW control is unnecessary in the rainy season. In contrast, pesticide interventions should be envisaged in seasons of erratic rainfall, with a significant defoliation threshold level of around 50%, occurring at 8 and 5wk after planting weeks after planting, respectively for the early and late dry season.

Energy-based damage assessment method for masonry walls under seismic and fire loads

The evaluation of the out-of-plane (OOP) behavior for infilled walls is a critical aspect of regional seismic and fire resilience assessment. This study presents a detailed finite element (FE) model that comprehensively captures the seismic and fire behaviors of masonry walls. The FE model incorporates key factors governing the thermo-mechanical behavior of masonry walls, including temperature-dependent material properties, nonlinearities in geometry and material, block cracking and crushing, and mortar damage. Then, an energy-based damage criterion is proposed based on the principle of energy conservation, leveraging the combined mixed fracture energy and internal energy of elements. In addition, this study defines the damage levels of masonry walls under OOP loading and fire and determines corresponding damage indices using the proposed energy-based damage criterion. This criterion is further compared with a stiffness-based damage criterion. Finally, the proposed damage assessment method is employed to evaluate the damage evolution of infilled walls under seismic, fire and post-earthquake fire scenarios, and to conduct a fragility analysis. The results demonstrate a high degree of agreement between the predicted and measured damage states of masonry walls under seismic and fire loads. More severe seismic damage does not always result in diminished fire resilience. Evaluating post-earthquake fire damage requires considering the impact of displacement directions caused by earthquakes and fires.

Design of Bayesian evaluation test for missile damage effectiveness based on multiple damage level standards

The qualified missile damage effectiveness is an important guarantee for giving full play to combat effectiveness. In order to test whether the missile damage effectiveness meets the standard, it is particularly necessary to carry out damage effectiveness identification test research. In view of the limitation that the existing "single-shot damage probability" damage effectiveness quantitative characterization index is difficult to fully describe the missile damage effectiveness based on a single damage standard, considering the different damage level results formed by a single missile hitting the target, the damage effectiveness is characterized by the probability of occurrence of different damage level results. Missile identification from the perspective of multiple damage level standards is conducive to comprehensive inspection of missile damage effectiveness. In addition, in order to overcome the problem of insufficient information in small sample missile assembly tests, the Bayesian method is combined with the system contribution degree to fuse multi-source prior information in the identification test design, and a test scheme with full information utilization and controllable risks for both parties is designed. The example shows that compared with the quantitative characterization index of a single damage standard, this study can fully describe the missile damage effectiveness, and compared with the improved binomial distribution hypothesis test method, the superiority of this method is verified.

Enhancing Blood-Brain Barrier Integrity in Patients With Acute Ischemic Stroke Via Normobaric Hyperoxia.

Recent advancements in animal studies have demonstrated the potential of normobaric hyperoxia (NBO) as a promising intervention for preserving the integrity of the blood-brain barrier (BBB). However, there is still limited understanding of the effects of NBO on BBB function in patients with clinical stroke. Therefore, the objective of this study was to investigate the efficacy of NBO therapy in attenuating BBB damage and reducing brain injury in individuals undergoing endovascular treatment (EVT) for acute stroke. This study enrolled patients from the OPENS-1 (Normobaric Hyperoxia Combined With Reperfusion for Acute Ischemic Stroke) study, with 43 patients receiving NBO combined with EVT and 43 patients receiving EVT alone. The main outcome measures included serum levels of occludin, MMP-9 (matrix metalloproteinase-9), NSE (neuron-specific enolase), and S100b at 24 hours and 7 days, as well as the intracranial extravasation rate at 24 hours. Serum markers were assessed using ELISA, and intracranial contrast extravasation was visualized using dual-energy computed tomography scan. We analyzed a total of 86 patients and found that the 24-hour serum markers levels of BBB damage and brain injury were significantly lower in the group receiving NBO therapy combined with EVT compared with the group receiving EVT alone. Similarly, at 7 days, the levels of occludin, MMP-9, and NSE were lower in the NBO+EVT group. We also found that the 24-hour serum levels of occludin and MMP-9 were correlated with intracranial contrast extravasation. Additionally, the incidence of intracranial contrast extravasation was lower in the NBO+EVT group compared with the EVT group (35.9% versus 60.5%, P=0.031). This study offers valuable insights into the positive impact of NBO on maintaining BBB integrity and reducing brain injury in patients with acute stroke undergoing EVT.

Fatigue notch strengthening effect of nickel-based single crystal superalloys under different stress ratios

Nickel-based single crystal superalloys (Ni-SXs) are widely used in turbine blades of aircraft engines. With the increasing demand for higher temperature-bearing capacity, the introduction of film cooling holes, impingement holes, and trailing edge slots for cooling induces stress concentration, which compromises the structural integrity of the blades, generates complex multiaxial stress states, and adversely affects their operational performance. In this study, Ni-SXs, DD6, was utilized to investigate the influence of stress ratios on fatigue performance under complex stress states. Low cycle fatigue (LCF) tests were carried out at different stress ratios with stress concentration coefficient Kt = 1.0, 2.0 and 3.0. The results indicate that the notched specimens exhibit a significant fatigue notch strengthening effect under high stress ratios. The fracture surface and microstructure also indicate that under high stress ratios loading, the notches exhibit significant creep failure characteristics. This means that the main cause of fatigue notch strengthening is similar to creep notch strengthening effect. A macroscopic anisotropic constitutive model coupled with damage was developed and applied to finite element analysis of notched specimens. The results demonstrate that as the stress ratio rises, the stress relaxation effect at the notch becomes more pronounced, yet the level of damage diminishes. Additionally, a stress-equivalent model based on Bridgman stress was proposed, which effectively unifies the lifetime trends of notched and smooth specimens, predicting lifetimes within a threefold error band.

Multiple outcomes of the germline p16INK4a mutation affecting senescence and immunity in human skin.

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts invitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types invivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance invivo.

Agrobacterium virulence factors induce the expression of host DNA repair-related genes without promoting major genomic damage

This study aimed to investigate whether the plant DNA damage levels and DNA damage response (DDR) are regulated during Agrobacterium infection and potentially manipulated by Agrobacterium to facilitate T-DNA integration. We investigated the plant genomic response to Agrobacterium infection by measuring gamma H2AX levels, which reflect the levels of double-strand DNA breaks (DSBs), and by characterizing transcription of three major DNA repair marker genes NAC82, KU70, and AGO2. These experiments revealed that, globally, Agrobacterium infection did not result in a major increase in DSB content in the host genome. The transcription of the DNA damage repair genes, on the other hand, was elevated upon the wild-type Agrobacterium infection. This transcriptional outcome was largely negated by a mutation in the bacterial virB5 gene which encodes the virulence (Vir) protein B5, a minor component of Agrobacterium pilus necessary for the translocation of Vir effector proteins into the host cell, suggesting that the transcriptional activation of the cellular DNA damage repair machinery requires the transport into the host cell of the Agrobacterium effectors, i.e., the VirD2, VirD5, VirE2, VirE3, and VirF proteins. Most likely, a combination of several of these Vir effectors is required to activate the host DNA repair as their individual loss- or gain-of-function mutants did not significantly affect this process.

Effect of CAT gene polymorphism on sensitivity of human lymphocytes to genotoxic effect of organochlorine pesticide in vitro

Introduction. Over recent decades, toxicogenetic studies have focused on the issues of genome instability under the action of genotoxicants, taking into account biomarkers of sensitivity. The question about the genotoxic potential of chlorpyrifos remains open, since both positive and negative effects have been revealed in various tests. The aim of the study is the investigation of sensitivity of donor peripheral blood lymphocytes to chlorpyrifos in vitro and evaluation of the contribution of polymorphism of antioxidant defense system genes (CAT (rs1001179), SOD2 (rs4880)) to the response of human cells to the action of genotoxicant. Materials and methods. The DNA damaging effect of chlorpyrifos was assessed on lymphocytes from fifty two donors using DNA-comet assay with metabolic activation (+S9) and without it (–S9). The study of cytotoxic effects of chlorpyrifos on human lymphocytes was carried out using an automatic fluorescent cell analyzer ADAMII LS. Results. Chlorpyrifos had a pronounced cytotoxic effect on lymphocytes in most donors in the absence of metabolic activation system. With increasing concentration of the pesticide in the medium and time of cultivation, the viability of lymphocytes decreased, and the proportion of cells in late apoptosis and necrosis increased. Positive genotoxic effects were found on the cells of 33 donors (-S9). In the presence of the S9, mild but statistically significant effects were detected only on cells from 2 donors. % DNA values in the comet tail after exposure to the pesticide varied for cells from different donors. In the absence of metabolic activation, a statistically significant increase in the level of DNA damage was found in cells of individuals with genotype AA (homozygote for the minor allele) for the CAT G262A catalase gene (rs1001179), compared with homozygote for the dominant GG allele. Limitations. The genotoxicity of chlorpyryfos was studied in vitro. Conclusion. The results of the study shown cytotoxic and genotoxic effects of chlorpyrifos. The sensitivity of lymphocytes from different donors to the pesticide was found to be significantly different. The association of the level of DNA damage under exposure of chlorpyrifos in vitro with the G262A polymorphism of the catalase gene was found. The research also confirms the possibility of using a model test-system with peripheral blood lymphocytes to assess the potential genetic risk for humans and to study the contribution of gene polymorphism to individual sensitivity to the action of genotoxicants.

Roadmap for rebuilding the health system and scenarios of crisis path in Gaza.

The horrific attacks on Gaza have had a profound impact on Gaza's health system, culminating in a multidimensional crisis. The deliberate destruction of vital infrastructure, such as hospitals, schools, housing, and public facilities, coupled with the deaths and injuries of medical personnel and support workers has only exacerbated the situation and further highlighted the existing gaps. This unprecedented catastrophe proves the criticality of adopting a new national inclusive integrated approach to meeting the immediate and long-term needs of the population. In this perspective, we explore the recovery roadmap features for rebuilding the health system in Gaza, specifically focusing on determining the primary challenges that might emerge, the trajectory of recovery, and the expected crisis scenarios. The existing evidence and perspectives of key stakeholders, including state and non-state health authorities in Palestine were synthesised. Despite some local and international initiatives undertaken to generate a concrete road to recovery, there remains a need for realistic, innovative, and comprehensive Marshall plans to rebuild Gaza's health system. The article draws on insights and gaps in current efforts and underscores the urgent need to address the challenges of rebuilding the health system. The authors strive to offer an inclusive and realistic path with the potential scenarios toward recovery and resilience considering the mass levels of loss and damage, and ways to move forward for building back a resilient health system in Gaza.