Specific Damage Research Articles

Interspecific competitive interactions affect body size and oxidative status of two nonnative salmonid species

In fish, interspecific interactions between nonnative and other sympatric species are considered determinants in shaping species assemblages. Such interactions can also arise between nonnative fish species only, including salmonids such as the brown trout (Salmo trutta, Linnaeus, 1758) and the rainbow trout (Oncorhynchus mykiss, Walbaum, 1792), returning contrasting outcomes. The present manipulative experiment was aimed at exploring the effect of interspecific competition on the body growth and the oxidative status of parr (2 + -year-old individuals) of the brown trout and the rainbow trout. Allopatric (intraspecific competition) and sympatric (interspecific competition) populations of these species were experimentally recreated in two wild streams. At the end of a 2-month-long experiment, changes in specific growth rate (SGR), oxidative status (i.e., levels of reactive oxygen species and activity of antioxidant enzymes such as superoxide dismutase — SOD, catalase — CAT and glutathione peroxidase — GPx) and oxidative damage (i.e., lipid peroxidation) were investigated in brown and rainbow trout individuals maintained in allopatric or sympatric populations. Sympatric interactions between rainbow and brown trout parr resulted in a significant decrease in SGR of brown trout individuals only. Moreover, an overall modulation of the oxidative status, in terms of an increase in ROS levels coupled with the activation of SOD and CAT activity, occurred in brown trout individuals under sympatric conditions. These findings might suggest that, under sympatric conditions, parr of the rainbow trout are more competitive than brown trout for food acquisition. However, this competition affected the antioxidant defenses of the brown trout only, probably because of reduced ingestion of dietary antioxidants or increased physical activity and aggressive behavior. Thus, interspecific interactions can induce physiological and phenotypic effects on parr of nonnative salmonids, with potential consequences on the establishment of populations of these species in freshwater ecosystems.

What Is the Influence of Femoral Version on Size, Tear Location, and Tear Pattern of the Acetabular Labrum in Patients With FAI?

Femoral version deformities have recently been identified as a major contributor to femoroacetabular impingement (FAI). An in-depth understanding of the specific labral damage patterns caused by femoral version deformities may help to understand the underlying pathomorphologies in symptomatic patients and select the appropriate surgical treatment. We asked: (1) Is there a correlation between femoral version and the mean cross-sectional area of the acetabular labrum? (2) Is there a difference in the location of lesions of the acetabular labrum between hips with increased femoral version and hips with decreased femoral version? (3) Is there a difference in the pattern of lesions of the acetabular labrum between hips with increased femoral version and hips with decreased femoral version? This was a retrospective, comparative study. Between November 2009 and September 2016, we evaluated 640 hips with FAI. We considered patients with complete diagnostic imaging including magnetic resonance arthrography (MRA) of the affected hip with radial slices of the proximal femur and axial imaging of the distal femoral condyles (allowing for calculation of femoral version) as eligible. Based on that, 97% (620 of 640 hips) were eligible; a further 77% (491 of 640 hips) were excluded because they had either normal femoral version (384 hips), incomplete imaging (20 hips), a lateral center-edge angle < 22° (43 hips) or > 39° (16 hips), age > 50 years (8 hips), or a history of pediatric hip disease (20 hips), leaving 20% (129 of 640 hips) of patients with a mean age of 27 ± 9 years for analysis, and 61% (79 of 129 hips) were female. Patients were assigned to either the increased (> 30°) or decreased (< 5°) femoral version group. The labral cross-sectional area was measured on radial MR images in all patients. The location-dependent labral cross-sectional area, presence of labral tears, and labral tear patterns were assessed using the acetabular clockface system and compared among groups. In hips with increased femoral version, the labrum was normal in size (21 ± 6 mm 2 [95% confidence interval 20 to 23 mm 2 ]), whereas hips with decreased femoral version showed labral hypotrophy (14 ± 4 mm 2 [95% CI 13 to 15 mm 2 ]; p < 0.01). In hips with increased femoral version, labral tears were located more anteriorly (median 1:30 versus 12:00; p < 0.01). Hips with increased femoral version exhibited damage of the anterior labrum with more intrasubstance tears anterosuperiorly (17% [222 of 1322] versus 9% [93 of 1084]; p < 0.01) and partial tears anteroinferiorly (22% [36 of 165] versus 6% [8 of 126]; p < 0.01). Hips with decreased femoral version showed superior labral damage consisting primarily of partial labral tears. In the evaluation of patients with FAI, the term "labral tear" is not accurate enough to describe labral pathology. Based on high-quality radial MR images, surgeons should always evaluate the combination of labral tear location and labral tear pattern, because these may provide insight into associated femoral version abnormalities, which can inform appropriate surgical treatment. Future studies should examine symptomatic patients with normal femoral version, as well as an asymptomatic control group, to describe the effect of femoral version on labral morphology across the entire spectrum of pathomorphologies. Level III, prognostic study.

Oxidative Post-translational Protein Modifications upon Ischemia/Reperfusion Injury.

While reperfusion, or restoration of coronary blood flow in acute myocardial infarction, is a requisite for myocardial salvage, it can paradoxically induce a specific damage known as ischemia/reperfusion (I/R) injury. Our understanding of the precise pathophysiological molecular alterations leading to I/R remains limited. In this study, we conducted a comprehensive and unbiased time-course analysis of post-translational modifications (PTMs) in the post-reperfused myocardium of two different animal models (pig and mouse) and evaluated the effect of two different cardioprotective therapies (ischemic preconditioning and neutrophil depletion). In pigs, a first wave of irreversible oxidative damage was observed at the earliest reperfusion time (20 min), impacting proteins essential for cardiac contraction. A second wave, characterized by irreversible oxidation on different residues and reversible Cys oxidation, occurred at late stages (6-12 h), affecting mitochondrial, sarcomere, and inflammation-related proteins. Ischemic preconditioning mitigated the I/R damage caused by the late oxidative wave. In the mouse model, the two-phase pattern of oxidative damage was replicated, and neutrophil depletion mitigated the late wave of I/R-related damage by preventing both Cys reversible oxidation and irreversible oxidation. Altogether, these data identify protein PTMs occurring late after reperfusion as an actionable therapeutic target to reduce the impact of I/R injury.

Abstract PR007: The combination of TRIP13 and Aurora kinase A inhibition caused cell cycle specific DNA damage and death in Rb-deficient cancers

Abstract Many diverse, common, and lethal cancer types have inactivation of the retinoblastoma (RB1, Rb) tumor suppressor pathway including cancers caused by the human papillomavirus (HPV), which causes &amp;gt;5% of all cancers worldwide. Despite therapeutic advances, advanced Rb-deficient cancers are still lethal with therapy-related adverse effects. Moreover, there are no therapies that uniquely target HPV-driven or Rb-deficient cancers. Therefore, biomarker-selected, targeted therapy for Rb-deficient cancers represents both a substantial unmet need and a significant translational knowledge gap. Rb-deficient cancer cells depend on Aurora A kinases to bypass the spindle assembly checkpoint (SAC) and survive due to overexpression of the mitotic checkpoint protein Mad2. Thyroid hormone receptor interactor 13 (TRIP13) catalyzes the ATP-dependent conversion of Mad2 from its active to inactive form, which turns off the SAC. Our lab discovered that the combination of Aurora A inhibition with alisertib plus TRIP13 depletion induced extensive apoptosis selectively in Rb-deficient cancer cells. Moreover, our results demonstrated that the synthetic lethality between Aurora A and TRIP13 reflects mitotic catastrophe. The combination led to highly abnormal mitoses in Rb-deficient cancer cells, evidenced by unaligned, dispersed chromosomes, mitotic spindle defects, and G2/M arrest. Moreover, live cell imaging showed that alisertib treatment increased the duration of first mitoses and induced mitotic cell death, which was even more pronounced in second mitotic events. The combination resulted in both prolonged mitotic arrest and enhanced lethality, indicated by increased mitotic cell death after the first mitoses and interphase cell death following the first mitotic arrest. Furthermore, using degron tagging to rapidly degrade TRIP13, we showed that TRIP13 depletion led to transient mitotic arrest in cells that were in late G2, supporting the role of TRIP13 in regulating the SAC and mitotic progression. Since prolonged mitotic arrest is known to cause DNA damage and both Aurora A and TRIP13 are known to be involved in the DNA damage response, we also tested the effect of the combination treatment on DNA damage. Treating Rb-deficient cancer cells with the combination resulted in robust increases in gamma-H2AX, pTIF1 beta (KAP1, TRIM28), and DNA PKcs. The lethal effects of the combination required mitotic entry as concurrent CDK1 inhibition with RO-3306 prevented apoptosis and DNA damage induced by the combination. The selective effect of the combination in Rb-deficient cancer cells may have a wide therapeutic index resulting in less toxic and more effective therapy. Additionally, targeting mitosis may contribute to a cancer-specific effect due to cancer cells’ high proliferation rate. Our study suggests that targeting TRIP13 and Aurora A led to DNA damage and death specifically during mitosis in Rb-deficient cells. This work has potential to establish a foundation for future clinical trials and may change current clinical practice paradigms. Citation Format: Lacin Yapindi, Soma Ghosh, Tuhina Mazumdar, Faye M. Johnson. The combination of TRIP13 and Aurora kinase A inhibition caused cell cycle specific DNA damage and death in Rb-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr PR007.

Abstract IA020: Micronuclei are a nexus of DNA damage signaling and genomic instability

Abstract Micronuclei have classically been considered inert biomarkers of genomic instability arising from failed DNA damage repair and chromosome segregation errors in mitosis. Work from several groups including our own have now demonstrated that micronuclei are active contributors to the cellular response to DNA damage by driving chromothripsis and through induction of anti-viral gene expression programs mediated by the cGAS-STING pathway. We now show that the specific DNA damage type leading to micronuclei formation influences the capacity for cGAS localization and activation. This arises in part due to discrete chromatin features, present prior to DNA damage induction, that are retained in micronuclei several days after their formation. Together these data demonstrate that micronuclei connect the pre-damage chromatin status and the chromatin context of micronuclei-inciting lesions to the long-term signaling outcomes important for anti-tumor immunity. This finding implies that micronuclei represent archives for the nature of DNA repair failure and downstream signaling consequences. Based on this premise we will present our efforts in micronuclear proteomics where we uncover common features of micronuclei including splicing deficiencies. Such deficiencies presage exacerbated MN-associated DNA damage that is upstream of chromothripsis. These studies have direct implications for how cells sense the aftermath of DNA damage and how micronuclei contribute to ongoing genomic instability. Citation Format: Shane M. Harding. Micronuclei are a nexus of DNA damage signaling and genomic instability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA020.

Прионы и прионные болезни: мифы и реальность

The article contains modern data about prions and the main prion-associated diseases. The authors describe the main conditions that provide prion-associated infectious diseases, primarily the conformation changes of protein PrPС expressed in healthy tissues of humans and animals and forming the pathogenic PrPSc protein. All prion-caused diseases are considered to be neurodegenerative with fatal outcomes due to a specific spongy brain damage. Information on some aspects of pathogenesis and therapeutic options for prion diseases is presented. The data on the prion safety of biological preparations widely used in healthcare are also presented.

Chemically induced cone degeneration in the 13-lined ground squirrel.

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.

Adaptive Risk Management in Road Construction: Oyon-Ambo Highway Insights, El Niño 2019 Case Study

This research provides an in-depth analysis of the challenges faced during the construction of the Oyon-Ambo highway in Peru, particularly during the extreme rainfall events associated with the 2019 El Niño phenomenon. Situated in the high Andean area of the Pasco region, this rigid pavement road project encountered significant disruptions due to the extraordinary weather conditions. The adjacent Chaupihuaranga River experienced increased flow rates, causing extensive damage to the road and necessitating substantial modifications to the engineering plans. Focusing on 14 critical sectors identified in the project's technical file as prone to instability, the study details the accelerated degradation and eventual destruction of these sectors due to the intense rainfall. Emphasizing the importance of adaptive risk management in road construction, especially in regions susceptible to natural phenomena like El Niño, the paper underscores the need for responsive reengineering approaches based on specific damage types. It also highlights the critical role of continuous monitoring and evaluation in adapting to environmental changes. The insights from the Oyon-Ambo highway case offer valuable lessons for future road construction projects, underscoring the importance of proactive and adaptive risk management strategies to minimize the impacts of extraordinary natural events.

The role of density functional theory in decoding the complexities of hydrogen embrittlement in steels.

Hydrogen (H) is considered as the key element in aiding the initiated green energy transition. To facilitate this, efficient and durable technologies need to be developed for the generation, storage, transportation, and use of H. All these value chain stages require materials that can withstand continuous exposure to H. Once absorbed, H can eventually concentrate to critical levels in a stressed microstructure, inducing specific damage mechanisms and consecutive loss of mechanical properties. This is known as hydrogen embrittlement (HE). Being one of the most significant structural material types, steels are widely used throughout the H value chain. They can suffer from HE, and numerous attempts are made towards understanding and mitigating this complex phenomenon. While originating at a size scale of atoms, HE acts on multiple spatio-temporal scales, and combined efforts of experimental and modelling techniques are needed to deal with it. This perspective is devoted to assimilating the knowledge that can be generated by density functional theory (DFT) methods to understand interactions between H and iron-based materials, and to promote finding solutions to HE in metallic materials in general. We aim to provide a comprehensive understanding of the properties calculated using DFT that can help advance finding novel H-resistant high-strength materials that facilitate the green shift at sufficient performance levels to meet the growing future needs.

Study of different initiation and propagation criteria in the XFEM modelling of scarf adhesive joints

Scarf adhesive joints, characterized by an end-to-end connection between tapered adherents at a given scarf angle (α), are applicable in structural applications, e.g., fiber-reinforced structures, owing to their efficiency. This work presents an analysis on the tensile strength of scarf adhesive joints, considering a and the adhesive type as design parameters. A detailed numerical evaluation is presented, based on the eXtended Finite Element Method (XFEM), following the technique validation with experimental data, for adhesives with different characteristics. The XFEM technique was tested with varying damage initiation and propagation criteria. The XFEM technique was positively validated for specific damage initiation and propagation criteria.

Multi-scale analysis of the mechanical behaviour of a flax fibre reinforced composite under low-velocity impact

The use of biocomposite materials in different fields requires enhanced knowledge of the nonlinear phenomena related to their complex mechanical behaviour. Namely, nonelastic mechanisms such as damage, plasticity, and rupture, potentially coupled with viscosity incidence, affect the structure’s lifetime. In this context, the aim of this paper is to propose a simplified and accessible approach that leads to modelling the overall mechanical behaviour of the composite material. The studied laminate composites were made of thermoplastic Elium resin reinforced with flax plies. Experimental quasistatic and dynamic characterisations were conducted via tensile and cyclic tensile tests to investigate the structure’s mechanical properties and corresponding failure mechanisms. The test results clearly demonstrated the presence of significant nonlinear specific coupling effects due to both flax fibre and Elium resin. The proposed multi-scale modelling analysis assumes two principal entities: the ply constituted by one or more layers of unidirectional fibres and the fibre-matrix interface considered as a surface layer of resin. Each entity was characterized by specific damage variables that were determined by mechanical tests. Model parameters were experimentally identified and expressed in the behaviour model to simulate the composite structure subjected to low-velocity impact using the Pam-Crash F.E. numerical code.

MITOCHONDRIA – AS A TARGET OF ENVIRONMENTAL FACTORS

Mitochondria—tiny organelles in the cell that each possess their own DNA—have come under a growing scientific spotlight. The traditional view of mitochondria as static organelles has been reassessed. Scientists increasingly believe they play a central role in many, if not most, human illnesses. Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells, tissues, and organs. The purpose of this review is to discuss the mechanism and consequences of mitochondrial dysfunction caused by environmental factors. Recognition of the key role of mtDNA integrity and mitochondrial function in health has grown greatly in recent years. The environment can influence human health and disease in many harmful ways. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecule. Research shows that mitochondrial DNA is uniquely susceptible to the damaging effects of reactive oxygen species (ROS). These effects are more extensive and longer-lasting in mitochondrial DNA than they are in the nuclear genome. In humans, the most concerning chemicals may be mitochondrial toxins with long half-lives. Examples include lipophilic chemical mixtures such as persistent organic pollutants (POPs) and heavy metals. Other examples of chronic exposure to mitochondrial toxins are air pollution and cigarette smoking. Compared with its nuclear counterpart, mitochondrial DNA generally has less capacity to repair itself. It specifically can’t delete the large DNA helix–distorting adducts formed when mitochondrial DNA bases are damaged by mutagens such as polyaromatic hydrocarbons and ultraviolet radiation. Conclusion - Despite numerous existing researches, the specified question requires further study. it is necessary clearer understanding of what specific environmental factors damage mitochondria and how they do so, this is important way to prevent many diseases induced by mitochondrial dysfunction. Keywords: Mitochondria; Environmental Factors; Mitochondrial dysfunction;

Deep Learning Model for Classifying and Evaluating Soybean Leaf Disease Damage.

Soybean (Glycine max (L.) Merr.) is a major source of oil and protein for human food and animal feed; however, soybean crops face diverse factors causing damage, including pathogen infections, environmental shifts, poor fertilization, and incorrect pesticide use, leading to reduced yields. Identifying the level of leaf damage aids yield projections, pesticide, and fertilizer decisions. Deep learning models (DLMs) and neural networks mastering tasks from abundant data have been used for binary healthy/unhealthy leaf classification. However, no DLM predicts and categorizes soybean leaf damage severity (five levels) for tailored pesticide use and yield forecasts. This paper introduces a novel DLM for accurate damage prediction and classification, trained on 2930 near-field soybean leaf images. The model quantifies damage severity, distinguishing healthy/unhealthy leaves and offering a comprehensive solution. Performance metrics include accuracy, precision, recall, and F1-score. This research presents a robust DLM for soybean damage assessment, supporting informed agricultural decisions based on specific damage levels and enhancing crop management and productivity.

Mid-Regional Pro-Adrenomedullin Can Predict Organ Failure and Prognosis in Sepsis?

Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM value that, in addition to clinical diagnosis, can identify patients with localized infection or those with sepsis/septic shock, with specific organ damage or with the need for intensive care unit (ICU) transfer and prognosis. The secondary aim is to correlate the MR-proADM value with the length of stay (LOS). In total, 301 subjects with sepsis (124/301 with septic shock) and 126 with localized infection were retrospectively included. In sepsis, MR-proADM ≥ 3.39 ng/mL identified acute kidney injury (AKI); ≥2.99 ng/mL acute respiratory distress syndrome (ARDS); ≥2.28 ng/mL acute heart failure (AHF); ≥2.55 ng/mL Glascow Coma Scale (GCS) < 15; ≥3.38 multi-organ involvement; ≥3.33 need for ICU transfer; ≥2.0 Sequential Organ Failure Assessment (SOFA) score ≥ 2; and ≥3.15 ng/mL non-survivors. The multivariate analysis showed that MR-proADM ≥ 2 ng/mL correlates with AKI, anemia and SOFA score ≥ 2, and MR-proADM ≥ 3 ng/mL correlates with AKI, GCS < 15 and SOFA score ≥ 2. A correlation between mortality and AKI, GCS < 15, ICU transfer and cathecolamine administration was found. In localized infection, MR-proADM at admission ≥ 1.44 ng/mL identified patients with AKI; ≥1.0 ng/mL with AHF; and ≥1.44 ng/mL with anemia and SOFA score ≥ 2. In the multivariate analysis, MR-proADM ≥ 1.44 ng/mL correlated with AKI, anemia, SOFA score ≥ 2 and AHF. MR-proADM is a marker of oxidative stress due to an infection, reflecting severity proportionally to organ damage.

Damage scenario analysis of bridges using crowdsourced smartphone data from passing vehicles

AbstractBridge wear and deterioration occur over time under typical operations. Inspections can be resource intensive, infrequent, and sometimes require bridge closure. Instrumented passing vehicles may be used to record vibration responses and extract damage‐sensitive bridge frequency response characteristics. This paper presents a methodology for extracting bridge frequencies from crowdsourced dynamic response data recorded within passing vehicles. Detected bridge frequency changes and a novel point cloud methodology are used to identify critical damage scenarios and estimate remaining life. The use of a novel crowdsourced Welch methodology allows for spectra averaging that reduces the influence of noise and transient events. Numerical and experimental studies illustrate that bridge frequencies can be accurately estimated and that changes in bridge frequency caused by different damage scenarios can be characterized. Numerical examples for the damage scenario analysis, including estimation of remaining life, are provided for two bridge types and three specific damage scenarios.

Fracturas Supracondíleas Humerales Pediátricas. Comparación de dos Técnicas de Reducción

Objective: To analyze the results of the surgical technique placement of Kirschner pins lateral versus crossed in the management of supracondylar fractures of the humerus in pediatric patients. Methodology: All pediatric patients with humeral supracondylar fracture who required surgical intervention and were subsequently evaluated 24 hours and 6 months after surgical treatment to observe and compare the differences between each patient. surgical technique used. Taking into account the acute and late complications that occurred, through an analysis with the Mann-Whitney test. Results: For the present studies, 44 pediatric patients were evaluated, of whom 70% were men and 30% women, in whom nerve and angular complications presented without any significant importance with the sex and age of the patients, with ulnar nerve involvement being the most frequent with 33% in cross placement. When carrying out the comparison with discrimination of variables, it is obtained that the placement laterally presents fewer early and late post-surgical complications and that such are not due to chance. Or the present study, it is considered that a placement of Kirschner pins laterally regardless of the member, age, gender or classification; leads to better post-surgical results. Limitations or implications: In the present study, the type of mechanical damage that causes this type of fracture was not included, nor was the Baumann angle considered. Another limitation inherent in the pediatric population is the ability of the examiner to detect a neurological deficit, especially in young patients since reports of a physical examination are always subjective. Furthermore, given the limited details of the specific damage mechanism, the number of damages caused by high-energy mechanisms may be underestimated. Originality or value: Its importance lies in the fact that both surgical techniques were performed by the same surgeons and that it is a study in the mexican population, being a contribution to the literature of this country. Findings or conclusions: Both surgical techniques present post-surgical results with cases of nerve injury, angular deformity, pain and persistent edema, but the one that presents them less frequently in the technique of placement of Kirschner pins laterally, in addition to causing statistical significance in terms of the decrease of presenting cubitus valgus in the late follow-up of the patients.

The occurrence and development of autism from the perspective of perceptual ecology

This paper discusses three theoretical models to explain the occurrence and development of autism disorders. The psychological model regards developmental disorders or psychopathological disorders of autistic patients as the manifestation of impaired mental activities, the neurobiological model mainly considers specific brain structure damage and its effect on behavioral dysfunction in autism. The ecological model doesnt directly study the mind or brain, instead it tries to explain the behavior of autistic people by studying their interactions with the environment. This paper will mainly focus on the ecological model of autism, autism is a process in humans life development, people who is suffer from autism, the influences of this disease will along with the entire lifetime, autism is not caused by a moment, but is a life through process. Compared with psychological model and neurobiological model, the ecological model view of autism based on perceptual ecology theory highlights the interaction between individuals and the environment, which indicates that autism can also effect by environment, outside components can consider as triggers of autism as well.

Abstract B178: Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs

Abstract While poly-ADP-ribosylation (PAR) polymerase inhibitors (PARPi) are the only DNA damage repair (DDR) agent currently approved for clinical use, there are numerous ongoing clinical and preclinical drug development efforts of many other DDR-related targets, including ATR, ATM, CHK1 and others. One of the major challenges of these efforts is the ability to identify responsive populations and assign the right population for the right drug or drug combination. Patients are routinely assigned to PARPi or to on-going DDRi clinical trials based on the presence of BRCA mutation, or BRCAness profile encompassing various homologous recombination deficiencies (HRD). However, these biomarkers only partially represent the responsive populations, resulting in low response rates as well as misidentification of potential patient populations outside the genomic label. Since DNA replication and DNA repair mechanisms are dominated by signaling events, we hypothesized that HRD extends beyond the genomic status, and is manifested also in the level of protein expression and protein modification.In the current work, we compare the differences between cell lines that are either sensitive or resistant to a variety of DDR agents and highlight potential predictive biomarkers that are independent of HRD mutation status. We combined publicly available proteomic profiles of unperturbed cell lines, with both existing and newly generated proteomic and phosphoproteomic data of multiple cell lines before and after treatment of multiple DDR drugs.Analysis of HRD mutations showed that drug sensitivity is only partially explained by mutations. In addition, we found DNA replication and spliceosome as pathways that are consistently related to response regardless of drug and mutation status. While there is a general agreement between drugs in the pathway level, we identify smaller groups of proteins that are either drug or target-specific. We present here a proteogenomic approach to tackle the challenge of predictive biomarkers to DDR drugs. While DNA repair vulnerability is essential for DDR drug response, it is often not defined by mutations alone. We provide a proteomics-based framework that would enable future patient selection in DDR clinical trials. Citation Format: Gali Arad, Avital Hay-Koren, David Futorian, Oren Fischman, Dina Daitchman, Ofer Givton, Iris Alchanati, Yonatan Katzenelenbogen, Eran Seger, Kirill Pevzner. Proteomics platform identifies vulnerabilities for specific DNA damage repair drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B178.

Lipid-Mediated Modulation of DNA Damage Signaling As a Prognostic and Therapeutic Strategy Against Multiple Myeloma

Multiple myeloma (MM), characterized by the accumulation of tumor plasma cells in the bone marrow, is the second most common hematologic cancer. Occurrence of chemoresistance invariably leads patients to relapse and results in loss of clinical control over the disease. Cancer cells show a deregulation of different pathways, including lipid metabolism alterations and high genomic instability. Yet, no functional relationship between these two features has been identified. We have shown in a previous work that the metabolism of lipids impacts in how DNA damage is detected, signaled and repaired (Ovejero et al 2023 EMBO J). We reported that breaks in the DNA trigger the birth of lipid droplets (LD), a central lipid-storage organelle, and that this event is key for cells to tolerate this specific DNA damage. Given that MM cells are particularly dependent on DNA repair pathways for survival, we postulated that new therapeutic perspectives would emerge by targeting the formation of LD. Analysis of the LD formation gene expression profile of a cohort of newly diagnosed MM patients (UAMS-TT2 MM cohort, n = 345) allowed the establishment of a LD score comprising 13 genes associated with a significant prognostic value after multiple testing correction. The LD score gene expression-based risk score enabled the identification of MM patients with a poor outcome. The prognostic value of the LD score was validated in two other independent cohorts of newly diagnosed patients (HM cohort, n = 206; UAMS-TT3 MM cohort, n = 158) and in a cohort of patients at relapse treated with anti-CD38 MoAb (Mtp-Dara, n = 49). We subsequently studied the presence of LD in primary MM cells obtained from 34 patients. Importantly, we observed a significant positive correlation between the percentage of LD-positive cells and the value of the LD score (p = 0,02). This prompted us to investigate the therapeutic interest of interfering with LD formation to target MM cells. To this end, we treated 26 Human Myeloma Cell Lines (HMCLs) with drugs selected on an educated-guess basis and identified positive hits. These results were validated employing a shRNA strategy in selected HCMLs. Flow cytometry analyses revealed that this regime triggered a cell cycle halt, where cells accumulated in the G 1 phase at the expense of S and G 2. This was accompanied by a decrease in c-MYC expression, as well as an induction of cell proliferation arrest markers such as the G 1-checkpoint CDK inhibitors p21 and p27. Mechanistically, we observed a significant increase in Chk1 and Chk2 phosphorylations, two downstream events of DNA damage signaling despite that basal DNA damage levels remained unchanged. Together, these data convey the notion that limiting LD formation in MM cell lines boosts the detection of endogenously present DNA damage, thus enforcing a more robust DNA damage signaling which culminates in a drastic loss of proliferative capacity and viability. Of major importance, we validated the therapeutic interest of this strategy in primary MM cells from patients (n = 19). A significant higher toxicity in MM cells was found compared to normal cells from the microenvironment (tumoral: ****, p &amp;lt; 0.0001; normal: ***, p = 0,0006). Moreover, we tested the therapeutic interest of combining this approach with conventional treatments used in MM. Interestingly, we identified a synergistic effect when combined with melphalan, a DNA-alkylating agent used in MM treatment. This synergy was observed in HCMLs and in primary MM cells of patients (n = 7). Furthermore, significant synergistic effects were found in HMCLs by combining with the proteasome inhibitors bortezomib and carfilzomib. Altogether, these data unveil both the LD score and LD-bearing cell quantification as new prognostic factors in MM, and open new therapeutic perspectives to improve the treatment of MM patients by targeting LD metabolism.

Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) Survey: Perspectives of Physicians in Gulf Cooperation Council Countries on Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a genetic disorder that adversely impacts patients' physical and emotional well-being, yet research on the impact of SCD on quality of life is limited. The prevalence of SCD across Gulf Cooperation Council (GCC) countries ranges 0.24-5.8% (Abu-Shaheen et al. Expert Rev Hematol 2022). The Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) survey aimed to broaden understanding of the global burden of SCD. This analysis reports the experiences of physicians in GCC countries treating patients with SCD who participated in the SHAPE survey within the context of insights obtained globally. Methods: Physicians from Brazil, Canada, France, Germany, the UK, the US, and 2 countries in the GCC (Saudi Arabia and the United Arab Emirates [UAE]) completed a 12-minute online survey comprising close-ended questions about their experiences of treating patients with SCD. Physicians practicing for 3-35 years and currently caring for ≥10 patients with SCD were eligible. Results:Of 219 physicians globally who responded, 30 (13.7%; Saudi Arabia and the UAE, n=15 each) were from GCC countries. Physicians in GCC countries on average were caring for 16 patients with SCD and had 16 years of experience treating patients with SCD. The most common symptoms of SCD reported to physicians in GCC countries were bone aches (95%) in patients aged ≤11 years, fatigue/tiredness and bone aches (92% each) in patients aged 12-17 years, and bone aches (100%) in patients aged ≥18 years. Bone aches and yellow eyes/skin/nails were symptoms reported by a significantly higher proportion of patients in all age groups to physicians in GCC countries than all surveyed physicians (Figure 1). Most physicians agreed early treatment of SCD can help with managing/preventing severe symptoms (80% in GCC countries vs 87% globally) and that treating hemolytic anemia can improve most aspects of SCD including, reducing end-organ damage (87% vs 84%). A significantly greater proportion of physicians in GCC countries, compared with all surveyed physicians, reported they were confident in their knowledge of the consequences of hemolytic anemia (93% vs 50%), and they were significantly more likely to attribute the development of SCD complications such as chronic anemia, kidney damage, and blood clots to hemolytic anemia (Figure 2). A significantly greater proportion of physicians in GCC countries, compared with all surveyed physicians, agreed end-organ damage is unavoidable (87% vs 59%), and they were reluctant to discuss the potential future challenges/complications of SCD with a patient or their family (57% vs 37%). Most physicians agreed they were optimistic about future treatments for SCD (73% in GCC countries vs 81% globally). A significantly greater proportion of physicians in GCC countries reported considering the cost/benefit ratio to the patient and/or health care system before recommending a treatment compared with all surveyed physicians (87% vs 64%). Physicians in GCC countries, compared with all surveyed physicians, reported a significantly smaller proportion of patients were treated with hydroxyurea (24% vs 43%) and opioids (10% vs 29%). The top concerns physicians in GCC countries had were their patients not understanding the long-term effects/progression of SCD (47%), only seeking treatment/care when experiencing crises (47%), and lack of community support for patients (40%). Physicians reported wanting more support to educate their patients about the long-term effects of SCD (93% in GCC countries vs 83% globally). Conclusions: Physicians in GCC countries identified the symptom(s) most frequently reported by patients aged ≤11 years and ≥18 years as bone aches, and by patients aged 12-17 years as bone aches and fatigue/tiredness. Most physicians in GCC countries agreed end-organ damage is unavoidable, but over half were reluctant to discuss the potential future complications of SCD with patients and their families. Findings from the SHAPE survey underline the need for treatments that target specific SCD symptoms and delay end-organ damage, as well as the need of physicians in GCC countries for greater support when treating patients with SCD.