Genetic Vulnerability Research Articles

Trauma, Resilience, and Substance Use in Adolescents: A Review Article

Background: Adolescence is a sensitive phase of human life featuring changes in physical, emotional, and social characteristics. Many teens experience stressful events and trauma, which can affect their mental health and increase their risk of initiating and continuing substance use. Genetic vulnerabilities impact this relationship. In the face of trauma, while some adolescents are vulnerable, others navigate similar experiences differently, show resilience, and generally fare better without developing substance use problems. Understanding the multiple contributory factors that impact this relationship is critical in informing clinical approaches and program development. Objective: To describe the intricate dynamics between trauma, resilience, and substance abuse among adolescents. This review attempts to offer a synopsis that clarifies existing perspectives on trauma and substance use in adolescents while indicating areas for future research, clinical, and intervention programs in this critical area of adolescent well-being. Methods: A literature review was conducted to reveal available studies related to trauma, adolescent substance use, and resilience. Synthesis of findings from empirical studies, a detailed discussion on trauma and developmental factors while also addressing resilience elements alongside patterns of substance use is presented. Conclusion: Trauma, resilience, and substance use are linked in a tri-directional relationship, which is complex and dynamic. Adolescents with trauma are at higher risk of initiating and continuing substance. Resilience impacts treatment-seeking and engagement and may reduce relapse risk. Future research recommendations include improving the cultural sensitivity of interventions, studying the effects of marginalized identities, and ensuring rigorous evaluation of and progressive development of intervention programs. Results: The review highlights the bidirectional connections between trauma and substance use in adolescents. We include the consideration of resilience in adolescent responses to trauma. Resilience may reduce the risk of substance use, improve treatment-seeking and engagement in the treatment of SUD in adolescents, and reduce the risk of relapse, thereby suggesting it is a third dimension in the relationship between trauma and substance use. This review also provides evidence-based interventions and policies that are tailored to the specific needs of a diverse population of adolescents. We uncover the gaps in research, especially regarding cultural specifics and intersectionality among marginalized identities.

Common Genetic Influence on the Relationship Between Gaming Addiction and Attention Deficit Hyperactivity Disorder in Young Adults: A Twin Study.

Although the relationship between gaming addiction (GA) and attention deficit hyperactivity disorder (ADHD) is well established, the causal mechanism of this relationship remains ambiguous. We aimed to investigate whether common genetic and/or environmental factors explain the GA-ADHD relationship. We recruited 1413 South Korean adult twins (837 monozygotic [MZ], 326 same-sex dizygotic [DZ], and 250 opposite-sex DZ twins; mean age = 23.1 ± 2.8 years) who completed an online survey on GA and related traits. Correlational analysis and bivariate model-fitting analysis were conducted. Phenotypic correlation between GA and ADHD in the present sample was 0.55 (95% CI [0.51, 0.59]). Bivariate model-fitting analysis revealed that genetic variances were 69% (95% CI [64%, 73%]) and 68% (95% CI [63%, 72%]) for ADHD and GA respectively. The remaining variances (ADHD: 31%; GA: 32%) were associated with nonshared environmental variances, including measurement error. Genetic and nonshared environmental correlations between ADHD and GA were 0.68 (95% CI [0.62, 0.74]) and 0.22 (95% CI [0.13, 0.30]) respectively, which indicates that shared genes can explain 82% of the phenotypic correlation between ADHD and GA. Our study demonstrated that the ADHD-GA association was largely due to shared genetic vulnerability.

The association between aberrant salience and psychotic experiences in general population twins, and genetic vulnerability as a modifier

BackgroundPrevious studies assessing the hypothesis that the construct of ‘aberrant salience’ is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results.MethodsThe TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task.ResultsMeasures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282).ConclusionsVarious studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called ‘ultra-high risk’ patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum.

Unveiling the genetic link and pathogenesis between psoriasis and IgA nephropathy based on Mendelian randomization and transcriptome data analyses.

It has been reported that many people with psoriasis have been diagnosed with secondary IgA nephropathy (IgAN). However, the mechanisms behind the association between psoriasis and IgAN have not been well clarified. The connection between psoriasis and IgAN deserves deeper exploration. Mendelian randomization (MR) analysis would be employed to explore the link of causality between IgAN and psoriasis, psoriasis vulgaris, other and unspecified psoriasis, guttate psoriasis, and arthropathic psoriasis. Transcriptomic analyses were carried out against the Gene Expression Omnibus databases. We identified crosstalk genes through the analysis of Differentially expressed genes and weight gene co-expression network analysis. Functional annotations were enriched for these crosstalk genes. Subsequently, we established a protein-protein interaction network, and candidate genes would be discovered through the utilization of the MCODE and CytoHubba plug-in applications. Lastly, the predictive efficacy of these genes was examined via creating receiver operating characteristic curves. The MR analysis suggested that psoriasis vulgaris patients were at a higher risk for IgAN. [OR = 1.040, 95%CI (1.005,1.076), p = 0.026 < 0.05]. Additionally, arthropathic psoriasis may augment the incidence of IgAN [OR = 1.081, 95%CI (1.040-1.124), p < 0.01] in the European population. Through the analysis of DEGs and WGCNA, we identified 12 significant genes (NETO2, RRM2, SLAMF7, GBP1, KIF20A, CCL4, MMP1, IL1β, NDC80, CXCL9, C15orf48, GSTA3), which may be potential crosstalk genes between the two diseases. Then, the functional annotation results indicated that the crosstalk genes seemed primarily involved in immune and inflammatory responses. By establishing the PPI network, we further discovered that CXCL9, IL1β, CCL4, and MMP1 play a vital part in psoriasis and IgAN, and all have good diagnostic values. Our MR analysis provided evidence that genetic vulnerability to IgAN may be associated with an elevated risk of psoriasis vulgaris and arthropathic psoriasis respectively among Europeans. Doctors should be aware of these associations when patients with psoriasis present with renal dysfunction, especially those with psoriasis vulgaris and arthropathic psoriasis. Chronic inflammation, drug effects, and immunity may contribute to the generation and development of both diseases. IL1β, CXCL9, CCL4, and MMP1 may be core biomarkers for psoriasis and IgAN.

The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = −0.34, 95% CI = [−0.660, −0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Optimizing Peanut (Arachis hypogaea L.) Production: Genetic Insights, Climate Adaptation, and Efficient Management Practices: Systematic Review

Peanut production plays a crucial role in global food security, particularly in developing countries, where it provides essential nutrition and income. This paper examines the optimization of peanut production through genetic advancements, climate adaptation strategies, and sustainable practices. The primary objective is to increase yields by addressing challenges related to climate change, pests, and resource constraints. Globally, peanut production is hindered by rising temperatures, irregular rainfall, and declining soil quality, impacting both yield and quality. Developing countries, especially in Africa and Asia, face additional challenges, such as limited access to advanced agricultural technologies, inadequate infrastructure, and insufficient support for smallholder farmers. The vital issues include genetic vulnerabilities to pests, climate stress, and inefficient water use. Recent genetic research has provided insights into breeding more resilient, drought-resistant varieties, offering hope for improving yields, despite environmental challenges. The adoption of climate adaptation strategies, precision farming, and integrated pest management is essential for boosting productivity. These, along with optimized irrigation and nutrient management, have significantly impacted peanut production in resource-limited settings. Additionally, drought-resistant varieties have proven crucial, enabling farmers to increase resilience and yields in areas facing climate stress. In conclusion, optimizing peanut production requires continued investment in genetic advancements, infrastructure, and sustainable practices. Future efforts should focus on improving climate adaptation and sustainable farming techniques for long-term success.

A new 2-hit model combining serine racemase deletion and maternal separation displays behavioral and cognitive deficits associated with schizophrenia

Schizophrenia (SCZ) is a multifactorial psychotic disorder characterized by positive and negative symptoms as well as cognitive impairments. To advance the current treatments, it is important to improve animal models by considering the multifactorial etiology, thus by combining different risk factors. The objective of our study was to explore in a new mouse model, the impact of genetic deletion of serine racemase (genetic vulnerability) combined with an early stress factor induced by maternal separation (early environmental exposure) in the context of SCZ development. The face validity of the model was assessed through a wide range of behavioral experiments. The 2-hit mice displayed an increased locomotor activity mimicking positive symptoms, working memory impairment, cognitive deficits and recognition memory alterations, which could reflect neophobia. This new multifactorial model therefore presents an interesting phenotype for modelling animal model with partial behavioral and cognitive deficits associated with SCZ.

Environmental and Genetic Contributions to Attachment in Late Adolescence and Young Adulthood.

Adverse childhood experiences (ACEs) have been linked with attachment insecurity and psychopathology. However, some individuals remain securely attached and resilient following ACEs. Researchers have examined polymorphisms in the oxytocin receptor gene (OXTR), particularly rs53576, as a source of resilience, though examination of the biological mechanism by which rs53576 buffers the relation that would otherwise exist between ACEs and attachment insecurity is absent. The aim of the current study was to examine how ACEs interact with individual genetic and immune vulnerability to shape attachment security in older adolescents and young adults (n = 201). Moderated mediational models were tested in which ACEs acted as independent variables, attachment security acted as a dependent variable, inflammation (i.e., IL-6) was tested as a mediator, and rs53576 (i.e., AA, AG, GG genotypes) was tested as a moderator. Results indicated that physical abuse was significantly associated with decreased attachment security, with moderation by rs53576. A significant main effect of rs53576 on IL-6 was also noted. A similar pattern of results was evident across other ACEs and suggests that the effects of ACEs on attachment are buffered by the GG genotype. Association between GG and lower IL-6 suggests inflammation plays some role, though more research is needed.

Replication Stress is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSCRT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP and ATR inhibitors (PARPi, ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically-relevant models of DSRCT, including cell lines, a patient-derived xenograft (PDX)-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2/M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing the sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cGAS/STING innate immune pathway and cell surface expression of PD-L1. Taken together, these findings point towards a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT.

Impact of Estrogen Therapy on BRCA1-Associated Breast Cancer Progression in Transgender Women

The combination of hormone treatment and genetic liabilities in transgender women leads to a complicated situation for breast cancer growth particularly linked to BRCA1 mutations. Gender-affirming treatment relies heavily on estrogen and causes intense cell growth and differentiation in breast tissue driven by estrogen receptor mechanisms. Mutations in BRCA1 lead to weak DNA repair processes which enhance an individual's vulnerability to cancerous changes. Rodestrogens enhance the functioning of proliferative pathways like PI3K/AKT and MAPK pathways in cells with dysfunctional BRCA1. This collaborative action elevates the threats posed by benign growths such as fibroadenomas leading to invasive breast cancer. By affecting the expression of vital regulatory proteins linked to cell proliferation estrogen further compromises the genomic integrity in cells harboring BRCA1 mutations. The hormone environment influenced by exogenous estrogen therapy can shape the tumor microenvironment for better cancer progression and metastasis. Comprehending the relationship between estrogen signaling and pathways related to BRCA1 is important for identifying the enhanced risk of cancer in transgender women using hormone therapy. This detailed study aligns recent discoveries regarding genetic vulnerability and hormonal impacts with cell mechanisms to reveal a detailed insight into breast cancer progression in these individuals. The study emphasizes the necessity for custom-designed cancer screening methods and targeted treatments to help mitigate risks and support transgender care. Understanding these pathways greatly enriches our knowledge of hormone-induced carcinogenesis among those who carry certain genetic markers while also guiding the creation of personalized care for transgender women at enhanced risk of breast cancer.

Flow Cytometry Analysis of CD4⁺ and CD8⁺ T Lymphocytes in COVID- 19 Patients

The clinical presentation of COVID-19 varies greatly from case to another, with host characteristics playing a pivotal role. The immune system is a pivotal function in establishing the course of SARS-COV-2 infection. Severe instances of COVID-19 and the resulting death are caused less by the virus itself than by the destructive unrestrained immune response. Among the host determinants for poor disease prognosis is probably genetic vulnerability to dysregulated immune response. The objective of this work is to examine some of the host genetic variables that are being studied in relation to the severity of COVID-19. The complex relationship between autoimmunity and the pathophysiology of COVID-19 was examined. Patients with COVID-19 were recruited from AL-Dewaniyah Teaching Hospital and AL-Hussain Teaching Hospital in Karbala city. All patients had been diagnosed with the virus using real-time polymerase chain reaction. A total of 70 blood samples (35 from the mild group, 35 from the severe group, and 35 from the controlled group) were obtained in EDTA tubes. Orderly to investigate the correlation between the progression of disease and variations in specific regions of host immunoassays had been used by flow cytometry. The results of the flow cytometry were reported as the average percentage of positive cells for CD4 and CD8 immunological markers. Cases with COVID-19 had a substantially lower mean CD4 concentration than the healthy patients. Furthermore, the mean concentration of CD8 was significantly lower in cases with COVID-19 than in healthy. In addition, there is significant (P 0.001) decline in both CD4 and CD8 mean levels between patients with severe and mild COVID-19.

USING (GEN)OMICS TO DISENTANGLE DEPRESSION'S HETEROGENEITY

Psychiatric disorders are heterogeneous conditions with diverse symptom and course profiles. This complicates pathophysiology studies as different biological and environmental mechanisms could lead to the same disorders. Unravelling this heterogeneity is important to be able to provide precision medicine. Penninx focuses on further unravelling the heterogeneity of depression using genomics (DNA, RNA, epigenetics) as well as other ‘-omics’ (metabolomics, proteomics). In her Netherlands Study of Depression and Anxiety, detailed phenotyping is combined with biobanking in seven waves covering 15 years of data collection. Using these rich resources, it has been shown that about one-third of all depressed patients illustrates an immunometabolic depression profile, where atypical, energy-related symptoms (fatigue, hypersomnia, weight increase, leaden paralysis) are predominant and co-occur with higher (genetic vulnerabilities for) immunometabolic dysregulations. The other two-thirds of all depressed patients can be characterized by a more typical depression profile, with e.g. melancholia, and pathophysiology that is more characterized by HPA-axis dysregulations, adverse life events and a genetic vulnerability that is more overlapping with e.g. schizophrenia. Penninx's work illustrates that genomics in combination with other detailed phenotyping contributes to further disentangle the heterogeneity of mental disorders, paving the way towards personalized medicine.

Reviewing Genetic Testing for Lupus: Implications for Nephritis

Genetic testing has significantly changed our understanding and treatment of systemic lupus erythematosus (SLE), particularly its severe manifestation, lupus nephritis (LN). Nephrology faces great difficulty with LN, which is characterized by severe inflammation and kidney damage. To create individualized treatments, it is essential to identify the genetic variables that influence the LN susceptibility and progression. This review highlights the importance of genetic testing in diagnosing and managing LN, covering genetic predispositions, common markers, the role of ethnicity, specific renal genes, and epigenetic factors. Key genetic markers such as HLA-DRB1, ITGAM, FCGR2A, and IRF5 have been linked to LN, impacting immune regulation and disease progression. Asians, African Americans, and Hispanics have greater prevalence rates of genetic susceptibility than Caucasians, suggesting that ethnicity plays a major role in genetic vulnerability. Genes like APOL1, PDGFRA, and HAS2 play vital roles in renal function and fibrosis, affecting disease outcomes. New treatment targets are provided by epigenetic mechanisms that control gene expression in LN, such as DNA methylation and histone alterations. The progress made in genome-wide association studies (GWAS) has led to the discovery of new genetic loci linked to LN, which has improved our knowledge of its pathogenesis. This review highlights the critical role of genetic testing in LN, emphasizing its potential to improve diagnosis, treatment, and patient outcomes through personalized medicine.

Abstract C091: Uncovering genetic regulators of metabolic plasticity in renal cell carcinoma

Abstract We aim to offer new insights on the regulation of metabolic plasticity in renal cell carcinoma (RCC) and identify novel metabolic regulatory targets that can be used for potential treatment therapies of the disease. RCC affects an estimated 400,000 people worldwide each year with over 100,00 deaths annually that disproportionately affects racial/ethnic minorities in the United States. RCC is a term that covers an array of kidney cancer subtypes differing in incidence, histopathology, genetic and molecular alterations, as well as in clinical outcomes and prognoses. However, a common characteristic of many RCCs is that they are driven by metabolic rewiring, due to a high frequency of mutations in genes that regulate major metabolic processes in the cell. It was recently discovered that patient overall survival and prognosis has been linked to the expression of certain metabolic signatures in RCC tumor cells. Metabolic plasticity allows cancer cells to survive and adapt to different environments and metabolic stress conditions, such as nutrient deprivation. Therefore, exploring and exploiting metabolic rewiring in these cells may reveal genetic vulnerabilities and dependencies. This could lead to discovery of novel biomarkers and molecular targets that can be implicated as future therapeutic interventions for this disease. To this end, we applied functional genomic screening to expose genetic dependencies and vulnerabilities under different physiologic and metabolic conditions in patient derived medullary (PDM) RCC cells. The medullary RCC is a rare and aggressive RCC subtype that disproportionately affects the African American/Black population. We applied a CRISPR- based combinatorial screening platform that is based on co-expression of Cas9 and Cas12a nucleases and libraries of hybrid guide RNAs (hgRNA) to achieve ultra-efficient gene knockout (Aregger et al., 2021; Gonatopoulos-Pournatzis et al., 2020) in PDM RCC cells. Additionally, cells were screened under different media conditions that mimic human physiological nutrient conditions and a media deprived of lipids, one of the major metabolic substrates of the cell. By utilizing a genome-wide pooled CRISPR gene knockout screen we were able to systematically uncover genes required for cell survival and proliferation in a panel of patient-derived RCCs. We have begun to uncover genetic dependencies and major metabolic pathways that can be elucidated and exploited for future studies, such as those involving ferroptosis which is a targetable pathway for the development of cancer treatment therapies. Our findings demonstrate some of the key genetic drivers underlying cellular adaptations to different physiological environments and nutrient deprivation. In future studies we will further explore the relationship between different key metabolic regulatory genes in RCC and map for genetic interactions in major metabolic pathways. Citation Format: Chelsee Holloway, Josef Horak, Youngkyu Jeon, Michael Aregger. Uncovering genetic regulators of metabolic plasticity in renal cell carcinoma [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C091.

Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR.

Graph-based explainable vulnerability prediction

Significant increases in cyberattacks worldwide have threatened the security of organizations, businesses, and individuals. Cyberattacks exploit vulnerabilities in software systems. Recent work has leveraged powerful and complex models, such as deep neural networks, to improve the predictive performance of vulnerability detection models. However, these models are often regarded as “black box” models, making it challenging for software practitioners to understand and interpret their predictions. This lack of explainability has resulted in a reluctance to adopt or deploy these vulnerability prediction models in industry applications. This paper proposes a novel approach, Genetic Algorithm-based Vulnerability Prediction Explainer, (herein GAVulExplainer), which generates explanations for vulnerability prediction models based on graph neural networks. GAVulExplainer leverages genetic algorithms to construct a subgraph explanation that represents the crucial factor contributing to the vulnerability. Experimental results show that our proposed approach outperforms baselines in providing concrete reasons for a vulnerability prediction.

Optimal methods for analyzing targeted pairwise knockout screens.

Synthetic lethality offers a promising strategy for cancer treatment by targeting genetic vulnerabilities unique to tumor cells, leading to selective tumor cell death. However, single-gene knockout screens often miss functional redundancy due to paralog genes. Multiplex CRISPR systems, including various Cas9 and Cas12a platforms, have been developed to assay genetic interactions, yet no systematic comparison of method to identify synthetic lethality from CRISPR screens has been conducted. We evaluated data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using three bioinformatic approaches to identify synthetic lethal interactions: delta log fold change (dLFC), Z-transformed dLFC (ZdLFC), and rescaled dLFC (RdLFC). Both ZdLFC and RdLFC provided more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method. The ZdLFC method offers a robust framework for scoring synthetic lethal interactions from paralog screens, providing consistent results across different cell lines without requiring a training set of known positive interactors.

Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model.

Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Mapping the neurodevelopmental predictors of psychopathology.

Neuroimaging research has uncovered a multitude of neural abnormalities associated with psychopathology, but few prediction-based studies have been conducted during adolescence, and even fewer used neurobiological features that were extracted across multiple neuroimaging modalities. This gap in the literature is critical, as deriving accurate brain-based models of psychopathology is anessential steptowards understanding key neural mechanisms and identifying high-risk individuals. As such, we trained adaptive tree-boosting algorithms on multimodal neuroimaging features from the Lifespan Human Connectome Developmental (HCP-D) sample that contained 956 participants between the ages of 8 to 22 years old. Our feature space consisted of 1037 anatomical, 1090 functional, and 192 diffusion MRI features, which were used to derive models that separately predicted internalizing symptoms, externalizing symptoms, and the general psychopathology factor. We found that multimodal models were the most accurate, but all brain-based models of psychopathology yielded out-of-sample predictions that were weakly correlated with actual symptoms (r2 < 0.15). White matter microstructural properties, including orientation dispersion indices and intracellular volume fractions, were the most predictive of general psychopathology, followed by cortical thickness and functional connectivity. Spatially, the most predictive features of general psychopathology were primarily localized within the default mode and dorsal attention networks. These results were mostly consistent across all dimensions of psychopathology, except orientation dispersion indices and the default mode network were not as heavily weighted in the prediction of internalizing and externalizing symptoms. Taken with prior literature, it appears that neurobiological features are an important part of the equation for predicting psychopathology but relying exclusively on neural markers is clearly not sufficient, especially among adolescent samples with subclinical symptoms. Consequently, risk factor models of psychopathology may benefit from incorporating additional sources of information that have also been shown to explain individual differences, such as psychosocial factors, environmental stressors, and genetic vulnerabilities.

The Study of Dissociative Identity Disorder: Etiology, Cognitive Ability and Treatment

This paper provides an overview of Dissociative Identity Disorder (DID), its etiology, cognitive aspects, and treatment options. It explains the concept of dissociation and dissociative disorders, leading to the specific focus on DID. The etiology section discusses the multifaceted nature of DID, including biological factors like genetic vulnerabilities and neurobiological abnormalities. Psychological factors, particularly trauma and maladaptive schemas, and social factors, including societal influences and media portrayals, are also explored. This paper delves into cognitive abilities and their impact on individuals with the disorder. Like the relationship between sleep disturbances, trauma, dissociation, and cognitive abilities in individuals with DID and post-traumatic stress disorder (PTSD). The last part focuses on its treatment approaches, the holistic treatment approach that includes symptom reduction, engagement with traumatic memories, and integration and rehabilitation. Psychotherapy, such as cognitive behavioral therapy and eye movement desensitization and reprocessing, is the primary treatment modality, while medication may be used. This work also discusses the need for further research. It discusses potential connections between childhood trauma and cognitive strategies, the role of DID in enhancing aggression and self-protection abilities, and the impact of comorbid PTSD on treatment outcomes. By addressing these research gaps, more effective treatments for DID can be developed.