Functional Role Research Articles

Endogenous preparatory control is associated with increased interaction between default mode and dorsal attention networks

Abstract It is increasingly recognized that cognitive control requires integration across large-scale brain networks anchored in frontal and parietal cortices. While the functional role of individual networks has been studied extensively, their cross-network interactions in the service of cognitive control are poorly understood. Beyond in-the-moment regulation of goal-relevant information processing (e.g., of sensory information), cognitive control encompasses preparatory processes in anticipation of upcoming stimuli and actions. Such preparatory control is often endogenous, that is, it is based on internal representations without relying on external cues or events. Here, we assessed network interactions that support such endogenously driven preparatory control. We recorded fMRI (N = 25) during a perceptual decision task with highly variable intertrial intervals. In half of the blocks, trial onset was cued, while in the remaining blocks, participants maintained readiness without relying on cues. We studied endogenous preparatory control in the intertrial period preceding uncued (vs. cued) trials. Behavioral outcomes confirmed heavier cognitive control demands in the uncued condition. Endogenous preparatory control was associated with increased activity of the dorsal attention network (DAN). This contrasted with in-the-moment control over stimulus-response processing during the trial itself, which was supported foremost by the right-hemispheric fronto-parietal network (FPN). Cross-network interactions were strengthened exclusively during endogenous preparatory control; the default mode network (DMN) showed more positive connectivity with the DAN and to a lesser degree the cingulo-opercular network (CON). Our results demonstrate that cross-networks interactions are particularly important for endogenously driven preparatory control. They further suggest that the DMN may be implicated in internally harnessing resources for cognitive control. This notion extends the DMN’s known role in internally-oriented processing to the domain of cognitive control when preparation cannot be aided by external events.

Evaluating consumer 3D printing nozzles as a low cost alternative for mesophase pitch-derived carbon fiber production

Synthetic fibers, such as Kevlar fibers, SiC fibers, and carbon fibers, are essential components for constructing high performance structures. Whether for engineering, sports, energy storage (batteries and supercapacitors), or aerospace applications, fiber microstructure plays a critical role in fiber properties and functionalities. However, studying fiber nozzle configurations and spinning parameters to achieve the desired microstructure remains challenging, costly, and time consuming. Here, mesophase pitch-derived fibers were used as an example to demonstrate that low cost, commercially available 3D printer nozzles can “print” fibers. Four different nozzles were used to “print” fibers and the effects of their features on fiber properties were observed and compared to other lab spun and commercial pitch-derived CF. A longer orifice length resulted in higher modulus fiber whereas a larger draw-down ratio yielded a stronger fiber. The findings provide a new opportunity for 3D printer hardware application and open opportunities for developing low-cost fibers.

Children under fire: The role of maternal caregiving, reflection functioning, and posttraumatic stress disorder.

The study seeks to examine the psychological maladjustment of children who are exposed to continuous terror attacks. It is hypothesized that maternal posttraumatic stress disorder (PTSD) may hinder mothers' sensitive and responsive caregiving, reflective functioning, and viewing of her child (as "difficult"), which can subsequently negatively impact their children's psychological adjustment. A cohort of 235 mother-child dyads participated in the study. The children's (aged 7-11; 43% boys) psychological maladjustment was assessed by the PAQ. The mothers completed the DSM-5 checklist for PTSD, Caregiving System Functioning scale, Rumination-Reflection Questionnaire, and Difficult Child scale. High levels of maternal PTSD, high scores of avoidant caregiving, and low reflective functioning of the mother predicted the child's psychological maladjustment. Maternal levels of PTSD moderated the associations between maternal avoidant caregiving and reflection, and child's maladjustment, whereas perceiving the child as difficult moderated the association between maternal reflection and child maladjustment. The findings suggest that, to enhance the psychological adjustment of children confronted with stressful life situations, their mothers must be able to process their traumatizing experiences, or else they may struggle to provide their children with emotional regulation and support. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

An electrochemical-thermal coupling model for lithium-ion battery state-of-charge estimation with improve dual particle filter framework

Lithium-ion battery state-of-charge (SOC) estimation plays an indispensable role in the battery management system functionalities. To achieve SOC estimation with high accuracy, a precise battery model is required. Among various battery models, electrochemical model (EM) stands out for its ability to provide insights into the electrochemical mechanisms of the battery. However, the model parameters will vary with the battery running and aging, besides, the model-based methods cannot well handle the model errors. Therefore, to ensure estimation accuracy, selecting a more insightful battery model and a more effective estimation algorithm becomes crucial. This paper proposes an electrochemical model-based SOC estimation method with online parameter adjustment and an optimized algorithm. Firstly, a single particle model (SPM) with electrolyte and thermal dynamics is introduced and simplified by an approximate solution. Secondly, the particle swarm optimization (PSO) method is used to solve the problem of the particle filter (PF) algorithm, such as particle degradation and particle diversity decrease. Finally, during SOC estimating, a double-scale dual particle filter (D-PF) is utilized to adjust parameters as battery aging and temperature changes. The battery tests are applied under different working conditions and temperatures. Experimental results show that the error of SOC estimation reduces significantly compared to the previous electrochemical model-based method, and the proposed method has a higher accuracy and effectiveness.

Distinct Gut Microbial Enterotypes and Functional Dynamics in Wild Striped Field Mice (Apodemus agrarius) across Diverse Populations.

Rodents, including the striped field mouse (Apodemus agrarius), play vital roles in ecosystem functioning, with their gut microbiota contributing significantly to various ecological processes. Here, we investigated the structure and function of 94 wild A. agrarius individuals from 7 geographic populations (45°57' N, 126°48' E; 45°87' N, 126°37' E; 45°50' N, 125°31' E; 45°59' N, 124°37' E; 46°01' N, 124°88' E; 46°01' N, 124°88' E; 46°01' N, 124°88' E), revealing two distinct enterotypes (Type1 and Type2) for the first time. Each enterotype showed unique microbial diversity, functions, and assembly processes. Firmicutes and Bacteroidetes dominated, with a significant presence of Lactobacillus and Muribaculaceae. Functional analysis highlighted metabolic differences, with Type1 emphasizing nutrient processing and Type2 showing higher energy production capacity. The analysis of the neutral model and the null model revealed a mix of stochastic (drift and homogenizing dispersal) and deterministic processes (homogenous selection) that shape the assembly of the microbiota, with subtle differences in the assembly processes between the two enterotypes. Correlation analysis showed that elevation and BMI were associated with the phylogenetic turnover of microbial communities, suggesting that variations in these factors may influence the composition and diversity of the gut microbiota in A. agrarius. Our study sheds light on gut microbial dynamics in wild A. agrarius populations, highlighting the importance of considering ecological and physiological factors in understanding host-microbiota interactions.

Comprehensive analysis of Brassica napus aldehyde dehydrogenase superfamily genes and demonstration of BnALDH7B2 in clubroot resistance

Oilseed rapa (Brassica napus), an important oil crop worldwide, is often threatened by various adversity stresses, especially Plasmodiophora brassicae, resulting in abnormal growth and decreased yield. The aldehyde dehydrogenase (ALDH) family is crucial for plant growth and environmental stress adaptations. Nevertheless, BnALDH members and their responses to P. brassicae are unclear in B. napus. Here, 53 B. napus ALDH members were identified and classified into 10 subfamilies. Collinearity analyses revealed that the BnALDHs gene family primarily underwent expansion through segmental duplication. Structural analyses illustrated that the BnALDHs in each specific subfamily were relatively conserved. Analysis of cis-elements in BnALDH promoter regions revealed the presence of multiple elements related to stress response and plant hormones. Transcriptome analyses indicated that BnALDHs were expressed throughout B. napus multiple tissues and growth stages. Most BnALDHs were differentially expressed under different stress treatments, with BnALDH7B2 significantly upregulated during P. brassicae stress. In addition, the BnALDH7B2 overexpression transgenic plants conferred tolerance to P. brassicae stress. Molecular docking results showed that BnALDH7B2 was more functionally dependent on NAD+ than on NADP+, while phenylacetaldehyde, benzaldehyde, trans-2-nonenal, α-aminoadipate-semialdehyde, and 4-guanidinobutyraldehyde could potentially be used as substrates for BnALDH7B2. The results provide insights into the function of BnALDHs in B. napus, serving as a baseline for identifying the functional role of BnALDH7B2 under P. brassicae stress.

Relationships between rhizosphere microbial communities, soil abiotic properties and root trait variation within a pine species

Abstract Rhizosphere microbes play important roles in plant performance and ecosystem functioning. It is becoming increasingly clear that rhizosphere communities vary with soil properties and variation in root traits among plant species. However, less is known about whether and how variation in root traits within plant species influences the rhizosphere microbial communities. We evaluated the intraspecific root traits variation and explored their associations with bacterial and fungal communities in rhizosphere by focusing on an ectomycorrhizal tree species, that is Pinus massoniana, in 22 sites in subtropical China. The first dimension of the principal component analysis on root traits revealed evidence for the ‘conservation’ gradient of the root economics space. Overall, root traits explained more variation in fungal communities than in bacterial communities in the rhizosphere. Functional composition of rhizosphere microbial communities changed significantly along the ‘conservation’ gradient, with fast‐growing copiotrophic bacteria and symbiotic ectomycorrhizal fungi were significantly enriched on the ‘acquisition’ side, while slow‐growing oligotrophic bacteria were significantly enriched on the ‘conservation’ side of the gradient. Synthesis: Our study demonstrates that intraspecific variation in plant roots significantly influence rhizosphere microbial communities, which in turn can influence plant nutrition and therefore plant performance within the community.

Overexpression of OsDUF6 increases salt stress tolerance in rice

BackgroundSoil salinity is one of the primary environmental stresses faced in rice production. When plants are exposed to salt stress, a series of cellular balances will be disrupted. Dufulin is an immune-induced antiviral agent used in plants. The DUF gene family influences plant response to abiotic stress, and the functional role of OsDUF6(ABA98726.1) in rice response to salt stress is being investigated here.ResultsBased on the transcriptome analysis of Dufulin treatment in inducing salt tolerance in rice, we selected the OsDUF6 protein located on the cell membrane and studied its molecular function by overexpressing OsDUF6. Salt-induced decreases in root, stem, and leaf length and increased leaf yellowing rate and Na+ concentration in the wild-type plant were mitigated in the overexpressed lines. OsDUF6 overexpression increased the enzymatic antioxidant activities of superoxide dismutase, peroxidase, catalase, and phenylalanine ammonia-lyase. OsDUF6 also played a positive role in Na+ transport as reflected by the increased growth of a salt-sensitive yeast mutant complemented with OsDUF6 in the presence of salt stress. In addition, Reverse transcription quantitative PCR analysis confirmed that the overexpression of OsDUF6 significantly changed the expression level of other genes related to growth and stress tolerance.ConclusionsCombined with previously published data, our results supported the observation that OsDUF6 is an important functional factor in Dufulin-induced promotion of salt stress tolerance in rice.

Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes.

Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV in vitro in the presence of a panel of 38 kinase inhibitors then quantified the effect of each inhibitor on infection rate. We employed elastic net regularization on these data to obtain predictions of which of 291 kinases are regulating DENV infection. Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases - EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) - belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.

Family Functioning, Community Participation, and Rehabilitation Barriers in the Acquired Brain Injury Community: An Exploratory Analysis

Acquired brain injury (ABI) is the second most common cause of disability in America. Prior research highlights family functioning as an important predictor of psychosocial outcomes in the ABI population; however, there remains limited research aimed at understanding the role of family functioning in predicting rehabilitation progress and community participation. A quantitative, exploratory, descriptive research design was used for this study. A total sample of 49 individuals with mild-to-moderate ABI were recruited from a university medical center and outpatient rehabilitation center. Participants completed measures of demographics, community participation, family functioning, and perceived rehabilitation barriers. Data were analyzed using descriptive statistics and multiple regression (MR) analysis. Two MR models were examined, one with rehabilitation barriers as the dependent variable and one with community participation as the dependent variable. Financial support and perceived rehabilitation barriers contributed significantly to variance in community participation satisfaction, while financial support, family functioning, and community participation satisfaction each accounted for a significant portion of variance in perceived rehabilitation barriers. Overall, the full MR 1 model accounted for 33% of variance in community participation satisfaction, while the full MR 2 model accounted for 51% of variance in perceived rehabilitation barriers. Although more research with larger, more diverse samples is needed, this study provides rehabilitation and counseling professionals with important psychosocial concepts to consider in assessment and treatment and helps clarify the role of family in promoting positive rehabilitation and participation outcomes in the ABI community.

Abstract 2011: MAOA Drives Anti Androgen Therapy Resistance in Advanced Prostate Cancer by Conferring Neuroendocrine Plasticity via a Twist1 BRN2 Signaling Pathway

Abstract Background: Therapy resistance in cancer is often linked to cancer cell state or lineage changes. In prostate cancer (PCa), a subset of castration-resistant prostate cancer (CRPC) loses reliance on the androgen receptor (AR) signaling and gains neuroendocrine (NE) traits through a lineage switch along disease progression. However, the molecular mechanisms driving such cellular lineage plasticity remain unclear. This study investigated the functional and mechanistic role of monoamine oxidase A (MAOA) in driving adenocarcinoma (adeno)-to-NE lineage conversion in CRPC cells upon enzalutamide (ENZ), a FDA-approved newer-generation antiandrogen drug, and evaluated the efficacy of MAOA inhibitors for treating CRPC and overcoming ENZ resistance.Methods: ENZ-resistant C4-2B and CWR-R1 cells (C4-2BENZR and CWR-R1ENZR) CRPC cells were transfected with a PSA promoter-driven GFP expression construct for isolating a PSAlo/− cell population distinct from PSAhi cells, which was used for manipulation of MAOA expression levels and subsequent functional assays in vitro and in vivo. The MAOA expression levels were determined and correlated with NE parameters in PCa clinical samples by immunohistochemistry and data mining of multiple publicly available clinical datasets. Results: MAOA protein expression was significantly upregulated in the PSAlo/− ENZ-resistant cell population, accompanied by concomitant activation of NE markers and downregulation of luminal markers including AR and AR targets, compared to the PSAhi counterpart. Elevated MAOA expression was also found in PCa patient samples associated with NE features from multiple independent cohorts. Silencing MAOA suppressed the proliferation, migration, invasion, stem-like properties and NE plasticity of both PSAlo/- C4-2BENZR and CWR-R1ENZR cells. Moreover, co-culturing adeno LNCaP or C4-2B cells with MAOA-silenced PSAlo/- cells exhibiting a repressed secretory phenotype attenuated acquired induction of NE markers and proliferation of adeno cells as compared to controls. Mechanistically, MAOA induces Twist1, which directly activates the transcription and expression of BRN2, a master neural transcription factor known to confer NE differentiation and anti-AR therapy resistance in CRPC. Further, pharmacological inhibition of MAOA greatly enhanced the growth-inhibitory efficacy of ENZ with ENZ sensitivity restored in ENZ-resistant LuCaP PC PDX-derived organoids as well as a PSAlo/− CWR-R1ENZR xenograft mouse model.Conclusion: Our results suggest MAOA as a potential therapeutic target for reversing ENZ resistance in CRPC treatment by blockade of NE transdifferentiation.Funding Acknowledgements: This work was supported by the NIH/NCI grants R37CA233658 and R01CA258634 (to B. Wu) and the DOD Department of Defense EIRA award W81XWH-21-1-0218 (to J. Wei) Citation Format: Jing Wei, Jing Wang, Chia-hui Chen, Wen Guan, Boyang Wu. MAOA Drives Anti Androgen Therapy Resistance in Advanced Prostate Cancer by Conferring Neuroendocrine Plasticity via a Twist1 BRN2 Signaling Pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2011.

Abstract 7065: AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer, with emerging evidence highlighting the role of cancer stem cells (CSCs) in its progression. AMBRA1 has been implicated to exert both tumor-promoting and tumor-suppressive roles through regulating cell cycle and mitophagy in various solid tumors. However, the functional roles of AMBRA1 in modulating cancer stemness and tumorigenesis in HCC remain elusive. Initial analysis of The Cancer Genome Atlas data revealed a significant inverse correlation between AMBRA1 expression and stemness indices (TSS) in HCC patients, with low AMBRA1 levels associated with an upregulated oxidative phosphorylation (OXPHOS) gene signature. To elucidate the functional consequences of AMBRA1 modulation in liver tumor development and stemness maintenance, we exploited both hydrodynamic mouse models and human HCC cell lines. Our findings indicate that hepatic AMBRA1 deletion enhances cancer stemness and tumorigenesis both in vivo and in vitro. Moreover, HCC cells with reduced AMBRA1 expression demonstrated heightened mitochondrial activity, characterized by increased oxygen consumption, respiration, mitochondrial membrane potential, and intracellular ATP levels. Apart from OXPHOS, we also observed a concomitant up-regulation and enrichment of MYC targets in TSS-high and AMBRA1-low HCC patients, pointing towards a deregulated c-MYC signaling to promote cancer stemness under AMBRA1 regulation in HCC. Collectively, our results demonstrate that AMBRA1 loss enhances mitochondrial function to support hepatic tumorigenesis in HCC. Citation Format: Yan Liu, Yunong Xie, Yimiao He, Stephanie Ma, Man Tong. AMBRA1 coordinates mitochondrial function to regulate cancer stemness and tumorigenesis in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7065.

Abstract 2847: Study of spatial and temporal epigenetic heterogeneity in neuroblastoma suggests role of H3K27me3-mediated repression

Abstract Introduction: Trimethylation of Histone 3 Lysine 27 (H3K27) is widely understood to be a mark associated with gene repression and linked to gene silencing during development. Neuroblastoma, a developmental pediatric extracranial solid malignancy, has a relatively silent mutational landscape. Therefore, epigenetic modifications, including H3K27me3 mediated repression, could explain underlying developmental origins and the wide clinical heterogeneity observed. While previous studies have focused on the role of distinct super enhancer histone marks and their core regulatory circuits, less is understood about repressive control. We aimed to therefore investigate the role of H3K27me3-mediated repression in Neuroblastoma patients. Methods: Genome-wide H3K27me3 ChIP-Seq profiles were obtained from 48 diagnostic tissue biopsies covering all clinical and molecular patient subgroups. Transcriptome sequencing, ChIP-Seq of additional histone marks and WES/WGS was also performed on the same samples and on a panel of Neuroblastoma cell line models, with multiomics integrative analysis to validate findings. HMCAN, deepTools, DiffBind and ROSE packages were used to analyze the ChIP-seq data. Results: A comparison of H3K27me3 regions across all patient ChIP-Seq profiles, identified commonly repressed genes specific to Neuroblastoma. These genes are enriched in development and differentiation pathways, with significantly lower RNA expression levels than other publicly available pediatric tumor datasets. When compared to publicly available single cell RNAseq of the healthy adrenal medulla, we can further highlight a potential role of H3K27me3-mediated repression in regulating cell lineage commitment and differentiation ability. In addition, we identified that patient samples cluster into their clinical subgroups based on H3K27me3 patterns and differentially repressed genes, specifically between MYCN-amplified and non-amplified high-risk groups. A CRISPR screen to further validate the functional role of these repressed genes is being carried out. Conclusions: To our knowledge, this study shows for the first time that understanding of H3K27me3 mediated repression in Neuroblastoma, can uncover new insights into both disease development and clinical subclassifications. This knowledge will be important when considering future potential novel treatment options. Citation Format: Charlotte Butterworth, Alexandra Saint-Charles, Yasmine Iddir, Jaydutt Bhalshankar, Angela Bellini, Charles Bobin, Elisa Wecht, Young-Gyu Park, Caroline Louis, Virginie Raynal, Dominique Plantaz, Hervé Sartelet, Valérie Combaret, Gaelle Pierron, Isabelle Janoueix-Lerosey, Kai-Oliver Henrich, Olivier Delattre, Frank Westermann, Gudrun Schleiermacher. Study of spatial and temporal epigenetic heterogeneity in neuroblastoma suggests role of H3K27me3-mediated repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2847.

Abstract 6962: Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for prostate cancer

Abstract Distinguishing indolent from clinically significant localized prostate cancer and treatment of metastatic prostate cancer are two major clinical challenges in prostate cancer. The development of novel predictive biomarkers will help with risk stratification, and influence clinical decision-making between treatment and active surveillance, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2, an oncogenic transmembrane surface protein, is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that higher Trop2 expression is correlated with worse clinical features and elevated Trop2 expression at radical prostatectomy predicts worse overall survival in men undergoing radical prostatectomy. Additionally, we detected shed Trop2 in urine from men with clinically significant prostate cancer. We further define the functional role of shed Trop2 on metastasis in prostate cancer and identify that shed Trop2 increases cell migration, invasion, metastatic colonization, and spontaneous metastasis in vitro and in vivo. Proteomic profiling reveals that shed Trop2 modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. shed Trop2 binds to EGFR and results in the activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. Our study reveals the new function of shed Trop2 in driving prostate cancer progression and identifies Trop2 as a novel tissue prognostic biomarker and a candidate non-invasive marker for prostate cancer that could be used to optimize treatment decision-making. Citation Format: Shiqin Liu, Sarah Hawley, Christian Kunder, En-Chi Hsu, Michelle Shen, Merve Aslan, Fernando J. Marques, Chung S. Lee, Abel Bermudez, Lennart Westphalen, Heidi Auman, Lisa F. Newcomb, Daniel W. Lin, Peter S. Nelson, Ziding Feng, Maria S. Tretiakova, Lawrence D. True, Funda Vakar-Lopez, Peter R. Carroll, Jeffry Simko, Martin E. Gleave, Dean A. Troyer, Jesse K. McKenney, Donna Peehl, Sharon J. Pitteri, James D. Brooks, Michael A. Liss, Tanya Stoyanova. Shed Trop2 drives prostate cancer progression and Trop2 is a novel tissue prognostic biomarker and a candidate urinary marker for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6962.

Abstract 554: Determining the role of PROX1 in prostate cancer neuroendocrine trans-differentiation

Abstract Nonbiased mutational screening to identify essential genes and pathways in cancer is a powerful approach for understanding underlying biology as well as the identification of potential therapeutic targets. Epigenetic (EPI) and transcriptional factors (TF) play an important role in the change of phenotype and lineage plasticity from adenocarcinoma to castration resistant prostate cancer (CRPC), double negative (DN) or treatment-induced neuroendocrine prostate cancer (NEPC). When RB1 loss occurs in combination with TP53 alterations, stemness and lineage plasticity increase with one consequence being differentiation to a neuroendocrine (NE) lineage. Here, we are identifying and testing the functional role of epigenetic and transcription factors required for the viability of CRPC, DN and NEPC relative to a matrix of genotypic and phenotypic characteristics. We applied CRISPR-CAS9 dropout screens in prostate organoids and cell lines to identify gene/s associated with CRPC, DN and NEPC viability. We successfully CRISPR-engineered LNCaP clones of single (LNCaP-TP53-SKO, LNCaP-RB1-SKO) and double (LNCaP-TP53-RB1-DKO) gene knockouts, which were subsequently characterized for immuno-phenotype and transcriptome. Our dropout screens, targeting all TFs and EPIs, identified 117 TF and 40 EPI genes responsible for the viability of DN, NEPC and LNCaP models. We found known genes such as FOXA1 and ASCL1, as well as novel genes including PROX1 and KLF3, which were validated through guide RNA competition assays. Our results showed PROX1 is essential for cell viability in a DN organoid model, and its expression is associated with increased aggressiveness, indicating PROX1 has role in stemness/lineage plasticity in treatment resistant adenocarcinoma. RNA-seq analysis following overexpression of PROX1 in the LNCaP-TP53-RB1 null adenocarcinoma model, with and without enzalutamide, identified pathways enriched for cell proliferation, differentiation, neuronal development, and prostate gland development. In summary, our study has suggested an important role for PROX1 in the growth and differentiation of poorly differentiated prostate cancer, which may lead to the identification of potential therapeutic targets. Citation Format: Sonam Raj, Brian Capaldo, Joel Bowman, Margaret White, Xavier Moore, Berkley Gryder, Aian N. Alilin, David Takeda, Kathleen Kelly. Determining the role of PROX1 in prostate cancer neuroendocrine trans-differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 554.

Suicidal ideation in patients with diabetes and childhood abuse – The mediating role of personality functioning: Results of a German representative population-based study

AimsSuicidal ideation (SID) in patients with diabetes mellitus is increasingly acknowledged. Still, the underlying mechanisms are unclear. We examined SID prevalences in patients with diabetes, its association with different types of abuse, and a mediating effect of personality functioning. MethodsIn a representative population sample (N = 2,515), diabetes, SID, abuse (ICAST-R), personality functioning (OPD-SQS), and depression/anxiety (PHQ-4) were assessed by self-report. Statistical analyses comprised Chi2-Tests, logistic regression and mediation analyses. ResultsThe prevalence of SID (21.8 %) was three fold higher in patients with diabetes compared to the general population. Abuse further increased the likelihood to report SID in diabetes patients (sexual: 48.1 % vs. 18.2 %; χ2(1) = 12.233, p <.001; emotional: 35.7 % vs. 15.7 %; χ2(1) = 10.892, p <.001). A dose–response relationship between the number of abuse experiences and SID was observed (one abuse experience: OR = 1.138, 95 %-CI [0.433, 2.990], p =.793, >2 abuse experiences: OR = 2.693, 95 %-CI [1.278, 5.675], p =.009). Impaired personality functioning had an indirect effect on the association between emotional abuse and SID (b = 0.25, 95 %-CI [0.037, 0.551]). ConclusionsDiabetes patients experience increased SID prevalences, especially those with emotional or sexual abuse. In individuals with a history of emotional abuse, impaired personality functioning partly explained SID and should therefore be considered and addressed in this patient group.

Effect of Emotion Regulation on Anxiety/Depression Symptoms in Children With Attention-Deficit/Hyperactivity Disorder: The Mediating Role of Social Problems and the Moderating Role of Family Functioning

To investigate the mediating effect of social problems in the effect pathway of emotional dysregulation influencing anxiety/depression emotions in children with attention-deficit/hyperactivity disorder (ADHD) and to explore the potential moderating effect of family functionality. A total of 235 children diagnosed with ADHD were enrolled in the study. The paticipants' age ranged from 6 to 12. Emotion Regulation Checklist, Achenbach's Child Behavior Checklist (CBCL) Social Problems Subscale, CBCL Anxious/Depressed Subscale, and Family Assessment Device were used to evaluate the emotional regulation, social problems, anxiety/depression emotions, and family functionality of the participants. A moderated mediation model was employed to analyze whether social problems and family functionality mediate and moderate the relationship between emotional regulation and anxiety/depression emotions. Social problems partially mediated the impact of emotional dysregulation on anxiety/depression emotions in ADHD children, with the direct effect being 0.26 (95% confidence interval [CI]: [0.17, 0.36], P<0.001), the indirect effect being 0.13 (95% CI: [0.07, 0.19], P<0.001), and the mediating effect accounting for 33% of the total effect. Family functionality exhibited a positive moderating effect on the relationship between social problems and anxiety/depression emotions. This study contributes to the understanding of complex factors influencing anxiety/depression in children with ADHD, providing reference for the further development of targeted interventions for children with ADHD and the improvement of prognosis.

Partner’s unemployment and subjective well-being: The mediating role of relationship functioning

Unemployment affects not only the subjective well-being of the individual, but also that of the partner. Based on the life course perspective and the spillover-crossover-model, we examine the mediating role of relationship functioning for such crossover effects of partner’s unemployment on subjective well-being. We also test whether gender differences in the mechanism of relationship functioning can explain the larger overall crossover effects on women compared to men. We use data from the German Family Panel pairfam (2008/09–2018/19), which provide more direct and comprehensive measures of relationship functioning than previous research, and allow us to examine couples’ communication and interactions, their conflict styles and behaviors, relationship satisfaction, and perceived relationship instability as mediators. To analyze the impact of the partner’s transition to unemployment on subjective well-being, we use fixed effects panel regression models and the product method of mediation analysis to estimate the indirect effects of relationship functioning. The results show that a partner’s transition to unemployment has a negative impact on one’s own well-being. The effects are more pronounced for women than men which can be partly explained by gender-specific effects of the partner’s unemployment on various aspects of relationship functioning, rather than by differential effects of the latter on one’s own well-being.

Increased connections among soil microbes and microfauna enhances soil multifunctionality along a long‐term restoration chronosequence

Abstract The functional role of soil microbes in the restoration of degraded lands is greatly influenced by interactions within and between microbial communities, as well as by soil organisms at higher trophic levels (microfauna). However, little is known about how changes in connection patterns among soil microbes and their co‐existing microfauna contribute to associated changes in soil function over the ecosystem restoration process. In this study, the effects of afforestation and natural regeneration approaches on connection patterns among soil microbes and their co‐existing microfauna were assessed in ex‐arable lands on the Loess Plateau in China along a 50‐year restoration chronosequence. The relationships between soil network connections, microbial functional associations, and multiple soil functions (e.g. multifunctionality) were assessed quantitatively. Although both afforestation and natural regeneration approaches enhance connections among soil microbes and their co‐existing microfauna compared to recently abandoned sites, connection trends were opposed between these two approaches across the restoration chronosequence. Afforestation resulted in a higher number of soil microbial and microfauna species with a unimodal connection pattern, while natural regeneration resulted in a continuous increase in soil network connections over the progress of succession. These increases in soil network connections, particularly those of soil microfauna‐microbe and microbial inter‐kingdom connections, corresponded to enhanced microbial functional associations. This result is corroborated by significant correlations between microbial functional genes encoding different central functional pathways, which, in turn, were positively correlated with soil multifunctionality. Synthesis and applications. Changes in the connections among soil microbes and their co‐existing microfauna were positively associated with changes in soil multifunctionality, mediated by microbial functional associations. While in the early restoration stages, soil networks following afforestation contained more connections than those following natural regeneration, in later restoration stages, the number of connections of the afforestation network declined and was eventually surpassed by those following natural regeneration. These findings raise concerns about the ecological sustainability of afforestation measures in historic grasslands on the Loess Plateau, suggesting that natural regeneration is the preferred approach to achieve long‐term ecological restoration success.

Computational Investigation of Carbon Based Anode Materials for Li- and Post-Li- Ion Batteries.

Due to its negligible capacity with respect to sodium intercalation, graphite is not suited as anode material for sodium ion batteries. Hard carbon materials, on the other hand, provide reasonably high capacities at low insertion potential, making them a promising anode materials for sodium (and potassium) ion batteries. The particular nanostructure of these functionalized carbon-based materials has been found to be crucially linked to the material performance. However, there is still a lack of understanding with respect to the functional role of structural units, such as defects, for intercalation and storage. To overcome these problems, the intercalation of Li, Na, and K in graphitic model structures with distinct defect configurations has been investigated by density functional theory. The calculations confirm that defects are able to stabilize intercalation of larger alkali metal contents. At the same time, it is shown that a combination of phonon and band structure calculations are able to explain characteristic Raman features typically observed for alkali metal intercalation in hard carbon, furthermore allowing for the quantification of the alkali metal intercalation inbetween the layers of hard carbon anodes.