Broad Functions Research Articles

Communication Patterns of The Indonesian Ulema Council's Fatwa on Friday Prayers Virtually

The covid 19 pandemic that hit Indonesia caused several impacts on Indonesian society that had not happened before. one them, the phenomenon of Juma'at prayers that are carried out virtually. This study aims to examine the pattern of mass communication in harmonizing the MUI (Indonesian Ulema Council) fatwa on virtual Friday prayers, its effectiveness in building public understanding, and its influence on the implementation of the fatwa during the pandemic. Qualitative studies in the form of literature studies that collect and analyze literature sources. The results show that MUI (Indonesian Ulema Council) fatwa has three broad communication functions, namely helping to maintain religious values and norms in society, as legal guidelines and social tools that influence people's behavior, and showing unique changes in devotional practices in the digital era. MUI (Indonesian Ulema Council) fatwas show an important role in disseminating religious guidance and maintaining social cohesion in the midst of change. This study strengthens the theory of mass communication as an instrument of social influence in religious contexts by focusing solely on communication patterns and community responses to fatwas.

Molecular basis of vitamin K driven γ-carboxylation at membrane interface.

The γ-carboxylation of glutamate residues enables Ca2+-mediated membrane assembly of protein complexes that support broad physiological functions including hemostasis, calcium homeostasis, immune response, and endocrine regulation1-4. Modulating γ-carboxylation level provides prevalent treatments for hemorrhagic and thromboembolic diseases5. This unique posttranslational modification requires vitamin K hydroquinone (KH2) to drive highly demanding reactions6 catalyzed by the membrane-integrated γ-carboxylase (VKGC). To decipher underlying mechanisms, we determined cryo-electron microscopy structures of human VKGC in unbound form, with KH2 and four hemostatic and non-hemostatic proteins possessing propeptides and glutamate-rich domains in different carboxylation states. VKGC recognizes substrate proteins via knob-and-hole interactions with propeptides, thereby bringing tethered glutamate-containing segments for processive carboxylation within a large chamber that provides steric control. Propeptide binding also triggers a global conformational change to signal VKGC activation. Through sequential deprotonation and KH2 epoxidation, VKGC generates free hydroxide ion as an exceptionally strong base required to deprotonate the γ-carbon of glutamate for CO2 addition. The diffusion of this superbase, protected and guided by a sealed hydrophobic tunnel, elegantly resolves the challenge of coupling KH2 epoxidation to γ-carboxylation across the membrane interface. These structural insights and extensive functional experiments advance membrane enzymology and propel the development of novel treatments for γ-carboxylation disorders.

Methyltransferase-like 14 promotes ferroptosis in sepsis-induced acute kidney injury via increasing the m6A methylation modification of LPCAT3.

Acute kidney injury (AKI) is one of the most serious and common complications in the course of sepsis, known for its poor prognosis and high mortality rate. Recently, ferroptosis, as a newly discovered regulatory cell death, might be closely associated with the progression of AKI. METTL14 is a writer of RNA m6A, an abundant epigenetic modification in transcriptome with broad function. Hence, the purpose of our study is to explore the potential function and mechanism of METTL14 on the ferroptosis in sepsis-induced AKI. In this paper, TCMK-1 cells and mice treated with LPS were used to constructe AKI model in vitro and in vivo. Pathological changes of renal tissue were observed by HE staining. The fluorescent probe C11-BODIPY and 4HNE kits were used to measure the lipid peroxidation. The ferroptosis index was evaluated by MDA, GSH and Fe2+ kits. The total m6A levels were analyzed by EpiQuik M6A RNA methylation kit, and the m6A levels of LPCAT3 were examined by Me-RIP assay. Finally, the interaction between LPCAT3 and METTL14 was clarified using RIP and dual-luciferase reporter gene assays. Our works revealed that the m6A level and ferroptosis was markedly ascended in LPS-induced TCMK-1 cells. The silence of METTL14 lowered the cell viability, the levels of MDA, Fe2+ and lipid peroxidation in the LPS-stimulated AKI model in vitro and in vivo, but increase GSH levels. Moreover, the up-regulation of ferroptosis-related proteins by LPS was notably inhibited by the knockdown of METTL14. In addition, silencing METTL14 reduced the m6A and mRNA levels of LPCAT3. Furthermore, the efficacy of METTL14 downregulation on the ferroptosis in the LPS-induced TCMK-1 cells were antagonized by LPCAT3 overexpression. Taken together, our findings revealed that METTL14 knockdown resisted ferroptosis in sepsis-induced AKI through lessening the level of LPCAT3 mediated by m6A modification.

Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.

Amyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies.

NADPH Oxidases: Redox Regulation of Cell Homeostasis & Disease.

The redox signaling network in mammals has garnered enormous interest and taken on major biological significance in recent years as the scope of NADPH oxidases (NOXs) as regulators of physiological signaling and cellular degeneration has grown exponentially. All NOX subtypes have in common the capacity to generate reactive oxygen species (ROS) superoxide anion (O2.-) and/or hydrogen peroxide (H2O2). A baseline, normal level of ROS formation supports a wide range of processes under physiological conditions. A disruption in redox balance caused by either the suppression or "super" induction of NOX off balance with antioxidant systems is associated with myriad diseases and cell/tissue damage. Over the past two to three decades sour understanding of NOXs has progressed from almost entirely a phagocyte-, antimicrobial-centered perspective to that of a family of enzymes that is vital to broad cellular function and organismal homeostasis. It is becoming increasingly evident that highly regulated, targeted oxidative protein modifications are elicited in a spatiotemporal manner and initiated at cell membranes in humans by seven NOX isoforms (NOXs 1, 2, 3, 4, 5 and DUOXs 1 & 2). In a sense, this renders NOX-ROS signaling akin to that of other second messenger systems involving localized Ca2+ dynamics and tyrosine kinase transactivation. Accordingly, the study of ROS compartmentalization in subcellular organelles has been shown to be crucial to elucidating their role in cell phenotype modulation under physiological and pathophysiological conditions. The NOXs are as distinct in their distribution and activation as they are in their cellular functions, ranging from host defense, second messenger PTMs to transcriptional, epigenetic and (de)differentiating effects. The review integrates past knowledge in the field with new focus areas on the leading-edge of NOX-centered ROS signaling including how a new wave of structural information provides insights for NOX biology and targeted therapies.

The Microenvironment in DCIS and Its Role in Disease Progression.

Ductal carcinoma in situ (DCIS) accounts for ~20% of all breast cancer diagnoses but whilst known to be a precursor of invasive breast cancer (IBC), evidence suggests only one in six patients will ever progress. A key challenge is to distinguish between those lesions that will progress and those that will remain indolent. Molecular analyses of neoplastic epithelial cells have not identified consistent differences between lesions that progressed and those that did not, and this has focused attention on the tumour microenvironment (ME).The DCIS ME is unique, complex and dynamic. Myoepithelial cells form the wall of the ductal-lobular tree and exhibit broad tumour suppressor functions. However, in DCIS they acquire phenotypic changes that bestow them with tumour promoter properties, an important evolution since they act as the primary barrier for invasion. Changes in the peri-ductal stromal environment also arise in DCIS, including transformation of fibroblasts into cancer-associated fibroblasts (CAFs). CAFs orchestrate other changes in the stroma, including the physical structure of the extracellular matrix (ECM) through altered protein synthesis, as well as release of a plethora of factors including proteases, cytokines and chemokines that remodel the ECM. CAFs can also modulate the immune ME as well as impact on tumour cell signalling pathways. The heterogeneity of CAFs, including recognition of anti-tumourigenic populations, is becoming evident, as well as heterogeneity of immune cells and the interplay between these and the adipocyte and vascular compartments. Knowledge of the impact of these changes is more advanced in IBC but evidence is starting to accumulate for a role in DCIS. Detailed in vitro, in vivo and tissue studies focusing on the interplay between DCIS epithelial cells and the ME should help to define features that can better predict DCIS behaviour.

Nanoparticles Perspective in Skin Tissue Engineering: Current Concepts and Future Outlook.

Nanotechnology seems to provide solutions to the unresolved complications in skin tissue engineering. According to the broad function of nanoparticles, this review article is intended to build a perspective for future success in skin tissue engineering. In the present review, recent studies were reviewed, and essential benefits and challenging issues regarding the application of nanoparticles in skin tissue engineering were summarized. Previous studies indicated that nanoparticles can play essential roles in the improvement of engineered skin. Bio-inspired design of an engineered skin structure first needs to understand the native tissue and mimic that in laboratory conditions. Moreover, a fundamental comprehension of the nanoparticles and their related effects on the final structure can guide researchers in recruiting appropriate nanoparticles. Attention to essential details, including the designation of nanoparticle type according to the scaffold, how to prepare the nanoparticles, and what concentration to use, is critical for the application of nanoparticles to become a reality. In conclusion, nanoparticles were applied to promote scaffold characteristics and angiogenesis, improve cell behavior, provide antimicrobial conditions, and cell tracking.

Mapping the FGF2 Interactome Identifies a Functional Proteoglycan Coreceptor.

Fibroblast growth factor 2 (FGF2) is a multipotent growth factor and signaling protein that exhibits broad functions across multiple cell types. These functions are often initiated by binding to growth factor receptors and fine-tuned by glycosaminoglycan (GAG)-modified proteins called proteoglycans. The various outputs of FGF2 signaling and functions arise from a dynamic and cell type-specific set of binding partners. However, the interactome of FGF2 has yet to be comprehensively determined. Moreover, the identity of the proteoglycan proteins carrying GAG chains is often overlooked and remains unknown in most cell contexts. Here, we perform peroxidase-catalyzed live cell proximity labeling using an engineered APEX2-FGF2 fusion protein to map the interactome of FGF2. Across two cell lines with established and distinct FGF2-driven functions, we greatly expand upon the known FGF2 interactome, identifying >600 new putative FGF2 interactors. Notably, our results demonstrate a key role for the GAG binding capacity of FGF2 in modulating its interactome.

CD11b deficiency attenuates the ischemia/reperfusion-induced AKI-to-CKD process by regulatingmacrophage polarization.

Severe acute kidney injury (AKI) is a risk factor for the future development of chronic kidney disease (CKD), and macrophages are an essential cell group implicated in injury, repair, and fibrosis during this progress. However, the underlying mechanism of how macrophages participate in the development of the disease is largely unclear. CD11b (Integrin αM) is highly expressed in monocytes/macrophages and has been verified to mediate broad functions. We found that CD11b-knockout mice were protected from the ischemia/reperfusion-induced AKI-to-CKD process. Additionally, renal macrophages from the kidneys of CD11b-deficient mice presented an M2-like, anti-inflammatory phenotype. We demonstrated both invitro and invivo that enhanced alternative activation in CD11b-knockout macrophages is regulated by the interleukin (IL)-4/signal transducer and activator of transcription (STAT) 6 axis, which is mediated by the inactivation of the Src-family kinase (SFK) member Lyn. Importantly, the therapeutical administration of CD11b-neutralizing antibody can effectively prevent AKI-to-CKD progress. Thus, our study verifies that CD11b plays a critical role in limiting the alternative activation of macrophages and may be a potential therapeutic target during the AKI-to-CKD process.

Broad Microbial Community Functions in a Conventional Activated Sludge System Exhibit Temporal Stability.

Wastewater microbial communities within conventional activated sludge (CAS) systems can perform hundreds of biotransformations whose relative importance, frequency, and temporal stability remain largely unexplored. To improve our understanding of biotransformations in CAS systems, we collected 24 h composite samples from the influent and effluent of a CAS system over 14 days, analyzed samples using high-resolution mass spectrometry (HRMS), and conducted a nontarget analysis of our HRMS acquisitions. We found that over 50% of the chemical features in the influent were completely removed, and the daily number of detected features exhibited low variability with a coefficient of variation of 0.07. Additionally, we found 352 Core chemical features present in every sample at both locations. We used chemical features to search for evidence of 19 potential biotransformations and detected 9 of these biotransformations at a frequency of over 80 times per day, where evidence for dehydrogenations, hydroxylations, and acetylations was most frequently detected. The daily number of detections for the 9 biotransformations exhibited coefficients of variation ranging from 0.13-0.20, revealing the broad temporal stability for these wastewater microbial community functions. This stability contrasts with the previously observed temporal variability for micropollutant biotransformations, suggesting that micropollutant biotransformations are linked to specialized microbial community functions.

Enhanced Multi-Stress Tolerance in Escherichia coli via the Heterologous Expression of Zymomonas mobilis recA: Implications for Industrial Strain Engineering

This study investigated the role of the Zymomonas mobilis recA gene in conferring stress resistance when expressed in Escherichia coli. The recA gene was cloned and expressed in E. coli BL21(DE3), producing a 39 kDa polypeptide. The results of comparative analyses demonstrated that the recombinant strain significantly enhanced survival rates under various stress conditions. In oxidative stress tests, the recombinant E. coli pET-22b(+)-recA exhibited superior survival at 3 mM and 5 mM H2O2 concentrations. Heat stress experiments at 50 °C and 55 °C revealed increased survival for the recombinant strain. Under ethanol stress, particularly at 20% (v/v), E. coli pET-22b(+)-recA displayed higher viability than controls. UV-C exposure tests further highlighted the protective effect of recA expression, with the recombinant strain maintaining viability after 60 min of exposure, while control strains showed no survival. These results indicate that the Z. mobilis recA gene product enhances resistance to oxidative, heat, ethanol, and UV-C stresses when expressed in E. coli. This study elucidates the broad stress-protective functions of the RecA protein across bacterial species and suggests potential applications in developing stress-tolerant bacterial strains for biotechnological purposes.

Variability of functional and biodiversity responses to perturbations is predictable and informative

Perturbations such as climate change, invasive species and pollution, impact the functioning and diversity of ecosystems. However diversity has many meanings, and ecosystems provide a plethora of functions. Thus, on top of the various perturbations that global change represents, there are also many ways to measure a perturbation’s ecological impact. This leads to an overwhelming response variability, which undermines hopes of prediction. Here, we show that this variability can instead provide insights into hidden features of functions and of species responses to perturbations. By analysing a dataset of global change experiments in microbial soil systems we first show that the variability of functional and diversity responses to perturbations is not random; functions that are mechanistically similar tend to respond coherently. Furthermore, diversity metrics and broad functions (e.g. total biomass) systematically respond in opposite ways. We then formalise these observations to demonstrate, using geometrical arguments, simulations, and a theory-driven analysis of the empirical data, that the response variability of ecosystems is not only predictable, but can also be used to access useful information about species contributions to functions and population-level responses to perturbations. Our research offers a powerful framework for understanding the complexity of ecological responses to global change.

Proteasome associated function of UCH37 is evolutionarily conserved in Plasmodium parasites

Ubiquitin C-terminal hydrolase 37 (UCH37 also known as UCHL5) is a conserved deubiquitinating enzyme (DUB) with dual roles in proteasomal degradation and chromatin remodeling in humans. Its Plasmodium falciparum ortholog, PfUCH37, is unusual in that it possesses both DUB and deneddylating activities. While PfUCH37 is enriched in proteasome preparations, its direct interaction and broader functions in Plasmodium remain unclear, particularly given the absence of the chromatin remodeling complex INO80 homologs. This study utilizes transgenic parasites and proteomics to identify PfUCH37-associating proteins. We confirm a direct interaction with the proteasome and demonstrate that the interaction mechanism is evolutionarily conserved. Notably, we discover a divergence in localization compared to the human enzyme and identify novel interacting partners, suggesting alternative functions for PfUCH37 in Plasmodium. These findings provide insights into the unique biology of this enzyme in malaria parasites, potentially opening avenues for targeted therapeutic interventions.

Characterization of Platelet Receptors and Their Involvement in Immune Activation of These Cells.

The article characterises platelets, pointing out the role and contribution of their numerous receptors determining their specific and broad immune activity. Three types of platelet receptors are described, that is, extracellular and intracellular receptors-TLR (toll-like receptors), NLR (NOD-like receptor), and RLR (RIG-I-like receptor); extracellular receptors-selectins and integrins; and their other extracellular receptors-CLR (C-type lectin receptor), CD (cluster of differentiation), TNF (tumour necrosis factor), among others. Outlining the contribution of these numerous platelet receptors to the intravascular immunity, it has been shown that they are formed by their fusion with pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). They are initiating and effector components of signal transduction of these cells, and their expression and quantity determine the specific and broad functions of platelets towards influencing vascular endothelial cells, but mainly PRRs (pattern recognition receptors) of blood immune cells. These facts make platelets the fundamental elements that shape not only intravascular homeostasis, as previously indicated, but they become the determinants of immunity in blood vessels. Describing the reactions of the characterised three groups of platelet receptors with PAMP, DAMP and LAMP molecules, the pathways and participation of platelets in the formation and construction of intravascular immune status, in physiological states, but mainly in pathological states, including bacterial and viral infections, are presented, making these cells essential elements in the health and disease of mammals, including humans.

Research progress on FSH-FSHR signaling in the pathogenesis of non-reproductive diseases.

Follicle-stimulating hormone (FSH), a glycoprotein hormone synthesized and secreted by the anterior pituitary gland, plays a critical role in reproductive development and regulation by binding to FSH receptor (FSHR). Beyond reproductive tissue, FSHRs have been identified in various non-reproductive tissues, indicating broader functions. FSH levels chronically rise during menopause and remain elevated in postmenopausal life. This increase in FSH level has been indicated to be associated with heightened risk of several non-reproductive diseases, including osteoporosis, hypercholesterolemia, type 2 diabetes mellitus, obesity, cardiovascular disease, Alzheimer's disease, and certain cancers. In this review, we will examine the role of FSH-FSHR signaling in the pathogenesis of these non-reproductive diseases and explore therapeutic strategies targeting FSH-FSHR signaling pathways.

Photoredox-Catalyzed Three-Component Construction of Aryl Sulfonyl Fluoride Using KHF2: Late-Stage Drug Fluorosulfonylation.

Aryl sulfonyl fluorides are prominently featured in organic synthesis and medicinal chemistry. Herein, a metal-free photoredox-catalyzed three-component assembly of aryl sulfonyl fluoride via aryl sulfonyl ammonium salt intermediate has been reported. A variety of structurally diverse aryl sulfonyl fluorides were synthesized rapidly from dibenzothiophenium (DBT) salts under mild conditions by using KHF2 as the fluorine source. Notably, this methodology can be employed as an efficient and sustainable approach for late-stage drug fluorosulfonylation. Good yields and broad functionality tolerance were the features of this methodology. Moreover, the derivatization of aryl sulfonyl fluoride molecules was also demonstrated to showcase its synthetic utility.

Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.

Nickel-Catalyzed Enantioselective Reductive N-Cyclization-Thiolation Reaction of Alkene-Tethered Oxime Esters and Disulfides.

Asymmetric aza-Heck cyclization and coupling reactions offer efficient access to enantioenriched N-heterocycles, yet the current studies focus primarily on sequential C-N and C-C bond formation. Herein, we report an enantioselective reductive aza-Heck cyclization followed by a C-S coupling sequence, ultimately yielding sulfide-containing enantioenriched pyrrolines. The reaction is conducted under mild conditions and tolerates broad functionalities including alkynes, phenols, anilines, amides, nitriles, and bromides.

Insights into the multifaceted role of interleukin-37 on human immune cell regulation

Autoinflammatory diseases, while having a variety of underlying causes, are mediated by dysfunctional innate immune responses. Therefore, standard treatments target innate cytokines or block their receptors. Despite excellent responses in some patients, first-line treatments fail in others, for reasons which remain to be understood.We studied the effects of IL-37, an anti-inflammatory cytokine, on immune cells using multi-omics profiling of 325 healthy adults. Our findings show that IL-37 is associated with inflammation control and generally reduced immune cell activity. Further, genetic variants in IL37 are associated with impaired trained immunity, a memory phenotype of innate immune cells contributing to autoinflammation. To underpin the medical potential of IL-37, an explorative cohort of seven autoinflammatory disorders was built. In vitro stimulation experiments argue for recombinant IL-37 as a potential therapy in IL-6-, and IL-22-driven conditions.Concluding, IL-37 is highlighted as a cytokine with broad anti-inflammatory functions, implicating its potential as therapeutic intervention.

B - 65 Adolescent Cortico-Limbic Connectivity Mediates Associations between Internalizing Symptomology and Subsequent Neurocognitive Performance

Abstract Objective During development, internalizing symptoms negatively impact broad neurocognitive functioning. Hypoconnectivity between the Cingulo-Opercular network (CON) and limbic regions has been implicated in various psychiatric disorders. Here we attempt to investigate whether CON-limbic connectivity longitudinally mediates associations between internalizing behaviors and cognitive outcomes during adolescence. Method Internalizing symptoms were measured in 2668 youth (47% female) enrolled in the Adolescent Brain Cognitive Development study using the Child Behavior Checklist. Zero-order correlations were tested between baseline (ages 9–11) internalizing symptoms (anxiety, depression, somatic complaints) and performance on NIH Toolbox® neurocognitive measures at 4-year follow-up (ages 13–15). Significantly predicted tasks were included in a structural equation model (SEM), which tested whether a latent factor representing 2-year follow-up resting-state fMRI connectivity between the CON and limbic regions (i.e., bilateral hippocampus and amygdala) mediated associations between baseline internalizing symptoms and 4-year cognitive outcomes. Results Four neurocognitive tasks (Flanker, Picture Sequence, List Sorting, Pattern Comparison) regressed significantly onto at least one internalizing symptom. An SEM which tested the mediatory effects of CON-limbic connectivity on these associations fit the data well (CFI = 0.997; SRMR = 0.007; RMSEA =0.015 [0,0.027]). Increased anxiety and somatic symptoms significantly predicted reduced CON-limbic connectivity, while depression did not. Associations between anxiety and somatic symptoms and List Sorting performance were suppressed, indicating full mediation by CON-limbic connectivity on working memory. Connectivity also partially mediated a negative association between anxiety and Flanker performance. Conclusions Our findings point to CON-limbic hypoconnectivity as a potential mechanism underlying associations between late childhood internalizing symptoms and poorer executive functioning (most notably working memory) during early adolescence.