Clusters Of Sites Research Articles

Protein Binding Site Representation in Latent Space.

Interpretability and reliability of deep learning models are important for computer-based drug discovery. Aiming to understand feature perception by such a model, we investigatea graph neural network for affinity prediction of protein-ligand complexes. We assess a latent representation of ligand binding sites and investigate underlying geometric structure in this latent space and its relation to protein function. We introduce an automated computational pipeline for dimensionality reduction, clustering, hypothesis testing, and visualization of latent space. The results indicate that the learned protein latent space is inherently structured and not randomly distributed. Several of the identified protein binding site clusters in latent space correspond to functional protein families. Ligand size was found to be a determinant of cluster geometry. The computational pipeline proved applicable to latent space analysis and interpretation and can be adapted to work for different datasets and deep learning models.

A novel family of beta mixture models for the differential analysis of DNA methylation data: An application to prostate cancer.

Identifying differentially methylated cytosine-guanine dinucleotide (CpG) sites between benign and tumour samples can assist in understanding disease. However, differential analysis of bounded DNA methylation data often requires data transformation, reducing biological interpretability. To address this, a family of beta mixture models (BMMs) is proposed that (i) objectively infers methylation state thresholds and (ii) identifies differentially methylated CpG sites (DMCs) given untransformed, beta-valued methylation data. The BMMs achieve this through model-based clustering of CpG sites and by employing parameter constraints, facilitating application to different study settings. Inference proceeds via an expectation-maximisation algorithm, with an approximate maximization step providing tractability and computational feasibility. Performance of the BMMs is assessed through thorough simulation studies, and the BMMs are used for differential analyses of DNA methylation data from a prostate cancer study. Intuitive and biologically interpretable methylation state thresholds are inferred and DMCs are identified, including those related to genes such as GSTP1, RASSF1 and RARB, known for their role in prostate cancer development. Gene ontology analysis of the DMCs revealed significant enrichment in cancer-related pathways, demonstrating the utility of BMMs to reveal biologically relevant insights. An R package betaclust facilitates widespread use of BMMs.

Construction of a copper-bismuth catalyst featuring Bi-N4 sites and synergistic Bi clusters derived from TCPP(Bi)@HKUST-1 for enhanced formaldehyde to butynediol

The construction of functional catalysts that efficiently catalyze in a reducing atmosphere is considered rather challenging. In this study, the catalysts bridged by Bi-N4 between copper and bismuth species were prepared. Herein, Bi-N4 and bismuth cluster sites were incorporated into porous carbon–nitrogen networks along with copper nanoparticles (BiSAC&Clu-Cu-NC). For the synthesis, metalloporphyrin-modified HKUST-1 (TCPP(Bi)@HKUST-1) was employed as a precursor. Additionally, metalloporphyrin functioned as a capping agent during catalyst preparation, thereby enhancing the dispersion of Bi species after calcination. Notably, the BiSAC&Clu-Cu-NC catalyst demonstrated 93.8 % selectivity towards 1,4-butynediol over 20 h at a Bi loading of 0.6 wt% in a reducing atmosphere of acetylene and formaldehyde. Furthermore, a mechanistic model is proposed that elucidates the observed synergistic catalytic behavior based on experimental characterization and DFT calculations. This proposed model is termed “Nanoparticles with Cluster and Single Metal Sites”(NCS mechanism). The retention of the Bi cluster structure within the material matrix plays a pivotal role in enhancing the adsorption and activation of formaldehyde. Interfacial effects between different copper species favour the activation of the reaction substrate acetylene. Additionally, the Bi-N4 structure can function as a crucial conduit, facilitating electron transfer between Cu and Bi elements and consequently lowering the activation energy barrier for key reaction intermediates.

Exploring the conformational space of the mobile flap in Sporosarcina pasteurii urease by cryo-electron microscopy.

To fully understand enzymatic dynamics, it is essential to explore the complete conformational space of a biological catalyst. The catalytic mechanism of the nickel-dependent urease, the most efficient enzyme known, holds significant relevance for medical, pharmaceutical, and agro-environmental applications. A critical aspect of urease function is the conformational change of a helix-turn-helix motif that covers the active site cavity, known as the mobile flap. This motif has been observed in either an open or a closed conformation through X-ray crystallography studies and has been proposed to stabilize the coordination of a urea molecule to the essential dinuclear Ni(II) cluster in the active site, a requisite for subsequent substrate hydrolysis. This study employs cryo-electron microscopy (cryo-EM) to investigate the transient states within the conformational space of the mobile flap, devoid of the possible constraints of crystallization conditions and solid-state effects. By comparing two cryo-EM structures of Sporosarcina pasteurii urease, one in its native form and the other inhibited by N-(n-butyl) phosphoric triamide (NBPTO), we have unprecedently identified an intermediate state between the open and the catalytically efficient closed conformation of the helix-turn-helix motif, suggesting a role of its tip region in this transition between the two states.

Trimetallic FeNiCu Atomic Clusters Supported on Carbon Matrix: Highly Active Catalysts for C3H6-SCR of NO.

C3H6-SCR denitrification technology faces catalyst deactivation problems and low catalytic performance at medium-low temperatures. This study utilized the intermetallic synergies to prepare atomic cluster catalysts (FeNiCu/NC) by anchoring Fe-Ni-Cu on a carbon matrix to enhance the C3H6-SCR performance at medium-low temperatures. The synergistic effect of the Fe-Ni-Cu is reflected in the differences in the physicochemical properties of the catalysts, which is proved by several characterization techniques. Results showed that the FeNiCu/NC catalyst had a larger surface area (541.4 m2/g) and there were no metal oxides on the surface of the catalyst but abundant defective sites that anchored Fe/Ni/Cu atoms through N atoms to form M-Nx active sites and atomic clusters. The hollow carbon morphology provides sufficient active sites for C3H6-SCR. The coordination environments of active sites were M-Nx-C, Fe2/FeCu2/FeNi2, Ni3/NiFe/NiCu2, and Cu4/CuFe2/CuNi2, where the synergistic action of trimetal leads to the presence of Fe-Ni-Cu-Nx-C. The synergistic action of the Fe-Ni-Cu significantly improved the C3H6-SCR performance at medium-low temperatures. The FeNiCu/NC exhibited an 81% NO conversion at 150 °C under 2% O2, 15% and 20% higher than FeNi/NC and FeCu/NC catalysts, respectively. Even at 4% O2, the FeNiCu/NC catalyst was active to remove 78% NO and achieve a 93% N2 selectivity at 150 °C and maintained a 100% NO conversion at 300-425 °C. The DRIFTS results demonstrated that NO and C3H6 could combine with active O at metal cluster, M-Nx, or defective oxygen sites to produce various intermediate species, wherein acetates and nitrates were the main active intermediates. Based on the DRIFTS results, a reaction pathway for C3H6-SCR over the FeNiCu/NC catalyst was proposed.

Aggregative responses of marine predators to a pulsed resource.

Pulsed resources resulting from animal migrations represent important, transient influxes of high resource availability into recipient communities. The ability of predators to respond and exploit these large increases in background resource availability, however, may be constrained when the timing and magnitude of the resource pulse vary across years. In coastal Newfoundland, Canada, we studied aggregative responses of multiple seabird predators to the annual inshore pulse of a key forage fish species, capelin (Mallotus villosus). Seabird aggregative responses to fish biomass were quantified from weekly hydroacoustic and seabird surveys during July-August within an annually persistent foraging area (10 km2) associated with a cluster of capelin spawning sites across 10 years (2009-2010, 2012, 2014-2020). Seabird predators included breeding members of the families Alcidae (Common Murres Uria aalge, Razorbills Alca torda, Atlantic Puffins Fratercula arctica) and Laridae (Great Black-backed Gulls Larus marinus, American Herring Gulls L. argentatus smithsonianus) and Northern Gannets Morus bassanus, along with non-breeding, moulting members of the Family Procellariidae (Sooty Shearwaters Ardenna griseus, Great Shearwaters A. gravis). The inshore migration of spawning capelin resulted in 5-619 times (mean ± SE, 146 ± 59 times) increase in coastal fish biomass along with a shift towards more, larger and denser fish shoals. Within years, seabird abundance did not increase with inshore fish biomass but rather peaked near the first day of spawning, suggesting that seabirds primarily respond to the seasonal resource influx rather than short-term variation in fish biomass. Across years, the magnitude of the seabird aggregative response was lower during low-magnitude resource pulse years, suggesting that predators are unable to perceive low-magnitude pulses, avoid foraging under high competitor densities, and/or shift dietary reliance away from capelin under these conditions. The seabird response magnitude, however, was higher when the resource pulse was delayed relative to the long-term average, suggesting that predators increase exploitation during years of minimal overlap between the resource pulse and energetically demanding periods (e.g. breeding, moulting). This long-term study quantifying responses of multiple predators to a pulsed resource illustrates the ability of natural systems to tolerate natural and human-induced disturbance events.

Implementing palliative care in hepatocellular carcinoma ambulatory clinics—study protocol for Accelerated translational research in PRImary liver CAncer (APRICA) randomised controlled palliative care trial

BackgroundIntegration of symptom and palliative care for people with advanced cancer is established in many tumour types, but its role in people with hepatocellular carcinoma (HCC) has not been clearly defined. This study aims to evaluate the clinical and cost effectiveness of an intervention involving a suite of strategies designed to assess and treat palliative care symptoms and needs in adult outpatients with HCC attending four New South Wales (NSW) metropolitan tertiary hospitals.MethodsThis trial will use a pragmatic cluster-based randomised-controlled design, with ambulatory HCC services as the clusters. HCC patients will be recruited if they have Barcelona Clinical Liver Cancer (BCLC) stage A disease with active tumour or a current or prior diagnosis of BCLC stage B or C disease regardless of tumour activity. Patients with BCLC stage D disease will be excluded as palliative care is the standard of care (SOC) in this group. Cluster sites will be randomised to the study intervention or control where patients are managed according to SOC. All participants will complete the liver-specific Edmonton Symptom Assessment Scale (ESAS) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at regular ambulatory clinic appointments. At intervention sites, patients scoring ≥ 5 on any liver-specific ESAS symptom will be referred to palliative care physicians for consultation. The primary clinical outcome will be improvement in all symptoms scored ≥ 5 on the liver-specific ESAS by 50% within 3 months and the primary implementation outcome will recording the liver-specific ESAS in ≥ 80% of all participants attending clinic appointments. Caregivers of patients enrolled in the trial will be invited to perform Carer Support Needs Assessment Tool at each appointment.DiscussionThis trial will inform if earlier palliative care involvement significantly reduces the symptom burden associated with HCC. If found to be effective, earlier implementation of palliative care consultation should be included in HCC treatment guidelines.Trial registrationACTRN12623000010695. Registered on September 1, 2023.

Satellite Pd Single-Atom Embraced AuPd Alloy Nanoclusters for Enhanced Hydrogen Evolution.

The fabrication of hybrid active sites that synergistically contain nanoclusters and single atoms (SAs) is vital for electrocatalysts to achieve excellent activity and durability. Herein, we develop a ligand-assisted pyrolysis strategy using nanoclusters (Au4Pd2(SC2H4Ph)8) with alloy cores and protected ligands to build AuPd cluster sites embraced by satellite Pd SAs. In the thermal drive control process, different thermodynamic properties of the alloy atoms and the confinement effects of organic ligands allow for the mild spillover of the single-component metal Pd, resulting in the formation of AuPd alloy nanoclusters tightly encompassed by isolated Pd atoms. Experiments and theoretical calculations indicated that the satellite Pd atoms can optimize the electronic structure of the AuPd nanoclusters and Au sites in the alloy to facilitate the adsorption and dissociation of H2O, thus enhancing the hydrogen evolution reaction (HER) activity. The optimal AuPdNCs/PdSAs-600 exhibits outstanding electrocatalytic activity toward HER, with overpotentials of 21 and 38 mV at 10 mA cm-2 in acidic and alkaline media, respectively. Moreover, the mass activity and turnover frequency of AuPdNCs/PdSAs-600 are one order of magnitude higher than those of commercial Pd/C and Pt/C catalysts. This facile strategy for constructing hybrid catalytic centers using ligand-protected nanoclusters provides efficient insights for the further design of nanocluster-based electrocatalysts synergized by SAs.

Interfacial Ru nanoclusters in tandem with single atoms on oxygen-vacancy regulated CeO2 for anion exchange membrane seawater-splitting

A hydrogen spillover-bridged water dissociation/hydrogen formation could concurrently promote Volmer/Tafel process and improve the efficiency of hydrogen evolution reaction (HER) under alkaline conditions. However, it is still challenging to promote occurrence of hydrogen spillover for the large interfacial transport barriers of H2O and hydrogen on active sites. Herein, the strategy of energy barrier gradient to induce hydrogen spillover was proposed by constructing Ru nanoclusters coupled with single atom onto oxygen vacancy cerium dioxide (Ru/CeO2-Ov-2). Density functional theory (DFT) calculations uncover that the adsorption/desorption of H2O occurs at the Ru clusters sites and then the dissociated H* spontaneously overflows from Ru clusters with high binding energy into the adjacent Ru single atom sites with low binding energy, which facilitate the hydrogen formation. Consequently, the synthesized Ru/CeO2-Ov-2 exhibits a small overpotential of 41 mV at 10 mA cm−2 and good stability at 500 mA cm−2 for 100 h in alkaline seawater, which could be ascribed to the rapid hydrogen spillover and strong coupling interaction between Ru and CeO2-OV. This work provides a novel insight that synthesizing cooperative sites with energy barrier gradient helps to promote hydrogen spillover and accelerate the Volmer/Tafel process of HER.

Catalytic N‐Formylation of CO2 by Atomically Precise Au8Pd1(DPPF)42+ Clusters into a Two‐Dimensional Metal–Organic Framework

AbstractBy highly efficient ligand‐exchange strategy, atomically precise Au8Pd1(PPh3)82+ (PPh3=triphenylphosphine) cluster can be transformed into a Au8Pd1(DPPF)42+ (DPPF=1,1′‐bis(diphenylphosphino)ferrocene) cluster that can maintain the atomic‐packing structure but overcome the lability of Au8Pd1(PPh3)82+. Catalytic evaluation for the CO2 hydrogenation coupled with o‐phenylenediamine demonstrates that the Au8Pd1(DPPF)42+ catalyst can remarkably enhance both activity and stability compared to the Au8Pd1(PPh3)82+ catalyst. More notably, the direct construction of a two‐dimensional metal–organic framework (2D MOF) can be elaborately accomplished in the formylation process of o‐phenylenediamine, CO2 and H2 with zinc nitrate enabled by the Au8Pd1(DPPF)42+ catalyst. The 2D MOF further enables the capture and transformation of CO2 to combine in the organic synthesis with epoxides under mild conditions. This work provides opportunities for creating highly active cluster sites for the chemical recycling of CO2.

Catalytic N-Formylation of CO2 by Atomically Precise Au8Pd1(DPPF)4 2+ Clusters into a Two-Dimensional Metal-Organic Framework.

By highly efficient ligand-exchange strategy, atomically precise Au8Pd1(PPh3)8 2+ (PPh3=triphenylphosphine) cluster can be transformed into a Au8Pd1(DPPF)4 2+ (DPPF=1,1'-bis(diphenylphosphino)ferrocene) cluster that can maintain the atomic-packing structure but overcome the lability of Au8Pd1(PPh3)8 2+. Catalytic evaluation for the CO2 hydrogenation coupled with o-phenylenediamine demonstrates that the Au8Pd1(DPPF)4 2+ catalyst can remarkably enhance both activity and stability compared to the Au8Pd1(PPh3)8 2+ catalyst. More notably, the direct construction of a two-dimensional metal-organic framework (2D MOF) can be elaborately accomplished in the formylation process of o-phenylenediamine, CO2 and H2 with zinc nitrate enabled by the Au8Pd1(DPPF)4 2+ catalyst. The 2D MOF further enables the capture and transformation of CO2 to combine in the organic synthesis with epoxides under mild conditions. This work provides opportunities for creating highly active cluster sites for the chemical recycling of CO2.

Manufacturing Single‐Atom Alloy Catalysts for Selective CO2 Hydrogenation via Refinement of Isolated‐Alloy‐Islands

AbstractSingle‐atom alloy (SAA) catalysts exhibit huge potential in heterogeneous catalysis. Manufacturing SAAs requires complex and expensive synthesis methods to precisely control the atomic scale dispersion to form diluted alloys with less active sites and easy sintering of host metal, which is still in the early stages of development. Here, we address these limitations with a straightforward strategy from a brand‐new perspective involving the ‘islanding effect’ for manufacturing SAAs without dilution: homogeneous RuNi alloys were continuously refined to highly dispersed alloy‐islands (~1 nm) with completely single‐atom sites where the relative metal loading was as high as 40 %. Characterized by advanced atomic‐resolution techniques, single Ru atoms were bonded with Ni as SAAs with extraordinary long‐term stability and no sintering of the host metal. The SAAs exhibited 100 % CO selectivity, over 55 times reverse water‐gas shift (RWGS) rate than the alloys with Ru cluster sites, and over 3–4 times higher than SAAs by the dilution strategy. This study reports a one‐step manufacturing strategy for SAA's using the wetness impregnation method with durable high atomic efficiency and holds promise for large‐scale industrial applications.

Manufacturing Single-Atom Alloy Catalysts for Selective CO2 Hydrogenation via Refinement of Isolated-Alloy-Islands.

Single-atom alloy (SAA) catalysts exhibit huge potential in heterogeneous catalysis. Manufacturing SAAs requires complex and expensive synthesis methods to precisely control the atomic scale dispersion to form diluted alloys with less active sites and easy sintering of host metal, which is still in the early stages of development. Here, we address these limitations with a straightforward strategy from a brand-new perspective involving the 'islanding effect' for manufacturing SAAs without dilution: homogeneous RuNi alloys were continuously refined to highly dispersed alloy-islands (~1 nm) with completely single-atom sites where the relative metal loading was as high as 40 %. Characterized by advanced atomic-resolution techniques, single Ru atoms were bonded with Ni as SAAs with extraordinary long-term stability and no sintering of the host metal. The SAAs exhibited 100 % CO selectivity, over 55 times reverse water-gas shift (RWGS) rate than the alloys with Ru cluster sites, and over 3-4 times higher than SAAs by the dilution strategy. This study reports a one-step manufacturing strategy for SAA's using the wetness impregnation method with durable high atomic efficiency and holds promise for large-scale industrial applications.

Customized Heteronuclear Dual Single‐Atom and Cluster Assemblies via D‐Band Orchestration for Oxygen Reduction Reaction

AbstractAdvanced oxygen reduction reaction (ORR) catalysts, integrating with well‐dispersed single atom (SA) and atomic cluster (AC) sites, showcase potential in bolstering catalytic activity. However, the precise structural modulation and in‐depth investigation of their catalytic mechanisms pose ongoing challenges. Herein, a proactive cluster lockdown strategy is introduced, relying on the confinement of trinuclear clusters with metal atom exchange in the covalent organic polymers, enabling the targeted synthesis of a series of multicomponent ensembles featuring FeCo (Fe or Co) dual‐single‐atom (DSA) and atomic cluster (AC) configurations (FeCo‐DSA/AC) via thermal pyrolysis. The designed FeCo‐DSA/AC surpasses Fe‐ and Co‐derived counterparts by 18 mV and 49 mV in ORR half‐wave potential, whilst exhibiting exemplary performance in Zn‐air batteries. Comprehensive analysis and theoretical simulation elucidate the enhanced activity stems from adeptly orchestrating dz2‐dxz and O 2p orbital hybridization proximate to the Fermi level, fine‐tuning the antibonding states to expedite OH* desorption and OOH* formation, thereby augmenting catalytic activity. This work elucidates the synergistic potentiation of active sites in hybrid electrocatalysts, pioneering innovative targeted design strategies for single‐atom‐cluster electrocatalysts.

Diagnostic Ratios and Ecological Risk of Non-carcinogenic Polycyclic Aromatic Hydrocarcarbons (ncPAHs) in Egi Crude Oil Communities, Nigeria

The loadings of PAHs, its diagnostic ratios and ncPAHs at three cluster communities in Egi sub district of Niger-Delta with geographic coordinates of latitude 150 32ʹ 50ʺ N and longitude 60 34ʹ 42ʺ E were ascertained using Gas Chromatography (GC-FID, HP 5890 Series). The diagnostic ratios showed that Obagi had an LMW/HMW ratio of 0.2340, Ibewa's was 0.2222, and Obite's was 0.2549. In Obagi, the proportion of Low Molecular Weight (LMW) PAHs compared to High Molecular Weight (HMW) PAHs was 19%, while in Obite it was 18%, and in the Ibewa cluster it was 20%. The sediments of the Obagi, Obite, and Ibewa cluster sites exhibited a significant abundance of PAHs derived from pyrogenic sources, as evidenced by the presence of LMW/HWM ratios below 1. The identified ncPAHs include: Naphthalene, Acenaphthene, Acenaphthylene, Fluorene, Anthracene, Phenanthrene, Fluoranthene, Pyrene and Benzo(ghi)perylene. According to the results obtained the Obite cluster area exhibited the lowest concentrations (1.503mg/Kg) amongst the ncPAHs, while the Obagi study zone demonstrated the highest concentrations (1.5733mg/Kg). Among the nc(PAHs) examined, benzo (g,h,i) perylene exhibited the highest concentrations (2.086mg/Kg) across all locations, whereas acenaphthylene displayed the lowest concentration (0.123mg/kg) across the three cluster areas. However, none of the three study locations had any ncPAHs that are above the maximum permissible limit. Results from the application of risk quotient models (RQNCs and RQMPCs) to assess the ecological risk of ncPAHs as presented indicated that all the sites where these rivers' sediments were tested had RQNCs values for specific ncPAHs below 1, implying that these ncPAHs pose little or no danger to ecosystems. Also, the RQMPC score is less than 1, it means that the contamination from individual ncPAHs chemicals do not necessitate immediate remediation. Because the RQNCs and RQMPCs for a single PAH molecule are both less than 1, the contamination it generates might be considered low risk. Thus, few measures of control or correction would be required. The ecological risk of non-carcinogenic PAHs using RQMPCs and RQNCs indicated a very negligible risk which could be due to factors like heavy flooding that washed away soil surfaces. Application of Detoxification by chemical reaction technology should be used as future remediation method if there is need.

Tumor suppressor NME1/NM23-H1 modulates DNA binding of NF-κB RelA.

The dimeric NF-κB family of transcription factors activates transcription by binding sequence-specifically to DNA response elements known as κB sites, located within the promoters and enhancers of their target genes. While most NF-κB remain inactive in the cytoplasm of unstimulated cells, a small amount of RelA, one of its members, persists in the nucleus, ensuring low-level expression of genes essential for homeostasis. Several cofactors have been identified that aid in DNA binding of RelA. In this study, we identify NME1 (nucleoside diphosphate kinase 1) as a cofactor that enhances RelA's ability to bind κB sites within the promoters of a subset of its target genes, promoting their expression under both unstimulated and stimulated conditions. Depletion of NME1 influences activation or repression of several genes that are unresponsive to TNFα, despite containing κB sites in their promoters but not in clusters. This suggests that clustering of kB sites may be necessary for RelA-dependent transcription complex assembly. NME1 appears to act as a cofactor for other transcription factors to regulate these genes. NME1 does not directly contact κB DNA but interacts with RelA, with this interaction being further strengthened in the presence of κB DNA. Notably, NME1 alone has a marginal effect in enhancing RelA's DNA binding, suggesting that NME1 likely cooperate with other cofactors to regulate DNA binding and transcription through RelA. These observations underscore the intricate assembly of transcription complexes centered on NF-κB.

A multi-pathogen behavioral exposure model for young children playing in public spaces in developing communities.

Diarrheal disease is the second leading cause of death among children under five in developing communities, despite active interventions to improve access to water, sanitation, and hygiene resources. Even interventions with high fidelity and compliance saw minimal improvements in health outcomes, necessitating a need for looking beyond traditionally targeted exposure pathways. This study focuses on the pathogen exposure a young child may receive while playing in the public spaces of informal settlements, where animal feces, human feces, and garbage are frequently observed. The study utilized 79 soil samples previously collected across ten cluster sites in Corail, Haiti and processed using DelAgua cultural assays and quantitative Polymerase Chain Reaction methods. Molecular assays screened for Aeromonas, Vibrio cholera, and several pathogenic Escherichia coli species. Behavioral observations of young children (<5 years old) were also conducted in overlapping areas with the environmental sampling to quantify frequency of risky and mitigating behaviors. Environmental and behavioral data were combined to obtain the posterior distribution of children's pathogen exposure from playing in a public space for one hour. The model estimated that children have a likelihood of approximately 70% of being exposed to a pathogen during one hour of play and a greater than 30% chance of being exposed to multiple pathogens in the same period. While children and toddlers practice fewer risky behaviors compared to infants, they were shown to have higher likelihood of exposure and slightly higher pathogen dose per exposure. As anticipated, a high correlation between genes from the same E. coli species was observed in the model output. These findings demonstrate the need to consider public spaces as an important exposure pathway for young children for both future research and interventions.

Tumor suppressor NME1/NM23-H1 modulates DNA binding of NF-κB RelA.

The dimeric NF-κB family of transcription factors activates transcription by binding sequence-specifically to DNA response elements known as κB sites, located within the promoters and enhancers of their target genes. While most NF-κB remain inactive in the cytoplasm of unstimulated cells, a small amount of RelA, one of its members, persists in the nucleus, ensuring low-level expression of genes essential for homeostasis. Several cofactors have been identified that aid in DNA binding of RelA. In this study, we identify NME1 (nucleoside diphosphate kinase 1) as a cofactor that enhances RelA's ability to bind κB sites within the promoters of a subset of its target genes, promoting their expression under both unstimulated and stimulated conditions. Depletion of NME1 influences activation or repression of several genes that are unresponsive to TNFα, despite containing κB sites in their promoters but not in clusters. This suggests that clustering of kB sites may be necessary for RelA-dependent transcription complex assembly. NME1 appears to act as a cofactor for other transcription factors to regulate these genes. NME1 does not directly contact κB DNA but interacts with RelA, with this interaction being further strengthened in the presence of κB DNA. Notably, NME1 alone has a marginal effect in enhancing RelA's DNA binding, suggesting that NME1 likely cooperate with other cofactors to regulate DNA binding and transcription through RelA. These observations underscore the intricate assembly of transcription complexes centered on NF-κB.

18F-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography Measures of Spatial Heterogeneity for Predicting Platinum Resistance of High-Grade Serous Ovarian Cancer.

The purpose of this study is to construct models for predicting platinum resistance in high-grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18F-FDG PET/CT images. A retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki-67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki-67 and p53 was assessed by Spearman's correlation coefficient (ρ). A total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU_Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki-67 scores with ρ = 0.753. Adding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki-67 and p53 scores.

Cooperativity among clustered κB sites within promoters and enhancers dictates transcriptional specificity of NF-κB-RelA along with specific cofactors.

The functional role of weak DNA binding sites for transcription factor (TF) recruitment and gene expression remains largely unknown. Our study reveals that the weak NF-κB DNA binding sites, which are abundant in gene promoters and enhancers, appear in clusters and exhibit minimal to undetectable NF-κB binding activity in isolation in vitro, yet they play prominent roles in gene regulation within native context in cells. We found nuclear concentration of RelA/p65, the predominant NF-κB, is approximately 0.2 µM in stimulated cells, challenging the idea that these weak κB sites operate through mass action-dependent binding mechanisms. Through proteomic analysis, we identified a range of nuclear factors, including various other TFs, interacting with RelA at these κB-sites. ChIP-seq, RNA-seq and phase-separated condensation analyses suggest these additional TFs, referred to as the cofactors of NF-κB, facilitate dynamic recruitment of NF-κB to clustered κB sites of specific target genes. Overall, our findings demonstrate the collective contribution of both strong and weak κB sites in occupancy of NF-κB at the promoters and enhancers, with the recruitment facilitated by a variety of cofactors. This congregation of multiple factors forming larger dynamic complexes appearing as a transcription condensate is likely to be common to all transcriptional programs.