A backbone-centred energy function of neural networks for protein design.

A protein backbone structure is designable if a substantial number of amino acid sequences exist that autonomously fold into it1,2. It has been suggested that the designability of backbones is governed mainly by side chain-independent or side chain type-insensitive molecular interactions3-5, indicating an approach for designing new backbones (ready for amino acid selection) based on continuous sampling and optimization of the backbone-centred energy surface. However, a sufficiently comprehensive and precise energy function has yet to be established for this purpose. Here we show that this goal is met by a statistical model named SCUBA (for Side Chain-Unknown Backbone Arrangement) that uses neural network-form energy terms. These terms are learned with a two-step approach that comprises kernel density estimation followed by neural network training and can analytically represent multidimensional, high-order correlations in known protein structures. We report the crystal structures of nine de novo proteins whose backbones were designed to high precision using SCUBA, four of which have novel, non-natural overall architectures. By eschewing use of fragments from existing protein structures, SCUBA-driven structure design facilitates far-reaching exploration of the designable backbone space, thus extending the novelty and diversity of the proteins amenable to de novo design.

A Machine Learning Method for a Blood Diagnostic Model of Pancreatic Cancer Based on microRNA Signatures.

This study aimed to construct a blood diagnostic model for pancreatic cancer (PC) using miRNA signatures by a combination of machine learning and biological experimental verification. Gene expression profiles of patients with PC and transcriptome normalization data were obtained from the Gene Expression Omnibus (GEO) database. Using random forest algorithm, lasso regression algorithm, and multivariate cox regression analyses, the classifier of differentially expressed miRNAs was identified based on algorithms and functional properties. Next, the ROC curve analysis was used to evaluate the predictive performance of the diagnostic model. Finally, we analyzed the expression of two specific miRNAs in Capan-1, PANC-1, and MIA PaCa-2 pancreatic cells using qRT-PCR. Integrated microarray analysis revealed that 33 common miRNAs exhibited significant differences in expression profiles between tumor and normal groups (P value < 0.05 and |logFC| > 0.3). Pathway analysis showed that differentially expressed miRNAs were related to P00059 p53 pathway, hsa04062 chemokine signaling pathway, and cancer-related pathways including PC. In ENCORI database, the hsa-miR-4486 and hsa-miR-6075 were identified by random forest algorithm and lasso regression algorithm and introduced as major miRNA markers in PC diagnosis. Further, the receiver operating characteristic curve analysis achieved the area under curve score > 80%, showing good sensitivity and specificity of the two-miRNA signature model in PC diagnosis. Additionally, hsa-miR-4486 and hsa-miR-6075 genes expressions in three pancreatic cells were all up-regulated by qRT-PCR. In summary, these findings suggest that the two miRNAs, hsa-miR-4486 and hsa-miR-6075, could serve as valuable prognostic markers for PC.

Low shear stress-induced blockage of autophagic flux impairs endothelial barrier and facilitates atherosclerosis in mice.

Atherosclerosis preferentially occurs in areas with low shear stress (LSS) and oscillatory flow. LSS has been demonstrated to correlate with the development of atherosclerosis. The sphingosine 1-phosphate receptor 1 (S1PR1), involving intravascular blood flow sensing, regulates vascular development and vascular barrier function. However, whether LSS affects atherosclerosis via regulating S1PR1 remains incompletely clear. In this study, immunostaining results of F-actin, ß-catenin, and VE-cadherin indicated that LSS impaired endothelial barrier function in human umbilical vein endothelial cells (HUVECs). Western blot analysis showed that LSS resulted in blockage of autophagic flux in HUVECs. In addition, autophagy agonist Rapamycin (Rapa) antagonized LSS-induced endothelial barrier dysfunction, whereas autophagic flux inhibitor Bafilomycin A1 (BafA1) exacerbated it, indicating that LSS promoted endothelial barrier dysfunction by triggering autophagic flux blockage. Notably, gene expression analysis revealed that LSS downregulated S1PR1 expression, which was antagonized by Rapa. Selective S1PR1 antagonist W146 impaired endothelial barrier function of HUVECs under high shear stress (HSS) conditions. Moreover, our data showed that expression of GAPARAPL2, a member of autophagy-related gene 8 (Atg8) proteins, was decreased in HUVECs under LSS conditions. Autophagic flux blockage induced by GAPARAPL2 knockdown inhibited S1PR1, aggravated endothelial barrier dysfunction of HUVECs in vitro, and promoted aortic atherosclerosis in ApoE-/- mice in vivo. Our study demonstrates that autophagic flux blockage induced by LSS downregulates S1PR1 expression and impairs endothelial barrier function. GABARAPL2 inhibition is involved in LSS-induced autophagic flux blockage, which impairs endothelial barrier function via downregulation of S1PR1.

The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.

Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.

Relative Adrenal Insufficiency Is a Risk Factor for Pediatric Sepsis: A Proof-of-Concept Study.

Glucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. About 32.8% of patients with pediatric septic develop relative adrenal insufficiency (RAI). But whether GC therapy should be determined by RAI status is controversial. This study utilized 21-day-old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice exhibited a substantially higher mortality rate in cecal ligation and puncture and cecal slurry-induced sepsis. These mice featured persistent inflammatory responses and were effectively rescued by GC therapy. RNA sequencing analysis revealed persistent inflammatory responses in RAI mice, caused by transcriptional dysregulation of AP-1 and NF-κB, and cytokine-induced secondary inflammatory response. Our findings support a precision medicine approach to guide GC therapy for pediatric patients based on the status of RAI.

Identification of key regulatory molecules in the early development stage of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, the incidence of which increases with age, and the pathological changes in the brain are irreversible. Recent studies have highlighted the essential role of long noncoding RNAs (lncRNAs) in AD by acting as competing endogenous RNAs (ceRNAs). Our aim was to construct lncRNA-associated ceRNA regulatory networks composed of potential biomarkers for the early stage of AD. AD related datasets come from AlzData and GEO databases. The R package 'Limma' identifies differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases for functional enrichment analysis. Protein-protein interactions (PPIs) in DEGs were constructed in the STRING database, and Cytoscape software identified DEGs. Convergent functional genomics (CFG) analysis of differentially expressed hub genes (referred to as early-DEGs) in the brain before the development of AD pathology. The AlzData database analyses the expression levels of early-DEGs in different nerve cells. The lncRNA-miRNA-mRNA regulatory network was established according to the ceRNA hypothesis. We identified four lncRNAs (XIST, NEAT1, KCNQ1OT1 and HCG18) and four miRNAs (hsa-let-7c-5p, hsa-miR-107, hsa-miR-129-2-3p and hsa-miR-214-3p) were preliminarily identified as potential biomarkers for early AD, competitively regulating Atp6v0b, Atp6v1e1 Atp6v1f and Syt1. This study indicates that NEAT1, XIST, HCG18 and KCNQ1OT1 act as ceRNAs in competitive binding with miRNAs to regulate the expression of Atp6v0b, Atp6v1e1, Atp6v1f and Syt1 before the occurrence of pathological changes in AD.

Crosstalk of disulfidptosis-related subtypes identifying a prognostic signature to improve prognosis and immunotherapy responses of clear cell renal cell carcinoma patients.

BACKGROUND: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. METHODS: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. RESULTS: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. CONCLUSION: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients.

Genome-wide analysis of the KNOX gene family in Moso bamboo: insights into their role in promoting the rapid shoot growth.

BACKGROUND: KNOTTED1-like homeobox (KNOX) genes, plant-specific homologous box transcription factors (TFs), play a central role in regulating plant growth, development, organ formation, and response to biotic and abiotic stresses. However, a comprehensive genome-wide identification of the KNOX genes in Moso bamboo (Phyllostachys edulis), the fastest growing plant, has not yet been conducted, and the specific biological functions of this family remain unknown. RESULTS: The expression profiles of 24 KNOX genes, divided into two subfamilies, were determined by integrating Moso bamboo genome and its transcriptional data. The KNOX gene promoters were found to contain several light and stress-related cis-acting elements. Synteny analysis revealed stronger similarity with rice KNOX genes than with Arabidopsis KNOX genes. Additionally, several conserved structural domains and motifs were identified in the KNOX proteins. The expansion of the KNOX gene family was primarily regulated by tandem duplications. Furthermore, the KNOX genes were responsive to naphthaleneacetic acid (NAA) and gibberellin (GA) hormones, exhibiting distinct temporal expression patterns in four different organs of Moso bamboo. Short Time-series Expression Miner (STEM) analysis and quantitative real-time PCR (qRT-PCR) assays demonstrated that PeKNOX genes may play a role in promoting rapid shoot growth. Additionally, Gene Ontology (GO) and Protein-Protein Interaction (PPI) network enrichment analyses revealed several functional annotations for PeKNOXs. By regulating downstream target genes, PeKNOXs are involved in the synthesis of AUX /IAA, ultimately affecting cell division and elongation. CONCLUSIONS: In the present study, we identified and characterized a total of 24 KNOX genes in Moso bamboo and investigated their physiological properties and conserved structural domains. To understand their functional roles, we conducted an analysis of gene expression profiles using STEM and RNA-seq data. This analysis successfully revealed regulatory networks of the KNOX genes, involving both upstream and downstream genes. Furthermore, the KNOX genes are involved in the AUX/IAA metabolic pathway, which accelerates shoot growth by influencing downstream target genes. These results provide a theoretical foundation for studying the molecular mechanisms underlying the rapid growth and establish the groundwork for future research into the functions and transcriptional regulatory networks of the KNOX gene family.

A framework and process for community-engaged, mixed-methods cancer needs assessments.

PURPOSE: Community health needs assessments are required for most state and local public health agencies and non-profit hospitals. Typically based on community health improvement planning models, these assessments encompass overall community health and multiple diseases to inform program planning. National Cancer Institute (NCI)-designated Cancer Centers and community-based cancer-focused programs share the goal of reducing cancer burden in the catchment areas they serve. However, to date, no published models exist to guide cancer-specific needs assessments for a determined geographic area that can inform both public health and research initiatives. The purpose of this article is to outline a cancer needs assessment (CNA) framework and community-engaged, mixed-methods process, along with a case study of how we applied it in Kentucky. METHODS: We convened a steering committee of key organizational partners to provide input throughout the process. We developed a conceptual framework of multi-level determinants affecting cancer-related outcomes. We incorporated both quantitative and qualitative data gathered through a variety of means, including a novel application of group concept mapping to guide definition of priorities. RESULTS: The resulting CNA has helped guide strategic planning and priorities for Kentucky's Cancer Action Plan, Markey Cancer Center, state agencies, and community-based organizations. CONCLUSION: This framework and process can be used collaboratively by cancer center Community Outreach and Engagement offices, public health agencies, oncology programs, and community partners to plan impactful cancer control programs and research in their catchment areas. Universities can also use them to inform the planning of community engagement and health equity research efforts.

Accurate and efficient protein sequence design through learning concise local environment of residues.

MOTIVATION: Computational protein sequence design has been widely applied in rational protein engineering and increasing the design accuracy and efficiency is highly desired. RESULTS: Here, we present ProDESIGN-LE, an accurate and efficient approach to protein sequence design. ProDESIGN-LE adopts a concise but informative representation of the residue's local environment and trains a transformer to learn the correlation between local environment of residues and their amino acid types. For a target backbone structure, ProDESIGN-LE uses the transformer to assign an appropriate residue type for each position based on its local environment within this structure, eventually acquiring a designed sequence with all residues fitting well with their local environments. We applied ProDESIGN-LE to design sequences for 68 naturally occurring and 129 hallucinated proteins within 20 s per protein on average. The designed proteins have their predicted structures perfectly resembling the target structures with a state-of-the-art average TM-score exceeding 0.80. We further experimentally validated ProDESIGN-LE by designing five sequences for an enzyme, chloramphenicol O-acetyltransferase type III (CAT III), and recombinantly expressing the proteins in Escherichia coli. Of these proteins, three exhibited excellent solubility, and one yielded monomeric species with circular dichroism spectra consistent with the natural CAT III protein. AVAILABILITY AND IMPLEMENTATION: The source code of ProDESIGN-LE is available at https://github.com/bigict/ProDESIGN-LE.

Risk subgroups and intervention effects among infants at high risk for peanut allergy: A model for clinical decision making.

BACKGROUND: The Learning Early About Peanut Allergy (LEAP) trial showed that early dietary introduction of peanut reduced the risk of developing peanut allergy by age 60 months in infants at high risk for peanut allergy. In this secondary analysis of LEAP data, we aimed to determine risk subgroups within these infants and estimate their respective intervention effects of early peanut introduction. METHODS: LEAP raw data were retrieved from ITNTrialShare.org. Conditional random forest was applied to participants in the peanut avoidance arm to select statistically important features for the classification and regression tree (CART) analysis to group infants based on their risk of peanut allergy at 60 months of age. Intervention effects were estimated for each derived risk subgroup using data from both arms. Our main model was generated based on baseline data when the participants were 4-11 months old. Specific IgE measurements were truncated to account for the limit of detection commonly used by laboratories in clinical practice. RESULTS: The model found infants with higher predicted probability of peanut allergy at 60 months of age had a similar relative risk reduction, but a greater absolute risk reduction in peanut allergy with early introduction of peanut, than those with lower probability. The intervention effects were significant across all risk subgroups. Participants with baseline peanut sIgE ≥0.22 kU/L (n = 78) had an absolute risk reduction of 40.4% (95% CI 27.3, 51.9) whereas participants with baseline peanut sIgE<0.22 kU/L and baseline Ara h 2 sIgE <0.10 kU/L (n = 226) had an absolute risk reduction of 6.5% (95% CI 2.6, 11.0). These findings were consistent in sensitivity analyses using alternative models. CONCLUSION: In this study, risk subgroups were determined among infants from the LEAP trial based on the probability of developing peanut allergy and the intervention effects of early peanut introduction were estimated. This may be relevant for further risk assessment and personalized clinical decision-making.

TRPV1 Dysfunction Impairs Gastric Nitrergic Neuromuscular Relaxation in High-Fat Diet-Induced Diabetic Gastroparesis Mice.

Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron-mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation.

Characteristics and patient-reported outcomes of long-term cancer survivors after apatinib-based therapy: an online survey.

BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.

Dispersion Behavior of a Droplet Impacting a Single Fiber.

The high-gravity reactor, known for its excellent mass transfer capability, plays a crucial role in the carbon capture process. The wire mesh packing serves as the core structure for enhancing mass transfer performance. Understanding the underlying dispersion mechanism requires a thorough exploration of the dynamics of droplet impact on a single fiber. This work aimed to numerically study the process of a droplet impacting a single fiber by applying the volume of fluid method. The effects of initial velocity (u0), initial diameter (D0), impact eccentric distance (e), and impact angle (θ) on the deformation evolution and dispersion characteristics of a droplet impacting a single fiber were systematically studied. Central or vertical impacts can be categorized into four main stages: splitting, merging, stretching, and breaking. Meanwhile, asynchronous breaking, sliding splitting, and oblique stages were observed during eccentric and nonvertical impacts. Subsequently, dimensionless time (t*) and the rate of increase of the gas-liquid interfacial area (η) were introduced to quantitatively analyze the dispersion characteristics postimpact. Increasing the initial velocity, reducing the droplet diameter, minimizing the impact eccentric distance, and maximizing the impact angle all contribute to enhanced dispersion performance. A correlation for the maximum increase rate of the gas-liquid interfacial area of the droplet was proposed, with errors less than ±15%. Finally, the deformation mechanism of droplet impact on a fiber was summarized by analyzing the influences of differential pressure inside and outside the liquid film, as well as gas vortices.

Frailty in patients with ovarian cancer and the role of healthcare access, race, and ethnicity.

OBJECTIVE: Ovarian cancer has poor 5-year survival, particularly among non-Hispanic (NH) Black patients. Efforts to identify patients at high-risk of functional limitations and frailty may improve outcomes. In this study, we examined how healthcare access (HCA) and race/ethnicity relate to frailty among patients with ovarian cancer. METHODS: We identified Hispanic, NH Black, and NH White patients diagnosed at ages ≥6 5 years with ovarian cancer between 2009 and 2015 using SEER-Medicare. Log-binomial regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between HCA and race/ethnicity with pre- or post-diagnosis frailty, adjusting for age and comorbidities. RESULTS: A total of 6041 patients with ovarian cancer were included, including 91.8% NH White, 6.6% NH Black, and 1.7% Hispanic. Pre-diagnosis, 14.7% of patients were defined as frail (NH White: 14.3%; NH Black: 17.9%; Hispanic: 20.8%). Post-diagnosis, frailty prevalence increased to 58.8% (NH White: 58.2%; NH Black: 65.2%; Hispanic: 70.2%). No statistically significant associations were observed between race/ethnicity and pre- or post-diagnosis frailty in fully adjusted models. After adjustment for patient characteristics and healthcare accessibility and availability, higher healthcare affordability was associated with a decreased prevalence of pre-diagnosis frailty (PR: 0.91, 95% CI: 0.8 5, 0.98). CONCLUSIONS: Patients with ovarian cancer have a high prevalence of frailty after diagnosis, particularly NH Black and Hispanic patients. Improving healthcare affordability may prevent or help manage frailty in Medicare patients, improve receipt of cancer treatment, and increase cancer survival.

Lewis Acid-Catalyzed Formal [4 + 2] Reaction of Alkynyl Sulfides and 2-Pyrones To Access Polysubstituted Aryl Sulfides.

A practical and efficient method to access polysubstituted aryl sulfides has been discovered via a Lewis acid-catalyzed reaction between alkynyl sulfide and 2-pyrone, involving a Diels-Alder/retro-Diels-Alder pathway. Alkynyl sulfide as an electron-rich dienophile and 2-pyrones as electron-poor dienes are conjunctively transformed into a series of polysubstituted aryl sulfides with broad functional group compatibility in good to excellent yields (40 examples, 43-88% yield). The robustness and practicality of the protocol has been demonstrated through gram-scale synthesis and the ease of transformation of the resulting products.

Synthesis of γ-Thiapyrones by Diels-Alder/Retro-Diels-Alder Reaction of α-Pyrones with 5-H-1,2,3-Thiadiazoles.

The efficient synthesis of γ-thiapyrones by a base-mediated Diels-Alder/retro-Diels-Alder reaction of α-pyrones with 5-H-1,2,3-thiadiazoles is reported herein. Thioketenes in situ generated from thiadiazoles as electron-poor dienophile and electron-rich 4-hydroxy-2-pyrones as dienes are conjunctively transformed into a series of γ-thiapyrones with broad functional group compatibility in good to excellent yields (35 examples, 67% average yield).

Development and Validation of a User Friendly Morphology Grading System (PATENT) Predicting Aortic Remodelling After Thoracic Endovascular Aortic Repair in High Risk Uncomplicated Type B Aortic Dissection.

OBJECTIVE: This study aimed to create a morphology grading system, solely based on 2D images from computed tomography angiography, to predict negative aortic remodelling (NAR) for patients with high risk uncomplicated type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR). METHODS: This single centre retrospective cohort study extracted and analysed consecutive patients diagnosed with high risk uncomplicated TBAD. Negative aortic remodelling was defined as an increase in the false lumen or total aortic diameter, or decrease in the true lumen diameter. The multivariable Cox regression model identified risk factors and a prediction model was created for two year freedom from NAR. A three category grading system, in which patients were classified into low, medium, and high risk groups, was further developed and internally validated. RESULTS: Of 351 patients included, 99 (28%) developed NAR. The median age was 52 years (interquartile range 45, 62 years) and 56 (16%) were female. The rate of two year freedom from NAR was 71% (95% CI 65 - 77%). After the multivariable Cox regression analysis, Patent false lumen, Aberrant right subclavian artery, Taper ratio, abdominal circumferential Extent, coeliac artery or reNal artery involved, and four channel dissection (Three false lumens) remained independent predictors and were included in the PATENT grading system. The risk score was statistically significantly associated with NAR (HR 1.21; 95% CI 1.14 - 1.29; p < .001). The medium and high risk groups demonstrated a higher rate of NAR (medium risk, HR 2.82; 95% CI 1.57 - 5.01; p = .001; high risk, HR 4.39; 95% CI 2.58 - 7.48; p < .001). The grading system was characterised by robust discrimination with Harrell's C index of 0.68 (95% CI 0.63 - 0.75). CONCLUSION: The PATENT grading system was characterised by good discrimination and calibration, which may serve as a clinician friendly tool to aid risk stratification for TBAD patients after TEVAR.

Silica Nanoparticle Size Determines the Mechanisms Underlying the Inhibition of Iron Oxide Nanoparticle Uptake by Daphnia magna.

Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO2 NPs) on the uptake of iron oxide NPs (Fe2O3 NPs) by the zooplankton Daphnia magna. Both SiO2 NPs and Fe2O3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO2 NPs inhibited the uptake of Fe2O3 NPs, the underlying mechanisms differed. SiO2 NPs smaller than the average mesh size (∼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe2O3 NPs through uptake competition, whereas larger SiO2 NPs inhibited the uptake of Fe2O3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.

Algal Extracellular Organic Matter Induced Photochemical Oxidation of Mn(II) to Solid Mn Oxide: Role of Mn(III)-EOM Complex and Its Ability to Remove 17α-Ethinylestradiol.

Photosensitizer-mediated abiotic oxidation of Mn(II) can yield soluble reactive Mn(III) and solid Mn oxides. In eutrophic water systems, the ubiquitous algal extracellular organic matter (EOM) is a potential photosensitizer and may have a substantial impact on the oxidation of Mn(II). Herein, we focused on investigating the photochemical oxidation process from Mn(II) to solid Mn oxide driven by EOM. The results of irradiation experiments demonstrated that the generation of Mn(III) intermediate was crucial for the successful photo oxidization of Mn(II) to solid Mn oxide mediated by EOM. EOM can serve as both a photosensitizer and a ligand, facilitating the formation of the Mn(III)-EOM complex. The complex exhibited excellent efficiency in removing 17α-ethinylestradiol. Furthermore, the complex underwent decomposition as a result of reactions with reactive intermediates, forming a solid Mn oxide. The presence of nitrate can enhance the photochemical oxidation process, facilitating the conversion of Mn(II) to Mn(III) and then to solid Mn oxide. This study deepens our grasp of Mn(II) geochemical processes in eutrophic water and its impact on organic micropollutant fate.