Molecular testing can detect actionable genomic alterations and tumor cell surface proteins in patients with non–small cell lung cancer (NSCLC). However, utilization remains suboptimal, representing missed treatment opportunities. This study aimed to identify challenges and potential solutions to obtaining percutaneous lung needle biopsy specimens for successful molecular testing in patients with advanced NSCLC.This interdisciplinary qualitative study included ten radiologists and four pathologists from academic and community settings across the United States who routinely perform and analyze percutaneous lung needle biopsies. Participants underwent semi-structured one-on-one interviews (Phase 1). Interview questionnaires were constructed based on a literature review of key lines of inquiry and conducted by professional market researchers using the theoretical domains framework. Primary barriers to molecular testing were identified using thematic analysis. Subsequently, multidisciplinary focus groups were convened to identify potential solutions (Phase 2).Four themes emerged as barriers to molecular testing and were matched to the clinical workflow: (1) biopsy request, (2) biopsy procedure, (3) specimen analysis, and (4) communication. The nineteen potential solutions included adding a “checkbox” to indicate molecular testing in the biopsy request, leveraging pre-procedural imaging to guide biopsies, conserving tissue through appropriate allocation strategies and next generation sequencing panels instead of sequential single-gene assays, instituting reflex-molecular testing upon NSCLC diagnosis, tracking and communicating biopsy outcomes at multidisciplinary tumor boards, and improving integration of radiologists and pathologists into oncology care teams.Potential solutions exist to increase successful molecular testing of lung needle biopsy specimens in patients with advanced NSCLC. Nearly three in four patients with non–small cell lung cancer (NSCLC) present with advanced disease at the time of diagnosis –3. SixtyWhile percutaneous lung needle biopsy is safe in the setting of advanced NSCLC , 20, conThis study sought to identify real-world challenges and potential solutions to obtaining percutaneous lung needle biopsy specimens for successful molecular testing in patients with advanced NSCLC.An interdisciplinary qualitative study consisting of semi-structured interviews and focus group discussions with radiologists and pathologists was conducted. Participants voluntarily agreed to have their interviews and focus group discussions transcribed and analyzed for the purposes of this study. The study was exempt from institutional review board approval [45 Code of Federal Regulations 46.104 (d) (2)].The authors identified participants in an iterative process, targeting interventional and thoracic radiologists and pathologists across the United States who routinely perform and analyze percutaneous lung needle biopsies. Participants worked in academic or community-based clinical settings, and four were involved in developing the latest College of American Pathologists (CAP) thoracic biopsy guidelines . Of 11 iData collection occurred in two phases. In phase 1, trained moderators from the market research firm  conducted 14 semi-structured one-on-one 60-min interviews via videoconference from February to March 2021. Researchers developed lines of inquiry which included the following: goals of lung needle biopsy, awareness of molecular testing, typical lung biopsy scenarios and procedures, perceived and experienced challenges to obtaining tissue samples of sufficient quantity and quality for molecular testing, workflow, and communications between requesting providers and other team members, the role of liquid biopsy, and suggestions for improvement. The theoretical domains framework for the interview focused on knowledge, skills, intentions, context, resources, and consequences . QuestioIn phase 2, two 90-min multidisciplinary focus groups were convened via videoconference in April and May 2021. The first group was comprised of six participants , and the second comprised of seven participants , all of whom had participated in the phase 1 interviews. Discussions were led by a trained moderator from the market research firm who presented findings from the semi-structured interviews and facilitated discussions to elicit divergent and convergent views regarding the interview findings and potential solutions  biopsy request, (2) biopsy procedure, 3) specimen analysis, and (4) communication  limited pre-procedural imaging due to insurance coverage, (2) radiologist skill and comfort with image-guided lung needle biopsies, (3) lesion size, location, and density, (4) patient tolerance for the procedure, (5) lack of standardization for intraprocedural tissue evaluation, and (6) differing lab instructions for sample preparation. Participants cited being unsure of how much tissue was “enough.”Participants differed in their opinions regarding the best approach for judging sample adequacy. While rapid on-site evaluation (ROSE) by a pathologist was described as the best practice in theory, radiologists noted that accurate assessment of a biopsy sample with minimal processing during ROSE requires extensive experience, lengthens the needle dwell time, increases the patient’s risk for complications, may not change the procedural steps for the radiologist, and does not appear to affect patient callback rate. Some pathologists noted that ROSE was not always necessary, may not be feasible in all cases, and may be more helpful for inexperienced radiologists. ROSE seemed more prevalent in academic settings due to pathologist availability. Most radiologists did not perform fine needle aspirations (FNA) and performed core biopsies only. Needle size was a matter of personal preference, and there was no consensus that larger needles were better for molecular testing.Review available imaging, including computed tomography (CT) and positron emission tomography (PET), prior to the procedure and stratify targets by imaging characteristics. For example, absence of 18-fluorodeoxyglucose uptake and intravenous contrast enhancement can identify necrotic tissue.Utilize real-time  CT guidance during the procedure.Obtain multiple tissue cores using coaxial technique while angling the biopsy device in all four quadrantsTarget the periphery of large tumors to avoid central necrosis.During ROSE, have the cytotechnologist verify that the specimen contains viable tumor cells.Collect at least four tissue cores once ROSE confirms viable tumor cells.Consider a higher tolerance for potential risk and obtain additional tissue cores if molecular testing is likely to affect survival, especially in suspected advanced NSCLC.Participants noted (1) a lack of awareness of current guidelines on molecular testing for patients with advanced NSCLC, (2) varying testing methods by lab, (3) varying sample requirements between multiple available testing platforms, and (4) rapidly changing best practices. Although most study participants were aware of the 2020 CAP thoracic biopsy guidelines, awareness of current NCCN guidelines for molecular testing was low. Some participants mentioned relying on institutional or departmental guidelines.Clarify how to allocate the specimens depending on institutional laboratory requirements.Perform next generation sequencing (NGS) assays instead of sequential single-gene assays to conserve tissue and provide more comprehensive molecular testing.If feasible, bank tissue for future molecular testing.Institute “reflex-molecular testing” following histologic diagnosis of NSCLC to reduce turnaround time.Participants reported the absence of formal, consistent communication feedback loops between radiologists, pathologists, and clinical care teams regarding molecular testing results of lung needle biopsy specimens. Feedback was lacking on amount of viable tumor cells and molecular testing success unless a repeat biopsy was requested. Hospital-based radiologists can access biopsy results through the electronic medical record, while radiologists outside of hospital systems may not have access at all to the results.Track frequency of insufficient tissue, reasons for insufficiency, molecular testing results , and complications from the biopsy procedure.Integrate radiologists who perform lung needle biopsies more closely into the oncology care team and foster a culture of continuous feedback and follow-up Fig. .Include data-driven discussions of biopsy outcomes into multidisciplinary tumor boards.not free-form comments) in the molecular testing report [Report amount of viable tumor cells in uniquely identified fields  biopsy request, (2) biopsy procedure, (3) specimen analysis, and (4) communication. Nineteen potential solutions were identified and seem intuitive. This study is important because it identifies barriers and potential solutions to enhance molecular testing in patients with advanced NSCLC, a prerequisite to translate the discovery of novel targeted therapies and immunotherapy into potential cures .Potential solutions identified in this study Table  are in lThree potential solutions may be of interest for future implementation studies based on the projected low implementation cost. First, improving the biopsy request with the addition of a “checkbox” in the electronic health record to indicate the need for molecular testing would facilitate coordination between radiologists, pathologists, and referring providers. Knowing that molecular testing is the goal of the biopsy would affect the biopsy procedure and specimen processing in that radiologists would be prompted to collect more tissue and pathologists could optimize tissue processing. Second, as already studied by Lim et al. educating referring clinicians on the importance of molecular testing may increase testing rates . SpecialPotential solutions in our study were geared towards crafting a framework that promotes successful molecular testing, including strategies to increase the yield of the biopsy procedure itself, which could be disseminated via workshops at specialty society meetings in addition to the literature. Biopsies should be performed using coaxial technique and target the periphery of large tumors to avoid central necrosis . Review EGFR, ALK, and ROS1) [EGFR testing workflows have been reported and allow treatment with EGFR-directed therapies within days, all without compromising NGS workflows [Potential solutions to optimize specimen analysis relate to tissue allocation techniques and testing methods. Herbst et al. advocate using minimal tissue for histology to conserve tissue for molecular testing and developing a histology protocol that allocates sections up front for molecular and immunohistochemistry analyses . The Natnd ROS1) . Multiplnd ROS1) , 42–44. nd ROS1) . Althougorkflows . Archiviorkflows , and chaorkflows .The limitations of this study should be interpreted within the context of its design and the absence of oncologists and pulmonologists. The questionnaires were designed by professional market researchers; this may have led to biases in the questionnaires influencing participant responses. However, by outsourcing the research, design, and execution of the study, inherent biases held by participants were avoided. Participation was voluntary; thus, the panel was susceptible to self-selection bias. The intentional selection of physicians who had helped develop the current CAP guidelines may have skewed responses, but the inclusion of academic and community practices provided a diverse perspective. Although the sample size was limited, participants from across the United States ensured geographic diversity.Increased molecular testing is required to harness the benefits of novel targeted therapies and immunotherapy for patients with advanced NSCLC. Barriers and potential solutions to obtaining percutaneous lung needle biopsy specimens for successful molecular testing in patients with advanced NSCLC relate to the biopsy request, biopsy procedure, specimen analysis, and communication. As the number of therapies continues to grow, the need to overcome these barriers to performing molecular testing requires a coordinated effort among radiologists, pathologists, and referring clinicians. Implementation studies should aim to investigate the efficacy of the proposed potential solutions.


Rotational foam molding has attracted more and more attention due to the inexpensive machines required, low residual stresses, and flexible design for special and high-value-added applications. However, it is a great challenge to control cell sizes and morphology because of its coalesce and collapse during prolonged heating or at different temperatures. A novel tailored polyethylene blend with a unique chain structure for rotational foam molding was creatively proposed and demonstrated, and the effects of crystallization temperature and viscosity–temperature sensitivity on foaming were also investigated. The polyethylene blends with few chain branches in the low-molecular-weight part and many chain branches in the high-molecular-weight part effectively improved the crystallization temperature and the viscosity–temperature sensitivity for better prevention of coalesce and collapse during the foam-shaping stage. Recently, polymeric foams have attracted extensive attention in the industry due to their numerous benefits, such as low cost per unit volume, superior thermal insulation, low coefficient of thermal expansion, excellent sound isolation, and high stiffness for a given weight. ,2. The gThe mechanism of the foaming process is the essential universal prerequisite for fabricating high-quality foamed plastic articles ,13,14,15There are several challenges to producing fine, uniform cells and high-expansion-ratio foams for the rotational-molding process. Firstly, it is well-known that only atmospheric pressure is applied during the conventional rotational-molding process. This will lead to relatively few bubble nucleations, the dimensions of bubble nucleation are typically greater than 150 μm, and the bubble growth only depends on the gas diffusion. The power of gas diffusion mainly comes from the competition between the internal pressure produced by the decomposition gas of the foaming agent and the external pressure of the polymer melt. Secondly, the temperature in the polymer melt is not uneven and changes significantly with the increase in processing time. Thirdly, the presence of cells in the foamed products results in a reduced heat-conduction velocity and a longer cooling process. Too long of a cooling time will cause coalesce and collapse in the polymer melt and make the surface of the foamed article less smooth.The melt characteristics of polymer play important roles in determining the foaming properties. Lower shear viscosity can facilitate sintering behavior. However, very low shear viscosity may not be desirable for the foaming process because the associated reduction in melt strength will lead to severe deformed cellular structure, so it is very difficult to select suitable polyethylene resins for pressureless foaming ,17. MetaTo improve the pressureless foaming properties of high-melt-index polyethylene, different methods have been proposed to avoid cell coalescence by increasing the melt viscosity ,22,23. IHowever, to the best of our knowledge, no studies reported the relationship between molecular structure, crystallization temperature, viscosity–temperature sensitivity, and rotational-foaming properties of the polyethylene blends. The main objective of this work is to design and produce novel, tailored polyethylene blends with unique structures for rotational foam molding. In particular, the effects of the polymeric structure on crystallization temperature and viscosity–temperature sensitivity will be investigated, as well as their effects on foaming properties, including cell size and morphology.The raw polyethylene materials  were supplied by Shenhua Coal Chemical Industrial Company, the raw material labeled M0.5/D868 was purchased from Dow Chemical Company, and the polyethylene labeled M0.06/D948 was purchased from Saudi Polymers. Herein, M and D represent the melt index and density of raw materials in The foaming agent was a commercialized azodicarbonamide (AZ), provided by Adamas Reagent Co., Ltd., Shanghai, China. The particle size of the industrial grade ranged from 12 μm to 18 μm, and the average particle size was about 13.25 μm. The gas yield was 220 mL/g, and its decomposition temperature was closed to 205 °C. Zinc oxide (ZnO) powder, provided by Sinopharm Chemical Reagent Co., Ltd., Shanghai, China, was selected as an activator to modify the decomposition temperature of the blowing agent for this foaming system. Based on the resin mass of 100 phr, the amounts of AZ and zinc oxide were 3 phr and 0.12 phr, respectively. The foaming agents and polyethylene blends were mixed under the setting temperature of 135 °C using a twin-screw extruder. The extruder has a diameter of 26 mm and an L/R ratio of 40. Then, the polyethylene blends with the additives were milled to 35 mesh under 60 °C for rotational foam-molding.Rotational foam-molding experiments were carried out on a laboratory-scale bi-axially rotating machine with an electrically heated oven and a circulation fan. The diameter of the oven was 1500 mm, and a 500 mm × 500 mm × 300 mm box mold made of a thick sheet of aluminum was used for all foam-molding tests. The whole process involved the following: The polyethylene samples were placed into the mold, and we put the mold into the oven at a suitable temperature for heating for the required time. Then, we took the mold out of the oven to cool using the circulation fan and removed the rotomolded article from the mold. The oven temperatures could reach 300 °C. Herein, the oven temperature was under 285 °C, and the heating time was 25 min. Any specimens were cut out of these articles.Gel permeation chromatography (GPC) was carried out using a Polymer Char machine with a multi-detector to measure the molecular weight (Mw) and molecular weight distribution (MWD). The measurement was carried out at 150 °C at a flowing rate of 1.0 mL/min. In GPC analysis, the number-average molecular weight (Mn), weight-average molecular weight (Mw), and z-average molecular weight (Mz) can be simultaneously determined. Furthermore, the Mw/Mn ratio is used to evaluate the molecular weight distribution (MWD). All GPC curves are showed in The polymer crystallization elution fraction (CEF) test was carried out using a Polymer Char CEF machine with a viscosity detector and an IR6 detector. A total of 8 mg of polyethylene sample was dissolved into 10 mL1,2,4-trichlorobenzene at160 °C for 180 min, and then 200 μL of the solution was injected into the instrument at 150 °C, rapidly cooled to 95 °C, and then procedurally cooled from 95 °C to 35 °C at a rate of 2 °C/min, and the flow rate was kept at 0.05 mL/min. The heating process was from 35 °C to 150 °C at a rate of 4 °C/min, and the flow rate of the heating section was 1.0 mL/min. All CEF curves are showed in Rheological measurements were performed using a controlled strain rheometer (TA instruments) in oscillatory mode with a parallel plat fixture (20 mm in diameter) at a gap of 1.0 mm under a nitrogen atmosphere. The frequency sweep model was used at 200 °C over an angular frequency range of 0.05–100 rad/s, and the viscosity-frequency curves are showed in Viscous flow activation energy (Ea) is used to describe the viscosity–temperature dependence of a polymer using the rheometer. Its apparent viscous flow activation energy is higher, so the influence of temperature on the characteristics of the melt is stronger. The shear-viscosity data were obtained by melt rheology experiments. The relationship between the apparent shear viscosity of the polymer and the temperature is in accordance with the Arrhenius empirical formula. The curves of the melt shear viscosity of the six polyethylene blends with temperature are shown in Differential scanning calorimetry (DSC) analysis was carried out using a Q2000 instrument to evaluate the thermal properties of the polyethylene blends before the foaming process. Specimens at least 6 mg in weight were placed in aluminum pans. The heating and cooling runs were performed from 20 °C to 200 °C under a nitrogen atmosphere at a heating and cooling rate of 10 °C/min. All DSC crystallization curves are showed in The foam expansion ratio was calculated based on the following equation: VER = ρ/ρf. Herein, ρ and ρf represent the density of polyethylene blends before and after foaming. Density was measured by weighing each sample with a precision of 0.0001 mg and calculating its volume as the volume of water displaced in a calibrated pycnometer where the sample was submerged.To determine the cell size (CS) and cell diameter distribution (CSD), a micrograph of each sample was taken using an optical microscope. The cell diameter distribution (CSD) was also obtained by measuring and counting the observed bubbles. All cells morphology of foamed parts is showed in Two kinds of PE blends with different structures were designed and prepared in the first round of trials to validate our hypothesis. One was PE-B2, with few chain branches in the high-molecular-weight part and many chain branches in the low-molecular-weight part. Contrary to the polymeric chain structure of PE-B2, the other sample labeled PE-B4 had a unique chain structure with many chain branches in the high-molecular-weight part and few chain branches in the low-molecular-weight part. W) of PE-B2 was higher than that of PE-B4, which was consistent with the value of the melt index (MI2.16), and the molecular weight distribution (MWD) of PE-B2 was wider than that of PE-B4, which was also consistent with the value of MI21.6/MI2.16 in The molecular weight  prepared foamed articles with an expansion ratio of about 8–9. However, there were some differences in the morphology and cell sizes. With the increase in the high-molecular-weight component with a high branching degree, the bubbles collapsed, and the morphology became worse, as shown in 2.16 > 8 g/10 min) first produced a larger expansion ratio, around 8, with smaller cell sizes (<600 μm) and a narrow cell size distribution. A higher melt index is very important for rotational foam molding when fabricating complex-structure products. However, the relationship between the composition and viscosity–temperature sensitivity needs further investigation.In this paper, a novel method to control morphology and cell sizes during the foam-cooling stage was revealed, and tailored polyethylene blends with unique structures were proposed and prepared. Novel tailored polyethylene blends with few chain branches in the low-molecular-weight part and many chain branches in the high-molecular-weight part effectively improved the crystallization temperature and the viscosity–temperature sensitivity. Higher crystallization temperature and higher viscosity–temperature sensitivity effectively increased the melt strength around bubble cells during the foam-shaping stage to better prevent coalescence and collapse. The experimental polyethylene blends with a higher melt index (MI


Philip Seeman's isolation of the dopamine D2 receptor is an example of a small step that can lead to major change in the way that we conceptualize the etiology of schizophrenia. It is usually impossible to attribute progress in science to any one discovery because each new step builds on incremental advances in technology and in experimental results emerging unexpectedly in various corners of the world, in disciplines not necessarily one's own. This paper tries to trace the contributions to understanding brain mechanisms leading to schizophrenia attributable to Philip Seeman, a Canadian neuropharmacologist who died on 9 January 2021. He became interested in schizophrenia in 1961 when Phil's wife, the author of this piece, began her residency in psychiatry at Manhattan State Hospital on Ward's Island in New York City. At the time, Phil was starting his PhD program at the Rockefeller Institute. He was surrounded by ‘Great Names.’ His supervisor was the already very famous George Palade, discoverer of ribosomes. Palade was later to receive the Nobel Prize in Physiology/Medicine, sharing it with Albert Claude and Christian de Duve, and awarded for their breakthrough discoveries of the components of cell structure. These discoveries were made possible by advances in the technology of the electron microscope Oatley, .Phil Seeman had been well trained. Before receiving his medical degree from McGill University in 1960, he had completed a Master's degree, supervised by Professor Arnold Burgen, who was to become Sir Arnold in 1976, an acknowledgement of his significant work in drug-receptor interactions in the central nervous system and mechanisms of secretion. Phil's Master's thesis was on the secretion and flow of saliva. In hindsight, parallels can probably be drawn between saliva and the secretion and flow of dopamine in the brain.At Rockefeller, students were expected to come up with their own scientific questions and pursue their own journeys of discovery. You were continually being inspired by your mentors, but there wasn't much hands-on instruction. Phil knew he wanted to use the potential of the electron microscope for his PhD; that was why he was drawn to the Palade lab. But he couldn't figure out what to use the electron microscope for. I was 6 months pregnant with our first child and hadn't yet told my residency boss that I would soon be needing a leave of absence. Lest he throws me out of the program for the sin of concealing a pregnancy, I needed, I reasoned, to prove myself indispensable. This led to many sleepless nights until I hit on a bright idea. ‘Why don't you,’ I said to Phil, ‘figure out how these new ‘major tranquillizers,’ that we rely so much on, do their work? That could serve as your PhD thesis, should be fairly easy to do (I was very naïve), and would guarantee them wanting me back.’Phil liked the plan. He conceived the idea that the new drugs – there were six or seven available at that time  – had to enter neurons through the cell membrane, and, since the membranes of red cells were similar to those of neurons, why not visualize under the electron microscope what these drugs did to red cell membranes.Our baby was born and I was on leave from work for a few months so, every morning, I rolled up Phil's shirt sleeve, took his blood in a specially marked vial, which he walked down to the lab, made a blood smear on a slide, mixed different doses of the various antipsychotic drugs, and other drugs as well, into the blood, and looked to see what the microscope showed. He took photographs of the red cell membranes under the influence of different drugs and we later hired one of my patients, who loved the precision that the work required and was excellent at it, to carefully measure the widths of Phil's red cell membranes.The upshot of all this was that I wasn't thrown out of the program, that the patient/research assistant got well and became a successful New York artist, and Phil got his PhD after a few years. But he didn't discover how antipsychotic drugs worked. Instead, his PhD work led to the membrane theory of anesthetic action Seeman, .Before Phil graduated, Carlsson and Lindqvist  had repoAs a result, dopamine was much discussed when Phil and I went to England so he could do a post-doc with his former mentor, Arnold Burgen, now at Downing College, Cambridge. Needless to say, there were many inspiring ‘Great Names’ in Cambridge, and Burgen figured among them. He had become a pioneer in the use of nuclear magnetic resonance in pharmacology Aellig, . Among o‘When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have far going consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology. Obviously such an overstimulation might be caused by overproduction of dopamine, production of substances with dopamine actions (methoxy derivatives), abnormal susceptibility of the receptors, etc.’ ] and a state of low-affinity (D2Low). The D2(High) state in animal models of schizophrenia leads to dopamine supersensitivity whether produced by brain lesions, drugs such as amphetamine or cocaine, prolonged social isolation, or gene deletions in key brain pathways Seeman, . In humaToward the end of his life, in collaboration with John Neumeyer, Phil tried to find a way of imaging the D2High state in humans, hoping to show that its presence correlated with psychotic symptoms (Inkster, Sromek, Akurathi, Neumeyer, & Packard, He would have been thrilled to know that therapies for dopamine supersensitivity and the D2High state are gradually becoming possible (Kruyer et al., Small steps can lead to transformative change.


Non-alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver with varying severity. Heterogeneity in terms of molecules and immune cell infiltration drives NAFLD from one stage to the next. However, a precise molecular classification of NAFLD is still lacking, and the effects of complex clinical phenotypes on the efficacy of drugs are usually ignored.via consensus clustering, and a weighted gene co-expression network analysis was used to identify eight co-expression modules. Further, eigengenes of eight modules were analyzed with regard to Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, the infiltration rates of 22 immune cell types were calculated with CIBERSORT and the ESTIMATE algorithm.We introduced multiple omics data to differentiate NAFLD subtypes In total, 111 NAFLD patients from three independent GEO datasets were divided into four molecular subtypes, and the corresponding clinical features and immune cell infiltration traits were determined. Based on high gene expression correlations, four molecular subtypes were further divided into eight co-expression modules. We also demonstrated a significant correlation between gene modules and clinical phenotypes. Moreover, we integrated phenotypic, immunologic, and genetic data to assess the potential for progression of different molecular subtypes. Furthermore, the efficacy of drugs against various NAFLD molecular subtypes was discussed to aid in individualized therapy.Overall, this study could provide new insights into the underlying pathogenesis of and drug targets for NAFLD. With the growing incidence of non-alcoholic fatty liver disease (NAFLD), a corresponding increase in attention has been given to its classification in clinical practice. Traditionally, liver biopsy is considered the gold standard for the diagnosis and subtyping of NAFLD, but methodological challenges and evaluation uncertainties related to histological classifications could result in errors. Molecular subtypes are an effective supplement and an improvement to traditional histological classifications , and comNAFLD is a manifestation of metabolic syndrome in the liver and a combination of hepatic and extrahepatic symptoms with different severity, but its complex clinical phenotypes with respect to the efficacy of drugs are usually ignored. Some clinical trials have not obtained satisfactory results. Some new drugs, for example, are effective for some phenotypes but ineffective or even harmful for others. The principal reason for this is the heterogeneity in NAFLD, and drug sensitivity among different subtypes has not been well differentiated. Further, current treatments for NAFLD are mainly based on lifestyle interventions, which is largely due to the lack of accurate studies from molecular and immunological perspectives. A new NAFLD classification should be precise in terms of dividing populations and defining the disease.In summary, heterogeneity in terms of molecules and immune cell infiltration drives NAFLD from one stage to the next. This study focused on integrating phenotypes, immune cell infiltration, and genetic data to identify subpopulations with distinct pathogenic mechanisms and eigengenes. In addition, our work aimed to match specific treatment strategies with specific disease-driving factors and to evaluate the potential for progression of different NAFLD molecular subtypes to aid in individualized therapy.https://www.ncbi.nlm.nih.gov/geo/) datasets  and 54 non-alcoholic steatohepatitis (NASH), as well as 86 healthy controls (HCs)) were collected from three Gene Expression Omnibus  and calculating the rationality of different numbers of clusters. For each cluster, the paired consensus values were calculated according to the occurrence rates of two samples in the same subsample of the same cluster, which were then stored in a consensus matrix. The consensus matrices were summarized in several graphs to help determine a reasonable number and the membership of clusters. Here, the K-means algorithm in the ConsensusClusterPlus R package was introduced to perform consensus clustering based on the Euclidean distance among NAFLD samples . The cluA pairwise comparison based on arithmetic utilization was used to test the differences among the subgroups with regard to the clinical characteristics , the average expression value of genes between two groups was set to be more than 0.2 with an adjusted p-value less than 0.05.To sort DEGs in the four subgroups, gene set enrichment analysis (GSEA) was conducted by utilizing the predefined set of genes from those subgroups . Then, tWeighed gene co-expression network analysis (WCGNA) was performed on all NAFLD samples based on the DEGs in the four molecular subtypes  and the The relationships among the characteristic genes of eight co-expressed modules, the NAFLD activity score, and the body mass index (BMI) in NAFLD patients were systematically analyzed.After the acquisition of eight co-expression modules from WCGNA, eigengenes in the eight co-expression modules were analyzed for enrichment to visualize biological processes, and the most significantly enriched processes in each module were demonstrated.The MSigDB database  was usedThe rates of infiltration of 22 types of immune cells in each NAFLD sample were calculated using the CIBERSORT algorithm and the expression data of 22 immune infiltrating cells, namely, the LM22 data . The ESTIn total, 197 samples were collected from three separate studies, including 57 SS, 54 NASH, and 86 HC cases. The clinical characteristics of each dataset are shown in A). However, when the samples from three platforms were combined, the overall expression in the samples was distributed uniformly, indicating that the sample batch effects that influenced the calculation of molecular biological differences were eliminated . Furthermore, multiway ANOVA was used to compare the interaction between the two main effects, subgroups of the NAFLD activity score and BMI, as well as the interaction effect of the two variables on the NAFLD activity score Table 1.In the differential expression analysis among the four molecular subtypes, 46 DEGs were upregulated in subtype I, 130 DEGs were upregulated in subtype II, 52 DEGs were upregulated in subtype III, and 99 DEGs were upregulated in subtype IV. In addition, GSEA was conducted, and the results showed that those genes were significantly enriched in their respective molecular subtypes.WCGNA was performed based on 327 total genes that were differentially expressed among the four molecular subtypes of NAFLD as described. First, the soft threshold function of WGCNA was utilized to calculate the soft threshold, and a scale-free topological model was established  analysis and Gene Ontology (GO) enrichment analysis were performed using the STRING online tool Figure 6To further explore the signaling pathways associated with the gene modules that regulate the clinical phenotypes, KEGG enrichment analysis was performed using the eigengenes in the co-expression modules, and the pathways that were most significantly enriched were selected for display Figure 7The Kruskal–Wallis test was used to compare the expression levels of characteristic genes among the four different molecular subtypes Figure 8The results showed that the panorama of immune cells varied greatly among patients  can recruit monocytes for infiltration and further promote inflammatory mediator production and oxidative damage by inducing differentiation into activated M1 macrophages . Clinica). In summary, the results of immune cell infiltration, gene enrichment, and molecular expression data all suggested that molecular subtype II was closely associated with microbial infection. Microbial infection is an underlying cause of NAFLD, and treatment options based on targeting the microbiota comprise a recent hot topic in this field , a major gene involved in the NAFLD stress response, can trigger inflammatory responses by activating nuclear factor-kB (NF-kB) signaling in saturated fat cells . The expSelonsertib is a potent and selective apoptotic signaling regulated kinase-1 (ASK1) inhibitor that ameliorates liver steatosis and inflammation . ASK1 exvia IL-13  agonist that reduces liver enzymes and improves the degree of liver fibrosis. FXR expression was significantly higher in the molecular subtype III than in the other molecular subtypes . ACC expMolecular subtype IV had the smallest lesion intensity, the mildest severity, and the lowest lesion stage. Except for a small range of steatosis, other indicators of NAFLD grading were low. According to its histological characteristics, molecular subtype IV was named primary NAFLD. Levels of clinical indictors, including ALP, BMI, HbA1c, and low-density lipoprotein cholesterol, were all lower in molecular subtype IV than in the other molecular subtypes, indicating that molecular subtype IV had the mildest clinical manifestation. Further, molecular subtype IV had the lowest immune score. The ratio of M1 to M2 macrophages was also lowest among all molecular subtypes, which indicated that molecular subtype IV exhibits the mildest inflammatory response. The gray module of molecular subtype IV was involved in the apoptotic process of B cells, as well as the negative regulation of T-cell cytokine production (Pioglitazone is an insulin sensitizer that acts on the peroxisome proliferator-activated receptor γ (PPARγ) to reduce steatosis by increasing lipid oxidation, thereby preventing NASH . PPARγ e). According to one study  we identified four molecular subtypes of NAFLD with unique pathogenic mechanisms and eigengenes; 2) we matched specific treatment strategies to specific disease-driving factors for specific patients; 3) we also evaluated the differences in drug efficacy among the four molecular subtypes. Moreover, these results could provide new insights into the underlying pathogenesis of and drug targets for NAFLD.https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE48452; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89632; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151158.Publicly available datasets were analyzed in this study. This data can be found here: ZL conceived the idea, performed all bioinformatics analysis, drew charts, and wrote the whole manuscript. YL and CY helped perform the analysis with constructive discussions and revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Key Project of Developmental Biology and Breeding from Hunan Province (2022XKQ0205).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Nevertheless, because of their radical character, it remains very difficult to reliably predict the electronic properties of the larger n-coronenes with conventional computational approaches. In order to circumvent this, the various electronic properties of n-coronenes (n = 2–11) are investigated using thermally-assisted-occupation density functional theory (TAO-DFT) , a very efficient electronic structure method for studying nanoscale systems with strong static correlation effects. The ground states of the larger n-coronenes are shown to be polyradical singlets, where the active orbitals are mainly localized at the zigzag edges.To fully utilize the great potential of graphene in electronics, a comprehensive understanding of the electronic properties of finite-size graphene flakes is essential. While the coronene series with  To fully utilize the great potential of graphene in electronics, a comprehensive understanding of the electronic properties of finite-size graphene flakes is essential. I.1–5 For example, its high carrier mobility, saturation velocity, and long spin diffusion length have enabled us to build promising graphene-based electronics and spintronics.1,2,6 Nevertheless, its applications have been partially impeded by its zero band gap. One scenario to introduce a band gap in graphene is the finite-size effect by cutting infinite graphene lattice into specific geometrical arrangements with smooth edges attached by hydrogen atoms.7–9 The resulting planar hydrocarbons can be classified into different categories according to the shape, geometry, size, or edges.10,11 Besides, all these fragments with a size less than 30 nm are referred to as graphene quantum dots (GQDs).12,13The discovery of graphene has attracted much scientific attention in recent years, owing to its fascinating properties and promising applications in industry.14 and bottom-up15 approaches. The top-down approach is to prepare the wanted samples through cutting graphene sheets in nanoscale technology. This approach demands for expensive equipment, and is hard to control precisely on the zigzag or armchair edges. By contrast, the bottom-up approach is to obtain the designed samples through oxidation, cage opening, and fragmentation of fullerene (C60) or other carbon fibers with chemical breakdown. Some studies have reported the successful synthesis of GQDs within a very wide range of diameters as well as the corresponding visible photoluminescence (PL) spectra.10,16–18 Kim et al. have fabricated a series of GQDs with an average diameter ranging from 5 to 35 nm through chemical cutting of graphene sheets.18 Their results have shown that for the GQDs keeping circular shape less than 17 nm, the peak frequency of G band is increasing versus increasing size. While for those larger than 17 nm, the value is decreasing versus increasing size. Pan et al. have reported a chemical route to obtain ultrafine GQDs from graphene sheets.16 They observed a strong blue PL peak and two characteristic PL excitation (PLE) peaks. The novel optical phenomena were explained by the carbene-like triplet ground state, which originates from the free zigzag edge sites. All these findings, together with other studies,19–24 have proven that the electronic and optical properties of 2-dimensional (2D) hydrocarbons cutting from infinite graphene sheets are highly affected by their nanostructure, size, shape, and periphery conditions, which can be qualitatively described in terms of the superposed Clar's structures or superaromatic stabilization energy.25–29There are two main approaches for the preparation of GQDs: the top-down7–9,19–24,30–42 In 2004, Bendikov et al. adopted the complete-active-space self-consistent-field (CASSCF) method to study acenes ,31 showing that the larger acenes  possess radical character in their ground states. Similar results were also found from other high-level ab initio calculations.32,36Among several 2D structures of hydrocarbons, quasi-one-dimensional strips are the most popular ones. They are officially referred to as graphene nanoribbons (GNRs), which have been actively studied in recent years.D6h-symmetric hexagon-shaped series with chemical stoichiometry Cn26Hn6 are referred to as coronene (n = 2), circumcoronene (n = 3), circumcircumcoronene (n = 4), and so on, with n being the number of fused benzene rings at each side. For brevity, Cn26Hn6 is designated as n-coronene in this work ,43 demonstrating that the energy difference between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), i.e., the HOMO–LUMO gap, of n-coronene decreases very slowly with the length scale (n). This suggests that the smaller n-coronenes should possess non-radical character in their ground states. However, as n-coronene (n → ∞) reduces to graphene, the larger n-coronenes are expected to have vanishingly small HOMO–LUMO gaps, and hence possess radical character in their ground states. Accordingly, with increasing n, there should be a transition from the non-radical character of the smaller n-coronenes to the radical character of the larger n-coronenes. However, the existing studies of the larger n-coronenes  remain too limited to address this issue.44 Besides, it remains unclear if the larger n-coronenes possess di-, tri-, or even higher polyradical ground states.Despite the intensive studies of strip-like-shape hydrocarbons, the understanding of the correlations between the electronic properties and geometrical arrangements of 2D hydrocarbons remains rather limited. Among other geometrical arrangements, a class of 2D hydrocarbons that deserve our exploration are the regular-hexagon-shaped benzenoid hydrocarbons, which can be extended from coronene . The work see . In 2009n-coronenes are expected to be energetically stable, it remains challenging to realize the precise regular-hexagon-shaped benzenoid hydrocarbons with smooth edges. This may be due to the following four reasons: (1) in order to cut graphene sheets or open the cage fullerene to make graphene flakes, the process involves a series of chemical reactions with many byproducts generated, where the fraction of desired organic structures are very low; (2) it is very hard to separate the pure molecules due to similar chemical properties; (3) due to a series of redox reactions, the prepared samples are usually attached by derivatives rather than pure hydrocarbons; (4) the expensive equipment, long manufacture period, raw material toxicity procedures, and some other realistic factors also constrain the experimental results.16,45–50 Therefore, due to these technical reasons, the fabrication of circumcoronene and the larger members remains very challenging.On the experimental side, there were scarce experimental studies of the members larger than coronene. Although the smaller 51 with the widely used exchange-correlation (XC) density functionals is computationally efficient, but can yield enormous errors for systems with strong static correlation effects .52 To reliably describe the properties of systems with radical character, accurate ab initio multi-reference methods are usually needed.53 Nonetheless, accurate multi-reference calculations are prohibitively expensive for large systems . Consequently, it remains very challenging to investigate the electronic properties of the larger n-coronenes using conventional electronic structure methods.On the theoretical side, Kohn–Sham density functional theory (KS-DFT)35 for studying large ground-state systems with strong static correlation effects. TAO-DFT has similar computational cost as KS-DFT for single-point energy and analytical nuclear gradient calculations, and reduces to KS-DFT in the absence of strong static correlation. In contrast to KS-DFT, TAO-DFT is a density functional theory with fractional orbital occupations, wherein strong static correlation is explicitly described by the entropy contribution (see eqn (26) of ab initio multi-reference methods, TAO-DFT is computationally efficient, and hence promising for the study of large polyradical systems. With some trivial modifications, existing semilocal and hybrid XC density functionals in KS-DFT may also be adopted in TAO-DFT.38,42 Recently, a self-consistent scheme for the determination of the fictitious temperature in TAO-DFT has been developed,54 further extending the applicability of TAO-DFT for a very wide range of systems. Since 2015, TAO-DFT has been widely applied to study several nanoscale systems with strong static correlation effects, including zigzag GNRs,35,38,39,41,42 cyclacenes,55 alternant polycyclic aromatic hydrocarbons (PAHs),29 and linear carbon chains.56 The results obtained with TAO-DFT have been shown to be in good agreement with the available experimental and highly accurate ab initio data. Besides, recent studies29,40 have shown that the orbital occupation numbers obtained with TAO-DFT are qualitatively similar to the natural orbital occupation numbers (NOONs), i.e., the eigenvalues of one-electron reduced density matrix,57 obtained with highly accurate ab initio multi-reference methods, which can be very useful for the assessment of the possible polyradical character of large systems.To address these challenges with minimum computational complexity, in 2012, Chai developed thermally-assisted-occupation density functional theory (TAO-DFT)n-coronenes (n = 2–11). To make our data convincing, our results are also compared with the available experimental data as well as those obtained with various XC density functionals in KS-DFT. However, experimental and high-level ab initio data for n-coronenes (n = 3–11) are currently unavailable for comparison.In view of its reasonable accuracy and computational efficiency for nanoscale systems with strong static correlation effects, in this work, TAO-DFT is employed to study the various electronic properties of II.58 using the 6-31G basis set with the numerical grid containing 75 Euler-Maclaurin radial grid points and 302 Lebedev angular grid points. Results are computed using TAO-LDA,35i.e., TAO-DFT with the local density approximation (LDA) XC density functional59,60 and the LDA θ-dependent density functional ELDAθ (see eqn (41) of θ = 7 mhartree ], even when a local XC density functional is employed in TAO-DFT. Similar to the static correlation energy of a system, the entropy contribution in TAO-DFT is always nonpositive, yielding insignificant contributions for a single-reference system, and significantly lowering the total energy of a multi-reference system.On the basis of the physical arguments given in Section III(E) of i.e., KS-DFT with the LDA59,60 and B3LYP61 XC density functionals, respectively). Since TAO-LDA with θ = 0 reduces to KS-LDA, we examine the performance of KS-LDA here to evaluate the importance of TAO-LDA.For comparison, some results are also computed using KS-LDA and KS-B3LYP (n-coronene (n = 2–11), we perform spin-unrestricted TAO-LDA, KS-LDA, and KS-B3LYP calculations for the lowest singlet and triplet energies of n-coronene on the respective geometries that were optimized at the same level of theory. The singlet–triplet energy (ST) gap of n-coronene is calculated as (ET − ES), the energy difference between the lowest triplet (T) and singlet (S) states of n-coronene. When performing spin-unrestricted calculations on systems with an even number of electrons, it is usually necessary to break alpha/beta symmetry in the initial guess to ensure that the lowest energy solution is obtained. In our spin-unrestricted calculations, we have considered explicit symmetry breaking of the initial density guess . Specifically, 30% of LUMO is added to HOMO for the alpha orbitals  to break alpha/beta symmetry in the initial guess. In addition, our preliminary examinations show that the lowest singlet energies of n-coronenes (n = 2–8)  obtained from spin-unrestricted calculations with different initial guesses , but not the beta orbitals) are essentially the same  as those reported in this work. Our preliminary TAO-LDA results show that the 6-31G basis set adopted in this work should be reasonably large, especially for the larger n-coronenes , the value of 〈Ŝ2〉 obtained with conventional XC density functionals in KS-DFT can be very different 62 from the exact value S (S + 1), where S can be 0 (singlet), 1/2 (doublet), 1 (triplet), 3/2 (quartet), and so on. For such a system, conventional XC density functionals in KS-DFT can yield inaccurate results. To adequately predict the electronic properties of systems with radical character, it can be essential to employ accurate ab initio multi-reference methods53 for small-sized systems or TAO-DFT35,38,42 for medium- to large-sized systems.In addition, we adopt the expectation value of the total spin-squared operator, 〈III.A.EST) of n-coronene, obtained with spin-unrestricted TAO-LDA, KS-LDA, and KS-B3LYP. For n = 2, the calculated ST gaps are in good agreement with the available experimental data.50 However, in contrast to the smooth EST curve obtained with TAO-LDA, the EST curves obtained with KS-LDA and KS-B3LYP are unsmooth for n ≥ 9 and for n ≥ 6, respectively. For KS-B3LYP, n-coronene (n = 8) is even predicted to have a triplet ground state, which is in strong contrast to the results obtained with TAO-LDA and KS-LDA  character ). However, with the increase of the side length, the lowest singlet and triplet states of n-coronene are increasingly affected by spin contamination , implying that the larger n-coronene should possess increasing multi-reference  character in the lowest singlet and triplet states. With KS-LDA, the effect of spin contamination becomes noticeable for n ≥ 9, while with KS-B3LYP, the effect of spin contamination becomes noticeable for n ≥ 6. Besides, the effect of spin contamination for the lowest triplet state of n-coronene is found to be more severe than that for the lowest singlet state of n-coronene. As spin contamination is not a systematic error, the difference in energy between states can be adversely affected. Therefore, for the larger n-coronenes, the unsmooth EST curves obtained with KS-LDA and KS-B3LYP should be artifacts closely related to spin contamination.To investigate the causes of discrepancies, the values of 〈glet see  and tripglet see  states on-coronene, obtained with the exact theory, should be the same, because of the symmetry constraint. To examine the possible symmetry-breaking effects, we additionally perform spin-restricted TAO-LDA, KS-LDA, and KS-B3LYP calculations for the lowest singlet energies on the respective optimized geometries. The spin-restricted and spin-unrestricted KS-LDA energies for the lowest singlet state of n-coronene are the same for the smaller n, but can be different for the larger n, due to the aforementioned spin contamination. Similar results are also found for KS-B3LYP. By contrast, the spin-restricted and spin-unrestricted TAO-LDA energies for the lowest singlet state of n-coronene are essentially the same , suggesting that essentially no unphysical symmetry-breaking effects occur in our spin-unrestricted TAO-LDA calculations. On the basis of our TAO-LDA results, EST monotonically decreases as n increases, and the ground states of n-coronenes are singlets for n = 2–11 .On the other hand, the spin-restricted and spin-unrestricted energies for the lowest singlet state of B.i.e., the lowest singlet state) geometry of n-coronene (with N electrons), spin-unrestricted TAO-LDA is employed to calculate the vertical ionization potentialEN is the total energy of the N-electron system.At the ground-state  is within the most interesting range (1 to 3 eV), showing promise for applications of n-coronenes in nanophotonics  of n-coronene, using spin-restricted TAO-LDA. In fi (varying from 0 to 1) is the occupation number of the ith orbital obtained with TAO-LDA, which is qualitatively similar to the occupation number of the ith natural orbital.29,35,38 For a system without strong static correlation ({fi} are close to either 0 or 1), SvN yields insignificant contributions, while for a system with strong static correlation , SvN increases with the number of active orbitals.In order to assess the possible polyradical character of vN value of n-coronene monotonically increases with increasing n, implying that the larger n-coronenes should possess increasing polyradical character in their ground states th orbital, and the LUMO is the (N/2 + 1)th orbital, with N being the number of electrons in n-coronene. For brevity, HOMO, HOMO−1, …, and HOMO−8 are denoted as H, H−1, …, and H−8, respectively, while LUMO, LUMO+1, …, and LUMO+8 are denoted as L, L+1, …, and L+8, respectively.To illustrate the reasons of the increase of Sn, clearly demonstrating that the polyradical character of n-coronene indeed increases with the side length. On the basis of our TAO-LDA results, the smaller n-coronenes  possess non-radical character, and the larger n-coronenes  possess increasing polyradical character in their ground states  for the lowest singlet states of some representative n-coronenes, obtained with spin-restricted TAO-LDA , and so are the LUMO and LUMO+1. For the smaller n-coronene , the active orbitals are delocalized over the whole molecule. However, with the increase of the side length of n-coronene, the active orbitals have an increased tendency to localize at the zigzag edges. For the larger n-coronene , the active orbitals are mainly localized at the zigzag edges. Similar to previous findings for zigzag GNRs32,36,39 and cyclacenes,55 the increasing polyradical character of the larger n-coronenes should be closely correlated with the localization of active orbitals at the zigzag edges, which increases with the increase of the side length.To show the transition from the non-radical character of the smaller -LDA see . For eacIV.n-coronenes (n = 2–11), involving EST, IPv, EAv, Eg, SvN, active orbital occupation numbers, and real-space representation of active orbitals, using the recently proposed TAO-DFT. While KS-DFT with the widely used XC density functionals is computationally efficient, it can yield enormous errors for systems possessing radical character. On the other hand, high-level ab initio multi-reference calculations are prohibitively expensive for large systems . Consequently, TAO-DFT is an ideal electronic structure method for the study of the larger n-coronenes . The specific advances obtained with our TAO-DFT findings are as follows. First, our results are in reasonable agreement with the available experimental data. Secondly, from our TAO-DFT results, the ground states of n-coronenes are singlets for n = 2–11 . Thirdly, with the increase of the side length of n-coronene, EST, IPv, and Eg decrease monotonically, while EAv and SvN increase monotonically. Finally, with increasing n, there is a transition from the non-radical character of the smaller n-coronenes  to the increasing polyradical character of the larger n-coronenes . Moreover, the latter should be closely related to the localization of active orbitals at the zigzag edges, which increases with the increase of the side length.In conclusion, we have presented a systematic computational study on the electronic properties of n-coronenes from relatively affordable ab initio multi-reference methods are called for.Our work has further extended the understanding of correlations between the electronic properties and geometrical arrangements of 2D hydrocarbons. With the more 2D structures investigated, we believe that a solid foundation for a universal theory qualitatively describing the effect of the geometrical arrangements of 2D hydrocarbons on their electronic properties can be properly established. However, in view of the approximate nature of TAO-LDA, to examine the accuracy of our results, the electronic properties of There are no conflicts to declare.RA-008-C8RA01336E-s001


The reported substitutional growth strategy offers an effective and new pathway for the design of efficient and durable non‐noble metal‐based OER catalysts.Developing low‐cost electrocatalysts for efficient and robust oxygen evolution reaction (OER) is the key for scalable water electrolysis, for instance, NiFe‐based materials. Decorating NiFe catalysts with other transition metals offers a new path to boost their catalytic activities but often suffers from the low controllability of the electronic structures of the NiFe catalytic centers. Here, we report an interfacial atom‐substitution strategy to synthesize an electrocatalytic oxygen‐evolving NiFeV nanofiber to boost the activity of NiFe centers. The electronic structure analyses suggest that the NiFeV nanofiber exhibits abundant high‐valence Fe via a charge transfer from Fe to V. The NiFeV nanofiber supported on a carbon cloth shows a low overpotential of 181 mV at 10 mA cm An electrocatalytic oxygen‐evolving NiFeV nanofiber was synthesized by an interfacial atom‐substitution strategy to boost the activity of the NiFe centers. The electronic structure analyses suggest that the NiFeV nanofiber exhibits abundant high‐valence Fe via a charge transfer from Fe to V. The reported substitutional growth strategy offers an effective and new pathway for the design of efficient and durable non‐noble metal‐based oxygen evolution reaction (OER) catalysts. The electronic structure analyses suggest that the NiFeV nanofiber exhibits abundant high‐valence Fe via a charge transfer from Fe to V. The electrocatalytic tests show that the NiFeV nanofiber displays a low overpotential of 263 mV at 10 mA cm−2. Meanwhile, the NiFeV nanofiber supported on a carbon cloth (CC) shows an ultralow overpotential of 181 mV to attain 10 mA cm−2, along with long‐term stability (>20 h) at a high current density of 100 mA cm−2. Especially, the constructed alkaline water electrolyzer using commercial Pt/C/CC and NiFeV nanofibers/CC electrodes deliver a current density of 10 mA cm−2 at a low cell voltage of 1.47 V, as well as favorable durability, therefore holding great potential for practical application. It is believed that the interfacial atom‐substitution strategy offers an effective strategy to optimize the OER performance of NiFe catalysts and enhance their activity and stability for water electrolysis, thus opening a general path for the rational design of highly efficient and durable non‐noble metal‐based OER catalysts.Herein, we report an interfacial atom‐substitution strategy to synthesize an electrocatalytic oxygen‐evolving NiFeV nanofiber to boost the activity of NiFe hydroxides. We first fabricated V3O7 nanofiber as template and V source to achieve the controllable V substitution during the growth of NiFe hydroxides via a solvothermal reaction .As shown in Figure 3O7 nanofibers have a uniform diameter of about 120 nm, as indicated by the scanning electron microscopy (SEM) images. After substitutional growth of NiFeV hydroxide, a hierarchical nanofiber structure with rougher surfaces was obtained  plane, cyan) and NiFeV (lattice spacing: 0.27 nm corresponding to (101) plane, yellow) can be clearly observed, indicating the substitutional growth of NiFeV from V3O7 nanofiber template. The selected area electron diffraction (SAED) pattern  line scan results . The above results demonstrate that the NiFeV nanofiber consists of a core (V3O7)‐shell (NiFeV) heterostructure.Figure 3O7 nanofiber templates can gradually release V atoms to coprecipitate with Fe, Ni, and hydroxyl ions to form NiFeV hydroxide nanosheets along the nanofiber during the solvothermal process. In order to reveal the important role of reaction time in regulating the growth and performance of NiFeV nanofibers, we have evaluated the materials obtained from 1 h to 24 h by monitoring their morphologies , electronic structures , and electrocatalytic activities on OER . Under steady control of the reaction time, well‐defined oxygen‐evolving NiFeV nanofibers can finally be obtained, and 15 h is the optimal synthetic condition for efficient OER. Additionally, a series of catalysts were fabricated by directly regulating the proportion of Ni over the Fe; the optimum performance was found when the feed ratio of Ni to Fe was 3 to 1 . It is noteworthy that when iron(III) nitrate nonahydrate replaces iron(II) sulfate heptahydrate as the iron source, the fiber structure of the V3O7 is destroyed, and the catalytic performance of OER decreased . For comparison, pure NiFeV and NiFe nanosheets  were also prepared by a similar solvothermal reaction.Thus, we predict that the V3O7 and NiFeV as references, which confirms the successful synthesis of heterostructures after corresponding solvothermal treatment. The XRD spectrum of NiFeV nanofibers shows a series of peaks located a 2θ=10.8°, 18.9°, 24.7°, 30.7°, 38.4°, and 47.2°, which can be assigned to the (110), (020), (320), (311), (710), and (540) planes of V3O7, respectively (PDF #85‐2401), and the peaks at 2θ=33.5° and 60.0° match very well with the (101) and (110) planes of α‐Ni(OH)2, respectively (PDF #38‐0715). The prepared NiFeV and NiFe exhibit poor crystallinity and are isostructural to α‐Ni(OH)2  can be attributed to Fe in the 3+ oxidation state  and 712.44 eV in the NiFeV nanofibers (ΔE=0.50 eV)  in NiFeV nanofibers is higher than that in NiFeV . The high‐resolution XPS analyses indicate that the interfacial atom‐substitution strategy results in more electron transfer to the V in NiFeV nanofiber than that in NiFeV. This phenomenon can be attributed to the stronger interaction between NiFe and V, which further supports the atomic doping of V into NiFe hydroxide. In the O 1s region, a peak that occurs at 531.4 eV indicates oxygen ions in metal hydroxides .The X‐ray diffraction (XRD) pattern of the hierarchical NiFeV nanofibers is presented in Figure 3O7 and NiFeV, which can change the local electron distribution, thus regulating the adsorption energies of oxygen intermediate species and tuning the catalytic performance.[The increasing binding energy of Fe in NiFeV nanofibers suggests a higher valence state, which is advantageous to the OER performance.formance.11, 23E0) to calculate the valance states of the Fe atoms  than the NiFeV (<3+) and Fe2O3 (≈3+), which is in good accordance with XPS data.Furthermore, X‐ray absorption structure (XAS) spectroscopy measurements at the Fe K‐edges were carried out to compare the electronic properties of NiFeV nanofibers and NiFeV as a function of controllable V substitution in the NiFeV nanofiber. The normalized X‐ray absorption near edge structure (XANES) spectra for the Fe K‐edges of NiFeV nanofibers, NiFeV, and standard samples are shown in Figure s Figure c, the NiThe extended X‐ray absorption fine structure (EXAFS) spectra of the NiFeV nanofibers and reference samples provide further structural information Figure d. The pe−2, which is much lower than the NiFeV hydroxides (337 mV), commercial RuO2 (308 mV), and previously reported catalysts  and the loading mass of the catalysts at the overpotential of 300 mV  and mass activity (93.6 A g−1) . The calculated electrochemical double‐layer capacitance (Cdl) and ECSA exhibit a similar trend to the OER activity . Figure −1), which is smaller than NiFe (141 mV dec−1), NiFeV (76 mV dec−1), and RuO2 (72 mV dec−1). Accordingly, the NiFeV nanofibers proceed a faster oxygen evolution kinetics. Moreover, electrochemical impedance spectroscopy (EIS) has been performed to examine the electron‐transfer kinetics during the electrocatalytic process , while the lower frequency region semicircles are attributed to charge‐transfer resistances at the electrode‐electrolyte interface (RL).[As shown in Figure ace (RL).27 Both −2 , and the mass loading of 1 mg cm−2. After running 80 000 s for each step, only a 7 mV shift was observed at 20 mA cm−2, and 72 mV for 100 mA cm−2 ,2/Ni3S2||MoS2/Ni3S2 (1.56 V),2∥Ni/Ni(OH)2 (1.58 V),To further evaluate the application potentials of this material, we also evaluated the overall water splitting performance in a two‐electrode system (1 M KOH) by using the NiFeV nanofibers/CC electrode as anode and commercial Pt/C supported on CC substrate (Pt/C/CC) as the cathode (the cell is named as NiFeV nanofibers/CC||Pt/C/CC). For comparison, the overall water splitting performance made from commercial catalysts RuOe Figure b. BenefiCombining the above results, we can conclude that the interfacial atom‐substitution strategy achieves higher controllability on electronic structures of V‐doped NiFe electrocatalysts compared with the conventional one‐pot strategy. Although the OER active sites of NiFe catalysts are controversial, it is increasingly convinced that the high‐valence transition metals, especially Fe, can optimize the OER intermediates’ free energy, thus enhancing the catalytic activity and kinetics.22a In o2 and previously reported NiFeV compounds. We are convinced that applying such a substitutional growth strategy constitutes a new and promising approach to developing other efficient and durable non‐noble metal‐based OER catalysts.In summary, our findings on the synthesis of electrocatalytic oxygen‐evolving NiFeV nanofibers suggest that the interfacial atom‐substitution strategy offers an effective way to optimize the OER performance of NiFe catalysts and enhance the activity and stability for high‐performance OER catalysis. The electronic structure analysis demonstrated that the high oxidation state of Fe species could be stabilized in the NiFeV nanofibers via the partial electron transfer from Fe to V species. The electrocatalytic tests validated that NiFeV nanofiber exhibited much higher OER catalytic performance than commercial RuOThe authors declare no conflict of interest.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.