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  • Article
    Taha M, Li Y, Morren J.
    Cureus. 2023 Mar;15(3):e36351.
    In this article, we described two patients with myasthenia gravis-related ptosis who experienced sustained improvement with the use of oxymetazoline hydrochloride ophthalmic solution 0.1%. Despite the commonly used treatments for ptosis in myasthenia gravis (MG), such as acetylcholinesterase inhibitors and corticosteroids, complete remission of ptosis is not always achieved, and these treatments are often accompanied by systemic side effects. Our case report suggests the long-term efficacy of daily use of oxymetazoline eye drops in improving ptosis, providing a potential alternative or adjunctive treatment option without significant adverse effects. Further research is necessary to confirm these observations across larger cohorts of MG patients and establish the effectiveness of oxymetazoline eye drops in MG-related ptosis.
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  • Article
    Du Z, Zhang W, Zhang D, Yu S, Hao Y.
    Sci Rep. 2016 11 16;6:36351.
    We explored the threshold effects of meteorological factors on hand, foot and mouth disease (HFMD) in mainland China to improve the prevention and early warning. Using HFMD surveillance and meteorological data in 2011, we identified the threshold effects of predictors on the monthly incidence of HFMD and predicted the high risk months, with classification and regression tree models (CART). The results of the classification tree showed that there was an 82.35% chance for a high risk of HFMD when the temperature was greater than 24.03 °C and the relative humidity was less than 60.9% during non-autumn seasons. According to the heatmap of high risk prediction, the HFMD incidence in most provinces was beyond the normal level during May to August. The results of regression tree showed that when the temperature was greater than 24.85 °C and the relative humidity was between 80.59% and 82.55%, the relative risk (RR) of HFMD was 3.49 relative to monthly average incidence. This study provided quantitative evidence for the threshold effects of meteorological factors on HFMD in China. The conditions of a temperature greater than 24.85 °C and a relative humidity between 80.59% and 82.55% would lead to a higher risk of HFMD.
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  • Article
    Goto T, Sato A, Adachi S, Iemura S, Natsume T, Shibuya H.
    J Biol Chem. 2013 Dec 20;288(51):36351-60.
    In the canonical Wnt signaling pathway, the translocation of β-catenin is important for the activation of target genes in the nucleus. However, the molecular mechanisms underlying its nuclear localization remain unclear. In the present study, we found IQGAP1 to be a regulator of β-catenin function via importin-β5. In Xenopus embryos, depletion of IQGAP1 reduced Wnt-induced nuclear accumulation of β-catenin and expression of Wnt target genes during early embryogenesis. Depletion of endogenous importin-β5 associated with IQGAP1 also reduced expression of Wnt target genes and the nuclear localization of IQGAP1 and β-catenin. Moreover, a small GTPase, Ran1, contributes to the nuclear translocation of β-catenin and the activation of Wnt target genes. These results suggest that IQGAP1 functions as a regulator of translocation of β-catenin in the canonical Wnt signaling pathway.
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  • Article
    Chen YY, Liang L, Tian PC, Feng JY, Huang LY, Huang BP, Zhao XM, Wu YH, Wang J, Guan JY, Li XQ, Zhang J, Zhang YH.
    Medicine (Baltimore). 2023 Nov 24;102(47):e36351.
    The aim of this study was to investigate the clinical characteristics and prognosis of patients hospitalized with heart failure with preserved ejection fraction (HFpEF) and low N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Seven hundred ninety consecutive patients hospitalized with HFpEF from 2006 to 2017 were enrolled. Clinical characteristics and outcomes were compared between low NT-proBNP group (<300 ng/L) and elevated NT-proBNP group (≥300 ng/L). 108 HFpEF patients (13.7%) presented with low NT-proBNP levels. Age, body mass index, atrial fibrillation, New York Heart Association functional class, and albumin were independent predictors of low NT-proBNP levels in HFpEF patients. During the median follow-up duration of 1103 days, 11 patients (10.2%) in low NT-proBNP group suffered from primary endpoint event. Elevated NT-proBNP group had a higher risk of all-cause death or heart transplantation than low NT-proBNP group (adjusted HR [95%CI]: 2.36 [1.24,4.49], P = .009). Stratified analyses showed that the association between NT-proBNP (elevated NT-proBNP group vs low NT-proBNP group) and risk of all-cause death or heart transplantation was stronger in non-atrial fibrillation patients than in atrial fibrillation patients (P value for interaction = .025). Furthermore, the associations between NT-proBNP and risk of all-cause death or heart transplantation were stronger in younger and male patients than in older and female patients. However, both subgroups only reached borderline significant (P values for interaction = .062 and .084, respectively). Our findings suggest that low NT-proBNP levels were common in patients hospitalized with HFpEF. Patients with HFpEF and low NT-proBNP levels had a better prognosis than those with elevated NT-proBNP levels, particularly in younger, male, and non-atrial fibrillation patients.
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  • Article
    Baysan M, Arbous MS, Mik EG, Juffermans NP, van der Bom JG.
    BMJ Open. 2020 05 17;10(5):e036351.
    INTRODUCTION: The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO2) in vivo at the bedside. MitoPO2might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study.
    METHODS AND ANALYSIS: We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO2, which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods.
    ETHICS AND DISSEMINATION: The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peer-reviewed journals and presented at scientific conferences.
    TRIAL REGISTRATION NUMBER: NCT03092297.
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  • Article
    Tinoco LW, Da Silva A, Leite A, Valente AP, Almeida FC.
    J Biol Chem. 2002 Sep 27;277(39):36351-6.
    PW2 (HPLKQYWWRPSI) was selected from phage display libraries through an alternative panning method using living sporozoites of Eimeria acervulina as target. Synthetic PW2 shows anticoccidial activity against E. acervulina and Eimeria tenella with very low hemolytic activity. It also displays antifungal activity but no activity against bacteria. We present the solution structure of the PW2 bound to SDS micelles. In the absence of an interface, PW2 is in random coil conformation. In micelles, structural calculation shows that Trp-7 forms the hydrophobic core that is important for the peptide folding. Lys-4, Tyr-6, Trp-8, and Arg-9 are in the same surface, possibly facing the micelle interface. This possibility was supported by the fact that chemical shift differences for these residues were more pronounced when compared with PW2 in water and in SDS. PW2 gains structure upon binding to SDS micelles. Lys-4, Tyr-6, Trp-8, and Arg-9 were found to bind to the micelle. Trp-7, Trp-8, and Arg-9 composed the WW+ consensus found in the sequence of the peptides selected with the phage display technique against E. acervulina sporozoites. This suggested that Trp-7, Trp-8, and Arg-9 are probably key residues not only for the peptide interaction with SDS micelles but also for the interaction with E. acervulina sporozoites surface.
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  • Article
    Wu JQ, Wang X, Beveridge NJ, Tooney PA, Scott RJ, Carr VJ, Cairns MJ.
    PLoS One. 2012;7(4):e36351.
    BACKGROUND: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.
    METHODOLOGY/PRINCIPAL FINDINGS: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.
    CONCLUSIONS: This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
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  • Article
    Roberts BJ, Whitelaw ML.
    J Biol Chem. 1999 Dec 17;274(51):36351-6.
    The basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor (DR) translocates to the nucleus upon binding of aromatic hydrocarbon ligands typified by dioxin, whereupon it partners the Ah receptor nuclear translocator and initiates transcription. Concurrently, ligand binding down-regulates receptor levels via an unknown mechanism. In this study we show that receptor levels are dependent upon cellular compartmentalization, with entry into the nucleus leading to the rapid destruction of the DR. Ligand-induced DR translocation was bypassed by adding a heterologous nuclear localization signal to the DR, creating a constitutively nuclear form of the dioxin receptor (DRNLS). The DRNLS protein was shown to be unstable with a half-life of </=1 h whether partnering ARNT or HSP90. Thus, the structural changes induced by ligand binding have no inherent effect on DR stability but are critical in transporting the receptor prior to degradation. The proteolytic pathway that degrades the nuclear receptor is suggested to involve ubiquitination as it was inhibited by the proteasome inhibitor MG132 or co-expression of DRNLS with the ubiquitin mutant UbK48R. Incubation of cells expressing DRNLS with the phosphatase inhibitor calyculin resulted in the rapid phosphorylation and ubiquitination of DRNLS, suggesting that a nuclear kinase is required to trigger receptor proteolysis. Overall, this study demonstrates a novel mechanism of proteolysis whereby the simple relocation of a transcription factor from cytoplasm to nucleus initiates its rapid destruction.
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  • Article
    Chen Y, Zhang W, She C, Li G, Zhang L, Liu S, Cheng Y, Jing C, Chu J.
    RSC Adv. 2019 Nov 04;9(62):36351-36357.
    A sodium citrate (SC) doped polypyrrole (PPy)/PS capillary sensor was prepared for ultra-small volume HCl gas detection. A PS film was formed in advance on the inner wall of a silica glass capillary tube, which enabled us to prepare a high-qualified PPy sensitive film inside the tube. The crystallinity, morphology, microstructure and carrier transport properties of the PPy film were characterized by XRD, SEM, FTIR and Hall effect system, respectively. The results indicated that the as-prepared tube sensor sample was able to detect 0.2 mL 30 ppm HCl gas while the plane-shaped PPy/PS sensor failed to probe. The improvement of sensing properties was attributed to the trend of crystallinity, pore (or gap) morphology and the long-narrow gas cell. The tube-like gas cell and the featured PPy/PS film of the tube sample contribute to sensing the small volume of HCl gas, which may be applied in breath analysis for potential nonintrusive disease diagnosis.
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  • Article
    Teoh NSC, Oakley A.
    JMIR Dermatol. 2022 Oct 06;5(4):e36351.
    BACKGROUND: A teledermoscopy service was established in January 2010 wherein patients attended nurse-led clinics for the imaging of lesions of concern and remote diagnosis by a dermatologist.
    OBJECTIVE: This study aims to review the number of visits, patient characteristics, the efficiency of the service, and the diagnoses made.
    METHODS: We evaluated the waiting times and diagnoses of skin lesions for all patient visits from January 1, 2010, to May 31, 2019. The relationships between patient characteristics and the diagnosis of melanoma were specifically analyzed.
    RESULTS: The teledermoscopy clinic was attended by 6479 patients for 11,005 skin lesions on 8805 occasions. Statistically significant risk factors for the diagnosis of melanoma and melanoma in situ were male sex (P<.001), European ethnicity (P=.001), an age of 65 to 74 years (P=.001), and Fitzpatrick skin type 2 (P=.001). Attendance was maximal during 2015 and 2016. The seasonal variations in visits from 2011 to 2018 revealed a consistent peak at the end of summer and a dip at the end of winter. In the year 2010, a total of 306 patients attended the clinic; 76.1% (233/306) of these patients were discharged to primary care, and 23.9% (73/306) were referred to a hospital for a specialist assessment. For patients who were diagnosed with suspected melanoma by a dermatologist from January 1, 2010, to May 31, 2019, the median waiting time for an imaging appointment was 44.5 (mean 57.9; range 8-218) days. The most common lesions diagnosed were benign naevus (2933/11,005, 26.7%), benign keratosis (2576/11,005, 23.4%), and keratinocytic cancer (1707/11,005, 15.5%); melanoma was suspected in 4.6% (507/11,005) of referred lesions. The positive predictive value of melanoma and melanoma in situ was 61.1% (320 true positives and 203 false positives). The number needed to treat (ie, the ratio of the total number of excisions to the number with a histological diagnosis of melanoma or melanoma in situ) was 2.02.
    CONCLUSIONS: A teledermoscopy service offered by nurse-led imaging clinics can provide efficient and convenient access to dermatology services by streamlining referrals to secondary care and prioritizing patients with skin cancer for treatment.
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  • Article
    Liu C, Xin L, Li J.
    Environ Sci Pollut Res Int. 2022 May;29(24):36351-36375.
    Environmental regulation is a crucial way to achieve manufacturing green transformation. However, few studies have explored the spatial spillover effects and regional boundaries of environmental regulation on manufacturing carbon emissions from the perspective of local government competition. Based on the manufacturing panel data of 30 provinces in China from 2007 to 2019, this paper uses the spatial Durbin model to examine the impact mechanisms, spatial spillover effects, regional boundaries and industry heterogeneity of environmental regulation, and local government competition on manufacturing carbon emissions. The results show that (1) environmental regulation suppresses local manufacturing carbon emissions, local government competition increases local manufacturing carbon emissions, but the interaction indicates that local governments tend to top-to-top competition under the constraints of environmental regulation. (2) The spatial spillover effect of environmental regulation has regional boundaries. The regional boundary with a positive spillover effect is 600 km, and the regional boundary with a negative spillover effect is 1600 km. (3) Environmental regulation and local government competition have spatial heterogeneity in the carbon reduction effects of seven-type manufacturing industries. These findings suggest concrete evidence for developing policies for further encouraging green development in manufacturing.
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  • Article
    Su Z, Wang H, He J, Guo Y, Qu Q, Tian X.
    ACS Appl Mater Interfaces. 2018 Oct 24;10(42):36342-36351.
    The orientation of ultrahigh aspect ratio thermally conductive fillers can construct a heat transfer path to enhance the thermal conductivity of composite materials effectively with low filler loading. Nevertheless, single orientation (vertical or horizontal) limited the application of these materials when there was the need for isotropic heat transferring. Here we report a novel strategy to prepare thermally conductive flexible cycloaliphatic epoxy resin nanocomposites with an oriented three-dimensional staggered interconnected network of vertically aligned h-BN (hexagonal boron nitride) platelets and randomly dispersed CNT-NH2 (aminated carbon nanotubes). In this structure, h-BN platelets coated with magnetic particles could respond to the external magnetic field; however, the CNT-NH2 couldn't. The obtained composites exhibited both through-plane (0.98 ± 0.037 W/m·K) and in-plane (0.99 ± 0.001 W/m·K) thermal conductivity enhancement at low h-BN loading of 30 wt %, and also presented excellent electrical insulating properties (<1.2 × 10-12 S/cm). In addition, the equal value of thermal conductivity of two directions (in-plane and through-plane) was shown when the content of h-BN was about 26.43 wt % and of CNT-NH2 was 2 wt %, displaying no difference between the thermal conductivity of two directions (in-plane and through-plane). The infrared imaging tests showed the outstanding heat dissipation capability of the composites by capturing the surface temperature variations of a heater with the composites as the heat dissipating material.
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  • Article
    Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE, Lanzer M.
    J Biol Chem. 2014 Dec 26;289(52):36336-51.
    Mutations in the "chloroquine resistance transporter" (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest that PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT, which could be exploited to design potent inhibitors of this key mediator of drug resistance.
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  • Book
    editors, E. Christopher Ellison, Gilbert R. Upchurch Jr. ; associate editors, Philip A. Efron [and 16 others].
    Summary: "Many of us who trained over the last 40 years have used Mastery of Surgery (MOS) as the primary textbook prior to entering the operating room (OR) in order to best prepare ourselves to perform a surgical procedure. First edited by Nyhus and Baker, and then masterfully continued by Dr. Fischer, we as editors of this new edition understood the significant role this textbook has played in helping to train generations of surgeons. We as an editorial board, along with a stated commitment from the editorial team at Wolters Kluwer, wanted to reimagine and improve MOS to ensure that it would remain the primary resource that many future generations of surgeons use prior to going to the operating room or in preparing for board examinations. We fully embraced this responsibility to not only carry on what previous editors had generated with its classic presentation and content, but we also committed our team to modernizing and improving this edition"-- Provided by publisher.
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  • Article
    Ohashi K, Fujiwara S, Watanabe T, Kondo H, Kiuchi T, Sato M, Mizuno K.
    J Biol Chem. 2011 Oct 21;286(42):36340-51.
    Lamellipodium extension is crucial for cell migration and spreading. The rate of lamellipodium extension is determined by the balance between the rate of actin polymerization and the rate of actin retrograde flow. LIM kinase 1 (LIMK1) regulates actin dynamics by phosphorylating and inactivating cofilin, an actin-depolymerizing protein. We examined the role of LIMK1 in lamellipodium extension by measuring the rates of actin polymerization, actin retrograde flow, and lamellipodium extension using time-lapse imaging of fluorescence recovery after photobleaching. In the non-extending lamellipodia of active Rac-expressing N1E-115 cells, LIMK1 expression decelerated and LIMK1 knockdown accelerated actin retrograde flow. In the extending lamellipodia of neuregulin-stimulated MCF-7 cells, LIMK1 knockdown accelerated both the rate of actin polymerization and the rate of actin retrograde flow, but the accelerating effect on retrograde flow was greater than the effect on polymerization, thus resulting in a decreased rate of lamellipodium extension. These results indicate that LIMK1 has a dual role in regulating lamellipodium extension by decelerating actin retrograde flow and polymerization, and in MCF-7 cells endogenous LIMK1 contributes to lamellipodium extension by decelerating actin retrograde flow more effectively than decelerating actin polymerization.
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  • Article
    Eapen A, Sundivakkam P, Song Y, Ravindran S, Ramachandran A, Tiruppathi C, George A.
    J Biol Chem. 2010 Nov 19;285(47):36339-51.
    Calcium signaling and calcium transport play a key role during osteoblast differentiation and bone formation. Here, we demonstrate that DMP1 mediated calcium signaling, and its downstream effectors play an essential role in the differentiation of preosteoblasts to fully functional osteoblasts. DMP1, a key regulatory bone matrix protein, can be endocytosed by preosteoblasts, triggering a rise in cytosolic levels of calcium that initiates a series of downstream events leading to cellular stress. These events include release of store-operated calcium that facilitates the activation of stress-induced p38 MAPK leading to osteoblast differentiation. However, chelation of intracellular calcium and inhibition of the p38 signaling pathway by specific pharmacological inhibitors and dominant negative plasmid suppressed this activation. Interestingly, activated p38 MAPK can translocate to the nucleus to phosphorylate transcription factors that coordinate the expression of downstream target genes such as Runx 2, a key modulator of osteoblast differentiation. These studies suggest a novel paradigm by which DMP1-mediated release of intracellular calcium activates p38 MAPK signaling cascade to regulate gene expression and osteoblast differentiation.
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  • Article
    Fed Regist. 1984 Sep 14;49(180):36326-51.
    The Food and Drug Administration (FDA) is issuing a final rule that requires manufacturers and importers of medical devices, including diagnostic devices, to report to FDA whenever the manufacturer or importer receives or otherwise becomes aware of information that reasonably suggests that one of its marketed devices (1) may have caused or contributed to a death or serious injury or (2) has malfunctioned and that the device or any other device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. FDA is taking this action under the Medical Device Amendments of 1976. The final rule is intended to assure that FDA is informed promptly of all serious problems or potentially serious problems associated with marketed devices. FDA is the principal public health agency responsible for ensuring that devices are safe and effective. To carry out its responsibilities, the agency needs to be informed whenever a manufacturer or importer receives or otherwise becomes aware of information about device problems. Only if FDA is provided with such information will it be able to evaluate the risk, if any, associated with a device and take whatever action is necessary to reduce or eliminate the public's exposure to this risk. Depending on the facts and circumstances, these steps could include contacting the manufacturer or importer of the device and monitoring its voluntary actions to respond to the problem, initiating a consumer or user education program, or initiating regulatory action, such as injunction, seizure, or other enforcement action.
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