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Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. Cancer Res; 77(17); 4613–25. ©2017 AACR.

Background Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. Methods Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. Results Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). Conclusion Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

Half-Cr-doped YMnO 3 single crystal films have been grown on YAlO 3 substrates with various compressive strains by using magneto sputtering and ex-situ annealing process. We report on effects of the compressive strain on their multiferroic properties. Anisotropic polarization shows a monotonous dependence on the compressive strain along the corresponding crystal axis. Furthermore, relative ratio between the remanent magnetic moments along the a - and c -axes is found to be strongly related to the lattice parameter c . These results are ascribed to the modification of magnetic structure under various compressive strains, i.e. , the compressive strains along the a- and c -axes predominantly stabilize the E -type antiferromagnetic and bc -cycloidal phases, respectively.

The identity and E-value in GBSSI-1 of Rubus species by alignment with reference genome of diploid R. occidentalis L. (DOCX 96 kb)

Sucrose is an important substance that promotes the ripening of strawberries, while the ripening of fruits is regulated by many different plant hormones (and plant growth regulators). In this paper, different plant hormones and their mixed treatment withsucroseare sprayed on strawberry in growing season, to explore the effects of different treatments on the ripening of strawberry fruit. Use distilled water as a control, while BA (cytokinin), ACC (1-aminocyclopropane-1-carboxylic acid), JA (jasmonic acid), 2, 4-D (plant growth regulator) are treated. The strawberry fruit in the light green period was sprayed, and the change of maturity and the physiological indicators related to maturity were counted. The results showed that different treatments had different effects on the ripening speed of strawberry fruit, and the mixed treatment effect of sucrose and jasmonic acid was the best.

In this experiment, Hongyan, Zhangji, Xiaobai, Jiaoji, Zuixia, Shengdanhong and Taikong 2008 strawberry were used as experimental materials to measure and analyze the sensory quality and nutritional quality indicators so as to screen out suitable production and cultivation in Hanyuan area. The comprehensive traits of the excellent strawberry varieties. The results showed that the Hongyan strawberry fruit has a large fruit with an average fruit weight of 19.65g. The fruit is sweet and sour. The flavor is excellent. It shows good performance in nutritional quality indicators such as soluble solids, vitamin C, anthocyanins and flavonoids. It is also moderate, 2.03N, good storage and transportation performance, and it is an ideal high-quality and large-fruit strawberry variety for strawberry production and cultivation. Xiaobai strawberry has the highest sugar and acid ratio and vitamin C content, which were 16.28 and 82.52 mg•100g−1, respectively. Taikong 2008 strawberry showed better performance in soluble solids and flavonoids, 10.60% and 49.17 mg/100g, respectively, superior to the other 6 varieties. Jiaoji has the highest total phenol content, 222.69 mg/100g. Shengdanhong has the highest hardness of 2.13N, but its single fruit weight is only 13.70g. Zhangji performed moderately in terms of single fruit weight, vitamin C, soluble solids, flavonoids, total phenols, and anthocyanins, but its hardness was low, 1.85N, which was not conducive to long-distance transportation.

The cut flowers of Zantedeschia aethiopica were selected as materials to study the effect of six different concentrations bamboo vinegar on the preservation of cut flowers of Zantedeschia aethiopica. The vase life, water balance value, soluble sugar, soluble protein and MDA content were tested. The results showed that bamboo vinegar at 1000∼1500 times could effectively decrease the loss of water, slow the rate of decline of soluble sugar and protein content and the rate of generation of MDA of cut flowers during vase holding, thus extending the vase life of cut Zantedeschia aethiopic flowers, especially the 1500 times is better. In all, bamboo vinegar of proper concentration can delay the senescence and extend florescence of cut Zantedeschia aethiopic flowers.

The concentration and proportion of individual glucosinolates in different tissues of the three stem mustards. A: glucosinolate concentration. B: proportion.

Survey on the species number and ploidy levels of Rubus taxonomy. (DOCX 93 kb)

Strawberries are popular because of their sweetness, rich nutrition, and significant health benefits. However, in the actual production and cultivation, the ripening and aging cycle of strawberry is short, especially in spring and summer. The ripening and softening process of strawberry due to temperature and light conditions is rapid, resulting in poor fruit quality and flavor. Therefore, the quality of ABA of strawberry fruit ripening is studied. The content and the influence of the antioxidant system are of great significance. In this experiment, the effect of exogenous glutathione on the regulation of strawberry fruit ripening was studied by injecting 100 mM glutathione solution into the light green stage fruit. The results of the study showed that there was no significant change in the maturity-related parameters of the treated group compared with the control. The main antioxidants, total flavonoids and ascorbic acid content also increased, antioxidant capacity increased, and only the total phenolic content decreased slightly. In addition, in the early stage of fruit growth, ABA content was significantly higher than the control, but decreased in the later stage, slightly lower than the control. The results of this experiment indicated that the application of appropriate concentration of glutathione solution during the cultivation process could not significantly change the strawberry fruit ripening index, but could increase the content of endogenous antioxidants and improve the antioxidant capacity of strawberry. The increase of ABA content may be due to the decrease of active oxygen content, the stress mechanism inside the fruit, and the increase of ABA content to induce H2O2 to maintain the redox balance in the fruit.

List of studied Rubus taxa, herbarium information, ploidy level, locality, and GenBank accession numbers of GBSSI-1 variants, and outgroups from family Rosaceae in this study. (DOCX 130 kb)

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.

Conversion-type lithium–metal fluoride batteries with high energy density, are considered to be very promising candidates for the next generation of low-cost lithium-ion batteries. Unfortunately, metal fluoride cathodes generally suffer from poor conductivity, sluggish reaction kinetics, and irreversible structural changes. Reducing particle size to nanoscale is an effective way to solve the large volume change and poor electronic conductivity of metal fluoride cathodes. In this study, a nano-control strategy was proposed, using n-propanol as an auxiliary solvent to achieve the conversion of micrometer-scale FeF3·3H2O to nanoscale FeF3·0.33H2O. Meanwhile, the particle size and morphology of iron fluorides could be controlled by regulating the synthesis temperature. The distribution of relaxation times (DRT) was used to analyze the electrochemical impedance spectroscopy (EIS). FeF3·0.33H2O synthesized at 180 °C with lower resistance showed a high capacity of 200 mAh g−1 after 160 cycles with excellent rate performance and cycle stability.

Fragaria pentaphylla has fragmented distribution in southwest China, and its populations have been shrinking. In the present study, we report the complete chloroplast genome sequence of F. pentaphylla using next-generation sequencing technology. The complete chloroplast genome size is 155,640 bp. The genome contained 128 genes, including 30 tRNA genes, 78 protein-coding genes, and four rRNA genes, and multiple copies of 19 of these genes. Phylogenetic analysis based on nine complete chloroplast genomes revealed that F. pentaphylla is closely related to Fragaria vesca subsp. vesca. The complete chloroplast genome of F. pentaphylla would provide a good foundation for understanding the diversification and evolution of the genus Fragaria, and might help in conserving the precious natural populations of wild white strawberry.

Summary Deregulation of the PRC2 complex, comprised of the core subunits EZH2, SUZ12, and EED, drives aberrant hypermethylation of H3K27 and tumorigenicity of many cancers. Although inhibitors of EZH2 have shown promising clinical activity, preclinical data suggest that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (proteolysis-targeting chimera) to efficiently target EED for elimination. Our PROTACs bind to EED (pKD ∼ 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50 ∼ 8.1) and induce rapid degradation of not only EED but also EZH2 and SUZ12 within the PRC2 complex. Furthermore, the PROTACs selectively inhibit proliferation of PRC2-dependent cancer cells (half maximal growth inhibition [GI50] = 49–58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent cancer through a PROTAC-mediated degradation mechanism.

In this paper, a novel delay calibration system is presented to distinguish recycled FPGAs from unused FPGAs. This system, which is composed of all-digital delay calibration module, periphery circuits and selected path, is used to identify the true age of the chips. The change of one frequently used path delay before and after usage can be directly obtained through Delay Calibration Module. In addition, the support vector machine is employed to determine the difference between the recycled and unused FPGAs. Simulation results on 28nm technology show the delay degradation measurement accuracy is better than 15ps, and identification rate for fresh and 3-months recycled FPGAs is more than 97% within several microseconds calibration time. Besides, the proposed system is of low-cost, robust against process variations, and easy to be implemented.

Deregulation of the PRC2 components EZH2, SUZ12, and EED plays critical roles in driving aberrant hypermethylation of H3K27 and tumorigenicity of many solid and hematological malignancies. Although SAM competitive small molecule inhibitors of EZH2 show promising clinical activity in PRC2-dependent cancers, preclinical data suggests that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (Proteolysis Targeting Chimera) to efficiently target EED for elimination. Our EED-targeting PROTACs bind to EED (pKD= 9.02-9.27) and promote stable ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50= 8.11-8.17) that results in a decrease in H3K27me3 levels in cells. Interestingly, EED-targeting PROTACs induce rapid degradation of EED, as well as its associated proteins, including EZH2 and SUZ12 in the PRC2 complex. Inhibition of the ubiquitin proteasome pathway abrogates PROTAC-mediated degradation of EED and its associated proteins. Furthermore, the EED targeting PROTACs selectively inhibit proliferation and survival of PRC2-dependent cancer cells (GI50= 49-58 nM). In summary, our data demonstrate a novel therapeutic modality in treating PRC2 dependent cancer through PROTAC mediated platform. Citation Format: Jessie Hao-Ru Hsu, Timothy Rasmusson, James Robinson, Fiona Pachl, Jon Read, Sameer Kawatkar, Daniel H O'Donovan, Sharan Bagal, Erin Code, Philip Rawlins, Argyrides Argyrou, Ronald Tomlinson, Ning Gao, Xiahui Zhu, Elisabetta Chiarparin, Kelly Jacques, Minhui Shen, Haley Woods, Emma Bednarski, David M. Wilson, Lisa Drew, M. Paola Castaldi, Stephen Fawell, Andrew Bloecher. EED targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A09. doi:10.1158/1535-7163.TARG-19-LB-A09

Despite being a brassicaceous vegetable that is widely consumed in winter and spring in Southwest China, there is lack of information available on baby mustard. The aim of this study was to determine the contents of soluble proteins, soluble sugars, chlorophylls, carotenoids, ascorbic acid, proanthocyanidins, flavonoids, total phenolics, and glucosinolates, as well as the antioxidant activity of the whole edible parts and seven individual edible parts (swollen stem: petioles, peel, flesh; lateral bud: leaves, petioles, peel, flesh) of baby mustard. The results showed that significant differences in health-promoting compounds and antioxidant activity existed between the different edible parts. The lateral bud of baby mustard possessed greater health-promoting compounds than the swollen stem. In particular, the lateral bud leaves possessed abundant antioxidant compounds and antioxidant activity, indicating that these should be conserved during harvesting due to their potential contribution to human health. Furthermore, aliphatic glucosinolates were predominant, and sinigrin was the most abundant glucosinolate in all the assessed parts of baby mustard, the content of which was 15.81 μmol g

A new chemistry of azo compounds that is a radical generation and addition in situ of azocarboxylic tert-butyl esters to synthesize hydrazines has been described. The protocol provides a novel strategy for the synthesis of various hydrazines. The advantages of the transformation include broad substrate scope, benign conditions, and convenient operation.

Eukaryotic cells contain distinct organelles, but not all of these compartments are enclosed by membranes. Some intrinsically disordered proteins mediate membraneless organelle formation through liquid–liquid phase separation (LLPS). LLPS facilitates many biological functions such as regulating RNA stability and ribonucleoprotein assembly, and disruption of LLPS pathways has been implicated in several diseases. Proteins exhibiting LLPS typically have low sequence complexity and specific repeat motifs. These motifs promote multivalent connections with other molecules and the formation of higher-order oligomers, and their removal usually prevents LLPS. The intrinsically disordered C-terminal domain of TAR DNA-binding protein 43 (TDP-43), a protein involved in motor neuron disease and dementia lacks a dominant LLPS motif, however, and how this domain forms condensates is unclear. Using extensive mutagenesis of TDP-43, we demonstrate here that three tryptophan residues and, to a lesser extent, four other aromatic residues are most important for TDP-43 to undergo LLPS. Our results also suggested that only a few residues may be required for TDP-43 LLPS because the α-helical segment (spanning ∼20 residues) in the middle part of the C-terminal domain tends to self-assemble, reducing the number of motifs required for forming a multivalent connection. Our results indicating that a self-associating α-helical element with a few key residues regulates condensate formation highlight a different type of LLPS involving intrinsically disordered regions. The C-terminal domain of TDP-43 contains ∼50 disease-related mutations, with no clear physicochemical link between them. We propose that they may disrupt LLPS indirectly by interfering with the key residues identified here.

Summary Background Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. Methods This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. Findings The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66–0·90] for progression-free survival and 0·74 [0·58–0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57–0·91] for progression-free survival and 0·60 [0·45–0·79] for overall survival) and immunotherapy (HR 0·75 [0·56–1·00] and 0·64 [0·47–0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65–1·17, p interaction =0·61] for progression-free survival and 1·03 [0·80–1·34, p interaction =0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40–0·70]), but no associations observed in women (HR 0·85 [0·61–1·18, p interaction =0·03]). Interpretation Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. Funding ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

The TAR DNA-binding protein of 43kDa (TDP-43) has been identified as the main component of amyotrophic lateral sclerosis (ALS) cytoplasmic inclusions. The link between this proteinopathy and TDP-43's intrinsically disordered C-terminal domain is well known, but recently also, this domain has been shown to be involved in the formation of the membraneless organelles that mediate TDP-43's functions. The mechanisms that underpin the liquid-liquid phase separation (LLPS) of these membraneless organelles undergo remain elusive. Crucially though, these factors may be the key to understanding the delicate balance between TDP-43's physiological and pathological functions. In this study, we used nuclear magnetic resonance spectroscopy and optical methods to demonstrate that an α-helical component in the centre (residues 320-340) of the C-terminal domain is related to the protein's self-association and LLPS. Systematically analysing ALS-related TDP-43 mutants (G298S, M337V, and Q331K) in different buffer conditions at different temperatures, we prove that this phase separation is driven by hydrophobic interactions but is inhibited by electrostatic repulsion. Based on these findings, we rationally introduced a mutant, W334G, and demonstrate that this mutant disrupts LLPS without disturbing this α-helical propensity. This tryptophan may serve as a key residue in this protein's LLPS.

Early haemoperfusion (HP) therapy has been found to be very effective in acute paraquat (PQ) poisoning, but the effective rescue window is still uncertain. Demographic data and the type of therapies administered of 621 patients were included as confounding factors in this retrospective study. After receiver operating characteristic curve analysis and intra-group/subgroup analysis, the initiation of glucocorticoid therapy within 3 hrs of exposure with a second treatment given

Background. Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM. Methods. Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays. Results. Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC50), 6‐354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity. Conclusions. SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM.

SummaryRecent studies point to a pivotal role of Polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss-of-function approaches targeting individual PRC2 subunits have, however, generated findings that are difficult to reconcile. Here, we prevent assembly of both Ezh1- and Ezh2-containing PRC2 complexes by conditional deletion of Eed, a core subunit, and assess hematopoiesis. We find that deletion of Eed exhausts adult bone marrow hematopoietic stem cells (HSCs), although fetal liver HSCs are produced in normal numbers. Eed-null neonatal HSCs express HSC signature genes but are defective in maintenance and differentiation. Comparative gene expression profiling revealed that neonatal and adult HSCs lacking Eed upregulated gene sets of conflicting pathways. Deletion of Cdkn2a, a PRC2 target gene, in Eed-null mice enhances hematopoietic stem/progenitor cell (HSPC) survival but fails to restore HSC functions. Taken together, our findings define developmental-stage-specific requirements for canonical PRC2 complexes in normal HSC function.

FeTe, a non-superconducting parent compound in the iron-chalcogenide family, becomes superconducting after annealing in oxygen. Under the presence of magnetism, spin-orbit coupling, inhomogeneity and lattice distortion, the nature of its superconductivity is not well understood. Here we combine the mutual inductance technique with magneto transport to study the magnetization and superconductivity of FeTe thin films. It is found that the films with the highest T C show non-saturating superfluid density and a strong magnetic hysteresis distinct from that in a homogeneous superconductor. Such a hysteresis can be well explained by a two-level critical state model and suggests the importance of granularity to superconductivity in this compound.