Rubesanolides F and G: Two Novel Lactone-Type Norditerpenoids from Isodon rubescens.

A phytochemical investigation of the leaves of the medicinal plant Isodon rubescens led to the isolation of the two new degraded abietane lactone diterpenoids rubesanolides F (1) and G (2). Their structures were elucidated based on the analyses of the HRESIMS and 1D/2D NMR spectral data, and their absolute configurations were determined by ECD spectrum calculations and X-ray single crystal diffraction methods. Compounds 1 and 2, with a unique γ-lactone subgroup between C-8 and C-20, were found to form a carbonyl carbon at C-13 by removal of the isopropyl group in an abietane diterpene skeleton. Rubesanolide G (2) is a rare case of abietane that possesses a cis-fused configuration between rings B and C. The two isolates were evaluated for their biological activities against two cancer cell lines (A549 and HL60), three fungal strains (Candida alba, Aspergillus niger and Rhizopus nigricans) and three bacterial strains (Escherichia coli, Staphylococcus aureus and Bacillus subtilis).

Two new bioactive diterpenes identified from Isodon interruptus.

In the course of our ongoing studies to discover bioactive chemical constituents from plants in the genus Isodon, two new diterpenes, kunminolide A (1) and rabdokunmin F (2) were isolated from the leaves of the medicinal plant Isodon interruptus. Kunminolide A (1) is a novel abietane-like diterpene with a novel skeleton, herein designated as 9, 10-seco-neoabietane. Rabdokunmin F (2) is an ent-kaurene diterpene with C-18 oxidized to a carboxylic acid group. The structures were determined by spectroscopic means including analysis of 1D- and 2D-NMR spectral data. Crystals of 1 obtained from methanol were suitable for X-ray analysis, which confirmed the chemical structure. Kunminolide A (1) demonstrated chemopreventive potential by inducing QR1 activity with a CD value of 14.3 µM, and rabdokunmin F (2) was found to have cytotoxic activities with IC50 values in the range of 1.1-3.0 µM.

Comparative research on 99mTc-Rituximab and 99mTc-sulfur colloid in sentinel lymph node imaging of breast cancer.

BACKGROUND: 99mTc-Rituximab is a new specific radiopharmaceutical that binds to the CD20 receptor which is highly expressed on the surface of B cells. We conducted a study in which 99mTc-Rituximab was compared with filtered 99mTc-sulfur colloid (fTcSC) for sentinel lymph node (SLN) detection in patients with breast cancer. METHOD: The study is divided into three parts. 1. Initially, 25 patients were selected for an internal controlled trial to received both 99mTc-Rituximab and fTcSC, the interval time is separated by ≥2 days. 2. Then, 91 patients were selected for a randomized controlled trial (41 and 50 patients in the 99mTc-Rituximab and fTcSC groups, respectively). All patients were administered either agent at the 6- and 12-o' clock positions by subareolar injection technique. SLN mapping was then performed 2 h after injection. 3. Serial dynamic images were further acquired for 2 h in 31 patients (22 and 9 patients from 99mTc-Rituximab and fTcSC cohorts, respectively). RESULTS: The identification rate of lymphoscintigraphy and SLNB in all and axilla regions for 99mTc-Rituximab and 99mTc-SC were 98.5% vs 98.7, 100% vs 98.4%, respectively. The mean number of SLNs identified by 99mTc-Rituximab and fTcSC was respectively 2.72 and 3.28, with a significant difference of P = 0.013 (paired sample t-test). The difference exists in the internal mammary and clavicular area, not in the axillary. The mean number of axillary sentinel lymph node biopsy (SLNB) for 99mTc-Rituximab and fTcSC was 2.95 vs 3.14, respectively, and no significant difference existed. 99mTc-Rituximab also exhibited a significantly faster injection site clearance rate when compared with fTcSC (0.193 ± 0.057 h- 1 vs 0.021 ± 0.007 h- 1, respectively). CONCLUSION: No significant difference was observed in identification rate and number of axillary SLN imaging and SLNB, between the two tracers. Compared to fTcSC, 99mTc-Rituximab based imaging demonstrated a fewer number of secondary lymph nodes and had faster injection site clearance rate. TRIAL REGISTRATION: www.chictr.org.cn, ChiCTR1900024990 (retrospectively registered August 6, 2019).

Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.

BACKGROUND: To investigate the relationship between time elapsed since completion of radiotherapy (RT) and quality of life (QOL) of patients with breast cancer. METHODS: A total of 300 patients with breast cancer were treated at the First Affiliated Hospital of Anhui Medical University between January 2013 and April 2016. Of these, 212 patients were included in the study. Patients were divided into 4 groups based on the time elapsed since completion of RT. The generic cancer questionnaire, EORTC QLQ-30, and the breast cancer-specific questionnaire, QLQ-BR23, were used to assess the QOL. RESULTS: Analysis of time elapsed since completion of RT and QOL revealed changes in the scores for role function with passage of time; the third year's scores were the highest. Pain symptoms during the 3rd and 4th years after RT were lower than those during the 1st and 2nd years after RT; scores for financial difficulties fluctuated with passage of time; perception of own body scores improved within first 3 years; sexual activity and enjoyment of sexual activity showed a significant decrease during the 2nd to 4th year post RT. Scores pertaining to concerns about future state of health showed a significant increase during the 2nd to 4th year after RT, while breast symptoms score showed fluctuations with passage of time. CONCLUSIONS: Social function, pain symptoms, and concerns about future state of health tended to improve with passage of time after RT. Other scales showed no correlation with time elapsed since completion of RT.

Two cytotoxic 6,7-seco-spiro-lacton-ent-kauranoids from Isodon rubescens.

The present study was performed to investigate the chemical components of the branches and leaves of Isodon rubescens. Two 6,7-seco-spiro-lacton-ent-kauranoids were obtained. Based on the extensive spectroscopic analyses, their structures were elucidated as 6-epi-11-O-acetylangustifolin (1) and 11-O-acetylangustifolin (2), respectively. The structure of 2 was further comfirmed by X-ray crystallography analysis. MTT method was employed to evaluate their cytotoxity against human lung cancer cell lines A549 and leukemia cell lines K562.

Synergetic adsorption and photocatalytic degradation of pollutants over 3D TiO2-graphene aerogel composites synthesized via a facile one-pot route.

A series of composites consisting of anatase TiO2 nanocrystals and three-dimensional (3D) graphene aerogel (TiO2-GA) were self-assembled directly from tetrabutyl titanate and graphene oxides via a one-pot hydrothermal process. TiO2 was found to uniformly distribute inside the 3D network of GA in the resulting composites with large surface areas (SBET > 125 m(2) g(-1)) and high pore volumes (Vp > 0.22 cm(3) g(-1)). In comparison with GA and TiO2, the composites possessed much higher adsorption capacities and visible light photocatalytic activity in the degradation of rhodamine B (RhB). With an initial concentration of 20.0 mg L(-1) of RhB, the adsorptive decolourization of RhB was as high as 95.1% and the total decolourization value reached up to 98.7% under visible light irradiation over 5.0 mg of the resulting composites. It was elucidated that the physical and chemical properties of the TiO2-GA composites could be ascribed to their unique 3D nanoporous structure with high surface areas and the synergetic activities of graphene nanosheets and TiO2 nanoparticles.

Modified translaminar screw fixation in the cervicothoracic junction (C7-T2): a technical note.

PURPOSE: To describe and illustrate a modified technique for using translaminar screw in the cervicothoracic junction (C7-T2). METHODS: 12 patients (8 males and 4 females, average age was 52 years) underwent insertion of unilateral or bilateral translaminar screws by using our modified technique. With this modified technique, a tiny unicortical "hole" was made at the middle of the contralateral lamina, and the screw can be directly visualized through the unicortical "hole" to prevent violating the spinal canal. RESULTS: With this modified technique, the mean operation time was 205 min (range 145-360) and mean estimated blood loss was 445 ml (range 260-1250). The mean length of the laminar screws was 27 (range 24-30) mm. The results of the 12 patients with an average follow-up of 17 (6-33) months demonstrated this modified technique to be safe and effective in the fixation of cervicothoracic junction. CONCLUSION: In this modified technique, a tiny unicortical "hole" which was made at the middle of the dorsal lamina of cervicothoracic junction (C7-T2). By directly visualizing the screw inserting against the dorsal cortices of the lamina, this modified technique can reduce the risk of violation of the spinal canal and shorten the operation time.

Henrin A: A New Anti-HIV Ent-Kaurane Diterpene from Pteris henryi.

Henrin A (1), a new ent-kaurane diterpene, was isolated from the leaves of Pteris henryi. The chemical structure was elucidated by analysis of the spectroscopic data including one-dimensional (1D) and two-dimensional (2D) NMR spectra, and was further confirmed by X-ray crystallographic analysis. The compound was evaluated for its biological activities against a panel of cancer cell lines, dental bacterial biofilm formation, and HIV. It displayed anti-HIV potential with an IC50 value of 9.1 µM (SI = 12.2).

Diagnosis of poorly differentiated adenocarcinoma of the stomach by confocal laser endomicroscopy: A case report.

BACKGROUND: In recent years, confocal laser endomicroscopy (CLE) has become a new endoscopic imaging technology at the microscopic level, which is extensively performed for real-time in vivo histological examination. CLE can be performed to distinguish benign from malignant lesions. In this study, we diagnosed using CLE an asymptomatic patient with poorly differentiated gastric adenocarcinoma. CASE SUMMARY: A 63-year-old woman was diagnosed with gastric mucosal lesions, which may be gastric cancer, in the small curvature of the stomach by gastroscopy. She consented to undergo CLE for morphological observation of the gastric mucosa. Through the combination of CLE diagnosis and postoperative pathology, the intraoperative CLE diagnosis was considered to be reliable. According to our experience, CLE can be performed as the first choice for the diagnosis of gastric cancer. CONCLUSION: CLE has several advantages over pathological diagnosis. We believe that CLE has great potential in the diagnosis of benign and malignant gastric lesions.

Abietane diterpenoids from Isodon amethystoides and their biological activities.

Seven undescribed abietane diterpenoids [abietamethinols A-G (1-7)] were isolated from the twigs and leaves of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic methods including 2D NMR, and they were further confirmed by X-ray crystallographic data. Lophanic acid was considered as the precursor of 1-7 in the biosynthesis pathway hypothesis. These compounds were evaluated for their cytotoxic, anti-bacterial and anti-AIV (avian influenza virus) activities. Compound 5 showed 42.9% inhibitory activity against the cancer cell line SMMC-7721 at the concentration of 40 µM, 3 and 4 could inhibit the bacterial growth of Streptococcus sobrinus by 55.3% and 63.2% at the concentrations of 148.6 and 141.9 µM, respectively, and 4 was demonstrated with antiviral activity against AIV with the inhibitory effect of 68.4% at 25 µM.

External Validation of the International IgA Nephropathy Prediction Tool in Older Adult Patients.

Purpose: The International IgA Nephropathy Prediction Tool (IIgAN-PT) can predict the risk of End-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥ 50% for adult IgAN patients. Considering the differential progression between older adult and adult patients, this study aims to externally validate its performance in the older adult cohort. Patients and Methods: We analyzed 165 IgAN patients aged 60 and above from six medical centers, categorizing them by their predicted risk. The primary outcome was a ≥50% reduction in estimated glomerular filtration rate (eGFR) or kidney failure. Evaluation of both models involved concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier survival curves, and calibration plots. Comparative reclassification was conducted using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: The study included 165 Chinese patients (median age 64, 60% male), with a median follow-up of 5.1 years. Of these, 21% reached the primary outcome. Both models with or without race demonstrated good discrimination (C-statistics 0.788 and 0.790, respectively). Survival curves for risk groups were well-separated. The full model without race more accurately predicted 5-year risks, whereas the full model with race tended to overestimate risks after 3 years. No significant reclassification improvement was noted in the full model without race (NRI 0.09, 95% CI: -0.27 to 0.34; IDI 0.003, 95% CI: -0.009 to 0.019). Conclusion: : Both models exhibited excellent discrimination among older adult IgAN patients. The full model without race demonstrated superior calibration in predicting the 5-year risk.

Atomically Dispersed Copper on N-Doped Carbon Nanosheets for Electrocatalytic Synthesis of Carbamates from CO2 as a C1 Source.

The synthesis of carbamates by electrocatalytic reduction of CO2 is an effective method to realize the utilization of CO2 resources. The development of high-performance electrocatalysts to complete this process more efficiently is of great significance to sustainable development. Owing to their unique structural characteristics, single-atom catalysts are expected to promote the reaction process more efficiently. In this study, an atomically dispersed Cu species on N-doped carbon nanosheet composite material (Cu-N-C) was prepared by metal-organic framework derivatization. Compared with traditional Cu bulk electrodes, the Cu-N-C material has better catalytic performance for the synthesis of methyl N-phenylcarbamate; and the optimized yield reached 71 % at room temperature and normal pressure. The Cu-N-C material has good stability that the catalytic performance does not decrease after repeated use for 10 times. In addition, the Cu-N-C material has good applicability to this catalytic system, and a variety of amines can be smoothly converted into corresponding carbamates.

Gene Expression Profile of the Human Colorectal Carcinoma LoVo Cells Treated With Sporamin and Thapsigargin.

Sporamin, a proteinase inhibitor isolated from the sweet potato (Ipomoea batatas), has shown promising anticancer effect against colorectal cancer (CRC) in vitro and in vivo but its mechanisms of action are poorly understood. In the present study, high throughput RNA sequencing (RNA-seq) technology was applied to explore the transcriptomic changes induced by sporamin in the presence of thapsigargin (TG), a non-12-O-tetradecanolphorbol-13-acetate type cancer promoter, in the LoVo human CRC cells. Cellular total RNA was extracted from the cells after they were treated with vehicle (CTL), 1 µM of thapsigargin (TG), or 1 µM of TG plus 30 µM of sporamin (TGSP) for 24 h. The migratory capacity of the cells was determined by wound healing assay. The gene expression profiles of the cells were determined by RNA-seq on an Illumina platform. GO enrichment analysis, KEGG pathway analysis, protein-protein interaction (PPI) network construction, and transcription factors (TF) prediction were all performed based on the differentially expressed genes (DEGs) across groups with a series of bioinformatics tools. Finally, the effect and potential molecular targets of the sporamin at the transcriptome level were evaluated. Sporamin significantly inhibited the migration of cells induced by TG. Among the 17915 genes detected in RNA-seq, 46 DEGs were attributable to the effect of sporamin. RT-PCR experiment validated that the expression of RGPD2, SULT1A3, and BIVM-ERCC5 were up-regulated while NYP4R, FOXN1, PAK6, and CEACAM20 were down-regulated. Sporamin enhanced the mineral absorption pathway, worm longevity regulating pathway, and pyrimidine metabolism pathway. Two TFs (SMIM11A and ATOH8) were down-regulated by sporamin. HMOX1 (up-regulated) and NME1-NME2 (down-regulated) were the main nodes in a PPI network consisting of 16 DEGs that were modulated by sporamin in the presence of TG. Sporamin could favorably alter the gene expression profile of CRC cells, up-regulating the genes that contribute to the homeostasis of intracellular metal ions and the activities of essential enzymes and DNA damage repairment. More studies are warranted to verify its effect on specific genes and delineate the mechanism of action implicated in the process.

Electrocatalytic carboxylation of halogenated compounds with mesoporous silver electrode materials.

Mesoporous silver materials are used as electrocatalysts for halogenated compounds. The mesoporous silver materials have uniform mesoporous size (8 nm), large specific surface area (12 m2 g-1), high pore volume (0.07 cm3 g-1), and a good 3D network structure of the metallic silver skeleton. The results show that the prepared materials exhibit high performance in electrocatalytic carboxylation of halogenated compounds to acid (78%).

Evaluating the inhibitory effect of eight compounds from Daphne papyracea against the NS3/4A protease of hepatitis C virus.

Hepatitis C virus (HCV) infection is a global threat to human health with an estimated 1.75 million new cases in 2015. Our previous studies showed that the ethyl acetate extraction of Daphne papyracea exhibited an inhibitory effect towards the HCV NS3/4A protease and eight compounds were identified from the extract. In this study, we investigated which of the eight compounds was responsible for the inhibitory effect of the extract against the HCV NS3/4A protease. From both molecular docking and enzyme inhibition studies, (+)-usnic acid was shown to be the most active compound and could be used as a lead compound in developing novel anti-HCV agents.

Ordered Mesoporous Carbon Embedded with Cu Nanoparticle Materials for Electrocatalytic Synthesis of Benzyl Methyl Carbonate from Benzyl Alcohol and Carbon Dioxide.

We prepared a series of ordered mesoporous carbons embedded with different contents of Cu nanoparticles (Cu/OMC-X) and applied them to electrocatalytic synthesis of benzyl methyl carbonate. The materials were characterized by many measurements, which showed that Cu/OMC-X materials maintain highly ordered mesoporous structures with high surface area and highly dispersed Cu nanoparticles. As expected, the materials exhibit good electrocatalytic performance. The optimal yield of benzyl methyl carbonate reaches 69.7% on Cu/OMC-3.

Standard-dose epirubicin increases the pathological complete response rate in neoadjuvant chemotherapy for breast cancer: a multicenter retrospective study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become the best comprehensive treatment choice for breast cancer. Epirubicin is a crucial drug widely used in breast cancer chemotherapy, but it is often used with a reduced dosage in NAC for Chinese patients for its notable cardiotoxicity and frequent adverse events. This study aimed to investigate the efficacy and safety of standard-dose epirubicin in NAC for Chinese breast cancer patients retrospectively. METHODS: We retrospectively collected clinicopathological parameters of breast cancer patients who underwent epirubicin-based NAC and a later surgery from three separate medical centers. Patients were divided into standard-dose and low-dose groups according to the epirubicin dose. The pathological complete response (pCR) rate, as the main therapeutic outcomes, and the incidence of adverse events were recorded and compared. RESULTS: The pCR rate of the standard-dose group was 41.2%, while the low-dose group was 10.1% (P<0.001). The univariate analysis showed that ER status (HR, 2.519; 95% CI, 1.057-5.988, P=0.037) and epirubicin dose (HR, 6.200; 95% CI, 2.374-16.193, P<0.001) were associated with pCR rates. The multivariate analysis showed that patients receiving standard-dose epirubicin chemotherapy (HR, 6.925; 95% CI, 2.537-18.902, P<0.001) showed more possibility to achieve pCR after NAC. There was no significant difference in the incidence rates of grade III/IV adverse events between these two different dose groups. CONCLUSIONS: Standard-dose epirubicin increases the pCR rate in breast cancer patients treated with NAC, and no other toxicity is noted.

Minimally invasive maxillary sinus augmentation with simultaneous implantation on an elderly patient: A case report.

BACKGROUND: In this case study, a minimally invasive transalveolar approach using platelet-rich fibrin and bone substitute with simultaneous implantation was carried out in an elderly patient. We analyzed the cone-beam computed tomography (CBCT) findings to evaluate bone regeneration. CASE SUMMARY: A 65-year-old female with no contraindications for dental implants and loss of maxillary bilateral molars is described. Examination by CBCT showed the available vertical bone height in the bilateral posterior maxilla was 0.5-6.8 mm in the left and 2.8-6.5 mm in the right. The patient underwent a transalveolar approach using platelet-rich fibrin and bone substitute with simulataneous placement of an implant 10 mm in length. Six months post-surgery, the implant showed excellent osseointegration with the bone graft. Thereafter, full-ceramic crowns were fitted. Follow-up at 2 years demonstrated satisfactory prognosis. CONCLUSION: Platelet-rich fibrin and bone substitute can be used to augment the maxillary sinus with a vertical bone height less than 4 mm.

[Symbiotic bacteria facilitate algal growth and oil biosynthesis in Scenedesmus obliquus]. / å ±ç”ŸèŒä¿ƒè¿›æ–œç”Ÿæ 藻生长和油脂合成.

We isolated bacteria from the phycosphere of Scenedesmus obliques and sequenced 16S rDNAs to establish algae-bacterial co-culture systems. Further, we examined effects of the bacteria on algal growth, and parameters associated with physio-biochemical and oil-producing characteristics of S. obliquus. Seven bacterial strains were isolated, including Micrococcus (strains 1-1, 1-2 and 1-3), Pseudomonas sp. (strains 2-1 and 2-2), Exiguobacterium (strain-3) and Staphylococcus sp. (strain-4). Among them, two bacteria (strain 1-2 and strain 2-1) were characterized as the dominant growth-promoting bacterial strains, which significantly increased algal growth, pigment production, and oil enrichment. After eight days cultivation under microalgal-bacterial (strain 1-2) symbiotic systemat at an initial ratio of 1:10, biomass of S. obliquus was 4.27 g·L-1, about 46.0% higher than that of the control. The contents of chlorophyll a, chlorophyll b and carotenoids were increased by 12.1%, 16.7% and 25.0%, respectively. Oil content was increased by 14.0% and reached to 25.7%, and the oleic acid content was significantly higher than that of the control and up to 16.4%. When co-cultured with Pseudomonas sp. (strain 2-1) for eight days at an initial ratio of 1:5, algal biomass, chlorophyll a, chlorophyll b and carotenoids contents were higher than that of the control by 47.9%, 16.0%, 17.5% and 19.9%, respectively. The total oil (27.1%) and oleic acid (18.2%) contents were increased by 20.4% and 64.0%, respectively. We concluded that Micrococcus (strain 1-2) and Pseudomonas sp. (strain 2-1) could significantly promote algal growth and increase oil production by their beneficial interaction with S. obliques, which could be potentially used in commercial production of S. obliques.

Sporamin suppresses growth of xenografted colorectal carcinoma in athymic BALB/c mice by inhibiting liver ß-catenin and vascular endothelial growth factor expression.

BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy of the digestive tract and the fifth leading cause of cancer-related mortality in China. Sporamin, a Kunitz-type trypsin inhibitor isolated from sweet potato, is a potential anti-cancer agent with activities against a number of malignant tumor cells in vitro. The liver secretes a myriad of endocrine factors that may facilitate the growth and transformation of tumors in the development of CRC. AIM: To investigate the effects of sporamin on liver morphology and biomarkers of xenografted CRC in the liver of athymic BALB/c mice. METHODS: Twenty-seven male BALB/c nude mice were randomly divided into control, vehicle, and sporamin groups. Mice in the latter two groups were intraperitoneally xenografted with LoVo colorectal carcinoma cells and intragastrically infused with saline or sporamin (0.5 g/kg body weight/d), respectively, for 3 wk. Hematoxylin and eosin (HE) staining of the sections was performed to observe morphological changes in hepatic tissue and real-time fluorescent quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to measure the expression of ß-catenin and vascular endothelial growth factor (VEGF) in the liver. RESULTS: Sporamin significantly reduced the number and weight of tumor nodules formed in the abdominal cavity. Compared with the vehicle group, the mean tumor weight (± SD) in the sporamin group was significantly reduced (0.44 ± 0.10 g vs 0.26 ± 0.15 g) and the total number of tumors decreased from 93 to 55. HE staining showed that enlargement of the nucleus and synthesis of proteins within hepatocytes, as well as infiltration of inflammatory cells into the liver, were attenuated by sporamin. Immunohistochemical staining and ELISA showed that the concentrations of ß-catenin and VEGF in the liver were significantly reduced by sporamin. Compared with the vehicle group, the expression of ß-catenin measured in integrated optical density units per area was reduced in the sporamin group (47.29 ± 9.10 vs 26.14 ± 1.72; P = 0.003). Expression of VEGF was also reduced after sporamin intervention from 20.78 ± 2.06 in the vehicle group to 15.80 ± 1.09 in the sporamin group (P = 0.021). Compared with the vehicle group, the concentration of ß-catenin decreased from 134.42 ± 22.04 pg/mL to 109.07 ± 9.65 pg/mL after sporamin intervention (P = 0.00002). qPCR indicated that compared to the vehicle group, relative mRNA expression of ß-catenin and VEGF in the liver of mice in the sporamin-treated group was significantly reduced to 71% ± 1% (P = 0.000001) and 23% ± 7% (P = 0.00002), respectively, of the vehicle group levels. CONCLUSION: Sporamin down-regulates the expression and secretion of ß-catenin and VEGF in the liver, which subsequently inhibits the transcription of downstream genes involved in cancer progression and angiogenesis.