Each procedure was associated with initial improvement of renal f

Each procedure was associated with initial improvement of renal function and blood pressure control, which then later deteriorated with the development of further significant in-stent restenosis. It was then

decided to treat the restenosis using PTFE-covered stents. At XMU-MP-1 solubility dmso 12 months of follow-up, the blood pressure had remained stable and renal function had normalized. The covered stents remained free of any significant neointimal tissue or obstruction.”
“Climate warming threatens the survival of species at their warm, trailing-edge range boundaries but also provides opportunities for the ecological release of populations at the cool, leading edges of their distributions. Thus, as the climate warms, leading-edge populations are expected to utilize an increased range of habitat types, leading to larger population sizes and range expansion. Here, we test the hypothesis that the habitat associations of British butterflies have expanded over three decades of climate warming. We characterize the habitat

breadth of 27 southerly distributed species from 77 monitoring transects between 1977 and 2007 by considering changes in densities of butterflies across 11 habitat types. Contrary to expectation, we find that 20 of 27 (74%) butterfly species showed long-term contractions in their habitat associations, despite some short-term expansions in habitat breadth in warmer-than-usual years. Thus, we conclude that climatic click here warming has ameliorated

habitat contractions caused by other environmental drivers to some extent, but that habitat degradation continues to be a major selleck compound driver of reductions in habitat breadth and population density of butterflies.”
“Despite recent advances, cerebral vasospasm and delayed cerebral ischemia (DCI) still represent a major cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Although a significant portion of the morbidity and mortality associated with aSAH is related to the initial hemorrhagic ictus, cerebral vasospasm and DCI are still the leading cause of poor outcomes and death in the acute posthemorrhage period, causing long-term disability or death in more than one in five of all patients who have suffered aSAH and initially survived. Management of patients following aSAH includes four major considerations: (1) prediction of patients at highest risk for development of DCI, (2) prophylactic measures to reduce its occurrence, (3) monitoring to detect early signs of cerebral ischemia, and (4) treatments to correct vasospasm and cerebral ischemia once it occurs. The authors review the pertinent literature related to each, including both the current management guidelines supported by the literature as well as novel management strategies that are currently being investigated.”
“Heat shock proteins (HSPs) are ubiquitous and evolutionary conserved proteins induced by cell stress.

(C) 2011 Society of Chemical Industry”
“The mechanism of com

(C) 2011 Society of Chemical Industry”
“The mechanism of complexation of poly-L-lysine (PLL) with methyl orange (MO) and the appearance of induced circular dichroism (ICD) were investigated as a function of dye concentration and temperature and compared with that of the PLL-ethyl orange complex. The formation of stoichiometric complexes with uniform size and intensities of ICDs depended on the length of alkyl groups (methyl and ethyl) as determined from quartz crystal microbalance measurement, absorption spectra, and CD spectra data. Furthermore, at constant PLL concentration,

a dependence of the inversion of the ICD on the MO concentration (CMO) was observed in the PLL-MO complexes, which to our knowledge Daporinad manufacturer has not been reported for a constant dye concentration system. The positive ICD in the PLL-MO complexes observed at CMO lower than 2.0 x 10(-5) M showed reversible

changes in response to heating and cooling, whereas the negative ICD in PLL-MO complexes observed at higher CMO inverted to positive ICD values in response to a decrease in temperature. These results demonstrate the alkyl group substituent in the dye, dye concentration, and temperature play important roles in the formation of PLL-azo dye complex and ICD appearance. (C) 2011 Wiley Periodicals, Selleckchem PKC412 Inc. J Polym Sci Part A: Polym Chem 49: 1691-1698, 2011″
“Incompatibilities in interspecific hybrids, such as sterility and lethality, are widely observed causes of reproductive isolation and thus contribute to speciation. Because hybrid incompatibilities are caused by divergence in each of the hybridizing species, they also reveal genomic changes occurring on short evolutionary time scales that have functional consequences. These changes include divergence in protein-coding gene sequence, structure, and location, as well as divergence in noncoding DNAs. The most important unresolved issue is understanding the evolutionary causes of the divergence within species that in turn leads to

incompatibility between species. Surprisingly, much of this divergence does not appear to be driven by ecological adaptation but may instead result from responses to purely mutational Selleck AL3818 mechanisms or to internal genetic conflicts.”
“Purpose: To examine correlates of human papillomavirus (HPV) vaccine awareness and information sources in a state requiring schools to inform parents about HPV vaccine.\n\nMethods: Telephone survey of a North Carolina population-based sample of 696 parents of females aged 10-17 years about HPV vaccine awareness and information sources (daughters’ schools, healthcare provider, drug company advertisements, news stories) was conducted.\n\nResults: Overall, 91% of parents had heard of HPV vaccine.

Results Clinical and PDUS examination revealed at least one

\n\nResults. Clinical and PDUS examination revealed at least one abnormal enthesis in 23 (63.9%) and 35 (97.2%) AS patients, respectively. Furthermore, of 432 entheses examined in our 36 AS patients, 64 (14.8%) were VX-809 nmr considered abnormal by clinical examination and 192 (44.4%) by PDUS. US abnormalities most commonly found were enthesophytes (31.7%), calcifications (33.7%), thickening (29.8%) and hypoechogenicity (26.6%). We

found erosions and PD signals in 9.7 and 6% of examined entheseal sites, respectively. The evidence of entheseal abnormalities by clinical examination has a poor likelihood ratio (LR) for the presence of US abnormalities with

vascularization (LR = 1.61), without vascularization (LR = 1.24) or erosions (LR = 1.51) at all sites.\n\nConclusions. PDUS permits detection of structural and inflammatory abnormalities of the enthesis in AS and may complement the physical examination in order to better evaluate enthesitis.”
“Severe wilt and blight of entire plants of yacon (Smallanthus sonchifolius) grafts on sunflower (Helianthus annuus) were found in greenhouses in Kagawa Prefecture in the southwest region of Japan from April to May between 1997 and 1999. A mitosporic fungus, isolated MAPK inhibitor repeatedly from the diseased plants and identified as Botrytis cinerea, Cl-amidine was demonstrated to be virulent to both yacon and sunflower. The new disease on yacon was named gray mold of yacon. The disease on sunflower, gray mold of sunflower, is new to Japan.”
“Creatine kinase (CK) is a marker of muscle damage and pathology present as multiple tissue-specific circulating isoforms. CK is often measured using enzyme activity assays that are

unable to distinguish these isoforms. We have developed an immunoassay specific for the MM isoform of CK, found predominantly in skeletal muscle, which uses very small volumes of plasma (1-2 mu L). A sandwich enzyme-linked immunosorbent assay (ELISA) for CK-MM was developed using isoform-specific antibodies. Cross-reactivity with CK-BB and MB isoforms was also assessed. The ELISA was validated using plasma samples from a group of athletes, and the measured CK-MM concentrations were correlated with CK enzyme activity assays measured by a contractor using the same samples. The CK-MM ELISA has a limit of detection of 0.02 ng/mL, an IC(50) of 2.3 ng/mL, and 5.8% cross-reactivity with CK-MB. CK-MM concentrations measured using this assay correlate well (p < 0.

3%), followed by A (61, 25 7%) and C (14, 5 9%) The

dist

3%), followed by A (61, 25.7%) and C (14, 5.9%). The

distribution of HBV genotypes between patients with acute hepatitis and CHB (carriers + CHB + LC + HCC), or between carriers and disease states (CHB + LC + HCC), or between mild chronic infection (carriers + CHB) and complications of chronic HBV infection (LC + HCC) was similar. Eighty-seven patients had liver biopsy; the median histological activity index (HAI) and fibrosis stage at baseline were similar between genotype groups (four [1-9] genotype A [n = 28]), three (2-4) genotype C (n = 4) and four (1-10) genotype D (n = 55); P = 0.33 for HAI score; (0.5 [0-6] genotype A, 0.5 [0-4] genotype C and 1 [0-6] genotype D; P = 0.92 for fibrosis stage). The response to therapy was similar between the genotypes.\n\nClinical, histological severity and therapeutic responses AP24534 in vitro are similar among patients with HBV genotypes A and D.”
“Many plants accumulate substantial starch reserves in their leaves during the day and remobilize Dihydrotestosterone them at night to provide carbon and energy for maintenance and growth. In this paper, we explore the role of a sugar-signaling metabolite, trehalose-6-phosphate (Tre6P), in regulating the accumulation and turnover of transitory starch in Arabidopsis (Arabidopsis thaliana) leaves. Ethanol-induced overexpression of trehalose-phosphate synthase during the

day increased Tre6P levels up to 11-fold. There was a transient increase in the rate of starch accumulation in the middle of the day, but this was not linked to reductive activation of ADP-glucose pyrophosphorylase. A 2- to 3-fold increase in Tre6P during the night led to significant inhibition of starch degradation. Maltose and maltotriose did not accumulate, suggesting that Tre6P affects an early step in the pathway

of starch degradation in the chloroplasts. Starch granules isolated from induced plants had a higher orthophosphate content than granules from noninduced control plants, consistent either with disruption of the phosphorylation-dephosphorylation cycle that is essential for efficient starch breakdown or with inhibition of starch hydrolysis by beta-amylase. Nonaqueous fractionation of leaves showed that Tre6P is predominantly 4EGI-1 ic50 located in the cytosol, with estimated in vivo Tre6P concentrations of 4 to 7 mu M in the cytosol, 0.2 to 0.5 mu M in the chloroplasts, and 0.05 mu M in the vacuole. It is proposed that Tre6P is a component in a signaling pathway that mediates the feedback regulation of starch breakdown by sucrose, potentially linking starch turnover to demand for sucrose by growing sink organs at night.”
“BACKGROUND: Polyunsaturated fatty acids lower serum triglycerides by a mechanism that may involve the inhibition of stearoyl-CoA desaturase (SCD).\n\nOBJECTIVE: We sought to evaluate the effects of serum fatty acids on 1) the SCD index in a controlled clinical setting, and 2) SCD regulation in Hep G2 cells.

Univariate and multivariate analyses were used to analyse the ass

Univariate and multivariate analyses were used to analyse the association of PET-CT-related parameters and clinical variables, to assess downstaging and pCR.\n\nResults Downstaging occurred in 48 patients (31.7 %) and pCR in 19 patients (12.5 %). Univariate and multivariate analysis revealed post-CRT SUVmax as a significant factor for prediction of downstaging, with sensitivity of 60.4 %, specificity of 65.0 %, and accuracy of 55.9 %, for a cutoff value of 3.70. Regarding pCR, post-CRT SUVmax was again found as a significant parameter by univariate and multivariate analysis, with sensitivity of 73.7 %, specificity

of 63.7 %, and accuracy of 64.9 %, for a cutoff value of 3.55.\n\nConclusions The results indicate that post-CRT SUVmax independently predicts downstaging and pCR. However, the predictive values of post-CRT SUVmax for Selleck GSK3235025 tumour response after neoadjuvant CRT are too low in sensitivity AC220 clinical trial and specificity to change the treatment plan for LARC.”
“Two new ylangene-type sesquiterpenoids, postinins A (1) and B (2), were isolated from cultures of the fungus Postia sp. Structures 1 and 2 were elucidated on the basis of extensive spectroscopic analysis. The bioactivity evaluation showed that both compounds had significant inhibitory activities against protein tyrosine phosphatase 1B, and SH2-containing cytoplasmic

tyrosine phosphatase-1 and -2 with IC50 values of 1.6-6.2g/ml.”
“Dysphagia matters and endoscopic examination of patients with swallowing complaints is an important part of their evaluation. The 3 key adjuncts to flexible fiber optic laryngoscopy are (1) flexible endoscopic evaluation of swallowing, (2) assessment of pharyngeal squeeze, and (3) sensory testing. Patients undergoing flexible fiber optic laryngoscopy are then challenged with liquid or solid materials for intake. Fundamental clinical signs of swallowing parameters

are noted. The threshold at which the laryngeal adductor reflex is triggered is believed to be helpful in predicting swallowing capacity. This report deals solely with adult dysphagia evaluation.”
“What is the effectiveness of continued treatment with clomiphene citrate (CC) in women with see more World Health Organization (WHO) type II anovulation who have had at least six ovulatory cycles with CC but did not conceive? When women continued CC after six treatment cycles, the cumulative incidence rate of the ongoing pregnancy rate was 54% (95% CI 37-78%) for cycles 7-12. If women with WHO type II anovulation fail to conceive with CC within six ovulatory cycles, guidelines advise switching to gonadotrophins, which have a high risk of multiple gestation and are expensive. It is however not clear what success rate could be achieved by continued treatment with CC.

(C) 2009 Wiley Periodicals, Inc J Polym Sci Part A: Polym Chem 4

(C) 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2620-2630, 2009″
“PURPOSE: Physical activity (PA) has been shown to improve symptoms in people with chronic obstructive pulmonary disease (COPD). Despite the high health and financial costs, the uptake of management strategies, particularly participation in PA and pulmonary rehabilitation (PR), are low. The review objective here was to identify potential barriers and enablers, which people with COPD report being associated with their participation in PA programs, including PR.\n\nMETHODS: A systematic search was undertaken to identify studies (published Jan 2000 to

Aug 2011) reporting any barriers and enablers experienced by people with COPD regarding Selleckchem STA-9090 participation in PA and PR. Methodological quality of the studies was appraised using McMaster critical appraisal tools. A narrative summary of findings was undertaken reporting on individual study characteristics, country of origin, participants, and potential barriers and enablers.\n\nRESULTS: Eleven studies (8 qualitative and 3 quantitative) met the inclusion criteria for this systematic review. Several methodological issues (small sampling, poor description of data collection and analysis, issues with generalizability of the research findings) were common among included studies. Barriers identified included changing

health status, personal issues, lack of support, external factors, ongoing smoking, and program-specific barriers. Enablers identified included social support, professional support, personal drivers, personal benefit, control of condition, specific goals, and program-specific AZD1480 mw enablers.\n\nCONCLUSION: The findings from this review may assist health professionals, patients, care givers and the wider community to develop effective strategies to promote participation in PA and PR among people buy ACY-241 with COPD.”
“The purpose of this study was to compare the antioxidant activity of carotenoids to that of alpha-tocopherol by using a photochemiluminescence method (PCL). Comparisons to results obtained by using other established methods (alpha-TEAC, FRAP, DPPH,

LPSC) were carried out. A relationship between the chemical structure of carotenoids and their antioxidant activity could be discussed. The number of conjugated double bonds and functional groups had a positive influence. Additionally, the lipophilic antioxidant capacities of selected tomato products were analyzed using PCL and alpha-TEAC. HPLC was used to identify and quantify contents of carotenoids, tocopherols, and tocotrienols. The raw material fresh tomatoes had the lowest antioxidant effect in both assays due to the lower carotenoid content. Tomato ketchup had the highest AOC in PCL, and tomato puree, in alpha-TEAC. The antioxidant capacities were mainly dependent on the water content of the samples. Furthermore, a concentration-dependent effect could be observed in both assays.

The authors recommend that, in order to meet patients’ psychosoci

The authors recommend that, in order to meet patients’ psychosocial needs effectively, ambulance clinicians are provided with education and training in a number of skills and their own psychosocial support should be enhanced.”
“The objective of this

study was to identify risk factors for low birth weight in singleton live born infants in Rio Grande do Sul State, Brazil, in 2003, based on data from the Information System on Live Births. The study used both buy P005091 classical multivariate and multilevel logistic regression. Risk factors were evaluated at two levels: individual (live births) and contextual (microregions). At the individual level the two models showed a significant association between low birth weight and prematurity, number of prenatal visits, congenital anomalies, place of delivery, parity, sex, maternal age, maternal occupation, marital status, schooling, and type of delivery. In the multilevel models,

the greater the urbanization of the micro-region, the higher the risk of low birth weight, while in less urbanized microregions, single mothers had an increased risk of low birth considering all live births. Low birth weight varied according to micro-region and was associated with individual and contextual characteristics. Although most of the variation in low birth weight occurred at the individual level, the multilevel model identified an important risk factor in the contextual TH-302 supplier level.”
“Major trauma remains a significant

cause of mortality and morbidity in young people and adolescents throughout the western world. Both the physical and psychological consequences of trauma are well documented and it is shown that peri-traumatic factors play a large part in the emotional recovery of children involved in trauma. Indeed, parental anxiety levels may play one of the biggest roles. There are no publically available guidelines on pre-hospital accompaniment, and where research has been done on parental presence it often focuses primarily on the parents or staff, rather than the child themselves. Whilst acknowledging the impact on parents and staff, the importance of the emotional wellbeing of the child should be reinforced, to reduce the likelihood of SN-38 clinical trial developing symptoms in keeping with post-traumatic stress disorder. This non-systematic literature review, aims to examine the impact of parental accompaniment to hospital, following paediatric trauma, and to help pre-hospital clinicians decide whether accompaniment would be of benefit to their patient population. The lack of published data does not enable a formal recommendation of parental accompaniment in the helicopter to be mandated, though it should be the preference in land based conveyance. Future research is needed into the emotional recovery of children after trauma, as well as the experiences of patient, parent and staff during conveyance.

Seven days after islet transplantation,

insulin expressio

Seven days after islet transplantation,

insulin expression in the MSC-islets group significantly differed from that of the islets-alone group. We proposed that MSCs could promote anti-apoptotic gene expression by enhancing their resistance to H/R-induced apoptosis and dysfunction. This study provides an experimental basis for therapeutic strategies based on enhancing islet function. Copyright (C) 2010 John Wiley & Sons, Ltd.”
“Corynebacterium striatum is often dismissed as a contaminant when cultivated from blood samples; indeed, it is a skin saprophyte that may therefore be introduced into the clinical specimen accidentally. Nevertheless, the organism can be responsible for true bacteraemias, and multidrug resistance spread among nosocomial strains is of increasing concern. Specific criteria for testing have not been defined yet, but we however suggest to report clear resistances (i.e. absence of any inhibition zones with selleck chemical the disc test), in order to try to understand this species behaviour under antibiotic exposure. In this context, features of a blood isolate (strain DSM 45711) are here depicted.”
“To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding

of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 Screening Library research buy acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the

intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The Proteases inhibitor combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.

By accounting for the hydrostatic pressure and the stress asymmet

By accounting for the hydrostatic pressure and the stress asymmetry, the EWK model can successfully predict different failure modes in the welding strength tests, including the shear mode, which cannot be predicted by Gurson’s model. Moreover, characteristics of the spotweld, including residual stress, phase distributions, sizes and material roper ties of different zones, are obtained from an analysis with the SYSWELD software and are

then mapped into the failure prediction model to achieve a realistic description of the weldment. Both the simulated results of the FE model combining solid and shell elements MI-503 and those of the model with only solid elements show rather good consistency with the welding strength test data.”
“Small RNAs, a large class of ancient posttranscriptional regulators, have recently attracted considerable attention. A plethora of small RNAs has been identified and characterized, many of which Selleck Liproxstatin-1 belong to the major small noncoding RNA (sRNA) or riboswitch families. It has become increasingly clear that most small RNAs play critical regulatory roles in many processes and are, therefore, considered to be powerful tools for metabolic engineering and synthetic biology. In this review, we describe recent achievements in the identification, characterization, and application of small RNAs. We give particular attention to advances

in the design and synthesis of novel sRNAs and riboswitches for metabolic engineering. In addition, a novel strategy for hierarchical control of global metabolic pathways is proposed.”
“Human phospholipid scramblase I

(SCR) was originally described as an intrinsic membrane protein catalyzing transbilayer phospholipid transfer in the absence of ATP. More recently, Galardin in vivo a role as a nuclear transcription factor has been proposed for SCR, either in addition or alternatively to its capacity to facilitate phospholipid flip-flop. Uncertainties exist as well from the structural point of view. A predicted a-helix (aa residues 288-306) located near the C-terminus has been alternatively proposed as a transmembrane domain, or as a protein core structural element. This paper explores the possibilities of the above helical segment as a transmembrane domain. To this aim two peptides were synthesized, one corresponding to the 19 a-helical residues, and one containing both the helix and the subsequent 12-residues constituting the C-end of the protein. The interaction of these peptides with lipid monolayers and bilayers was tested with Langmuir balance surface pressure measurements, proteoliposome reconstitution and analysis, differential scanning calorimetry, tests of bilayer permeability, and fluorescence confocal microscopy. Bilayers of 28 different lipid compositions were examined in which lipid electric charge, bilayer fluidity and lateral heterogeneity (domain formation) were varied.

We observed three different situations: (a) the presence of triad

We observed three different situations: (a) the presence of triads (bottom structures characterized by a concomitant jump in turbidity, temperature, and salinity data) and high re-suspension phenomena related to the presence

of the Circumpolar Deep Water and its mixing with cold, salty shelf waters associated with gravity currents; (b) the absence of triads with high re-suspension, implying that when the gravity currents are no longer active the benthic nepheloid layer may persist until the suspended particles settle to the sea floor, suggesting that the turbidity data can be used to study recent gravity current events; and (c) the absence of turbidity and sediment re-suspension phenomena supports the theory that a steady situation had been re-established and the current interaction no longer occurred or had finished sometime before. (C) 2008 Elsevier Ltd. All rights reserved.”
“Background-Biological

check details pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca2+-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes with those with single-gene HCN2 transfer.\n\nMethods and Results-We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches of atrioventricular-blocked dogs. During steady-state gene expression (days 5-7), differences between AC1, HCN2/AC1, and HCN2 alone SB273005 purchase were evident in basal beating rate, escape time, and dependence on electronic backup pacing. In HCN2, AC1, and HCN2/AC1, these parameters were as follows: basal beating rate: 50 +/- 1.5, 60 +/- 5.0, and 129 +/- 28.9 bpm (P<0.05 for HCN2/AC1 versus HCN2 or AC1 alone), respectively; escape time: 2.4 +/- 0.2, 1.3 +/- 0.2, and 1.1 +/-.0.4 seconds (P<0.05 for AC1 and HCN2/AC1 versus HCN2); and percent electronic beats: 34 +/- 8%, 2 +/- 1%, and 6 +/- 2% (P<0.05 for

AC1 and HCN2/AC1 versus HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability and circadian rhythm analyzed via 24-hour Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 and a high degree of sympathetic CA4P modulation in animals injected with HCN2/AC1.\n\nConclusion-AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone. (Circulation. 2012;126:528-536.)”
“The SAMP8 strain spontaneously develops learning and memory deficits with characteristics of aging, and is a good model for studying the mechanism of cognitive dysfunction with age. Oxidative stress occurs systemically in SAMP8 from early on in life and increases with aging.