Inclusion of the laryngeal model increased the tracheal depositio

Inclusion of the laryngeal model increased the tracheal deposition of nano- and micrometer particles by factors ranging from 2 to 10 and significantly reduced deposition in the first three bronchi of the model. Considering localized conditions, inclusion of the laryngeal approximation decreased deposition at the main carina and produced a maximum in local surface deposition density in the lobar-to-segmental bifurcations (G2-G3) for both 40-nm and 4-mu m aerosols. These findings corroborate previous experiments and highlight the need to include a laryngeal representation in future computational and in vitro models of the TB region.”
“Childhood health

and illness have changed considerably over the past century calling for an increasing awareness of mental health Danusertib supplier problems. Consequently, the assessment of mental health problems is of major importance, not only focussing on mental health diagnoses but also on components

of health-related quality of life (HRQOL) and functioning with regard to the impact of an illness or injury, medical treatment, or health care policy. Recently, a number of HRQOL measures www.selleckchem.com/products/BMS-777607.html for children and adolescents have been developed and applied in a number of studies. The current paper presents multi-cultural tools for the assessment of HRQOL, which were developed within European projects, describes the application of these tools in cross-national studies and pinpoints important determinants of HRQOL and mental health problems. Future research needs are discussed. (c) 2011 Elsevier Ltd. All rights reserved.”
“Migraine is one of the most prevalent neurological disorders with some 30% of patients additionally suffering from focal neurological disturbances: the aura.

The underlying mechanism behind the aura is generally considered to be a form of cortical spreading depression (CSD). We used mechanical stimulation to induce hyperaemia associated with CSD in cats and rats, Copanlisib clinical trial and studied the effect of a glutamate, a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor, antagonist, and c-aminobutyric acid (GABA) A and GABAB receptor agonists, to understand better the pharmacology of CSD. All three were able to inhibit CSD-associated cerebral blood flow changes in the rat and in a proportion of cats studied; non-responders showed altered speed of propagation and time to induction. The data suggest AMPA and GABA receptors may be targets of migraine therapy in inhibiting CSD and thus may alter the frequency of migraine aura.”
“Porokeratosis is the common name of several diseases of unknown pathogenesis, which are similar in clinical appearance. It was first described in 1893 and was thought to be a disorder of sweat glands, hence the name porokeratosis. The lesion that can be found in all cases is annular, with atrophic center, and hyperkeratotic outer ring.

6%, p<0 001) Urological intervention

6%, p<0.001). Urological intervention ML323 solubility dmso was required in 37% and these patients had a larger average stone size. In young female patients with

a significantly sized ureteric calculus (>4 mm), the presence of hydronephrosis vs no hydronephrosis was 83% vs 17%, respectively. Among them, only three patients required ureteroscopy for stone removal.\n\nConclusion: Contrary to other studies there has been no “indication creep” in the use of CT KUB at our institution. However, the young female patient presenting with suspected urolithiasis presents a particular diagnostic problem, and the significant percentage of negative examinations in females implies that an improvement in current practice is needed. The indiscriminate use of CT KUB in all female patients with flank pain should be avoided, and it is suggested that they should be initially evaluated with ultrasound to detect the presence of hydronephrosis.”
“We present a calibration VX-680 chemical structure method for SD-OCT domain spectrometers based on the M-scan of a moving mirror. This method allows determination of the wavenumber sampling increment which determines the depth axis assigned to the structural image. It also allows wavelength calibration of individual pixels

which ensures correct re-sampling prior to Fast Fourier Transform. Determination of the spectrometer resolution, which determines sensitivity and resolution decay with depth, is also possible. The wavelength calibration results suggest that hardware calibration of the spectrometers is a necessary complement to the computational methods presented here.\n\nWavelength calibration (upper panel) and corresponding inaccuracy (lower panel) using the ‘Doppler-Fourier’ method\n\n[GRAPHICS]\n\n(C) 2009 by WILEY-VCH Verlag GmbH & Co. KGaA. Weinheim”
“Background:

in December 2006, the European Commission issued the Regulation 1901/2006 with the aim to improve the development of medicines for children, because currently many of the pediatric drugs are used outside their authorization. The aim of the INCB28060 clinical trial present study was to establish a status quo of the medical prescriptions to patients admitted to a neonatal intensive care unit.\n\nMethod: The records of all patients admitted during a three-month period were analyzed retrospectively. Study endpoints were all prescribed medications, including dosage, route and form of administration. Medications were categorized in three groups: licenced, unlicenced and off-label medications.\n\nResults: A total of 81 patients with a total of 84 admissions (3 re-admissions) had a median length of stay of 6 days (range: 1-101 days) in the intensive care unit. Of the 84 admissions, 20 were attributable to heart surgery conditions and 11 to extremely low birth weight (less than 1000g). A total of 748 prescriptions of 82 different medications were registered with an average of 6 (range: 1-38) different drugs per stay. 364 prescriptions (49%) were licenced, 250 (34%) were off-label, and 134 (18%) were unlicenced.

Following thermal denaturation, rabbit reticulocyte lysate and AT

Following thermal denaturation, rabbit reticulocyte lysate and ATP were added and luciferase activity measured. In the presence of NUD-1, nearly all of the luciferase activity was regained, indicating that unfolded intermediates complexed with NUD-1 could be refolded. These studies represent the first functional evidence for a member of this mitotically essential protein family as having chaperone activity and facilitates elucidation of the role such proteins play in chaperone complexes utilized in cell division.

P5091 order C. elegans NUD-1 is a member of an evolutionary conserved protein family of unknown function involved in the regulation of cytoskeletal dynamics. NUD-1 and its mammalian homolog, NudC, function with the dynein motor complex to ensure proper cell division, and knockdown or overexpression of these proteins leads to disruption of mitosis. In this paper, we show that NUD-1 possesses ATP-independent chaperone activity comparable to that of small heat shock proteins and cochaperones and that changes in phosphorylation

Immunology & Inflamm inhibitor state functionally alter chaperone activity in a phosphomimetic NUD-1 mutant.”
“JNK1 is activated by phosphorylation of the canonical T183 and Y185 residues, modifications that are catalysed typically by the upstream eukaryotic kinases MKK4 and MKK7. Nonetheless, the exact sites at which the most abundant JNK variant, JNK1 beta, is further modified by MKK4 for phospho-regulation has not been previously investigated. PD173074 molecular weight Aiming to characterise the nature of JNK1 beta phosphorylation by active MKK4 using mass spectrometry, a recognised yet uncharacterised phospho-site (S377) as well as two novel phospho-residues (T228 and S284) were identified. Interestingly, the identical sites were phosphorylated during

overexpression of JNK1 beta 1 in Escherichia coli, raising important questions that have significant implications for heterologous protein expression. (C) 2013 Elsevier Inc. All rights reserved.”
“The aim of this study was to evaluate the success rates of intrauterine insemination (IUI) in infertile women with unilateral proximal and distal tubal blockage. A total of 161 couples with unilateral tubal blockage and unexplained infertility were included. The primary outcome measure was the cumulative pregnancy rate (CPR). The CPRs after three cycles of IUI were 26.3% (10/38) in patients with unilateral tubal blockage, and 44.7% (55/123) in patients with unexplained infertility (p = 0.043). CPRs were similar in patients with proximal unilateral tubal blockage and unexplained infertility (38.1% vs 44.7%, respectively, p = 0.572). CPR was significantly lower in patients with distal unilateral tubal blockage than in patients with unexplained infertility (11.7% vs 44.7%, respectively, p = 0.01). In conclusion, IVF instead of IUI may be a more appropriate approach for distal unilateral tubal blockage patients.

Phosphorylation analysis of Parkin pathogenic mutants also sugges

Phosphorylation analysis of Parkin pathogenic mutants also suggests Ser65 phosphorylation is not check details sufficient

for Parkin translocation. Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy.”
“An organic/inorganic hybrid gel of alginate-SiO2 (ALG-SiO2) was used to immobilize the partially purified potato polyphenol oxidase (PPO) for the treatment of phenolic wastewater. The influences of alginate concentration, quantity of both enzyme and tetra methoxysilane (TMOS) on immobilization were investigated. The Michaelis constant for immobilized PPO was determined as 14.7 mmol L-1 at 25 degrees C, and the highest activity of immobilized PPO was achieved at pH 7.0. The ALG-SiO2 immobilized PPO was more stable than the free PPO or ALG(alone) immobilized PPO. This study suggests that ALG-SiO2 immobilized PPO might be a potential buy SNX-5422 tool for the removal of phenolic compounds from industrial wastewater. (c) 2008 Society of Chemical Industry”
“Background: FSCN1 and matrix metalloproteinase 14 (MMP14) are both invadopodia-related proteins. We herein elucidate the tumourigenicity of these proteins and identify novel therapeutic agents in esophageal squamous cell carcinoma

(ESCC). Methods: FSCN1 and MMP14 were evaluated by immunohistochemistry and

quantitative PCR, and microRNA Z-DEVD-FMK clinical trial (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. Results: The expression of FSCN1 or MMP14 was an independent poor prognostic factor according to a multivariate analysis of immunohistochemistry, and their co-expression correlated with the poorest overall survival (OS) out of all the examined factors. Additionally, their mRNAs significantly correlated and both inversely correlated with miR-133a in surgical specimens. Transfection of a miR-133a mimic decreased the mRNA and protein levels of both FSCN1 and MMP14 in ESCC cells. The knockdown of FSCN1 or MMP14 and transfection of a miR-133a mimic inhibited the proliferation and invasion of ESCC cells. Patients with a lower miR-133a expression have a significantly poorer OS than those with a higher expression. Conclusion: The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.”
“Recent research in neurodevelopment, neuroplasticity and genetics is providing new insights into the etiogenesis of psychopathology, but progress in treatment development has been hampered by reliance on diagnostic categories that are characterized by heterogeneity and based primarily on phenomenology.

In addition, Skp2(-/-)

epidermis exhibits an accumulation

In addition, Skp2(-/-)

epidermis exhibits an accumulation PR-171 manufacturer of p53-cofactor CBP/p300 that is associated with elevated apoptosis in hair follicles and decreased skin tumorigenesis. We conclude that p27(Kip1) accumulation is responsible for the hypoplasia observed in normal tissues of Skp2(-/-) mice but does not have a preponderant function in reducing skin tumorigenesis.”
“The aim of this study was to compare the effects of muscle strength and aerobic training on the basal serum levels of IGF-1 and cortisol in elderly women. The subjects were divided in three groups as follows. 1. Strength training group (SG) submitted to the weight training called 1-repetition maximum test (1-RM, 75-85%). This group contained 12 subjects of mean age = 66.08 +/- 3.37 years; and body mass index (BMI) =

26.0 +/- 3.72 kg/m(2). (2) Aerobic training group (AG) submitted to aquatic exercise; they were 13 subjects of the mean age = 68.69 +/- 4.70 years; and BMI = 29.19 +/- 2.96 kg/m(2). (3) A control group (CG) of 10 subjects, of mean age Selleck GSK126 = 68.80 +/- 5.41 years: BMI = 29.70 +/- 2.82 kg/m(2). The training periods were 12 weeks, Fasting blood was analyzed to measure lGF-1 and basal cortisol levels (by chemiluminescence method), both at the beginning and the end of the intervention. Student’s t-test revealed increased IGF-1 in the SG (p < 0.05) compared to the other two groups. Repeated-measure ANOVA showed also elevated IGF-1 (p < 0.05) in the SG compared to the other groups (AG and CG). There were no differences in cortisol levels. In conclusion, high-intensity training caused changes in IGF-1. This suggests that strength training

may provoke anabolic effects in elderly individuals. (C) 2008 Elsevier Ireland Ltd. All rights reserved.”
“Hyperglycemia in pregnancy is an opportunity for women at risk for complications during pregnancy and beyond to change their life course to improve outcomes for themselves and their offspring. Providers of diabetes care during pregnancy complicated by hyperglycemia in pregnancy have the unique opportunity to make a significant difference.”
“G-Protein-coupled receptors (GPCRs) integrate extracellular cues into intracellular signals to modulate the cellular state. Owing to their diverse PKC412 price modulatory functions, GPCRs represent one of the major drug targets of the pharmaceutical industry. Until now, the characterization and control of GPCRs and their intracellular signalling cascades have mainly relied on chemical compounds, which either activate or inhibit GPCR pathways, albeit with limited receptor and cell-type specificity. Recently, new approaches have been developed to control signalling cascades in cell- and receptor-type-specific ways. The chemical approach focuses on GPCR design and activation by an inert chemical compound, whereas the physical approach uses designer GPCRs and activation by physical stimuli, such as light.

Although significant progress in this arena has been realized thr

Although significant progress in this arena has been realized through system development and biologic application, further innovation continues to address challenges in camera sensitivity, spatial resolution, and image reconstruction Epigenetics inhibitor and quantification. The innumerable applications of small-animal SPECT

and SPECT/CT in drug development, cardiology, neurology, and oncology are stimulating further investment in education, research, and development of these dedicated small-animal imaging modalities.”
“The quaterisation process of 1,2-dibromoethane and pyridine is in situ traced by electronic absorption spectrum. Two absorption peaks, induced by mono- and bis-pyridinium salt of 1,2-dibromoethane, appear at 429 nm and 313 nm, respectively. To explain the phenomena. several kinds of alkyl bromides with special structures were selected and compared by experimental measurement and theoretical calculation. The results indicate that for mono-pyridinium salt of 1,2-dibromoethane, the electron donor property of

ortho-bromine group increases the electron cloud density of the carbon atom associated with pyridinium cation, which induces red-shift of absorption wavelength. (C) 2009 Elsevier B.V. All rights reserved.”
“In this article, we propose a methodology for the selleck rational design of scaffold constructs in bone-tissue engineering. The construct under investigation is a sandwich structure with an Intramedullary rod (IM), a Biological Sponge (BS) and an External sleeve (ES). The IM rod provides axial resistance, BS facilitates the growth of new bone and ES provides stability to the construct by resisting torsion and bending. We demonstrate

Bucladesine clinical trial that only select combinations of stiffness between IM and ES facilitate the growth of new bone. Perren’s interfragmentary strain theory is employed to clearly identify regions favoring bone growth from those favoring the formation of cartilage. Finally, design maps are constructed that clearly identify the combinations facilitating timely bone growth.”
“Safety and quality of healthcare provision are affected by a number of factors. These factors include the clinical skills of the treating surgeon or other physician, but also the way practitioners think and behave as members of a healthcare team, and the clinical environment in which care is provided. We first discuss Bahal et al.’s paper as a demonstration of the Systems Approach to clinical performance and patient safety. We then highlight recent advances driven by the Systems Approach in understanding and measuring clinical decision-making, teamworking, and the clinical environment. We conclude that human factors research can provide an understanding of how to balance conflicting opinions and priorities in clinical care with the best interests of the patient, in a manner which allows each doctor to fulfil their duty of care. (C) 2009 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Finally, in this study, the changes in life-history traits that o

Finally, in this study, the changes in life-history traits that occurred ontogenetically were not accompanied by significant changes in metabolic rate.”
“Introduction: The existing diagnostic algorithms for sputum smear-negative tuberculosis (TB) are complicated, time-consuming, and often difficult to implement. The decision to initiate TB treatment in resource-limited countries is often largely based on clinical predictors. We sought to determine the clinical predictors and accuracy

of empiric TB treatment initiation in HIV-infected sputum smear-negative TB suspects using sputum culture as a reference standard.\n\nSetting: S3I-201 cell line Out-patient HIV-TB integrated urban clinic in Kampala, Uganda.\n\nMethods: HIV-infected TB suspects were screened using sputum smear microscopy, and mycobacterial

sputum liquid and solid cultures were performed. Smear results were made available to the clinician who made a clinical decision on empiric TB treatment initiation for sputum smear-negative patients. Clinic records were reviewed for patients whose sputum smears were negative to collect data on socio-demographics, TB symptomatology, chest X-ray findings, CD4 cell counts and TB treatment initiation.\n\nResults: Of 253 smear-negative TB suspects, 56% (142/253) were females, median age 38 IQR (31-44) years, with a median CD4 cell count of 291 IQR (150-482) NCT-501 clinical trial cells/mm(3). Of the 85 (33.6%) smear-negative patients empirically initiated on TB treatment, 35.3% (n = 30) were sputum culture positive compared to only 18 (10.7%) of the 168 untreated patients (p < 0.001). Abnormal chest X-ray [aOR 10.18, 95% CI (3.14-33.00), p < 0.001] and advanced HIV clinical stage [aOR 3.92, 95% CI (1.20-12.85), Tariquidar concentration p = 0.024] were significantly associated with empiric TB treatment initiation. The sensitivity and specificity of empiric TB treatment initiation in the diagnosis of TB in HIV-infected patients after negative smear

microscopy was 62.5% and 73.7% respectively.\n\nConclusion: In resource-limited settings, clinically advanced HIV and abnormal chest X-ray significantly predict a clinical decision to empirically initiate TB treatment in smear-negative HIV-infected patients. Empiric TB treatment initiation correlates poorly with TB cultures. Affordable, accurate and rapid point-of-care diagnostics are needed in resource-limited settings to more accurately determine which HIV-infected TB suspects have smear-negative TB.”
“Clinical applications of quantitative computed tomography (qCT) in patients with pulmonary opacifications are hindered by the radiation exposure and by the arduous manual image processing. We hypothesized that extrapolation from only ten thoracic CT sections will provide reliable information on the aeration of the entire lung.

Dietary oxalate plays an important role in the formation of Ca ox

Dietary oxalate plays an important role in the formation of Ca oxalate, and a high dietary intake of Ca may decrease oxalate absorption and its subsequent urinary excretion. Oxalate-rich plants can be supplemented with Protein Tyrosine Kinase inhibitor other plants as forage for domestic animals, which may help to reduce the overall intake of oxalate-rich plants.

Non-ruminants appear to be more sensitive to oxalate than ruminants because in the latter, rumen bacteria help to degrade oxalate. If ruminants are slowly exposed to a diet high in oxalate, the population of oxalate-degrading bacteria in the rumen increases sufficiently to prevent oxalate poisoning. However, if large quantities of oxalate-rich plants are eaten, the rumen is overwhelmed and unable to metabolize the oxalate and oxalate-poisoning results. Based on published data, we consider that <2.0% soluble oxalate would be an appropriate level to avoid oxalate poisoning in ruminants, although blood Ca level may decrease. In the case of non-ruminants, <0.5% soluble oxalate may be acceptable. However, these proposed safe levels of soluble oxalate should be Pexidartinib chemical structure regarded as preliminary. Further studies, especially long-term studies, are needed to validate and improve the recommended safe levels in animals. This review will encourage further research

on the relationships between dietary oxalate, other dietary factors and renal failure in domestic animals.”
“Recent efforts have focused on the development of novel manufacturing processes capable of producing microstructures dominated by sub-micron grains. For structural applications, grain refinement has been shown to enhance mechanical properties such as strength, fatigue resistance, and fracture toughness. click here Through control of the thermo-mechanical processing parameters, dynamic recrystallization mechanisms were used to produce microstructures consisting of sub-micron grains in 9310 steel. Starting with initial bainitic grain sizes of 40 to 50 mu m, various levels of grain refinement were observed following hot

deformation of 9310 steel samples at temperatures and strain rates ranging from 755 K to 922 K (482 A degrees C and 649 A degrees C) and 1 to 0.001/s, respectively. The resulting deformation microstructures were characterized using scanning electron microscopy and electron backscatter diffraction techniques to quantify the extent of carbide coarsening and grain refinement occurring during deformation. Microstructural models based on the Zener-Holloman parameter were developed and modified to include the effect of the ferrite/carbide interactions within the system. These models were shown to effectively correlate microstructural attributes to the thermal mechanical processing parameters.

Under large retinal motions

with up to 1 mm amplitude at

Under large retinal motions

with up to 1 mm amplitude at 0.5 similar to a few Hz frequency check details range, motion artifact suppression in the PS-OCT images as well as standard deviation noise reduction in the frame averaged retardation images are presented. (C) 2013 Optical Society of America”
“Anaemia in children living in sub-Saharan Africa is common, but its causes are diverse. In 545 children below 5years of age from rural southern Rwanda, we assessed the role of iron deficiency (ID) and of the TMPRSS6 736(V) (rs855791) allele, known to reduce iron status and haemoglobin (Hb) levels, in anaemia and Hb concentrations. Anaemia (Hb smaller than 11g/dl) was present in 34.4% of the children and ID (ferritin smaller than 12ng/ml) in 17.6%. The TMPRSS6 736(V) allele was uncommon (allele frequency, 0.096) and not associated with ID. In multivariate analysis, ID was positively associated with anaemia (adjusted odds ratio, 1.67) to an extent comparable with (+)-thalassaemia, breastfeeding, inflammation and low household income, but the odds were substantially higher in Plasmodium falciparum infection (adjusted odds ratio, 10.3). These findings

were verified in a multivariate analysis of Hb concentrations. The TMPRSS6 736(V) allele only tended to be associated with low Selleck FK228 Hb levels. TMPRSS6 736(V) is comparatively rare among Rwandan children and may only slightly Selleck GSK1838705A contribute to low Hb concentrations. Preventable causes of anaemia, notably ID and P.falciparum infection, largely outweigh its impact and need to be addressed to improve the haematological status of children in the study area.”
“Small-scale household digesters have been promoted across Asia as a sustainable way of handling manure. The major advantages are that they produce biogas and reduce odor. However their disadvantages include the low recycling of nutrients, because digestate is dilute and therefore difficult to transport, and the loss of biogas as a result of cracks and the intentional release of excess biogas. In this study, life cycle assessment (LCA) methodology

was used to assess the environmental impacts associated with biogas digesters in Vietnam. Handling 1,000 kg of liquid manure and 100 kg of solid manure in a system with a biogas digester reduced the impact potential from 4.4 kg carbon dioxide (CO2) equivalents to 3.2 kg CO2 equivalents compared with traditional manure management. However, this advantage could easily be compromised if digester construction is considered in the LCA or in situations where there is an excess of biogas which is intentionally released. A sensitivity analysis showed that biogas digesters could be a means of reducing global warming if methane emissions can be kept low. In terms of eutrophication, farms with biogas digesters had 3 to 4 times greater impacts.


“When establishing the most appropriate cells from the hug


“When establishing the most appropriate cells from the huge numbers of a cell library for practical use of cells in regenerative medicine and production of various biopharmaceuticals, cell heterogeneity often found in an isogenic cell population limits the refinement of clonal cell culture. Here, we demonstrated high-throughput screening of the most suitable cells in a cell library by an automated undisruptive single-cell analysis and isolation system,

followed by expansion of isolated single cells. This system enabled establishment of the most suitable cells, such as embryonic stem cells with the highest expression of the pluripotency marker Rex1 and hybridomas with the highest antibody secretion, which could buy A-769662 not be achieved by conventional high-throughput cell screening systems (e. g., a fluorescence-activated cell sorter). This single cell-based breeding system learn more may be a powerful tool to analyze stochastic fluctuations and delineate their molecular

mechanisms.”
“A 66-year-old man presented with acute respiratory distress due to a tracheal tumor involving the posterior wall of the upper trachea, with nearly complete airway obstruction. Partial debulking of the tumor’s endoluminal component, via rigid bronchoscopy and yttrium-aluminum-perovskite laser, allowed timely and effective airway restoration. The diagnosis was benign tracheal glomus tumor. Two weeks later, elective tracheal sleeve resection with end-to-end anastomosis allowed complete resection of the lesion. No tumor recurrence was found at 21-month follow-up. We describe the multidisciplinary management SB203580 research buy of this extremely rare tracheal tumor, and review its features.”
“Fiberoptic Bragg grating sensors were embedded in composite structures in order to be used as the detection system for structural health monitoring purposes. Firstly, optical fibers had been embedded in several locations in between the layers of composite material and for the typical tensile

testing coupon configuration. It has been shown experimentally and with finite element analysis that embedding the optical fiber out of the neutral axis of the coupon, downgrades significantly the composite’s ultimate tensile strength. Secondly, a composite patch with embedded FBG has been used to restore a typical damage case on aluminum structure currently applied on advanced ‘aging’ vehicles. Data values taken from the FBG system during the experimental tension tests of the composite structures were calculated to axial strain values with the aid of an interrogator. Theoretical axial strain values of the composite pitch had been calculated by exploiting a newly-developed finite element model.