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PubMed2026

Probiogenomic analysis of functional potential and safety of L. plantarum 8p-a3 and DMC-S1 strains: in silico vs in vitro and in vivo data.

The molecular basis of the beneficial effects and the causes of the negative effects of probiotics are not entirely clear. Clarifying these issues is important for understanding the biology and assessing the safety of the microbes. Omics technologies have opened up new resources for obtaining relevant knowledge. Here, for the first time, we present the results of a comparative analysis of the functional potential and safety of two L. plantarum strains: the approved probiotic 8p-a3 and the Drosophila intestinal resident, which exhibit opposite effects on D. melanogaster as the model host organism. Through genomic analysis, extracellular vesicle studies, and in vitro and in vivo assays, we have identified the common and specific characteristics of the strains. The strains proved to be similar in a set of genes that determine benefits to the host organism, as well as in the presence of some risk factors. Significant differences between the strains are related to genes responsible for adhesion, sialic acid metabolism, mucin degradation, antimicrobial peptides, tannin resistance, and immunomodulation. In silico data correlated with in vitro and in vivo data, with the exception of antimicrobial sensitivity. Pronounced differences between the strains were found in terms of the composition and biological effects of their vesicles. In vivo data on the effects of the strains correlate with the corresponding data of their vesicles in the fruit fly model. The results obtained open up new facets in L. plantarum strains relevant for evaluating the functionality and safety of probiotics.IMPORTANCEUsing a probiogenomic approach, common and specific features regarding functionality and safety were identified in the strains (the approved probiotic strain L. plantarum 8p-a3 and the Drosophila intestinal bacterium L. plantarum DMC-S1), which exhibit opposite effects on the model host organism (D. melanogaster). The genomic analysis was supplemented by the analysis of extracellular vesicles of the strains. Comparative analysis of in silico data in combination with in vitro and in vivo studies was performed, and unexpected capabilities of the strains were discovered. Novel factors, essential for evaluating the safety of probiotics, were identified. New facets in the interplay of probiotic bacterium with host organism have been revealed.

Animals↗
PubMed2000

Comparing the performance of two indices for spatial model selection: application to two mortality data.

The statistical analysis of spatially correlated data has become an important scientific research topic lately. The analysis of the mortality or morbidity rates observed at different areas may help to decide if people living in certain locations are considered at higher risk than others. Once the statistical model for the data of interest has been chosen, further effort can be devoted to identifying the areas under higher risks. Many scientists, including statisticians, have tried the conditional autoregressive (CAR) model to describe the spatial autocorrelation among the observed data. This model has greater smoothing effect than the exchangeable models, such as the Poisson gamma model for spatial data. This paper focuses on comparing the two types of models using the index LG, the ratio of local to global variability. Two applications, Taiwan asthma mortality and Scotland lip cancer, are considered and the use of LG is illustrated. The estimated values for both data sets are small, implying a Poisson gamma model may be favoured over the CAR model. We discuss the implications for the two applications respectively. To evaluate the performance of the index LG, we also compute the Bayes factor, a Bayesian model selection criterion, to see which model is preferred for the two applications and simulation data. To derive the value of LG, we estimate its posterior mode based on samples derived from the BUGS program, while for Bayes factor we use the double Laplace-Metropolis method, Schwarz criterion, and a modified harmonic mean for approximations. The results of LG and Bayes factor are consistent. We conclude that LG is fairly accurate as an index for selection between Poisson gamma and CAR model. When easy and fast computation is of concern, we recommend using LG as the first and less costly index.

Asthma↗
PubMed1987

The classification of tymoviruses by cDNA-RNA hybridization and other measures of relatedness.

The relationships of twelve tymoviruses have been assessed by cDNA-RNA hybridization. In addition, the percentage molar nucleotide composition of the genome of the PD strain of Kennedya yellow mosaic virus and the percentage molar amino acid composition of the coat proteins of cacao yellow mosaic, Kennedya yellow mosaic and turnip yellow mosaic (Cardamine strain) viruses were estimated. These as well as published serological comparisons and genome and coat protein composition determinations were used to compute classifications of tymoviruses using various "metrics", and simple numerical methods were used to compare the classifications. Measures of relatedness estimated from cDNA-RNA hybridization and base ratio data correlated significantly with each other, but were less closely correlated with those calculated from amino acid data, and did not correlate with those calculated from serological tests. The serological relationships correlated significantly with estimates of relatedness calculated from amino acid data, but not with those based on hybridization or base ratio data. The differences between these classifications mostly resulted from the anomalous behaviour of eggplant mosaic virus, its particles are serologically close to those of other tymoviruses that naturally infect species of the tobacco family, whereas in cDNA-RNA hybridization tests eggplant mosaic virus is closest to the tymoviruses that infect legumes. Similar but smaller anomalies in the characteristics of other tymoviruses were also found.

Amino Acids↗
PubMed2005

Correlational analysis of proteins and nonmetallic nanoparticles in a deep-nulling microscope.

We present a method for label-free microscopic analysis of nonmetallic nanoparticles such as biopolymers or technical polymers diffusing freely in an aqueous environment. We demonstrate the principal feasibility of the approach with first measurements of 20-200 nm sized polystyrene spheres and of the approximately 10 nm protein complex Photosystem I (PS I) of Thermosynechococcus elongatus. The approach is based on the combination of a microscope setup with a deep-nulling interferometer for measuring minute refractive index changes or absorptions in the focal area of the microscope. It is possible to obtain transient nulls in a microscope setup on the order of 10(-5), corresponding to optical pathway differences of less than 0.6 nm and to stabilize the nulls to about 5.10(-4). With this level of stabilization it is possible to perform a fast (1 s) correlational analysis of aqueous solutions containing the protein complex PS I or 20 nm spheres and to detect in real time single diffusional transits of larger nanospheres through the focal area of the microscope. A modulated heating of the samples in the microscope focus is not necessary for detection. The interferometer correlation data correspond well to conventional two-photon excited fluorescence correlation (FCS) data measured in the same setup, providing evidence that the detection volumes are of a similar size (approximately 200 nm). We also conducted first nulling experiments using coherent near-field sources of about 30 nm diameter. Theoretical considerations indicate that this combination with nanometric near-field sources will even allow label-free single-protein analysis.

Bacterial Proteins↗
PubMed2006

Superficial femoral artery occlusive disease severity correlates with MR cine phase-contrast flow measurements.

PURPOSE: To evaluate how cine phase-contrast (PC) flow data correlate with the severity of peripheral vascular disease (PVD). MATERIALS AND METHODS: Flow waveforms were obtained in 48 patients proximal and distal to superficial femoral artery (SFA) disease using the 2D cine PC technique with velocity encoding (venc) = 100 cm/second. Flow data were correlated with SFA disease severity and compared with data from nine healthy volunteers. RESULTS: Of 96 arterial segments in 48 patients, 26 were patent or only mildly stenotic, 35 had moderate-to-severe stenosis, and 35 were occluded. The flow patterns tended to become low-resistant below severe stenoses or occlusion. The mean peak flow velocity above/below SFA lesions was significantly higher in patients with severe disease (1.9 +/- 1.0, P = 0.01) or occlusion (2.0 +/- 1.0, P = 0.003) compared to normal volunteers (1.4 +/- 0.6). The delay in peak velocity below the lesions showed a significant positive correlation with lesion severity (r = 0.65, P < 0.001). The mean flow volume ratio above/below SFA lesions was greater in patients with occluded vessels compared to normal volunteers (3.9 and 2.3 respectively; P = 0.04). CONCLUSION: Cine PC flow waveform changes across atherosclerotic lesions correlate with disease severity. This may help determine which lesions are hemodynamically significant.

Aged↗
PubMed2001

Mandibular distraction force: laboratory data and clinical correlation.

PURPOSE: In vitro data were collected to measure torque-force values of an internal distraction device. The measurements were correlated with in vivo torque readings in an attempt to better understand the force required to distract the osteogenic bone callus of the human mandible during distraction osteogenesis. METHODS AND MATERIALS: Five internal craniofacial distraction devices were mounted on an apparatus to test load limits and torque measurements. The apparatus aligned the devices so that weight provided a force opposite and parallel to the vector of distraction. Weights were added in 5-lb increments, and the devices were activated 0.5 mm for each torque reading. Torque readings were obtained from a calibrated torque wrench. Measurements were plotted on a graph and correlated with clinical torque readings obtained from 8 patients undergoing mandibular lengthening. RESULTS: The average torque for distracting the human mandible 0.5 mm twice a day was 4.2 +/- 1.6 Newton-centimeters (N-cm). The average slope of the in vitro data shows that 4.2 N-cm of torque is equivalent to a force of 35.6 N. The average force of device failure was 235.8 N. CONCLUSION: Torque-force diagrams offer an effective means for calibrating safety margins and load capabilities for internal distraction devices. Quantification of axial forces encountered in mandibular lengthening will help contribute to the overall understanding and biomechanics of mandibular distraction osteogenesis.

Adolescent↗
PubMed1985

Testing hypotheses about interclass correlations from familial data.

Testing problems concerning interclass correlations from familial data are considered in the case where the number of siblings varies among families. Under the assumption of multivariate normality, two test procedures are proposed for testing the hypothesis that an interclass correlation is equal to a specified value. To compare the properties of the tests, including a likelihood ratio test, Monte Carlo experiments are performed. Several test statistics are derived for testing whether two variables about a parent and child are uncorrelated. The proposed tests are compared with previous test procedures, using Monte Carlo simulation. A general procedure for finding confidence intervals for interclass correlations is also derived.

Analysis of Variance↗
PubMed1994

Human papillomavirus DNA in cervical carcinoma--correlation with clinical data and influence on prognosis.

Human papillomavirus (HPV) is a main factor in cervical carcinogenesis. However, data on the correlation of HPV with clinical features and the prognosis of cervical carcinoma remain controversial. The HPV status (positivity, type, copy number) in unfixed tissue specimens of 205 primary invasive cervical carcinomas was determined by Southern blot hybridization. A correlation with comprehensive clinical and histopathologic data and long-time survival was evaluated. HPV DNA was detected in 73% of the cases; 83% of the HPV-positive tumors contained HPV 16. HPV 16 was predominant among squamous-cell carcinomas (SCC) (p = 0.05). HPV 16 copy number was higher in keratinizing tumors (p < 0.05), and elevated levels of the SCC antigen were more common in patients positive for HPV 16 (p < 0.03). No association was found between the HPV status and 8 other clinical and histopathologic variables. Multivariate analysis after a median follow-up of 73 months demonstrated longer survival for patients with lower clinical stage (p = 0.001) and keratinizing SCC (p = 0.005). Women with HPV-negative tumors had a higher risk of death (RR 1.51; p = 0.07). HPV analysis does not clearly define biologically distinct sub-sets of cervical carcinoma. This underlines the importance of additional factors in cervical carcinogenesis.

Adenocarcinoma↗
PubMed1978

Small cell undifferentiated bronchogenic carcinoma: current status with emphasis upon the role of chemotherapy.

Current opinions concerning tumor biology and clinical characteristics of small cell undifferentiated bronchogenic carcinoma are reviewed. Special emphasis is placed upon chemotherapy for this lung cancer subtype and presently achievable response rates and survival times are presented. A series of 16 patients with small cell undifferentiated bronchogenic carcinoma is also presented. All patients were given cyclophosphamide, methotrexate, vincristine, and procarbazine as treatment for this neoplasm. Sixty-eight percent of patients responded and the survival time in partial responders was 33.4+ weeks as compared to 13.7 weeks with nonresponders. These data correlate well with the previous data of Alberto et al [Alberto P, Brunner KW, Martz G, Obrect JP: Cancer 38:2208--2216, 1976], who investigated the same agents for this tumor, but at higher dosages.

Adult↗
PubMed2000

Pharmacokinetic data support pharmacologically induced embryonic dysrhythmia as explanation to Fetal Hydantoin Syndrome in rats.

New studies suggest that the teratogenicity of phenytoin (PHT) is linked to its membrane-stabilizing pharmacological action via the rapid component of the delayed rectified potassium channel (lkr), resulting in embryonic cardiac dysrhythmia during a restricted sensitive period. In order to further elucidate this theory, PHT was administered to Sprague-Dawley rats on gestation day (GD) 11 with either a single dose of 150 or 100 mg/kg ip or 150 mg/kg po and developmental toxicity at term (GD 21) was studied. In satellite animals blood samples were withdrawn (0.5-24 h after dose) and total and free maternal plasma concentrations of PHT were measured. Pharmacokinetic data correlated well with pregnancy outcome data. At 150 mg/kg ip high concentrations of long duration (C(max) 240 microM and AUC 5300 microMhl(-1) - total) and marked developmental toxicity (embryonic death, decreased fetal weights, and orofacial clefts) were observed. After 100 mg/kg ip (C(max) 150 microM, AUC 2600 microMhl(-1) - total) only slight developmental toxicity (decreased fetal weights) was recorded and after 150 mg/kg po the plasma concentrations were even lower (C(max) 63 microM and AUC 1100 microMhl(-1) - total) and no adverse effects at all were observed. In separate experiments the effect of different concentrations of PHT on the embryonic heart was studied by adding PHT to GD 11 rat embryos cultured in vitro or by culturing GD 11 embryos from exposed dams. The decrease in heart rates was 3, 16, and 32% after culture with 50, 100, and 200 microM of PHT, respectively. After maternal administration of 150 mg/kg ip or po, the embryonic heart rate in vitro decreased by 25 and 7%, respectively, compared to controls. Altogether the results suggest that the development toxicity of PHT is caused by concentration-dependent induction of embryonic dysrhythmia and hypoxia related damage.

Abnormalities, Drug-Induced↗
PubMed2004

Three-dimensional display in staging hemodynamic brain ischemia for JET study: objective evaluation using SEE analysis and 3D-SSP display.

The Japanese EC-IC bypass trial (JET study) was established to evaluate the validity of MCA-STA anastomosis in intracranial arterial occlusive disease aiming at stroke prevention. This study must use an objective method to reliably estimate hemodynamic brain ischemia. We devised a method of objectively classifying the severity of hemodynamic ischemia using quantitatively analytical and display software, stereotactic extraction estimation for stereotactic brain coordinates and three-dimensional stereotactic surface projections (3D-SSP). We analyzed data from 16 patients registered in the JET study. Our method offers quantitative information and 3-dimensional displays of the CBF at rest and after Diamox challenge, vascular reserve and the severity of the hemodynamic brain ischemia. We compared the maximal projection counts with ROI data from tomographic images in the anterior commissure-posterior commissure plane. The maximal counts data correlated closely with the ROI data of rest and with Diamox SPECT images (both p < 0.0001). The slopes of the linear regression line were 1.15 and 1.12, respectively. The results of this study indicated that our method could simply and objectively evaluate the severity of impaired brain circulation. This procedure should support the evaluation of hemodynamic ischemia in the JET study although validation is required by several institutions using more study subjects.

Aged↗
PubMed1993

Predicting the leakage performance of bodyworn disposable incontinence pads using laboratory tests.

An international multi-centre project (The ISO Pad Leakage Project) was conducted to study the leakage performance of large bodyworn incontinence pads for heavily incontinent users and to create international standards for measuring their absorption capacities in the laboratory. This was achieved by recruiting 13 user test centres through which over 100 incontinent subjects tested each of six different products (each in three different sizes) for a period of about a week to a common protocol. Over 10,000 used pads were collected and weighed and the severity of leakage from each of them recorded. Correlations were sought between these data and the results from some 50 technical tests performed in a total of 16 technical test centres in order to discover the impact of different technical parameters on clinical pad performance. It was found that at low urine weights (less than 50 g, say) pad shaping was the most important predictor of pad leakage performance: shaped pads leaked less. With increasing urine weight, absorption capacity and absorption time increased in importance until at 350 g of urine these two parameters and shaping were of about equal significance: shaped pads with high absorption capacity and fast absorption time leaked least. A second series of analyses identified two absorption capacity tests which produced data correlating well with the overall leakage performance of pads, considering all urine weights together. Both tests were checked for repeatability (precision within laboratories) and reproducibility (precision between laboratories) and have been written up as working draft standards.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMedDate not supplied

A cell-centered database for electron tomographic data.

Electron tomography is providing a wealth of 3D structural data on biological components ranging from molecules to cells. We are developing a web-accessible database tailored to high-resolution cellular level structural and protein localization data derived from electron tomography. The Cell Centered Database or CCDB is built on an object-relational framework using Oracle 8i and is housed on a server at the San Diego Supercomputer Center at the University of California, San Diego. Data can be deposited and accessed via a web interface. Each volume reconstruction is stored with a full set of descriptors along with tilt images and any derived products such as segmented objects and animations. Tomographic data are supplemented by high-resolution light microscopic data in order to provide correlated data on higher-order cellular and tissue structure. Every object segmented from a reconstruction is included as a distinct entity in the database along with measurements such as volume, surface area, diameter, and length and amount of protein labeling, allowing the querying of image-specific attributes. Data sets obtained in response to a CCDB query are retrieved via the Storage Resource Broker, a data management system for transparent access to local and distributed data collections. The CCDB is designed to provide a resource for structural biologists and to make tomographic data sets available to the scientific community at large.

Animals↗
PubMed2000

Intercomparison of five PM10 monitoring devices and the implications for exposure measurement in epidemiological research.

Five different instruments for the determination of the mass concentration of PM10 in air were compared side-by-side for up to 33 days in an undisturbed indoor environment: a tripod mounted BGI Inc. PQ100 gravimetric sampler with a US EPA certified Graseby Andersen PM10 inlet; an Airmetrics Minivol static gravimetric sampler; a Casella cyclone gravimetric personal sampler; an Institute of Occupational Medicine gravimetric PM10 personal sampler; and two TSI Inc. Dustrak real-time optical scattering personal samplers. For 24 h sampling of ambient PM10 concentrations around 10 microg m(-3), the estimated measurement uncertainty for the two gravimetric personal samplers was larger (approximately +/- 20%) compared with estimated measurement uncertainty for the PQ100/Graseby Andersen sampler (< +/- 5%). Measurement uncertainty for the Dustraks was lower (approximately +/- 15% on average) but calibration of the optical response against a reference PM10 method is essential since the Dustraks systematically over-read PM10 determined gravimetrically by a factor approximately 2.2. However, once calibrated, the Dustrak devices demonstrated excellent functionality in terms of ease of portability and real-time data acquisition. Estimated measurement uncertainty for PM10 concentrations determined with the Minivol were +/- 5%. The Minivol data correlated well with PQ100/Graseby Andersen data (r= 0.97, n = 18) but were, on average, 23% greater. The reason for the systematic discrepancy could not be traced. Intercomparison experiments such as these are essential for assessing measurement error and revealing systematic bias. Application of two Dustraks demonstrated the spatial and temporal variability of exposure to PM10 in different walking and transport microenvironments in the city of Edinburgh, UK. For example, very large exposures to PM10 were identified for the lower deck of a double-decker tour bus compared with the open upper deck of the same vehicle. The variability observed emphasises the need to determine truly personal exposure profiles of PM10 for quantifying exposure response relationships for epidemiological studies.

Air Pollution, Indoor↗
PubMed1985

gamma-Fluoromethotrexate: synthesis and biological activity of a potent inhibitor of dihydrofolate reductase with greatly diminished ability to form poly-gamma-glutamates.

A methotrexate (MTX) analog containing fluorine at the gamma-carbon of the glutamate moiety, gamma-fluoromethotrexate (FMTX), has been synthesized and evaluated for its biochemical and pharmacological properties. FMTX inhibition of dihydrofolate reductase from several sources is nearly equivalent to that shown by MTX. Most important, FMTX is an exceedingly poor substrate for folylpoly (gamma-glutamate) synthetase, the enzyme that catalyzes the biosynthesis of the highly-retained, cytotoxic MTX polyglutamates. Uptake experiments in H35 hepatoma cells show that FMTX accumulates to approximately the same extent as MTX at steady state. The rapid efflux of both derivatives is also very similar. The major difference detected in cells between the two compounds is the meager glutamylation of FMTX, due to the electronegative properties of the fluorine adjacent to the potential amide-forming carboxyl group. Exposure of dividing cells to 50 microM MTX for 2 and 6 hr results in the formation of 55 and 130 nmol, respectively, of the polyglutamates (more than two glutamate residues)/g of cell protein. With FMTX these values were reduced by 98% and 93%, respectively. Growth inhibition studies show that MTX is only 12-fold more toxic than FMTX when the cells are exposed to each derivative continuously for 72 hr. When the exposure time is reduced, a greater disparity between the inhibitory effects is observed; with a 2-hr pulse, MTX is 2300-fold more effective than FMTX. These data correlate with the effects of pulses of FMTX and MIX on de novo thymidylate biosynthesis in intact cells. The results indicate that of the parameters examined, the vastly reduced toxicity of FMTX after its removal from the culture medium is best correlated with impaired glutamylation. The data strongly suggest that prolonged toxicity of MTX is a result of metabolic conversion to MTX polyglutamates and that these effects are far more dramatic in short-term than in long-term exposure to the antifolates.

Animals↗
PubMed2003

Dioxolane guanosine 5'-triphosphate, an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Steady state and pre-steady state kinetic analyses.

The frequency of human immunodeficiency virus, type 1 (HIV-1) mutations in response to antiviral therapy and resulting drug resistance is of major concern. Amdoxovir ((-)-beta-D-2,6-diaminopurine dioxolane), the prodrug of dioxolane guanosine (DXG), is currently in phase I/II clinical development for the treatment of HIV-1 infection. In vitro, HIV-1 mutants resistant to 3'-azido-3'-deoxythymidine (M41L/D67N/K70R/T215Y/K219Q) and (-)beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) (M184V) remain sensitive to DXG. HIV-1 with the reverse transcriptase mutations K65R, L74V, and/or Q151M were less sensitive to DXG, whereas the mutation K103N re-sensitized the virus to the inhibitory effect of DXG. In order to understand these observations at the enzyme level, we investigated the inhibition of the HIV-1 reverse transcriptase-catalyzed viral DNA synthesis by dioxolane guanosine 5'-triphosphate (DXG-TP), 3'-azido-3'-deoxythymidine-TP, and 3TC-TP by using steady state kinetic analysis and the incorporation of DXG-5'-monophosphate by using pre-steady state kinetic analysis. This mechanistic study provided detailed information on the amdoxovir-related drug resistance at a molecular level. Overall, the enzymatic data correlated well with the antiviral data obtained from cell culture experiments and further supported the use of amdoxovir for the treatment of nucleoside reverse transcriptase inhibitor-experienced patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

GFAP and S100beta expression in the cortex and hippocampus in response to mild cortical contusion.

We studied the acute response of glial fibrillary acidic protein (GFAP) and S100beta gene expression in the cerebral cortex and hippocampus to mild unilateral cortical contusion. Our goal was to evaluate and compare the expression patterns of each gene in the early stages of the astrocytic response to brain injury. RNA was extracted from the cerebral cortex and hippocampus of male rats at 0, 3, 12, 24, or 96 h after lesion or sham-operation, then quantified using an RNase protection assay. Contusion produced a robust elevation in GFAP mRNA by 12 h in both brain regions on the ipsilateral side to the contusion. In the cortex, but not the hippocampus, this elevation was sustained at 96 h. S100beta mRNA levels were elevated bilaterally in lesioned animals at 24 h in both brain regions. However, these data are difficult to interpret because sham mRNA levels decreased with time, making it unclear whether contusion stimulates S100beta gene expression or whether it mitigates the inhibitory effect of sham. We further analyzed the effect of contusion on GFAP and S100beta immunoreactive astrocyte density at 96 h postlesion or postsham by double-label immunocytochemistry. All detectable astrocytes under all conditions were S100beta immunoreactive in both brain regions. Furthermore, all S100beta immunoreactive astrocytes in the lesioned ipsilateral cortex were also GFAP immunoreactive, whereas only about 11% of S100beta positive cells were also GFAP labeled in the contralateral lesioned or the ipsilateral sham cortex. In the hippocampus, all S100beta immunoreactive cells were also GFAP immunoreactive under all conditions. These data correlate with the gene expression data at 96 h, and suggest that, at least in the cortex, resident S100beta-expressing astrocytes produce GFAP at levels that are undetectable by immunocytochemistry until they are activated in response to injury.

Animals↗
PubMed2006

Induced cell clustering enhances islet beta cell formation from human cultures enriched for pancreatic ductal epithelial cells.

A better understanding of the culture conditions that stimulate in vitro beta-cell differentiation from islet precursors would be useful for optimizing the production of tissue-engineered islets. In this study, high- and low-adherent substrates and high- and low-serum media were used to control the clustering of human pancreatic ductal epithelial cells and to determine its effect on their transdifferentiation to beta cells. While the initial epithelial cell cultures were devoid of any beta cells as assessed by dithizone staining, dithizone+ cells were generated during the next 3 weeks under all culture conditions. Although the rate of transdifferentiation was low, a approximately 4-fold greater number and percentage of dithizone+ cells were generated following 23-24 days of culture in the least adherent conditions (low-serum medium, low-adherent substrate), which stimulated cell clustering to the highest degree. Insulin immunohistochemistry data correlated well with the dithizone data (r(2) = 0.99), evidence that dithizone is a reliable measure of insulin+ cells. The preferential distribution of the dithizone+ cells to regions of cell aggregation and the increased efficiency of transdifferentiation in conditions that promote cell clustering suggest that cell-cell interactions and/or cell shape changes are important to the transdifferentiation of adult pancreatic ductal epithelial cells to beta cells in vitro.

Cell Aggregation↗