In vitro development of islets from human adult pancreatic tissues

Transplantation of isolated islets from cadaver pancreas is a promising possibility for the optimal treatment of type 1 diabetes. The lack of islets is a major problem. Here we have investigated the possibility of generating islets in tissue culture of human pancreatic cells. We first reproduced a previously reported method of in vitro generation of endocrine cells from human adult pancreatic tissue. By tracing the bromodeoxyuridine-labeled cells in differentiated islet buds, we found that the pancreatic progenitor cells represented a subpopulation of cytokeratin 19 (CK19)-positive ductal cells. Serum-free medium and Matrigel overlay were essential for the endocrine differentiation. We then examined the involvement of preexisting islet cells in islet neogenesis. About 6-10% of endocrine cells dedifferentiated and acquired a transitional phenotype by coexpressing CK19. Significant cell proliferation was only observed in CK19-positive cells, but not in chromogranin A-positive endocrine cells. The in vitro-derived human islets were morphologically and functionally immature when compared with normal islets. Their insulin mRNA levels were only 4-5% of that found in fresh human islets, and glucose-stimulated insulin release was 3 times lower than that of control islets. Moreover, some immature endocrine cells coexpressed insulin and glucagon. After transplantation in nude mice, the in vitro-generated islets became mature with one type of hormone per endocrine cell. In addition, we also found that also in both fresh islet transplants many cells coexpressed endocrine markers and ductal marker CK19 as a sign of ductal to endocrine cell transition. Finally, we studied the effects of clinically used immunosuppressive drugs on precursor cell proliferation and differentiation. Mycophenolate mofetil (MMF) severely hampered duct-cell proliferation, and significantly reduced the total DNA content indicating its antiproliferative effect on the precursors. Tacrolimus mainly affected differentiated beta cells by decreasing the insulin content per DNA as well as the proportion of insulin-positive cells. Sirolimus and daclizumab did not show any individual or synergistic side effects suggesting that these drugs are amenable for use in clinical islet transplantation. In summary, we confirm the capacity of endocrine differentiation from progenitors present in the adult human pancreas. The plasticity of differentiated cell types of human pancreas may be a potential mechanism of human pancreas regeneration. Ductal cell differentiation into endocrine cells in transplanted islets may be an important factor in sustaining the long-term function of islet transplants. The immunosuppressive protocol is likely to be an important determinant of long-term clinical islet graft function. Moreover, these results provide new information on the mechanisms of pancreatic islet regeneration and provide the basis for the development of new strategies for the treatment of insulin deficient diabetes mellitus.Haiman saarekesolujen siirto on lupaava tyypin 1 diabeteksen hoitomahdollisuus. Tässä väitöskirjatutkimuksessa selvitettiin mahdollisuutta kasvattaa soluviljelmissä uusia insuliinia tuottavia saarekesoluja ihmisen haimasoluista, jotka jäävät yli saarekkeiden eristyksen jälkeen. Tutkimusta varten kehitettiin viljelymenetelmä, jossa jakautuvat solut ovat pääasiassa haiman tiehyiden epiteelisoluja. Sopivissa olosuhteissa nämä solut muodostivat n. 4 viikon viljelyn aikana kystamaisia rakenteita, joiden pinnalta kehittyi uusia endokriinisiä, insuliinia ja glukagonia erittäviä saarekesoluja. Ensimmäisessä osatyössä optimoitiin soluviljelyolosuhteet tätä erilaistumista varten. Toisessa osatyössä tutkittiin tarkemmin niitä tapahtumia, jotka edeltävät endokriinistä erilaistumistapahtumaa viljelmissä. Havaittiin, että erilaistuneilla haimasoluilla on kyky muuttaa merkkiominaisuuksiaan viljelyoloissa. Osa valmiiksi erilaistuneista saarekesoluista alkoi ilmentää tiehytsoluille tyypillisiä merkkiominaisuuksia ja kadottaa samalla endokriinisten solujen ominaisuuksia. Tällöin solut myös pystyivät jakautumaan. Havaittu saarekkeiden uudismuodostus perustui ainakin osittain tällaisiin ilmiöihin, jotka osoittavat että haiman saarekesolujen plastisuus on paljon aiemmin luultua suurempi. Soluviljelyssä tuotetut saarekkeet olivat morfologisesti ja toiminnallisesti epäkypsiä. Kun näitä soluja kolmannessa osatyössä siirrettiin immuunipuutteisiin hiiriin, todettiin niiden kypsyvän ja alkavan muistuttaa normaaleja saarekesoluja. Neljännessa osatyössä tutkittiin kliinisisesti saarekesiirtopotilailla käytettävien immunosuppressiivisten lääkeaineiden vaikutuksia edellä kuvatussa soluviljelymallissa. Havaittiin, että laajasti käytetty lääkeaine, mykofenolaatti, oli voimakkaasti epiteelisolujen jakautumista estävä ja vähensi täten merkittävästi soluviljelmässä syntyvien uusien saarekesolujen määrää. Tämä lääkeaine ei kuitenkaan vaikuttanut negatiivisesti erilaistuneisiin endokriinisiin soluihin, toisin kuin toinen yleisesti käytetty lääke, takrolimuusi. Yhteenvetona, tutkimuksessa pystyttiin osoittamaan kokeellisessa mallissa ihmisen haiman saarekkeiden uudismuodostuminen esiasteisista soluista. Eräitä keskeisiä säätelymekanismeja tunnistettiin. Havainnot viittaavat siihen, että saarekesiirrännäisen pitkäaikainen toimivuus riippuu solujen uusiutumiskyvystä ja hyljinnän estoon käytetyillä lääkkeillä voi olla tässä tärkeä merkitys. Tutkimukset antavat myös uutta tietoa haiman saarekkeiden regeneraatiokyvystä, mikä tarjoaa mahdollisuuksia uusien insuliininpuutosdiabeteksen hoitokeinojen kehittämiselle

The Characteristics and Growth of the Black Women Embodied in Beloved

Beloved is a great novel that typifies the vantage of Toni Morrison, the first African American woman writer who won the Nobel Prize. In this novel, Toni Morrison reveals great and indelible contribution to the African American literature. It is Toni Morrison that makes the scholars of the American critical circle pay much attention to the interior world of the black women. In her fictional world, Toni Morrison reflected miseries, abnormalities and distortions of the black women’s feeling and mind under the oppressions of racism and sexism. As one of the important figures of Beloved, all kinds of the description of the black women contributes a lot to the success of the image-shaping. As for the structure of this paper, it divides into four parts: Brief introduction to the novel, the characteristics and growth of the black women, and the final conclusion. This paper mainly attempts to discuss the characteristics and growth of the black women in the novel. By analyzing the changes of the black women in the novel, it will show you a special and unique realistic perspective.

Health-Related Quality of Life in Chinese Patients with Chronic Liver Disease

Aim. To investigate the factors contributing to health-related quality of life (HRQOL) in Chinese patients with chronic liver disease (CLD). Methods. HRQOL was measured with SF-36v2 Chinese version. Demographic and clinical data were collected, and patients with liver cirrhosis were divided into Child's Class A, B, and C according to Child-Turcotte-Pugh scoring system. Results. A total of 392 Chinese patients with CLD and 91 healthy controls were enrolled. HRQOL in patients with CLD was lower than that in healthy controls. Score of PCS in healthy controls was 54.6 ± 5.5 and in CLD was 47.8 ± 8.8 (P = 0.000). Score of MCS in healthy controls was 56.4 ± 8.1 and in CLD was 51.7 ± 7.4 (P = 0.000). Increasing severity of CLD from no cirrhosis to advanced cirrhosis was associated with a decrease on all domains of the SF-36 (P < 0.05). Stepwise linear regression analysis showed that severity of disease, age, present ascites, present varices, and prothrombin time had significant effect on physical health area. Severity of disease, female, present varices, total bilirubin, prothrombin time, and hemoglobin had significant effect on mental health area. Conclusions. Patients with CLD had impaired HRQOL. Increasing severity of CLD was associated with a decrease on HRQOL. Old age, female gender, advanced stage of CLD, present ascites, hyperbilirubinemia, and prolonging prothrombin time were important factors reducing HRQOL

SCOPE: Scalable Composite Optimization for Learning on Spark

Many machine learning models, such as logistic regression~(LR) and support vector machine~(SVM), can be formulated as composite optimization problems. Recently, many distributed stochastic optimization~(DSO) methods have been proposed to solve the large-scale composite optimization problems, which have shown better performance than traditional batch methods. However, most of these DSO methods are not scalable enough. In this paper, we propose a novel DSO method, called \underline{s}calable \underline{c}omposite \underline{op}timization for l\underline{e}arning~({SCOPE}), and implement it on the fault-tolerant distributed platform \mbox{Spark}. SCOPE is both computation-efficient and communication-efficient. Theoretical analysis shows that SCOPE is convergent with linear convergence rate when the objective function is convex. Furthermore, empirical results on real datasets show that SCOPE can outperform other state-of-the-art distributed learning methods on Spark, including both batch learning methods and DSO methods

Analysis of the Spatio-temporal Dynamics of COVID-19 in Massachusetts via Spectral Graph Wavelet Theory

The rapid spread of COVID-19 disease has had a significant impact on the world. In this paper, we study COVID-19 data interpretation and visualization using open-data sources for 351 cities and towns in Massachusetts from December 6, 2020 to September 25, 2021. Because cities are embedded in rather complex transportation networks, we construct the spatio-temporal dynamic graph model, in which the graph attention neural network is utilized as a deep learning method to learn the pandemic transition probability among major cities in Massachusetts. Using the spectral graph wavelet transform (SGWT), we process the COVID-19 data on the dynamic graph, which enables us to design effective tools to analyze and detect spatio-temporal patterns in the pandemic spreading. We design a new node classification method, which effectively identifies the anomaly cities based on spectral graph wavelet coefficients. It can assist administrations or public health organizations in monitoring the spread of the pandemic and developing preventive measures. Unlike most work focusing on the evolution of confirmed cases over time, we focus on the spatio-temporal patterns of pandemic evolution among cities. Through the data analysis and visualization, a better understanding of the epidemiological development at the city level is obtained and can be helpful with city-specific surveillance.Comment: Accepted by IEEE Transactions on Signal and Information Processing over Network