The most common causes of childhood interstitial lung disease (chILD) are autosomal recessive mutations in the gene encoding ATP Binding Cassette A3 (ABCA3) protein, a lamellar body (LB) associated lipid transporter exclusively expressed within the alveolar epithelial type II cells (AEC2s) in the lung. Instability of primary AEC2s in culture has prevented studies of ABCA3 mutations, resulting in limited understanding of disease pathogenesis. To overcome this challenge, we developed AEC2-like cells from human pluripotent stem cells (PSCs) in vitro, allowing study of normal ABCA3 function and perturbations that result from ABCA3 mutations. To develop an AEC2 model that would recapitulate ABCA3 biology, we targeted human PSC lines with a knock-in GFP fusion reporter (ABCA3:GFP). Differentiations of PSCs into AEC2s (iAEC2s) resulted in exclusive expression of ABCA3:GFP in iAEC2s and intracellular localization to LAMP3+ vesicles, reminiscent of endogenous ABCA3. Moreover, we find these ABCA3:GFP+ iAEC2s express LBs, process surfactant proteins, and secret surfactant lipids, indicative of preserved ABCA3 function. To study the effects of ABCA3 mutations using our model, we generated two sets of PSC reporter lines: 1) two patient-derived iPSC lines carrying rare homozygous E690K and W308R ABCA3 mutations predicted to affect ABCA3 function or trafficking, respectively, and their two syngeneic gene-corrected lines each targeted with the AEC2-specific knock-in fluorescent reporter SFTPCtdTomato; and 2) three syngeneic ABCA3:GFP knock-in iPSC lines encoding wildtype, E690K, or W308R proteins. Directed differentiation of patient iPSCs into iAEC2s revealed attenuated secretion of surfactant-specific lipids, recapitulating clinical findings of surfactant deficiency. Examination of ABCA3 protein trafficking using the ABCA3:GFP fusion reporter revealed retained E690K and W308R mutant ABCA3 protein processing and trafficking compared to the wildtype protein by confocal microscopy and western blot analyses, however mutant iAEC2s exhibited smaller LBs, indicative of defective ABCA3-dependent lipid transport. Bulk RNA sequencing of mutant and gene-corrected SFTPCtdTomato- or ABCA3:GFP-expressing iAEC2s revealed enrichment of the TNF𝛼-NF𝜅B pathway in both W308R and E690K mutant iAEC2s, validated by lentiviral reporter assays and secretion of NF𝜅B-driven cytokines. Thus, we provide insights into how ABCA3 mutations alter AEC2 physiology and developed a platform to study other genetic AEC2 diseases through our ABCA3:GFP reporter system. / 2021-05-26T00:00:00Z

Dans cette thèse, nous présentons des constructions explicites de la correspondance AdS/CFT dans le contexte de la théorie des cordes de type II. Ces constructions sont visées à mieux comprendre aspects de la physique nonperturbative de théories des champs superconformes à d = 6,5,4 dimensions. Dans la première partie de la thèse nous introduisons les systèmes de NS5-Dp-D(p+2)-branes de Hanany-Witten, au moyen desquels on peut construire théories des champs avec 8 supercharges. Quand p = 6, le système de NS5-D6-D8-branes permet de construire théories des champs superconformes à 6 dimensions, caractérisées par des multiplets tenseur, vecteur et hypermultiplets de la superalgèbre chirale N = (1,0). Ces théories sont décrites par des «quivers» linéaires; nous analysons en détails leurs propriétés. Dans le cadre de la correspondance AdS/CFT, une théorie superconforme à (d - 1) dimensions décrit la même physique qu’un vide de la théorie des cordes de type II compactifiée sur un espace-temps Anti-de Sitter à d dimensions (AdSd). Par le biais de la géométrie complexe généralisée nous reformulons les équations qui doivent être résolues pour trouver ces vides AdS. La seconde partie contient les contributions originales. Nous présentons une classification exhaustive des vides de la théorie des cordes de type II compactifiée sur AdS7. En type IIB, il n’y a aucun vide; en type IIA massif, nous construisons une nouvelle classe infinie (et analytique) de vides. L’espace interne est topologiquement une 3-sphere, déformée par la présence de D6 et D8-branes. Les isométries de cet espace réalisent la symétrie R des théories superconformes N = (1,0) à 6 dimensions. Nos vides AdS7 sont les duaux holographiques de ces dernières, et peuvent être obtenus par une limite près de l’horizon des systèmes de NS5-D6-D8-branes. Le second résultat est la construction d’une classe infinie de vides analytiques AdS5 en type IIA massif. L’espace interne est le produit d’une 3-sphere par une surface de Riemann. Les isométries de cet espace réalisent la symétrie R des théories superconformes N = 1 à 4 dimensions, dont nos vides AdS5 sont les duaux holographiques. Nous décrivons une bijection entre ces derniers et les vides AdS7 susmentionnés. L’interprétation holographique indique que les théories N = 1 à 4 dimensions sont obtenues en compactifiant celles N = (1,0) à 6 dimensions sur la même surface de Riemann. Troisièmement, nous réduisons à deux equations différentielles le problème de classification des vides AdS6 en type IIB duaux à théories superconformes N = 1 à 5 dimensions. L’espace interne de ces vides contient une 2-sphere, réalisant la symétrie R des ces dernières. / In this thesis we present explicit constructions of the AdS/CFT correspondence obtained from type II string theory. These constructions are aimed at studying aspects of the nonperturbative physics of 6d, 5d, 4d SCFTs. In the first part we introduce NS5-Dp-D(p+2) Hanany--Witten brane systems, capable of engineering field theories with 8 Q supercharges. In particular, when p=6, the NS5-D6-D8 brane systems are known to engineer 6d SCFT featuring tensor, vector and hypermultiplets of the chiral N=(1,0) superalgebra. These theories can be described by linear quivers. We analyze in detail their properties. In AdS/CFT, the same physics can be equivalently described by a (d-1)-dimensional SCFT and by type II string theory compactified on a d-dimensional AdS space (AdSd), giving rise to a so-called AdSd vacuum. By using techniques derived from generalized complex geometry we reformulate the equations that need to be satisfied in order to find these AdS vacua. The second part of the thesis contains the original contributions. We present a full classification of vacua of type II string theory compactified on AdS7. In type IIB there are no such vacua; in massive type IIA, we construct a new infinite class of (analytic) vacua. The internal space is topologically a three-sphere, deformed by the presence of D6 and D8-branes. The isometries of this space realize the R-symmetry of the 6d (1,0) SCFTs. Our AdS7 vacua are the holographic duals of the latter, and can be obtained via a near-horizon limit of the NS5-D6-D8 brane systems. The second result is the construction of an infinite class of analytic AdS5 vacua of massive IIA. The internal space is a fibration of a (distorted) three-sphere over a Riemann surface. Its isometries realize the R-symmetry of putative 4d N=1 SCFTs, holographically dual to our AdS5 vacua. We describe a universal one-to-one map between the latter and the aforementioned AdS7 vacua. The natural interpretation of this is that the 4d N=1 SCFTs can be obtained by compactifying (in a twisted way) the 6d (1,0) ones on the same Riemann surface. In the third and last part, we reduce to two PDEs the classification problem of AdS6 vacua of type IIB supergravity, which should be the holographic duals to 5d N=1 SCFTs. The latter can be engineered by webs of (p,q)-fivebranes in type IIB string theory. The internal space of the AdS6 vacua is given by a fibration of a round two-sphere over a two-dimensional surface; the isometries of the fibers should realize the R-symmetry of the dual field theories. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22495号 / 農博第2399号 / 新制||農||1076(附属図書館) / 学位論文||R2||N5275(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 栗原 達夫, 教授 小川 順, 教授 木岡 紀幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Semiconductor nanocrystals, also referred to as quantum dots (QDs), have been the focus of great scientific and technological efforts in solar cells, as a result of their advantages of low-cost, photostability, high molar extinction coefficients and size-dependent optical properties. Due to the multi-electron generation effect, the theoretically maximum efficiency of quantum dots-sensitized solar cells (QDSCs) is as high as 44%, which is much higher than that of dye-sensitized solar cells (DSCs). Thus QDSCs have a clear potential to overtake the efficiency of all other kinds of solar cells. In recent years, the efficiency of QDSCs has been improved very quickly to around 5%. It is however still much lower than that of DSCs. The low efficiency is mostly caused by the high electron loss between electrolyte and electrodes and the lack of an efficient electrolyte. In this thesis, we have been working to enhance the performance of QDSCs with II-VI group nanocrystals by increasing the electron injection efficiency from QDs to TiO2 and developing new redox couples in electrolyte. To increase the electron injection, firstly, colloidal ZnSe/CdS type-II QDs were synthesized and applied for QDSCs for the first time, whose photoelectron and photohole are located on CdS shell and ZnSe core, respectively. The spatial separation between photoelectron and photohole can effectively enhance the charge extraction efficiency, facilitating electron injection, and also effectively expand the absorption spectrum. All these characteristics contribute to the high photon to current conversion efficiency. Furthermore, a comparison between the performances of ZnSe/CdS and CdS/ZnSe QDs shows that the electron distribution is important for the electron injection of the QDs in QDSCs. Secondly, colloidal CdS/CdSe quantum rods (QRs) were applied to a quantum rod-sensitized solar cell (QRSCs) that showed a higher electron injection efficiency than analogous QDSCs. It is concluded that reducing the carrier confinement dimensions of nanocrystals can improve electron injection efficiency of nanocrystal sensitized solar cells. In this thesis, two types of organic electrolytes based McMT-/BMT and TMTU/TMTU-TFO were used for QDSCs. By reducing the charge recombination between the electrolyte and counter electrode, fill factor (FF) of these QDSCs was significantly improved. At the same time, the photovoltages of the QDSCs were remarkably increased. As a result, the overall conversion efficiency of QDSCs based on the new electrolytes was much higher than that with a commonly used inorganic electrolyte. In addition, CdS QDSCs on NiO photoelectrode were studied which shows a n-type photovoltaic performance. This performance is attributed to the formation of a thin Cd metal film before CdS QDs formation on NiO. Since the CB edge of CdS sits between the Fermi level and the CB edge of Cd metal, a much strong electron transfer between Cd and CdS QD is obtained, resulting in the observed n-type photovoltaic performance of these CdS/NiO QDSCs. / QC 20120425

In introductory statistics courses, the concept of power is usually presented in the context of testing hypotheses about the population mean. We instead propose an exercise that uses a binomial probability table to introduce the idea of power in the context of testing a population proportion.

In introductory statistics courses, the concept of power is usually presented in the context of testing hypotheses about the population mean. We instead propose an exercise that uses a binomial probability table to introduce the idea of power in the context of testing a population proportion.

Assault of community-based mental health professionals is a worldwide phenomenon, and current extant literature examines the prevalence of client assault on counselors, social workers, and psychiatric personnel. While there is significant quantitative scholarship on the incidence of this phenomenon on social workers and psychiatric personnel, there are limited statistical data on client-perpetrated violence against community-based counselors and no qualitative studies found that examined how these professionals experience this occupation risk. Therefore, the purpose of this study was to explore how counselors who work in community-based settings make sense of these experiences. Through semi structured interviews, 6 community-based counselors living in the Southeastern region of the U.S. shared their lived experience of client assault. Hermeneutic was used as a methodological and theoretical framework to analyze the data. The following themes emerged from the data study: training as a management strategy, ambivalence as a new way of being, and connections for well-being. The results of this study have training, practice, supervision, and social change implications. Through adding counselors'€™ voices to the discourse on client assault, the findings of this study can be used to identify experiences and training that will assist counselors in caring for themselves in the aftermath of an assault. Furthermore, understanding these experiences may inform the development of protocols for keeping this vulnerable population safe.

Indiana University-Purdue University Indianapolis (IUPUI) / Type II nephronophthisis (NPHP2) is an autosomal recessive renal cystic disorder characterized by mutations in the inversin gene. Humans and mice with mutations in inversin have enlarged cystic kidneys. Increased kidney size in NPHP2 may involve altered cell growth, apoptosis, electrolyte transport and fluid accumulation in the cysts. To test this hypothesis, histology and transcriptome analysis were performed on one-day old wild-type and inv/inv mice to uncover molecular pathways altered in the mutant mice. Histology of inv/inv mice kidneys showed dilated cystic tubules compared to wild type. Pathway analysis of transcriptome data showed that inversin exerts its effects on kidneys, at least in part, through the transcriptional regulation of genes implicated in inflammation, immune response, cellular metabolism, cell cycle and ion transport. Genes involved in inflammation or immune response were upregulated whereas the genes involved in cell cycle progression and ion transport were downregulated. To validate the array findings from inv/inv mice kidneys, functional consequence of inversin loss on transepithelial ion transport was measured by electrophysiological techniques in shRNA mediated inversin-depleted renal cell type isolated from mouse cortical collecting duct (mCCD). Depletion of inversin decreased vasopressin-induced Na+ absorption, but did not alter Cl- secretion in mCCD cells. Addition of amiloride, a specific blocker of the epithelial sodium channel (ENaC), abolished basal ion transport in both inversin knockdown and control cells indicating ENaC involvement. Loss of inversin decreased Na+ absorption and this effect, in part, was mediated by transcriptional and post-translational regulation of ENaC mediators. To better understand inversin function in renal cells, transcriptome analysis was performed in control and inversin-depleted mCCD cells. Pathway analysis showed that inversin-depletion altered the genes represented in cell cycle, cellular assembly and organization, DNA replication, cell proliferation and ion transport in this isolated renal cell type. In concordance with the array data from inv/inv mice kidneys, a decrease in the expression of cell cycle, ion transport and apoptotic genes were observed accompanied by an upregulation of genes implicated in inflammatory or immune response indicating a direct effect of inversin on renal cells. Together, this study utilized a combination of transcriptome and functional analyses to unravel the role of inversin in renal cells. These data demonstrate that loss of inversin can cause a delay in cell cycle progression with a decrease in cell proliferation and apoptosis which in turn can perturb the development of the renal tubule. Also, a decrease in Na+ reabsorption together with differential regulation of other ion transporters can result in altered electrolyte transport contributing to cystogenesis, cyst growth, fluid accumulation and cyst expansion in NPHP2.

Osteoarthritis is a prevalent disease that affects the articular cartilage of the joints. Millions of people suffer worldwide and it is a major cause of disability in the United States. Current research for treatments of osteoarthritis are studying tissue-engineered cartilage in vitro generated by articular chondrocytes. A challenge faced in vitro for cartilage tissue engineering is the failure of chondrocytes to produce adequate expression of type II collagen. Surprisingly, the media commonly used in vitro lacks 14 vitamins and minerals present in the physiological environment of chondrocytes. Therefore, studying the interactions between micronutrients and chondrocytes may help in potentially increasing the amount of type II collagen expressed by these cells. This project studied the combinatorial effects of vitamins and minerals in defined chondrogenic media on type II collagen expression. Linolenic acid was determined to have predominantly negative effects on chondrogenesis and Vitamin B7 to have beneficial effects. Multiple vitamins and minerals displayed significant interactions, both positive and negative.

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