Common-Mode Modeling of Neutral Point Clamped Converter Based Dual Active Bridge

Modern power converters designed with wide-bandgap semiconductors are known to generate substantial conducted electromagnetic interference as a side effect of high edge rate and high frequency switching. With the advancement in power electronic converters, the significant EMI challenges need to be addressed for distribution level power systems. The goal is to provide a computationally efficient method of EMI characterization for conducted emissions for this future generation of power distribution systems. The first step in making this possible is through creating an accurate EMI characterization platform for the neutral point clamped dual active bridge. In this thesis, a formalized common-mode modeling approach is carried out for transforming this mixed-mode power system into its common-mode equivalent circuit. The approach is validated through comparison of time-domain waveforms predicted by detailed mixed-mode and common-mode equivalent models of the representative power distribution system, with a proposed future validation using hardware measurements. The experimental studies highlight the utility of the proposed modeling approach to assess design mitigation strategies

Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma

Abstract Background While aerobic glycolysis is linked to unconstrained proliferation in cancer, less is known about its physiological role. Why this metabolic program that promotes tumor growth is preserved in the genome has thus been unresolved. We tested the hypothesis that aerobic glycolysis derives from developmental processes that regulate rapid proliferation. Methods We performed an integrated analysis of metabolism and gene expression in cerebellar granule neuron progenitors (CGNPs) with and without Sonic Hedgehog (Shh), their endogenous mitogen. Because our analysis highlighted Hexokinase-2 (Hk2) as a key metabolic regulator induced by Shh, we studied the effect of conditional genetic Hk2 deletion in CGNP development. We then crossed Hk2 conditional knockout mice with transgenic SmoM2 mice that develop spontaneous medulloblastoma and determined changes in SmoM2-driven tumorigenesis. Results We show that Shh and phosphoinositide 3-kinase (PI3K) signaling combine to induce an Hk2-dependent glycolytic phenotype in CGNPs. This phenotype is recapitulated in medulloblastoma, a malignant tumor of CGNP origin. Importantly, cre-mediated ablation of Hk2 abrogated aerobic glycolysis, disrupting CGNP development and Smoothened-induced tumorigenesis. Comparing tumorigenesis in medulloblastoma-prone SmoM2 mice with and without functional Hk2, we demonstrate that loss of aerobic glycolysis reduces the aggressiveness of medulloblastoma, causing tumors to grow as indolent lesions and allowing long-term survival of tumor bearing mice. Conclusions Our investigations demonstrate that aerobic glycolysis in cancer derives from developmental mechanisms that persist in tumorigenesis. Moreover, we demonstrate in a primary tumor model the anti-cancer potential of blocking aerobic glycolysis by targeting Hk2

Negative parental responses to coming out and family functioning in a sample of lesbian and gay young adults

Parental responses to youths' coming out (CO) are crucial to the subsequent adjustment of children and family. The present study investigated the negative parental reaction to the disclosure of same-sex attraction and the differences between maternal and paternal responses, as reported by their homosexual daughters and sons. Participants' perceptions of their parents' reactions (evaluated through the Perceived Parental Reactions Scale, PPRS), age at coming out, gender, parental political orientation, and religiosity involvement, the family functioning (assessed through the Family Adaptability and Cohesion Evaluation Scales, FACES IV), were assessed in 164 Italian gay and lesbian young adults. Pearson correlation coefficients were calculated to assess the relation between family functioning and parental reaction to CO. The paired sample t-test was used to compare mothers and fathers' scores on the PPRS. Hierarchical multiple regression was conducted to analyze the relevance of each variable. No differences were found between mothers and fathers in their reaction to the disclosure. The analysis showed that a negative reaction to coming out was predicted by parents' right-wing political conservatism, strong religious beliefs, and higher scores in the scales Rigid and Enmeshed. Findings confirm that a negative parental reaction is the result of poor family resources to face a stressful situation and a strong belief in traditional values. These results have important implications in both clinical and social fields

Gender essentialism and occupational segregation in insolvency practice

Advances towards egalitarianism in professional recruitment may be offset by processes of occupational re-segregation. Drawing on gender theory this paper investigates horizontal segregation in the UK insolvency profession, as revealed through the lived experiences of female and male practitioners. It is shown that horizontal segregation pervades at different levels of practice and is undergirded by various elements of gender essentialism. Physical essentialism explains why insolvency practice has been traditionally gendered male. Interactional essentialism combines with the management of work-life balance to define the subfields of corporate and personal insolvency as masculine and feminine respectively. Gender essentialist assumptions also pervade the distribution of roles and the allocation of work tasks. Networks are identified as arenas for the reproduction and perpetuation of occupational segregation. The findings indicate the continuing potency of gender in everyday professional life, the limitations of diversity-orientated policies and the complexities of formulating transformative agendas

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells

To identify new candidate therapeutic targets for Glioblastoma multiforme (GBM), we combined functional genetics and GBM network modeling to identify kinases required for the growth of patient-derived brain tumor initiating cells (BTICs), but which are dispensable to proliferating human neural stem cells (NSCs). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top scoring GBM-lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B’s GLEBs domain activity is required to suppress lethal kinetochore-microtubule (KT-MT) attachment defects in GBM isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT-MT instability. These results indicate that GBM tumors have added requirement for BUB1B to suppress lethal consequences of altered KT function. They further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT-MT stability

Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A

To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We found that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3′ splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown in GSCs and also in NSCs or fibroblasts overexpressing MYC. Furthermore, PHF5A inhibition compromised GSC tumor formation in vivo and inhibited growth of established GBM patient-derived xenograft tumors. Our results demonstrate a novel viability requirement for PHF5A to maintain proper exon recognition in brain tumor-initiating cells and may provide new inroads for novel anti-GBM therapeutic strategies

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN