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Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone. Rare microdeletion PWS patients define a 91 kb minimum critical deletion region encompassing three genes, including the non-coding SNORD116. Induced pluripotent stem cells were generated from skin cells of three large deletion (5-6 Mb) PWS patients and one novel microdeletion (118 kb) PWS patient. We found that genes within the PWS region, including SNRPN and NDN, showed persistence of DNA methylation after iPSC reprogramming and differentiation to neurons. Genes within the PWS minimum critical deletion region remain silenced in both PWS large deletion and microdeletion iPSC following reprogramming. We find that NHLH2 and PC1 (protein and transcript) are reduced in PWS patient iPSC-derived neurons. Nhlh2 and Pcsk1 expression are reduced in hypothalami of fasted Snord116p-/m+ mice while hypothalamic AgRP and Npy remain elevated following refeeding in association with relative hyperphagia. Nhlh2-/- mice have growth deficiencies from 4-7 weeks of age, develop hyperphagic obesity as adults, and are hypogonadal. Nhlh2 promotes expression of the prohormone convertase, Pcsk1 (PC1). PC1 is a neuroendocrine prohormone convertase that catalyzes the processing of hormones to “mature,” active hormones. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased growth hormone, and hypoinsulinemic diabetes due to impaired prohormone processing. Snord116p-/m+ mice display in vivo functional defects in prohormone processing of proinsulin, proGHRH, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency which results from absence of functional SNORD116. In addition to hyperphagic obesity and endocrinopathies, global developmental delay (delayed motor milestones, delayed language development) is a major characteristic of the Prader-Willi syndrome (PWS). We identified neuroanatomical defects in iPSC-derived neurons of individuals with PWS and mice deficient for Snord116. iPSC-derived neurons from PWS patients and neurons from Snord116p-/m+ mice, have smaller soma and decreased numbers of neurites. Reduced neuron cell body size is apparent in utero and persists at least until 4 weeks of age in Snord116p-/m+ mice. The reduction in neuronal soma size is associated with smaller neuronal nucleoli. There are also developmental defects in the endocrine pancreas of Snord116p-/m+ animals that persist into adulthood (≥20 weeks). Mice lacking Snord116 have smaller pancreatic islets and within the islet the percentage of δ-cells is increased, while the percentage of α-cells is reduced. In Snord116p-/m+ isolated islets, Sst and Hhex are upregulated while Ins1, Ins2, Pdx1, Nkx6-1, and Pax6 are downregulated. There is a 3-fold increase in the percentage of polyhormonal cells in the neonatal islets of Snord116p-/m+ mice, which was due to an increase in cells co-positive with somatostatin. Snord116 may play a role in islet cell lineage specification. Overall, this work suggests that the Snord116 gene cluster is important for developmental processes in the brain as well as endocrine pancreas and prohormone processing in multiple tissues. Loss of elements within this cluster could account for the PWS by virtue of effects on the expression of PCSK1.

Brain development is an exquisitely coordinated process of progenitor cell proliferation followed by the migration of progeny to their final location in the developing brain. There are a myriad of points at which this process can be disturbed, and the examination of these perturbations help us further understand basic science, as well as epidemics sweeping through the world around us. Microcephaly, which is defined as a head circumference greater than 2 standard deviations below the mean, can occur through genetic, infectious, vascular, or metabolic etiologies, and the studies herein examine two forms by which microcephaly occurs. First, we investigate the role of the dynein regulatory protein Nde1 in the development of the neocortex, which is the outer region of the forebrain. NDE1 mutations are associated with severe microcephaly, and we find that unlike most microcephaly genes whose products have one role in the cell cycle, Nde1 is required at three discrete points in neuronal progenitors, termed radial glia progenitors (RGPs). We initially find that Nde1 is required to recruit dynein to the nuclear envelope to allow for interkinetic nuclear migration (INM) during G2. Additionally, Nde1 helps to initiate primary cilia resorption at the G1-to-S transition. Finally, there is a necessity for Nde1 at the G2-to-M transition after the completion of INM and prior to nuclear envelope breakdown. These three distinct roles for Nde1 illustrate the breadth of functions that the protein has during RGP proliferation, and help to explain why patients with NDE1 mutations have such severe microcephaly. As this work was ongoing there was a global outbreak of a new pathogen that had previously been dormant throughout Africa and Asia, only to emerge at epidemic proportions in the Western Hemisphere. This pathogen, the Zika Virus (ZIKV), is particularly alarming because of its subclinical course in adults but devastating consequences for fetal development, with the hallmark symptom being microcephaly. Using our organotypic brain slice model system, we demonstrate the ability of a variety of ZIKV isolates to infect and replicate in embryonic brain tissue. All ZIKV isolates that infect the organotypic slices lead to increases in apoptosis, though these increases are particularly pronounced in isolates from the Asian/American lineages. Notably, one isolate from a patient in Nigeria (termed 30656) does not replicate in mouse neuronal tissue, but electroporation of the 30656 ZIKV genome allows for a single cycle replication, suggesting that this isolate is unable to enter RGPs. All infectious isolates are pathogenic in early- and mid- gestation embryonic tissue, but only one isolate infects and replicates in late- gestation embryonic tissue. This was the most recently isolated sample tested, and it demonstrates a predilection for neurons, suggesting that ZIKV may be mutating as it spreads. These results provide foundational insight into the pathogenesis of ZIKV- associated microcephaly, and illustrate how studies of genetic forms of microcephaly can enhance and facilitate our understanding of infectious causes of the disease.

Thesis (M. A. (Psychology)) --University of Limpopo, 2017 / This study investigated the perceptions of African families of TBI. Caregivers and TBI victims were given the opportunity to talk about their TBI perceptions. The study revealed that people’s knowledge of TBI is not good. This is proven by the way in which the participants understood and explained the conditions the victims found themselves in, after the accidents and how their family members are. Findings reveal that culture does play a vital role in the perceptions of African people. The study illustrates that the perceptions are culturally-rooted. The study interviewed five individuals (n=5) with TBI and a total of nine caregivers (n=9) were interviewed. A total of fourteen (n=14) participants were interviewed. The study reveals that the causes of TBI were attributed a number of things. According to the participants TBI is caused by witchcraft, the will of God and ancestors. The study also helped highlight the beliefs and the cultural system of Africans. It also explained the reality of an African. The Afrocentric theory helped shape the study as it helped in explaining the importance of an Africans’ view. The Afrocentric theory postulates that Africans have a different reality from that of Westerns and it has been proven by the findings. Although the participants were told about TBI by the doctors, they still had their own explanations and attributions to the problem.

雖然由老化引發的腦白質病變是老年人認知障礙的一個重要誘因，其機理缺並不為人所知。最新的小樣本研究表明擴散核磁造影在很大程度上是對腦白質病變最為敏感的的成像檢測手段。加深對擴散核磁造影所給出的各種指數的理解和認知對於檢測腦白質病變的病理發展以及研發試驗療法的替代標記有重要的意義。 / 為了獲得更具有臨床價值的擴散核磁造影指數，我們首先需要重構腦白質纖維束並沿著重構出的腦白質纖維束採集數值。然而，傳統的腦白質纖維束重構技術對於腦白質病變十分敏感。此外，不同病人所重構出的腦白質纖維束間缺乏映射關係也使我們無法有效進行大樣本統計分析。 / 在這個課題裡，我們提出了一個可以解決以上問題的一個全新框架。我們將專家標註過功能區的全腦白質纖維束模板配準到各個個體的腦部。此方案可自動生成個體化的全腦白質纖維束以及纖維束的功能區標註。自由形變模型被用於在全局層面對配準進行約束。所重構纖維束的曲率被用於在局部對配準進行約束。為了減輕腦白質病變對配準的影響，我們運用了一種 魯棒的主成分分析手段來檢測被病灶所干擾的纖維束。為了指導這些被干擾纖維束的配準，我們提出了一種全新的沿纖維束的區域特徵作為替代。此外，我們也探究了通過在纖維束上建立坐標系來除去離群纖維已經提供更高相關性的辦法。 / 我們所提出的框架被運用於一個腦小血管病變的臨床研究。在64個研究對象中約半數是腦白質病變患者。試驗結果證實此算法成功地將全腦白質纖維束模板配準到了所有研究對象上。沿著特定纖維束改採集的指數與認知測試分數的相關性顯著地超越了傳統指數所給出的結果。我們同時也發現沿著不同功能區腦白質纖維改採集的指數與相應的認知測試分數統計相關。 / Although age-related white matter lesion(WML)is an important substrate for cognitive impairment in the elderly, the mechanisms whereby WML induces cognitive impairment are uncertain. Recent findings based on small studies suggested that diffusion tensor imaging (DTI) measures might be the most sensitive imaging predictors in patients with WML. Understanding the imaging predictors for such disease will be useful in monitoring disease progression and in devising surrogate marker for treatment trials. / In order to obtain DTI measurements with diagnostic significance, it is first necessary to reconstruct the white-matter fiber pathways inside the brain along which certain DTI-derived values are calculated. Nevertheless, the traditional approach of white-matter tract reconstruction, or tractography, is severely hindered by the abundant existence of lesions inside the brains of WML patients. The lack of correspondence between fiber bundles across patients also makes obtaining group statistics of individual fiber bundles dicult. / In this study, we propose a novel framework that can mitigate the aforementioned issues of traditional tractography approaches. An expert-labeled whole brain tractography template is registered onto individual patients. Fiber trajectories and anatomically meaningful fiber bundles are automatically obtained by this registration. The free-form deformations are used to regularize the transformations at the whole brain level and across fiber bundles. Fiber curvatures are penalized as the intra-fiber regularization to encourage the smoothness of transformed fibers. White matter (WM) lesion is one of the major factors affecting tractography and registration of subjects with neuro Logical disorders. The Robust Principal Component Analysis(RPCA) is used to automatically detect fiber tract segments that are affected by WM lesion and a novel along-fiber regional prior is learned from healthy subjects to facilitate the registration of these fiber tract segments. We also propose to establish bundle-wise coordinate system by utilizing low-rank constraints upon the DTI measurements. The eort elevates the summary for an anatomical bundle from a scalar statistic to a vector containing changes along the representative fiber pathway. It provides means to exclude the outlier fibers while retaining partially-complete fibers. / The proposed scheme is applied to a clinical study of cerebral small vessel diseases(SVD).Experimental results show successful registration of the whole brain tractography template onto all 64 subjects, including both healthy con¬trol subjects and SVD patients. The DTI measures measured along specific registered anatomical fiber bundles exhibit significant boost in correlation with cognitive functions as compared with traditional measures. It also shows that different anatomical WM structures correlate with multiple types of cognitive functions in different ways. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / He, Xiaotian. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 46-53). / Abstracts also in Chinese. / List of Figures --- p.ix / List of Tables --- p.xii / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Motivation --- p.1 / Chapter 1.2 --- Our Work and Contributions --- p.2 / Chapter 1.3 --- Related Work --- p.4 / Chapter 1.4 --- Thesis Organization --- p.5 / Chapter 2 --- Background --- p.6 / Chapter 2.1 --- Background of Neuroanatomy --- p.6 / Chapter 2.2 --- Background on Diffusion Tensor Magnetic Resonance Imaging (DTMRI) --- p.11 / Chapter 3 --- Free Form Fibers --- p.18 / Chapter 3.1 --- DTI Acquisition --- p.20 / Chapter 3.2 --- Fiber Model --- p.20 / Chapter 3.3 --- Fiber-to-DTI Registration --- p.21 / Chapter 3.3.1 --- Free-Form Fibers (FFFs) --- p.21 / Chapter 3.3.2 --- Tensor-Driven Fiber-to-DTI Registration --- p.23 / Chapter 3.3.3 --- Reliability Assessment by Robust Principal Component Analysis --- p.24 / Chapter 3.3.4 --- Contextual Feature --- p.26 / Chapter 3.3.5 --- Learning the Fiber Context Prior --- p.29 / Chapter 3.3.6 --- Registration Refinement Using the Fiber Context Prior --- p.29 / Chapter 4 --- Results --- p.31 / Chapter 5 --- Future Work --- p.39 / Chapter 5.1 --- Refinement on Large Bundles --- p.39 / Chapter 5.2 --- Outlier Fiber Removal in Fiber Template --- p.40 / Chapter 6 --- Conclusion --- p.44 / Bibliography --- p.46

The present study focuses on the biological functions of the transcription factor EMA/E2F-6, a member of the E2F-family of transcription factors that play an import role in cell cycle progression, differentiation and apoptosis. EMA/E2F-6 functions as a transcriptional repressor by recruiting a large protein complex, that includes polycomb group proteins, to specific target genes in order to silence their expression. To identify the biological functions of EMA/E2F-6 mice lacking this factor were developed and subsequently analysed. EMA/E2F6-/- mice are born with the expected frequency, are fertile and develop normally up to 18 months of age. Then about 25 % of these mice develop a paralysis of the hind limbs and present with a severe primary myelination defect of the spinal cord (and in part of peripheral nerves, too) that is accompanied by a massive infiltration of macrophages. Importantly, the histological findings were also detected in EMA/E2F-6-/- mice lacking clinical symptoms albeit to a lesser extend. With respect to EMA/E2F-6 association with polycomb group (Pc-G) proteins there were no significant findings such as skeletal transformations. In addition, only a mild proliferation defect of T-lymphocytes was observed that, in a more severe form, is typical for Pc-G mutations in the mice. Surprisingly, embryonic fibroblasts from EMA/E2F-6-/- mice have no obvious cell cycle defects. Accordingly, gene expression profiles showed that classical E2F target genes were normally regulated in these cells. However, EMA/E2F-6-/- fibroblasts ubiquitously express genes like alpha-tubulin-3 and -7 that are normally expressed in a strictly testis-specific manner. All EMA/E2F-6-dependent target genes identified contain a conserved E2F-binding site in their promoters that is required both for EMA/E2F-6 binding and regulation.