DNA repetitive sequences capable of adopting non-B DNA structures are a potent source of instability in eukaryotic genomes. They are strong inducers of chromosomal fragility and genome rearrangements that cause various hereditary diseases and cancers. In addition, a subset of repeats also has an ability to expand, which leads to more than 20 human genetic diseases that are collectively known as repeat expansion diseases. However, the mechanisms underlying the potential of these structure-prone motifs to break and expand are largely unknown. In this study, a systematic genome-wide screen was employed in yeast Saccharomyces cerevisiae to investigate the contributing factors of the instability of two representative non-B DNA-forming repeats: the triplex-adopting GAA/TTC tracts and the inverted repeats that can form hairpin and cruciform structures. The GAA/TTC screen revealed that DNA replication and transcription initiation are the two major pathways governing the GAA/TTC stability in yeast, as corresponding mutants strongly induce both fragility and large-scale expansions of the repeats. The inverted repeats screen and follow-up experiments revealed that both replication-dependent and -independent pathways are involved in maintaining the stability of palindromic sequences. We propose that similar mechanisms could operate in the human cells to mediate the deleterious metabolism of GAA and inverted repeats.

Although the knowledge and technology of seismic analysis and seismic risk assessment tools have rapidly advanced in the past several decades, current seismic design codes and damage estimation methods ignore the effect of successive earthquakes on structures. In light of recent strong seismic events, mainshock-damaged structures are shown to be more vulnerable to severe damage and collapse during subsequent events. The increase in vulnerability during aftershocks results in the likelihood of increased damage and loss-of-life and property. After a major earthquake, structural engineers must assess whether mainshock-damaged buildings can be re-occupied or not, with due consideration to the threat of aftershocks. The outcome of this post-earthquake inspection is utilized to quantifiably judge the current status of structures (so-called building tagging). This tagging criterion is closely related to the evaluation of the residual capacity of damaged buildings as well as the computation of the probability of being in a damage state after an aftershock (aftershock fragility). The increased vulnerability estimation associated with the additional damage plays a significant role in assessing potential losses to facilitate crucial decision making such as emergency response mobilization, inspection priority, recovery strategy, and re-occupancy decision. The main objective of this research is to develop a probabilistic framework for accounting for these increased vulnerabilities in terms of the extent of damage associated with mainshock ground motions. Aftershock fragility curves are developed accounting for both the uncertainty from the seismic hazard and the uncertainty from the structural capacity. This proposed approach also allows for the inherent variability, such as modeling characteristics associated with the design codes, present in non-ductile and ductile reinforced concrete frames found in California.

Chromosomal rearrangements play a major role in the evolution of eukaryotic genomes. Genomic aberrations are also a hallmark of many tumors and are associated with a number of hereditary diseases in humans. The presence of repetitive sequences that can adopt non-canonical DNA structures is one of the factors which can predispose chromosomal regions where they reside to instability. Palindromic sequences (inverted repeats with or without a unique sequence between them) that can adopt hairpin or cruciform structures are frequently found in regions that are prone for gross chromosomal rearrangements (GCRs) in somatic and germ cells in different organisms. Direct physical evidence was obtained that double-strand breaks (DSBs) occur at the location of long inverted repeats, a triggering event for the genomic instability. However, the mechanisms by which palindromic sequences lead to chromosomal fragility are largely unknown. The overall goal of this research is to elucidate the mechanisms of DSB and GCR generation by palindromic sequences in yeast, Saccharomyces cerevisiae.

There are many calamitous events such as earthquakes, hurricanes, tsunamis etc. that occur suddenly and cause great loss of life, damage, or hardship. Hurricanes cause significant damage to power distribution systems, resulting in prolonged customer outages and excessive delays in the reconstruction efforts. Accordingly, predicting the effects of power outages on the performance of power distribution systems is of major importance to government agencies, utilities, and customers. Unfortunately, the current tools to predict the performance of power distribution systems during catastrophic events are limited in both the performance measures considered, as well as in their ability to model real systems. The main goal of this research is to develop a methodology for simulating hurricanes of different intensity on power distribution systems of small and medium size cities. Our study includes a detailed comparison between the engineering-based and connectivity-based models of power distribution systems, as well as the impact of power re-routing algorithms on the system reliability. Our approach is based on fragility curves that capture the ability of the system to withstand a range of wind speeds. In addition, we develop a multiscale approach that facilitates efficient computation of fragility curves for large cities. With this approach, hurricanes are simulated over small zones of a city and fragility curves are obtained. These are used to estimate the damage for identical zones throughout the city. To validate our techniques, two testbeds, Micropolis and Mesopolis, were used. Micropolis is synthetic model for a small city and Mesopolis for a big city. Obtained results have validated our approach and have shown that they can be used to effectively predict hurricane damage.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [103]-137).

Submitted by EVERTON HENRIQUE GONÇALES CARDOSO null (evertonhgcardoso@gmail.com) on 2018-01-18T16:55:22Z No. of bitstreams: 1 Dissertação_Everton Cardoso_Mestrado Profissional Geo_versão final.pdf: 4947177 bytes, checksum: 68d017989abc9f1a0c8953ed62dada8f (MD5) / Approved for entry into archive by ALESSANDRA KUBA OSHIRO ASSUNÇÃO (alessandra@fct.unesp.br) on 2018-01-18T17:39:54Z (GMT) No. of bitstreams: 1 cardoso_ehg_me_prud.pdf: 4947177 bytes, checksum: 68d017989abc9f1a0c8953ed62dada8f (MD5) / Made available in DSpace on 2018-01-18T17:39:54Z (GMT). No. of bitstreams: 1 cardoso_ehg_me_prud.pdf: 4947177 bytes, checksum: 68d017989abc9f1a0c8953ed62dada8f (MD5) Previous issue date: 2017-12-05 / A presente pesquisa identificou os níveis de fragilidade ambiental do alto curso da bacia hidrográfica do Ribeirão Negrinha (Osvaldo Cruz e Parapuã/SP) aos processos erosivos e, mediante os resultados obtidos, promoveu ações de educação ambiental. Com base em Ross (1994), a aferição da fragilidade resultou do cruzamento dos subprodutos cartográficos curvatura da superfície, declividade do terreno, tipos de solo e uso e cobertura da terra. A produção do mapa de fragilidade foi realizado no SIG ArcGIS 10.3, com validação por meio de atividades de campo em dezenove pontos da bacia. O estudo revelou um ambiente com predominância das fragilidades média e forte, presentes em 49,81% e 43,25% da área, respectivamente. A identificação da fragilidade ambiental da bacia hidrográfica aos processos erosivos deve subsidiar a adoção de medidas que promovam manejos mais adequados do uso da terra, seja para a atividade agropecuária e para a expansão da urbanização, seja para a definição de áreas protegidas. Desse modo, a produção de conhecimentos se estendeu à comunidade, visando o desenvolvimento de uma cultura conservacionista diante da ocupação do ambiente. Assim, na segunda etapa do trabalho, buscou-se articular/mobilizar os conhecimentos produzidos no mapeamento da fragilidade para o desenvolvimento de ações de educação ambiental, por meio de um projeto interdisciplinar junto ao curso Técnico em Meio Ambiente da ETEC Amim Jundi, Osvaldo Cruz-SP, ao longo do primeiro semestre de 2017. As atividades foram norteadas pela metodologia “Estudo do Meio” (PONTUSCHKA, PAGANELI E CACETE, 2007). O projeto contou com ações interdisciplinares em sala, visitas técnicas e oportunidades de avaliações, abordando variáveis componentes da aferição da fragilidade ambiental, a presença de impactos ambientais na bacia hidrográfica e a adoção de medidas conservacionistas. Por meio desta pesquisa, pretendeu-se potencializar os laços entre a pesquisa e o ensino, bem como fomentar uma educação ambiental que supere a representação do conhecimento como algo fragmentado e distante dos problemas dos alunos. / The present study identified the levels of environmental fragility of the upper reaches of Negrinha River's basin (Osvaldo Cruz and Parapuã / SP) to erosive processes and, through the results obtained, promoted environmental education actions. Based on Ross (1994), fragility measurement resulted from mapping cross byproducts surface curvature, slope of terrain, soil types and land use and covering. The fragility map’s production was made in SIG ArcGIS 10.3, with validation through field activities in nineteen points of the basin. The study revealed an environment with predominance of medium and strong fragilities present in 49.81% and 43.25% of the area, respectively. The identification of river basin environmental fragility to erosive processes should support the adoption of measures that promote better management of land use, either for agricultural activity and for the expansion of urbanization, or for definition of protected areas. Thereby, the production of knowledge was extended to community, aiming the development of a conservationist culture before environment’s occupation. Thus, in the second stage of the research, we sought to articulate / mobilize the knowledge produced in mapping of fragility to development of environmental education actions, through an interdisciplinary project in the Environment’s Technical Course on of ETEC Amim Jundi, Osvaldo Cruz -SP, during the first semester of 2017. The activities were oriented by the methodology “Environment Study” (PONTUSCHKA, PAGANELI and CACETE, 2007). The project included interdisciplinary actions in classroom, technical visits and assessment opportunities, addressing variables that are components of environmental fragility assessment, the presence of environmental impacts in the river basin, and the adoption of conservation measures. Through this study, it was intended to strengthen the links between research and teaching, as well as to promote an environmental education that surpasses the representation of knowledge as something fragmented and distant from students' problems.

Made available in DSpace on 2014-12-17T15:54:59Z (GMT). No. of bitstreams: 1 JosePGB_DISSERT.pdf: 1710204 bytes, checksum: 5ee486fb6a3193951f164bedc0f67abc (MD5) Previous issue date: 2012-02-09 / Universidade Federal do Rio Grande do Norte / The semi-arid Northeast region are coming through changes since its formation causing changes in the landscape and increased degradation. The economic dynamics which was established at the Potiguar semiarid had for a long time settled in livestock, subsistence agriculture and cotton, however, these economies decline from the year 1970. Thus, the Potiguar spaces are undergoing by a process of space reordering marked by the growth of agricultural activities and the process of urbanization. In the Potiguar western region these changes weaken significantly transform the landscape. In these areas, the process of urbanization and agricultural activities have caused changes in the hinterland landscape changing the natural dynamics of the caatinga biome that has been subject to negative interference with the indiscriminate removal of vegetation. In this case, the specific study area of the watershed of Cajazeiras Creek located in the cities of Pau dos Ferros, ?gua Nova, Encanto and Rafael Fernandes, changes in the landscape has led to degradation and environmental fragility. From this perspective, the research objective is to assess the dynamics of the landscape of the watershed of Cajazeiras Creek, semiarid region of the state of Rio Grande do Norte, identifying the degrading factors, the most degraded areas and/or susceptible to degradation and environmental fragility. The research investigated the phenomena of light geosystems theory that emphasizes the integration of elements in shaping the landscape. During this reporting period, it was carried out exploratory and bibliographical research, and geoprocessing techniques to assess the social and environmental conditions of the researched area and its environmental fragility. To do so, first, it was made an multitemporal analisis on the basis of the years 1984, 1996 and 2009 demonstrating that the dynamics of use and land cover in the watershed of Cajazeiras Creek showed a significant change in the landscape, especially in the caatinga vegetation. This has been recovering in various areas of the watershed, especially in its upper course in the mountains of Bom Sera, in Encanto city. The analysis showed the need to develop policies and programs for the maintenance, restoration and preservation of the caatinga vegetation of the river network and of water bodies. In addition, it was identified the most degraded areas of the watershed, environmental fragility and potential emerging that take into account the landscape components such as climate, topography, geology, pedology, geomorphology and the use and occupation of the soil in an integrated manner. The results show that the landscape of the watershed has medium and high environmental fragility throughout its area, especially on the banks of the river network provided by the use and occupation of the soil in an inadequate way with the environmental conditions of the watershed / O semi?rido nordestino vem passando por mudan?as desde sua forma??o acarretando transforma??es na paisagem e aumento da degrada??o. A din?mica econ?mica que se estabeleceu no semi?rido potiguar durante muito tempo esteve assentada na pecu?ria, agricultura de subsist?ncia e algod?o, entretanto, essas economias declinam a partir dos anos de 1970. Desse modo, os espa?os potiguares est?o passando por um processo de reordenamento espacial marcado pelo crescimento das atividades agropecu?rias e pelo processo de urbaniza??o. Na regi?o do oeste potiguar tais mudan?as fragilizam e transformam significativamente a paisagem. Nessas ?reas, o processo de urbaniza??o e a atividade agropecu?ria t?m provocado mudan?as na paisagem sertaneja alterando a din?mica natural do Bioma Caatinga que passou a sofrer interfer?ncias negativas com a retirada indiscriminada da vegeta??o. No caso, espec?fico da ?rea em estudo a microbacia do Riacho Cajazeiras localizada nos munic?pios de Pau dos Ferros, ?gua Nova, Encanto e Rafael Fernandes as altera??es na paisagem tem provocado a degrada??o e a fragilidade ambiental. Nessa perspectiva, o objetivo da pesquisa consiste em avaliar a din?mica da paisagem da microbacia do Riacho Cajazeiras, semi?rido potiguar, identificando os fatores degradantes, ?s ?reas mais degradadas e/ou suscept?veis a degrada??o e as fragilidades ambientais. A pesquisa investigou os fen?menos a luz da teoria geossist?mica que enfatiza a integra??o dos elementos na forma??o da paisagem. Para a realiza??o do trabalho foram realizadas as pesquisa explorat?ria, bibliogr?fica, o trabalho de campo e t?cnicas de geoprocessamento para avaliar as condi??es socioambientais da ?rea de pesquisa e sua fragilidade ambiental. Para tanto, primeiramente, foi feito uma analise multitemporal com base nos anos de 1984, 1996 e 2009 demonstrando que a din?micade do uso e da ocupa??o do solo na microbacia do Riacho Cajazeiras mostrou uma mudan?a significativa na paisagem, especialmente, na vegeta??o de caatinga. Esta vem se recuperando em varias areas da microbacia, principalmente, em seu alto curso nas Serras do Bom Sera, do Encanto. A an?lise mostrou a necessidade de desenvolver pol?ticas e programas voltados para a manuten??o, recupera??o e preserva??o da vegeta??o de caatinga da rede fluvial e dos corpos d ?gua. Al?m disso, foram identificadas as ?reas mais degradadas da microbacia e a fragilidade ambiental potencial e emergente que levam em considera??o os componentes da paisagem tais como: clima, relevo, geologia, pedologia, geomorfologia e uso e ocupa??o do solo de forma integrada. Os resultados mostram que a paisagem da microbacia apresenta fragilidade ambiental m?dia e alta em toda sua ?rea, destacando-se, nas margens da rede fluvial proporcionada pelo o uso e ocupa??o do solo de forma inadequada com as condi??es ambientais da microbacia

A Reserva Biológica (REBIO) de São Donato é uma Unidade de Conservação localizada na fronteira oeste do Rio Grande do Sul, no trecho médio da bacia do rio Uruguai, no bioma Pampa. A área da REBIO é constituída por uma área úmida – banhado – característico do Pampa. Entretanto, desde o seu decreto em 1975, o banhado vem sofrendo impactos da rizicultura, essa região é a maior produtora do estado. Assim, o objetivo geral dessa dissertação é analisar a dinâmica e a fragilidade ambiental da Reserva Biológica de São Donato, a partir de geoprocessamento. Para atingir esse objetivo foram utilizados: dados de precipitação diários e imagens orbitais, de 1984 a 2016, que indicassem inundação no banhado e sua sub-região hidrográfica; reconhecimento de campo; análise de uso e cobertura do solo do raio de amortecimento da REBIO; análise da fragilidade ambiental a partir da metodologia do Processo Analítico Hierárquico (AHP). Os resultados de análise da inundação do banhado e sua sub-região hidrográfica indicaram três padrões: um padrão regional, que afeta grande parte do trecho médio e alto da bacia do rio Uruguai; um padrão de inundação sub-regional, que compreende a sub-região hidrográfica dos rios Butuí-Icamaquã; um padrão que afeta a área local que compreende o banhado da REBIO de São Donato. As análises do uso e cobertura do solo e da fragilidade ambiental indicaram que as áreas mais frágeis da REBIO correspondem ao banhado e sua vegetação adaptada a umidade, e áreas de planícies de inundação. A avaliação do AHP para a análise da Fragilidade Ambiental se mostrou coesa, confirmando observações realizadas principalmente com relação ao impacto ambiental gerado pelo cultivo de arroz. Espera-se que as informações possam contribuir para estudos futuros de planejamento e gestão da área, e como base para a elaboração do Plano de Manejo da REBIO de São Donato. / The San Donato Biological Reserve (REBIO) is a Conservation Unit located on the western border of Rio Grande do Sul, in the middle stretch of the Uruguay River basin, in the Pampa biome. The area of the REBIO is constituted by a wetland - marsh - characteristic of the Pampa. However, since its decree in 1975, the marsh has been suffering from the impacts of rice cultivation, this region is the largest in the state. Thus, the general objective of this dissertation is to analyze the dynamics and environmental fragility of the San Donato Biological Reserve, based on geoprocessing. To achieve this objective, daily precipitation data and orbital images from 1984 to 2016 were used to indicate flooding in the marsh and its sub-river basin; Field recognition; Use analysis and soil cover of the REBIO Damping Ray; Analysis of the environmental fragility from the Analytic Hierarchy Process (AHP) methodology. The results of flood analysis of the marsh and its hydrographic sub-region indicated three patterns: a regional pattern, which affects much of the middle and upper reaches of the Uruguay River basin; A subregional flood pattern comprising the sub-river basin of the Butuí-Icamaquã rivers; A pattern that affects the local area comprising the marsh of San Donato Biological Reserve. The analyzes of soil use and cover and environmental fragility indicated that the most fragile areas of REBIO correspond to the wetland and its vegetation adapted to humidity and floodplain areas. The evaluation of the AHP for the analysis of the Environmental Fragility showed to be cohesive, confirming observations made mainly in relation to the environmental impact generated by rice cultivation. It is hoped that the information may contribute to future planning and management studies of the area, and as a basis for the elaboration of the São Donato REBIO Management Plan.

The study of supercooled liquids and glasses remains one of the most divisive and divided fields in modern physics. Despite a vast amount of effort and research time invested in this topic, the answers to many central questions remain disputed and incomplete. However, the link between the behaviour of supercooled liquids and their energy landscapes is well established and widely accepted. Understanding this link would be a key step towards resolving many of the mysteries and controversies surrounding the glass transition. Therefore the study of glassy energy landscapes is an important area of research. In this thesis, I report some of the most detailed computational studies of glassy potential energy landscapes ever performed. Using geometry optimisation techniques, I have sampled the local minima and saddle points of the landscapes for several supercooled liquids to analyse their dynamics and thermodynamics. Some of my analysis follows previous work on the binary Lennard-Jones fluid (BLJ), a model atomic liquid. BLJ is a fragile glass former, meaning that its transport coefficients have super-Arrhenius temperature dependence, rather than the more usual Arrhenius behaviour exhibited by strong liquids. The difference in behaviour between these two classes of liquid has previously been attributed to differing degrees of structure in the relevant energy landscapes. I have studied models for both fragile and strong glass formers: the molecular liquid ortho-terphenyl (OTP) and viscous silica (SiO$_{2}$) respectively. My results for OTP agree closely with trends observed for BLJ, suggesting that the same diffusion mechanism is applicable to fragile molecular liquids as well as to atomic. However, the dynamics and energy landscape of OTP are made complicated by the molecular orientational degrees of freedom, making the analysis more challenging for this system. Dynamics of BLJ, OTP and silica are all dominated by cage-breaking events: structural rearrangements in which atoms change their nearest neighbours. I propose a robust and general method to identify cage breaks for small rigid molecules, and compare some properties of cage breaks between strong and fragile systems. The energy landscapes of BLJ and OTP both display hierarchical ordering of potential energy minima into metabasins. These metabasins can be detected by the cage-breaking method. It has previously been suggested that metabasins are responsible for super-Arrhenius behaviour, and are absent from the landscapes of strong liquids such as SiO2. My results indicate that metabasins are present on the silica landscape, but that they each contain fewer minima than metabasins in BLJ or OTP. Metabasins are associated with anticorrelated particle motion, mediated by reversed transitions between minima of the potential energy landscape. I show that accounting for time-correlation of particle displacement vectors is essential to describe super-Arrhenius behaviour in BLJ and OTP, but also required to reproduce strong behaviour in silica. I hypothesise that the difference between strong and fragile liquids arises from a longer correlation timescale in the latter case, and I suggest a number of ways in which this proposition could be tested. I have investigated the effect on the landscape of freezing the positions of some particles in a BLJ fluid. This “pinning” procedure induces a dynamical crossover that has been described as an equilibrium “pinning transition”, related to the hypothetical ideal glass transition. I show that the pinning transition is related to (and probably caused by) a dramatic change in the potential energy landscape. Pinning a large fraction of the particles in a supercooled liquid causes its energy landscape to acquire global structure and hence structure-seeking behaviour, very different from the landscape of a typical supercooled liquid. I provide a detailed description of this change in structure, and investigate the mechanism underlying it. I introduce a new algorithm for identifying hierarchical organisation of a landsape, which uses concepts related to the pinning transition but is applicable to unpinned liquids as well. This definition is complementary to metabasins, but the two methods often identify the same higher-order structures. The new “packings” algorithm offers a route to test thermodynamic theories of the glass transition in the context of the potential energy landscape. Over the course of this thesis, I discuss several different terms and methods to identify higher-order structures in the landscapes of model glass formers, and investigate how this organisation varies between different systems. Although little variation is immediately apparent between most glassy landscapes, deeper analysis reveals a surprising diversity, which has important implications for dynamical behaviour in the vicinity of the glass transition.

Common fragile sites are a set of genomic locations with a propensity to form lesions, breaks and gaps on mitotic chromosomes upon induction of replication stress. While the exact reasons for their fragility are unknown, CFS display instability in a cell-type specific manner, suggesting a substantial contribution from an epigenetic component. CFSs also overlap with sites of increased breakage and deletions in tumour cells, as well as evolutionary breakpoints, implying that their features shape genome stability in vivo. Previously, factors such as delays in replication timing, low origin density and transcription of long genes have been implicated in instability at CFS locations but comprehensive molecular studies are lacking. Chromatin structure, an important factor that fits the profile of cell-type specific contributor, has also not been investigated yet. Throughout their efforts to determine the factors that lead to the appearance of CFS lesions, investigators have focused on a single component at a time, potentially missing out complex interactions between cellular processes that could underlie fragility. Additional difficulties come from the cell-type specificity of CFS breakage: it indicates that only cell type-matched data would be informative, limiting the scope for studies using publicly available data. To perform a comprehensive study defining the role of different factors in determining CFS fragility, I explored replication timing, transcriptional landscapes and chromatin environment across a number of CFSs in two cell types exhibiting differential CFS breakage. Initially, I characterised the patterns of CFS fragility in the two cell types on both the cytogenetic and the molecular level. I then used a FISH-based technique to investigate the process of mitotic compaction at active CFS sites and found that the cytogenetically fragile core of these sites sits within larger regions which display a tendency to mis-fold in mitosis. The aberrant compaction of these regions could be observed on cytogenetically normal metaphase chromosomes, suggesting that finer scale abnormalities in chromosome structure underlie the cytogenetically visible breaks at fragile sites. I also investigated the links between transcription of long genes and CFS fragility using two approaches: I quantified levels of expression across all fragile sites using RNA-seq and modified transcription at a single active CFS using the CRISPR genome engineering methodology. My results indicate a complex interplay between transcription and CFS fragility: no simple linear correlation can be observed, but an increase of transcriptional levels at the active CFS led to a corresponding increase in fragility. To investigate the influence of the cell type specific replication programme and replication stress on CFS instability, I mapped replication timing genome-wide in unperturbed cells and under conditions of replication stress in both cell types. I found that replication stress induces bi-directional changes in replication timing throughout the genome as well as at CFS regions. Surprisingly, the genomic regions showing the most extreme replication timing alterations under replication stress do not overlap with CFS, implying that CFS instability is not fully explained by replication delays as previously suggested. Instead, I observed a range of replication-stress induced timing changes across CFS regions: while some CFSs appear under-replicated, others display switches to both earlier and later replication as well as differential recruitment of both early and late origins, implying that dis-regulation of replication timing and origin firing, rather than simply delays, underlie the sensitivity to CFS regions to replication stress. Finally, I investigated large-scale chromatin states at two active CFSs throughout S phase and into G2, the cell cycle stages most relevant stage for CFS breakage. I found that changes in large-scale chromatin architecture accompany the replication timing shifts triggered by replication stress, raising the possibility that such alterations contribute to instability. In conclusion, I assessed the influence of multiple relevant factors on CFS fragility. I found that bi-directional replication timing changes and alterations in interphase chromatin structure are likely to play a role, converging to promote mitotic folding problems which ultimately result in the well-described cytogenetic lesions on metaphase chromosomes and genomic instability.