Faculty of Biological and Environmental Sciences

 

Recent Submissions

  • Johari, Mridul (Helsingin yliopisto, 2021)
    Molecular genetics of late-onset neuromuscular diseases is often challenging to study due to limited patient and family material. This thesis aimed to unravel the genetics of late-onset myopathy patients with inclusion body myositis (IBM) and yet unknown inherited distal myopathy phenotype. IBM is an inflammatory myopathy of idiopathic nature showing characteristic quadriceps and finger flexor muscle weakness and rimmed vacuolar pathology. The molecular etiology of IBM is of key interest due to co-existing cytotoxic T-cell activity. However, the precedence of degenerative pathology and autoimmune features remain unclear, hampering the eventual development of appropriate therapeutic options. Using DNA and RNA sequencing-based data analysis, we aimed at understanding the different components of the molecular pathomechanisms in IBM. Using a limited case-control study, we identified the association of HLA-DQB1 in Finnish IBM patients. Additionally, by performing a comprehensive transcriptomics analysis we observed differential expression and splicing patterns in genes associated with maintaining calcium homeostasis, particularly during different T-cell activity and regulation stages. Disturbed antigen-driven T-cell hyperactivity and eventual loss of T-cell apoptosis could be one of the mechanisms behind the refractoriness of immune therapies in IBM patients. Patients with late-onset rare diseases often experience a long diagnostic journey in multiple and often invasive diagnostic procedures and ineffective symptomatic treatments. Due to limited study material, it is often difficult to ascertain the molecular diagnosis of previously unknown inherited myopathies. Identifying new rare disease-causing genes requires collaborations from different diagnostic centers, sharing deep phenotypic and genomic data. We identified a novel type of slowly progressing late-onset distal myopathy with rimmed vacuoles caused by mutations in the small muscle protein X-linked (SMPX) gene in patients from five different countries. Our genetic analysis revealed four different missense mutations, including two different founder mutations in Europe, indicating that the prevalence of this disease may be higher, and therefore SMPX should be considered in all unsolved male patients with late-onset rimmed vacuolar myopathy.
  • Duru, Ilhan Cem (Helsingin yliopisto, 2021)
    Food products produced by humans are usually not sterile and typically contain several types of microorganisms. While there are beneficial microorganisms that are used in production and preservation of food, there are also microorganisms that cause food spoilage and foodborne illness. This study investigated the gene-expression profiles of three types of food-related bacteria during food processes. Mesophilic lactic acid bacteria and Propionibacterium that are added in milk during Maasdam cheese production were examined in Chapter I. Metagenomic analysis suggested that Maasdam cheese microbiota mainly consisted of Lc. lactis, Lb. helveticus, Lb. rhamnosus, and Propionibacterium. Lc. lactis was the most dominant species. Metatranscriptome analysis during transition from the warm room to the cold room showed that flavor-production and central-metabolism genes were downregulated at cold-room temperatures for all species except Lc. lactis. Cold-shock and heat-shock gene expression of psychrotrophic spoilage lactic acid bacteria (LAB) was investigated in Chapter II. Psychrotrophic LAB are the dominant taxa in cold-stored modified-atmosphere packaged meat products. Their metabolic activities are responsible for meat spoilage. Transcriptomic analysis revealed that spoilage-related genes were upregulated in Le. gelidum at cold-shock temperatures. Moreover, cold-shock also caused upregulation of slime-production genes in Lc. piscium, and Plb. oligofermentans. Gene network analysis suggested that rRNA modification and efflux MFS transporter genes were part of the cold-shock response. At the heat-shock temperature Chaperone and Clp family genes were upregulated in all three species. L. monocytogenes is a foodborne pathogen and is the focus of Chapter III. High-pressure processing (HPP) is one of the common methods that inactivate L. monocytogenes in food products. However, L. monocytogenes can still recover from HPP. This study investigated the gene-expression response of L. monocytogenes during HPP recovery. It was predicted that HPP stress was activated by sigma factor B. The data indicated that sRNA Rli47, cobalamin biosynthesis genes, heat-shock genes and cell-wall-related genes were upregulated after HPP. Further downstream analysis using pbp2A mutants confirmed that among cell-wall-related genes, pbp2A played a significant role in HPP recovery. In conclusion, this thesis extends current knowledge of the role of microorganisms in food, ranging from food fermentations (cheese), towards spoilage (in meat) and foodborne pathogens.
  • Parviainen, Tuuli (Helsingin yliopisto, 2021)
    The risk of a large- scale oil spill remains significant as international maritime operations continue to grow globally. Oil spill risks can be considered as complex socio-ecological risks characterized by high levels of uncertainty and ambiguity, i.e. different understandings and perceptions of risks, and societal values. As a result, assessing and managing oil spill risks is challenging. As with other socio-ecological risks, science and scientific knowledge plays an invaluable role in the governance of oil spill risks. However, the role of natural sciences and technical expertise in risk governance is increasingly scrutinized; quantitative risk models and assessments alone are no longer seen as sufficient in addressing the highly value-laden nature of risks. Rather, the emphasis has shifted towards collaborative and participatory approaches that are considered to better account for the complex nature of many of the socio-ecological risks associated with global environmental change. By focusing on oil spill risks, this dissertation contributes to existing social-scientific research on marine risk governance and explores how to govern complex and contested socio-ecological risks. The main aim of this thesis is to explore how oil spill risks are rendered “manageable” by reducing the complexity associated with the risks, i.e. how risk governance is performed through governmentalities. By governmentalities, I refer to the ways risks are framed and constructed through the three inter-related processes of problematizations (the framing of risks), rationalities (discourses that support the adopted frame), and technologies (e.g. models that help to operationalize the adopted frame). The thesis also analyzes how the current governance approach could be improved by supporting new ways of producing knowledge to inform transformations in policy and practice. Therefore, the three sub-questions of the dissertation investigate 1) the problematizations and rationalities that determine and shape oil spill risk governance processes, 2) how scientific knowledge, more precisely, risk models, are used to assess and manage risks, and 3) the potential of Bayesian network (BN) models to act as boundary objects, i.e. objects that support collaborative knowledge production and turn knowledge into action. The study examines these issues with the help of a literature review on Bayesian network (BN) models for oil spill risk assessment (Article I) as well as two case studies (Articles II and III). In Article II, I used influence diagrams based on Bayesian graphical (causal) logic to explore how different stakeholders frame oil spill risks associated with offshore oil exploration and exploitation in the Norwegian Barents Sea. Article III analyzes the potential of risk models to act as boundary objects in governing oil spill risks from shipping in the Gulf of Finland (GoF), the Baltic Sea. The thesis provides insight into how oil spill risks are framed in a very constricted manner by the responsible authorities and institutions and alternative framings of risks are not explored or considered valid. Further, the governance processes are still largely based on techno-scientific knowledge where new knowledge from different scientific disciplines and from outside academia is not integrated into decision-making processes. The study suggests that the reliance on technical knowledge has led to pre-determined solutions where the root causes of risks, such as the expansion of industrial activities in highly ecologically and/or culturally sensitive areas, are not considered as problematic. Rather, risks are merely seen as results of, for example, poor management, lack of appropriate technology, and/ or insufficient scientific knowledge. Finally, the dissertation indicates the need for new, flexible marine risk governance approaches and tools that encourage deliberation and dialogue around competing goals, facilitate collaboration and co-production of knowledge, as well as promote social learning in innovative ways.
  • Talwelkar, Sarang (Helsingin yliopisto, 2021)
    The introduction of targeted therapies and immune checkpoint inhibitors has significantly improved outcomes for a subset of non-small cell lung cancer (NSCLC) patients. These treatments, however, are never curative as clinical resistance typically develops over time, resulting in disease recurrence and patient’s death. Furthermore, not all NSCLC patients can be matched with appropriate targeted or immune-based therapies. Therefore, to overcome drug resistance and provide therapeutic benefit to a larger NSCLC patient population, new therapeutic strategies are urgently needed. Functional profiling of tumor cells collected from cancer patients has the potential to tailor individualized cancer treatments. To assess the translational potential of this strategy for NSCLC, drug sensitivity and resistance testing were conducted using tumor-derived fresh uncultured (passage 0) or cultured (passage 4-10) cells from mouse models and clinical samples. The first part of this thesis concentrated on the utilization of cultures established from murine Kras mutant NSCLC tumors for pharmacological exploration. Drug sensitivity and resistance testing, in conjunction with biochemical dissection of treatment-adaptive RTK activity, led to the functional stratification of Kras mutant NSCLC, and the identification of subtype-selective treatments. The second study in this thesis demonstrated that NSCLC cells obtained from patients can be employed as a reliable pre-clinical model for the identification of single and combinatorial treatment strategies. By employing patient-derived ALK-rearranged NSCLC cells for drug screening, this study discovered PI3Kβ as a potential therapeutic target to improve ALK inhibitor sensitivity. The final section of this thesis assesses the utility of Fresh Uncultured Tumor-derived EpCAM+ Cells (FUTCs) for ex vivo drug response interrogation. The findings of this study showed that patient-derived FUTCs can be reliably utilized for ex vivo drug testing, and thus offering a promising functional diagnostic tool to support individualized cancer treatments. Overall, the results presented in this thesis demonstrate the clinical feasibility and utility of tumor-derived fresh uncultured or cultured cells for pharmacological research: primary cultures can be utilized to examine functional heterogeneity, understand drug resistance mechanisms, and identify combinatorial treatments to improve patient outcomes, whereas FUTC-based functional diagnostic test can be used to identify individualized cancer treatments.
  • Li, Honghong (Helsingin yliopisto, 2021)
    Food security, environmental change and biodiversity loss are immense challenges for global agriculture. Ecological intensification of agriculture is an ideal concept that was introduced to produce more output while reducing negative impacts on the environment, with increasing contributions from the nature itself and ecosystem services. Replacing or reducing the use of synthetic fertilizers by recycling animal wastes and intercropping legumes that can biologically fix nitrogen (N) is a promising strategic choice. In agricultural grasslands, soil microbial communities play important roles in the maintenance of ecosystem functioning and services. The aim of this thesis was to provide scientific insights and recommendations towards agricultural sustainability by investigating how the agricultural management regimes in sub-boreal grasslands affect soil microbial communities and their capacity for N cycling and how such changes might affect crop yield. To reach this aim, a three-year field study (2013 - 2015) was established at Viikki Experimental Farm with a split-plot design. Timothy (Phleum pratense L.) and red clover (Trifolium pratense L.) swards, either as pure stands or in mixture were sown in the experimental plots, with bare fallow as a reference. Except for the control plots that received no N fertilizer, the plots were fertilized with either organic fertilizer (urine in 2014 and manure slurry in 2015) or synthetic fertilizer calcium nitrate [Ca(NO3)2]. The fertilizers were applied two times per year with a reduced level in 2014 (55-60 kg N ha-1 year-1) and a normal Finnish level in 2015 (150 kg N ha-1 year-1). We determined crop growth and soil properties, soil bacterial taxa communities assessed by using 16S rRNA gene amplicon sequencing, and the size of N-cycling communities assessed by quantitative PCR applied to key N-cycling functional genes. The crop mixtures gave higher yields and were less prone to potential N loss than the pure stands. In 2015, the annual crop yield with synthetic fertilizer was 55% higher than the yield obtained by using organic fertilizer. N fertilizer application increased the annual yield of the mixture and timothy but not that of red clover, and the annual yield of the mixture without fertilizer was higher than that of the pure stands with fertilizers, with the exception of pure timothy with synthetic fertilizer. The bacterial communities changed over time, with higher temporal variations than the variations caused by the fertilization or intercropping treatments. The turnover of the bacterial composition over time was driven by shifts in relative abundance of the same taxa rather than by the gain or loss of different taxa. The major differences in soil bacterial community diversity and composition were observed between fallow and planted plots, with lower community diversity in fallow than in planted plots in 2015. These were mainly associated with the differences in soil nitrate and acidity level. The differences between pure red clover plots and pure timothy plots were restricted to differentially abundant operational taxonomic units (OTUs). The number of differential OTUs between organic and synthetic fertilizer plots increased gradually over time whereas no differential OTUs was found between the plots with no fertilizer and with synthetic fertilizer applied. At the last time point of the experiment, the bacterial community composition in plots that had received organic fertilizer was different from that in plots with no fertilizer or with synthetic fertilizer applied. This was mainly associated with differences in soil moisture and total carbon content. Except for the abundance of ammonia oxidizing bacterial (AOB) community, which was affected by fertilization, the abundances of all other N-cycling communities changed over time. Most of the N-cycling communities we measured were relatively conserved in response to the treatments. The fertilization effects or the combined fertilization and intercropping effects were observed only at single time points. For example, the abundances of nirK (gene encoding copper-based nitrite reductase), nirS (gene encoding cytochrome cd1 nitrite reductase), nosZI (gene encoding the clade I of nitrous oxide reductase), nosZII (gene encoding the clade II of nitrous oxide reductase) and nrfA (gene encoding cytochrome c nitrite reductase) were lower in pure red clover plots than in mixture and pure timothy plots at the first time point in June 2014, which was particularly clear for the plots with no applied N fertilizer. With correlation analysis, we found that nirS and nosZII communities were more sensitive to the changes in soil properties than their functional counterparts nirK and nosZI communities. Finally, by integrating the results with structure equation modelling analysis, we found that management affects the potential N retention and the mitigation of N2O indirectly as soil bacterial communities play important roles in mediating the management effects on crop yield and N cycling in grassland ecosystems.
  • Lesnikova, Angelina (Helsingin yliopisto, 2021)
    Induction of neuronal plasticity by drugs and physiological mechanisms has been an important topic in the modern neuroscience investigations due to its potential to restore functions in a wide range of disorders. However, significant progress in this area has been hampered by the lack of knowledge on the precise mechanisms and underlying molecular pathways. Perineuronal nets (PNNs), extracellular matrix structures that are particularly abundant around parvalbumin-containing (PV+) neurons, mature towards the end of the critical period in the brain development and inhibit neuronal plasticity. However, molecular pathways affected by PNN composition are not well known. On the other hand, tropomyosin receptor kinase B (TRKB), receptor for brain-derived neurotrophic factor (BDNF), is a well-recognized facilitator of plastic changes in the central nervous system. Whether these two opposing mechanisms converge on any common molecular pathway has not been identified previously. In the first study, we identified that perineuronal nets inhibit flexibility of neuronal cells and circuits through binding to receptor-like protein tyrosine phosphatase sigma (PTPσ), which subsequently dephosphorylates and inactivates TRKB. Specifically, we found that PNN component aggrecan restricts TRKB phosphorylation, while PNN removal by enzymatic activity of chondroitinase ABC (chABC) increases TRKB phosphorylation in neuronal cultures in vitro. We also found that a well-known ability of chABC to induce ocular dominance plasticity in the adult brain is dependent on TRKB, as mice deficient for TRKB in parvalbumin neurons (PV-TRKB+/-) do not exhibit enhanced plasticity in the visual cortex after chondroitinase treatment. We discovered that genetic knockdown of the PNN receptor PTPσ facilitates TRKB activation in vitro and in vivo, and that adult PTPσ+/- mice have juvenile-like plasticity in the visual cortex. We confirmed that TRKB and PTPσ display interaction in vitro, and identified that interaction occurs in the transmembrane domain. Finally, we found that the interaction between TRKB and PTPσ is diminished by antidepressant fluoxetine in vitro and in vivo. Altogether, our study suggests that chABC and antidepressant treatment induce plasticity through activation of TRKB by relaxing dephosphorylating control of PTPσ over it. In the second study, we focused on studying the molecular and behavioral phenotype of increased tonic plasticity displayed by genetic deficiency of PTPσ. We found that PTPσ+/- mice have increased phosphorylation of PLCγ1 but not Akt or Erk, suggesting that PTPσ specifically modulates PLCγ1 but not the other TRKB downstream signaling pathways. We did not find any changes in the expression levels of PSD-93, PSD-95 or in the number of excitatory synapses in their brain, suggesting that their phenotype cannot be explained by an altered number of synapses. We carried out a battery of behavior tests and discovered that PTPσ+/- mice have improved short-term and deteriorated long-term memory, as evident from their performance in the novel object recognition and fear conditioning tests. Finally, these mice do not exhibit any behavior abnormalities in elevated plus maze, open field, marble burying or forced swim test, suggesting that their behavioral changes are specific for tests requiring cognitive flexibility. We propose the term "hyperplasticity" to describe the PTPσ+/- mouse phenotype. Altogether, the current PhD project investigated the interaction between perineuronal nets, transmembrane phosphatase PTPσ and tyrosine receptor kinase TRKB in mediating plasticity in the brain.
  • Lu, Changyi (Helsingin yliopisto, 2021)
    Soils play a fundamental role in many ecological processes and in the provision of a multitude of vital ecosystem services not only in natural/semi-natural ecosystems but also in disturbed urban milieus. As many soil-derived ecosystem services are closely linked to human health and climate change, it is important to acknowledge the ability of urban soils to provide ecosystem services in the context of rapid urbanisation. Growing evidence shows that, despite various disturbances in urban landscapes, sparse vegetation can still control the provision of soil-derived ecosystem services in urban greenspaces due to the close linkages between aboveground and belowground milieus. Therefore, knowledge on the role of urban greenspace soils, in connection with plants, in providing ecosystem services likely leads to better urban planning and management practices. The main objective of this thesis was to explore the mechanisms by which plants – plant functional types (evergreen trees, deciduous trees, lawns) in particular – affect soil carbon (C) and nitrogen (N) dynamics in urban parks of varying ages and in natural/semi-natural forests acting as a reference. Field experiments, including litter decomposition, root production, soil greenhouse gas emission, and soil inorganic N leaching, were conducted in boreal cities. Additionally, soils underneath impervious surfaces were investigated for the effects of soil sealing on soil C and N storage to better understand the role of urban soils (greenspace soils vs. sealed soils) in C and N accumulation under boreal climate. I showed that evergreen trees (spruce, mostly Picea sp.) accumulate C and retain N in soils more than deciduous trees (linden, mostly Tilia x vulgaris) and lawn (grass/herb, mostly Poa and Festuca species). This was likely due to slow rates of litter decomposition and high root production of evergreen trees. Moreover, evergreen trees modified soil properties by lowering soil pH and soil moisture content efficiently, both of which can retard litter decomposition and N denitrification. Evergreen trees reduced soil greenhouse gas emissions and thus have a higher potential to mitigate the negative effects of anthropogenic N pollution and climate change in urban environments. Importantly, despite the various disturbances and management practices in urban parks, the mechanisms through which plant type controls soil C and N dynamics are independent of both habitat (urban parks vs. natural/semi-natural forests) and park age (young vs. old parks). Additionally, soil sealing has substantial, negative impacts on soil C and N storage, which critically hampers their ability to provide ecosystems services in cities under boreal climate. I am the first to study the mechanisms behind plant-soil interactions as affecting ecosystem services in urban greenspaces in boreal cities. This thesis clearly highlights the importance of urban greenspace soils in providing ecosystem services under boreal climate and suggests that selecting the right plant type, here evergreen trees, in urban greenspaces boosts the ability of urban soils in ecosystem services provision. As the build-up of organo-mineral associations strongly affects soil organic matter stabilisation, further research is needed to explore the potential effects of plant type on soil organo-mineral associations in urban greenspaces. Further research is also required to study how far away from trees plant-soil interaction extends in urban parks, which is important for determining optimal tree density in urban parks, and in accurately calculating C and N budgets at the park level.
  • Robinson, Sinikka (Helsingin yliopisto, 2021)
    Anthropogenic climate change is one of the biggest threats to biodiversity and ecosystem functioning in high-latitude ecosystems. These regions are warming faster than the global mean, prompting changes in soil temperature, precipitation, and the onset and length of seasons. Species-level responses to these changes, rooted in temperature-dependent metabolic processes, will have consequences which permeate all levels of biological organisation and ecosystem functioning. Using a naturally occurring soil temperature gradient spanning 5–30 °C in the Hengill valley in Iceland, I set out to provide insight into long-term responses of species, communities, and soil processes to soil temperature. Epigeal plant and invertebrate communities were sampled in the summers of 2013, 2015, and 2017. In 2018, in addition to sampling aboveground communities, belowground communities and soil physiochemical properties were also examined. Chapter I sets out to examine the effect of soil temperature on populationand communitylevel epigeal invertebrate and plant communities. We recorded a significant decrease in the α-diversity of plants and invertebrates with increasing temperature, apparently driven by warming-induced decrease in plant species richness, and changes in the dominance hierarchy of the invertebrate community. Warm-adapted species replaced species with lower thermal optima in warm patches, leading to significant turnover in community structure with warming. Mean body size decreased with warming, and together with an overall increase in the abundance invertebrates at warmer patches, led to no effect of temperature on community biomass. Despite clear community-level trends in diversity and biomass indices, population-level effects were inconsistent, driven by differential thermal tolerances. However, these baseline trends were not consistent throughout the active season, as revealed in Chapter II. Seasonal fluctuations in invertebrate diversity indices were dampened by warming, while variation in biomass increased. Consistent with our findings in Chapter I, we found that smaller species were found in warmer patches and tended to emerge earlier in the season, lending support to general temperature-size rules. Shifts in species and community-level responses can have cascading effects on species interactions and ecosystem functioning. Chapter III revealed that increasing temperature strengthened plant-invertebrate interactions. Warming increased herbivory at the community-level despite inconsistent trends at the species-level mediated by plant development stage and the composition of the surrounding vegetation. Our results in Chapter IV indicate that belowground communities may be more resistant to soil warming than aboveground communities. We found that soil organic matter (SOM), rather than temperature, governed spatial variation in soil attributes. Warming had no effect on decomposition, and while some effect on the activity of nitrifiers was observed, SOM appeared to be the driving force behind N mineralisation. Warming-induced changes in nutrient availability had a positive effect on aboveground plant biomass, while belowground plant biomass was negatively affected by increasing temperature. The results presented in this thesis suggest that despite warming having strong effects on populations and communities, ecosystem functioning in the long run may be driven more by changes in resources than by direct effects of temperature. This thesis contributes to a growing body of literature indicating that long-term responses to climate change are complex and still poorly understood. Further research is needed that examines the potential for ecosystems to adapt and acclimatise to changing abiotic conditions, so that climate change policies can prioritise those species, processes, and ecosystems which are most vulnerable to climate change.
  • Beresford, Jack (Helsingin yliopisto, 2021)
    Hybridization and gene flow between diverging populations is widespread among taxa, it can homogenize previously diverging populations and is often viewed as a counteractive force to speciation. While much work has focused on how populations accumulate barriers to gene flow in the gradual process of speciation, hybrids themselves have often received less attention. In this thesis I investigate fundamental questions about hybridization between two wood ant species, Formica aquilonia and F. polyctena. I utilized multiple different methods, including bioinformatics, transcriptomics and gene expression, population genetics, and mating behavioural assays. In Chapter I, I found evidence of widespread hybridization between these two species in southern Finland. Over half of the populations were hybrid, and my data indicated that they have had many independent origins. Furthermore, hybrid populations had variable levels of admixture, suggesting that hybridization has been historic and is ongoing in this system. In Chapter II, I characterised mate choice in virgin queens of F. aquilonia and hybrids, and compared this to the realized mate-choice of old queens in nature. I also recorded egg laying and hatching rates of old queens to study the consequences of hybridization. This study revealed asymmetric preferences of F. aquilonia and hybrid queens, which could lead to the persistence of hybrid populations in nature. Egg laying rates did not differ, however the eggs of hybrid queen hatched 83% less than those of F. aquilonia revealing the costs of hybridization. In Chapter III, I studied gene expression patterns associated with introgressed alleles at candidate barrier loci known to be under selection during development. This was achieved by developing two de novo transcriptomes of distinct hybrid lineages from a long-term study population of hybrid wood ants. I found that only a fraction of the transcriptomes were differentially expressed in association with introgression. In Chapter IV, I contributed towards the de novo genome assembly from a single hybrid male, which leveraged the large body size of these ants and recent advances in sequencing technology to create a cost-effect reference genome. Collectively the chapters of this thesis contribute fundamental knowledge towards our understanding of this emerging model system, as well as reference genomic and transcriptomic resources for future studies to investigate admixture and selection. My results add to the growing evidence of widespread hybridization between diverging taxa, advance our understanding of the genetic basis of selection in this system, and open new avenues of research into the persistence of Formica hybrids and their role in the future evolutionary trajectories of these species.
  • Jurgilevich, Alexandra (Helsingin yliopisto, 2021)
    There is a scientific consensus on the need to account for the dynamics of non-climatic factors of climate risk, i.e., vulnerability and exposure. However, there are a number of gaps and challenges associated with defining, conceptualizing and operationalizing it methodologically. Accounting for vulnerability dynamics is most pertinent in the urban context, due to the rapid pace of population and economic growth in cities, and a large concentration of people and assets subject to potential climate change risks. This thesis studies the phenomenon of urban vulnerability dynamics from theoretical, conceptual and methodological perspectives. Furthermore, it examines vulnerability dynamics from the perspective of urban adaptation governance and information needs. It begins with a systematic literature review, which canvasses the state of the art in urban vulnerability dynamics. The findings show that vulnerability dynamics is not widely taken into account in risk and vulnerability assessments at sub-national level. Moreover, many empirical studies assess future hazards while vulnerability and exposure are assessed at their current state. Next, the status of adaptation in local-level decision-making is explored with a survey to understand practitioners’ needs for adaptation and climate risk management information. The findings show that while practitioners use a wide range of information, there is still a need for non-climate services, i.e., tailored information on vulnerability and exposure as well as how it can be applied in risk management. Building on these results, I develop a novel mixed methods approach to study urban vulnerability dynamics as a process and apply it to the case of Helsinki, Finland, with the timeframe up to 2050. The aim of the study is to understand what socio-economic and land use changes influence future urban vulnerability, and to reconstruct pathways of vulnerability development. I integrate quantitative, qualitative and participatory methods for data collection, as well as quantitative and qualitative methods for data analysis. The results show the direct, indirect and cascading effects of changes in socio-economic drivers onto vulnerability, allowing for the reconstruction of vulnerability development pathways and the establishment of patterns of indicator changes. Finally, I draw on the epistemological foundations of futures research and on governance literature to find connections, and critically appraise the approach developed and the results of the case study to discern the methodological and conceptual contributions. I also draw connections between futures research, governance and vulnerability assessment literature, and, as a result, propose a framework for the epistemological positioning of vulnerability assessments. To conclude, this thesis advances our understanding of vulnerability dynamics, develops the methods to account for it and explores the implications of such knowledge for adaptation governance and urban planning.
  • Lak, Behnam (Helsingin yliopisto, 2021)
    The endoplasmic reticulum (ER) is a continuous network of multiple functional and structural subdomains. This largest membrane-bound organelle in eukaryotic cells is comprised of the nuclear envelope and a dynamic network of peripheral interconnected sheets and tubules. ER function requires an intricate balance between its dynamic, structures, and functions. ER sheets and tubules orchestrate a complex yet not fully understood role in giving ER its explicit structure and function. The ratio of sheet and tubule conformations differs significantly within cell types and during the cell cycle. Such balance is possible with a well-functioning set of factors that communicate with each other throughout the cell cycle, and are responsible for shaping the ER sheets and tubules. These factors bring about the dynamic nature of the ER. The ER membrane harbors many key proteins involved in lipid metabolism, protein synthesis, and membrane shaping, maintenance, and remodeling. This PhD thesis is centered on the study of the family with sequence similarity 134, member C protein (FAM134C) using advanced microscopy techniques. FAM134C localizes to high curvature ER: sheet edges and tubules. Similar to Reticulon family proteins (RTNs) and FAM134B, it promotes ER tubulation upon overexpression through its reticulon homology domain (RHD). Importantly, FAM134C maintains the ER shape, and the shape and structure of the ER accommodate its function. Multiple functions are associated with the ER; however, very little is known about the relative distribution of these functions within the ER subdomains. How various functions are spread within the ER network is an intriguing question in cell biology. The thesis dissected the ER structural subdomains using a combination of light microscopy and quantitative immuno-electron microscopy. The distribution of function in the ER network is highly dynamic and most likely shifting upon changes in the cellular environment and nutrient availability. Thus far, it is arguable that no subdomain is responsible for hosting one function exclusively. The ER is a communicative organelle and contacts almost all other organelles in the cell. It is the site for organelle biogenesis, such as phagophore formation. Phagophore, or the isolating membrane, is the central organelle in autophagy (cellular self-eating). Our functional studies on FAM134C revealed its specific role in regulating the size, number, and cargo of autophagosomes upon amino acid starvation. Obviously, structural proteins, either individually or in complex, serve not only structural-maintenance roles but also other crucial functions in the cell. Lastly, we investigated the subcellular localization of the structural protein, Golgi reassembly stacking protein (GRASP55), in autophagy flux. Upon glucose starvation, GRASP55 shifts its localization from medial- and trans-Golgi cisternae to the surface of autophagosome-lysosome, where it facilitates the membrane fusion between autophagosome and lysosome through its interaction with LC3 and LAMP2. The results obtained during this project have strengthened our understanding of the proteins and factors involved in ER structure, function, and biogenesis, and thereby provided valuable insights into normal cell functions. Identification of the proteins and forces that maintain the ER structural and functional subdomains would be a pivotal step towards unraveling the relation between many diseases and the ER. This in turn could be the basis for summoning future strategies with therapeutic potentials.
  • Liao, Wenfei (Helsingin yliopisto, 2021)
    How does urban nature work? This question has fascinated many ecologists in recent decades. Biodiversity in urban nature is a core focus of urban ecology, because it benefits the well-being of urban residents by providing ecosystem services and nature-based solutions. However, most research about urban biodiversity has been conducted in terrestrial urban habitats, while the blue component, i.e. water surfaces, and biodiversity in urban blue have often been neglected. Recognising what urban habitats exist and understanding the ecological patterns and processes in such habitats are important in incorporating ecological knowledge into urban planning and biodiversity conservation. In this thesis, I use diving beetles (Dytiscidae) as my focal taxon to investigate how landscape connectivity and predator-prey interactions affect aquatic biodiversity in Finnish urban ponds. Chapters I and II focus on landscape features, investigating how dytiscid assemblages change along a gradient of urbanisation and how dytiscid community similarity responds to the structural connectivity of urban ponds. The results suggest that urban ponds have the capacity to support biodiversity but low structural connectivity between urban ponds can restrict the dispersal of dytiscids. Chapters III and IV focus on predator-prey interactions, investigating how dytiscid assemblages are affected by the presence of fish predators and how different levels of predation risk modify dytiscids’ habitat use and habitat selection. I found that the presence of fish decreases dytiscid species richness and abundance, and that dytiscids, especially small-sized species, prefer fishless habitats. The availability of spatial prey refugia can ease the high predation pressure in ponds with fish. To conclude, both landscape features and habitat-specific features affect dytiscids assemblages in urban ponds. Providing high pond density can improve structural connectivity between ponds and facilitate the dispersal of dytiscids, as well as other aquatic organisms. Retaining fishless habitats in an urban pondscape is crucial to support aquatic biodiversity. Provision of spatial prey refuges, such as aquatic vegetation, can facilitate the coexistence of predators and prey in urban ponds. The findings of this thesis provide insights into freshwater biodiversity conservation in urban regions.
  • Sinclair-Waters, Marion (Helsingin yliopisto, 2021)
    Understanding the genetic architecture of adaptive traits is a common goal in evolutionary biology. However, there are relatively few well-characterized genetic architectures for adaptive traits in non-model systems, particularly in wild populations. In this thesis, we further characterize the genetic architecture of age at maturity in Atlantic salmon using a combination of genomic-enabled approaches. First, a large-scale genome-wide association study of ~11000 male Atlantic salmon, with ~500K single nucleotide polymorphisms (SNPs) genotypes, was used to identify loci underlying age at maturity. Significant associations were found on 28 of the 29 Atlantic salmon chromosomes, including two strong signals at the six6 and vgll3 gene regions. Furthermore, 116 candidate loci with varying effect sizes were identified revealing a mixed genetic architecture with a combination of large-effect loci and a polygenic component consisting of multiple smaller-effect loci. A combination of multi-SNP association methods and individual-level sequencing data was then used to resolve the genetic architecture within the 116 candidate loci for Atlantic salmon age at maturity. The genetic architecture within these candidate loci was relatively simple, where the association was driven by a single mutation. Finally, ~6000 male Atlantic salmon with a high frequency of recombinant alleles at a known large-effect locus spanning two linked genes, vgll3 and akap11, were reared to maturation age. Vgll3 SNP variation was strongly associated with maturation timing, however, akap11 SNP variation showed little to no association with maturation timing, suggesting that variation linked to vgll3 is driving the association at this large-effect locus. Together, these findings further refine our understanding of the genetic architecture for Atlantic salmon age at maturity. Additionally, this thesis provides an analytical framework for characterizing the genetic architecture of adaptive traits in non-model systems.
  • Wang, Yinyin (Helsingin yliopisto, 2021)
    Traditional Chinese medicine (TCM) has obvious efficacy on disease treatments and is a valuable source for novel drug discovery. However, the underlying mechanism of the pharmacological effects of TCM remains unknown because TCM is a complex system with multiple herbs and ingredients coming together as a prescription. Therefore, it is urgent to apply computational tools to TCM to understand the underlying mechanism of TCM theories at the molecular level and use advanced network algorithms to explore potential effective ingredients and illustrate the principles of TCM in system biological aspects. In this thesis, we aim to understand the underlying mechanism of actions in complex TCM systems at the molecular level by bioinformatics and computational tools. In study Ⅰ, a machine learning framework was developed to predict the meridians of the herbs and ingredients. Finally, we achieved high accuracy of the meridians prediction for herbs and ingredients, suggesting an association between meridians and the molecular features of ingredients and herbs, especially the most important features for machine learning models. Secondly, we proposed a novel network approach to study the TCM formulae by quantifying the degree of interactions of pairwise herb pairs in study Ⅱ using five network distance methods, including the closest, shortest, central, kernel, as well as separation. We demonstrated that the distance of top herb pairs is shorter than that of random herb pairs, suggesting a strong interaction in the human interactome. In addition, center methods at the ingredient level outperformed the other methods. It hints to us that the central ingredients play an important role in the herbs. Thirdly, we explored the associations between herbs or ingredients and their important biological characteristics in study III, such as properties, meridians, structures, or targets via clusters from community analysis of the multipartite network. We found that herbal medicines among the same clusters tend to be more similar in the properties, meridians. Similarly, ingredients from the same cluster are more similar in structure and protein target. In summary, this thesis intends to build a bridge between the TCM system and modern medicinal systems using computational tools, including the machine learning model for meridian theory, network modelling for TCM formulae, as well as multipartite network analysis for herbal medicines and their ingredients. We demonstrated that applying novel computational approaches on the integrated high-throughput omics would provide insights for TCM and accelerate the novel drug discovery as well as repurposing from TCM.
  • Hartikainen, Saara (Helsingin yliopisto, 2021)
    The attenuation of radiation in forest canopies has been studied in depth within the photosynthetically active radiation (PAR, 400-700 nm), but we are still lacking knowledge on how the spectral composition of ultraviolet radiation (UV-B 280-315 nm, UV-A 315-400 nm) varies. Advances in knowledge on the effects of UV radiation has led to growing interest in its study as a trigger of regulatory responses in plants, rather than as a stressor, which is now considered to be rare in plants growing under natural conditions. Furthermore, a growing number of studies suggest that there are complex interactions in perception, signalling and responses of plants to solar spectral irradiance. My dissertation research is focussed on the acclimation and adaptation of leaf flavonoids to solar radiation in plant taxa from contrasting environments assessed through the study of optically measured leaf traits. These responses were studied in forest understorey taxa growing in a seasonally dynamic, but mostly low UV radiation environment, and in taxa growing at high elevation experiencing a high UV radiation environment in a "common garden" setting. More precisely, we examined: 1) how understorey spectral irradiance changes across shade, leaf-shade and sunflecks through the spring and among different forest stands, 2) how optically measured leaf traits and leaf flavonoids in understorey plants change through the growing season, 3) how these patterns relate to seasonal changes in spectral irradiance especially those in UV region, 4) do the patterns of optically measured leaf traits from a large set of taxa, mainly growing at high elevation, follow their patterns of phylogenetic relatedness and 5) how do their leaf traits relate to climatic conditions at their original collection sites. To study these questions, we adopted relatively new monitoring approaches, enabling us both to measure simultaneously the in situ spectral irradiance from the UV to near infra-red (NIR) regions, and leaf flavonols/flavones in vivo repeatedly with a leaf-clip in the field. Our analysis revealed a hierarchy among those factors affecting spectral composition of solar radiation in forest understoreys; most importantly understorey position (sunflecks, shade or radiation transmitted through the canopy of leaves), then stand composition, and date during spring. We found the optically measured leaf flavonol/flavone index (Iflav) in forest understorey species to be plastic and to adjust to changes in climatic conditions. Furthermore, species' leaf retention strategy (e.g., summer green, overwintering leaves) and new leaf production were found to affect the Iflav of plants. All these factors are reflected in the seasonal trends we describe in leaf flavonoids, measured optically (Iflav) and via leaf extracts, across understorey plant communities. For mountain environments, our objectives were to determine factors that underpin leaf flavonoid accumulation of high elevation taxa and whether patterns in optically measured leaf traits followed their phylogenetic relatedness or climatic conditions at their origin. Both these patterns could potentially constrain plant responses. To see if either pattern was present, we tested for a phylogenetic signal particularly in Iflav from a large set of taxa growing in a high-elevation environment and the relationship of mean Iflav of plants to climatic variables. The tests for a phylogenetic signal (Pagel's λ, range from 0 to 1) gave intermediate fitted λ values with significant results for Iflav and anthocyanin index (Iant), while for the smaller set of taxa growing in Kumpula Botanical Garden (southern Finland) only chlorophyll index (Ichl) showed significant results. Despite the relatively low signal for Iflav, we identified certain genera with mainly positive local autocorrelations (local Moran's I) meaning they contained species showing either with mostly high or mostly low leaf trait values. This suggests potential limitations in their leaf flavonol/flavone accumulation responses. Hence, some of these genera may be less well prepared against higher maximum UV radiation and may encounter constraints in migrating upwards, if other compensatory photoprotection mechanisms fail. We did not find a relationship between Iflav and climate at the plants' origin, while our results suggested UV irradiance in the plants' current microhabitat to be important, albeit not the only driver for flavonoid accumulation. In most taxa, we did not find a clear indication of constraints on leaf flavonoid accumulation, thus no evidence that high UV radiation is a detrimental factor in their environment. The values of these optically measured leaf traits represent the outcome of complex interactions between the evolutionary and biogeographical history, and acclimation to the current growing conditions of the plants. In general across the three studies, these results provide evidence that optically measured leaf traits related to flavonoid accumulation are largely flexible and acclimate to local changes in the environment, as well as adjusting over the growing season.
  • Chiarini, Valerio (Helsingin yliopisto, 2021)
    “Structure is more conserved than sequence”. This unanimously accepted concept, which states that two proteins with low sequence similarity (~30%) still feature the same fold, holds true only regarding the correlation between the sequence and the secondary structure elements (mainly helices and sheets) thanks to which an ordinate, three-dimensional arrangement is formed (i.e. in globular domains). For this reason, proteins lacking defined secondary motifs usually display no tertiary structure and are therefore designated as “disordered”. As such, their sequence offers no information about their structure. Interestingly, multi-domain proteins face a similar problem. That is because, although the sequence is informative about the structure of the individual globular domains, their three-dimensional arrangement depends on the domains’ surfaces and degree of freedom upon folding, which cannot be drawn from the sequence. That also means that, while (as stated before) the fold of the individual domains is mainly resistant to mutations, their relative position may be easily altered by them. That is the reason why multi-domain proteins often exert the biological functions of adaptors or scaffold elements instead of performing catalytic activity, for which the formation of an active site at the domain-domain interface is usually required. Due to the limitations of deriving a biological function from sequences of multi-domain proteins, this study structurally and functionally characterizes a three-domain protein (BUBL), formed by an intein flanked by two ubiquitin-like-domains (ubl). It is here demonstrated that BUBL exerts both catalytic and decoying functions as it can conjugate by protein XI splicing one of the three domains (N-ubl) either to itself or to a separate protein (TthRas GTPase) which is specifically lured by the C-ubl (baiting function). Resulting non-canonical ubiquitination, occurring in a single, concerted step and without energy consumption, is a representative example of how molecular evolution can produce the same biological goal by subverting the structural conservation normally required for its achievement. In the case presented here, two different post translational modifications (ubiquitination and protein splicing) are shown to functionally coexist in a unique combination forming a post translational platform, originated by the serendipitous insertion of the intein domain which, in most cases, is biologically inconsequential. This thesis discusses the proposed scientific hypothesis by using bioinformatics, modelling and simulation approaches in combination with experimental techniques of biochemistry and structural biology.
  • Kaikkonen, Laura (Helsingin yliopisto, 2021)
    The oceans are facing increasing pressures from human activities. Growing industrialisation of the ocean space is giving room to both the expansion of existing and emergence of new ocean-based activities, with seabed mining one of the rapidly emerging sectors heralded as a solution to resource sufficiency. As ocean mining activities are still in exploratory stages, the development of seafloor mining is underpinned by high uncertainties on both the implementation of the activities and their consequences for the environment. Realising the full potential of the seas and oceans requires sustainable approaches to their economic development, mainly due to the issues related to the negative environmental effects, yet we lack tools and knowledge to comprehensively evaluate the impacts and further societal implications of emerging maritime sectors. To fill this gap, this thesis aims to provide a more detailed understanding of the environmental risks of seabed mining and how those risks are perceived. This thesis consists of four papers and draws on an interdisciplinary approach that includes quantitative and qualitative analyses, modelling, literature reviews and knowledge syntheses. Paper I synthesises how the environmental impacts of seabed mining have been studied in the past and draws on parallel industries, such as aggregate extraction, to increase the knowledge of the impacts on marine ecosystems. It underlines that most studies have assessed the impacts narrowly, with little appreciation of the uncertainties or cumulative effects. In this paper, I further reflect on areas that need development for comprehensive environmental risk assessments for seabed mining. Paper II contributes to the baseline information on marine mineral precipitates, estimating the distribution of ferromanganese (FeMn) concretions using spatial modelling techniques. In paper III, I develop a probabilistic modelling framework for assessing the risks of seabed mining through a series of interviews with a multidisciplinary group of experts. The risk model is then used to illustrate the impacts of FeMn concretion extraction on benthic fauna in the Baltic Sea, offering a quantitative means to highlight the many uncertainties around the impacts of mining. Paper IV examines whether people care about the impacts of human activities in remote locations. In this paper, I evaluate the dimensions of environmental care for the deep sea and relate this to the perceived risks of seafloor mining by comparing the deep sea to three other remote environments: Antarctica, the Moon, and remote terrestrial environments. The results of this work show that despite people’s low knowledge of the deep sea, people do care about mining activities harming deep-sea ecosystems, and that a stronger emotional connection to remote environments is positively connected to environmental care and perception of the severity of the risks of mining. This thesis contributes to a more comprehensive understanding of the environmental risks of seabed mining and advocates a more transparent approach to emerging industries and their risks. The combined findings of this work suggest that it is fundamental to both increase knowledge of the environment that will be affected by the risks, and to account for the underlying values and emotions towards the marine environment to fathom how those risk will be perceived. An improved appreciation of the risks of emerging maritime industries will be essential to avoid uncontrolled developments and to ensure good stewardship of the marine environment.
  • Conenna, Irene (Helsingin yliopisto, 2021)
    ABSTRACT Due to the perceived low biodiversity of arid environments, species inhabiting these regions have received less research compared to tropical areas and biodiversity hotspots. However, arid conditions are predicted to characterise a larger number of regions globally and there is a greater need to identify strategies that allow species to survive in these harsh environments. Bats occupy a wide variety of habitats, including some of the most arid habitats on Earth, thanks also to their nocturnal habits, ability of powered flight and species-specific physiological adaptations. However, knowledge of the mechanisms in place to face the variety of stressors linked with aridity is still relatively scarce, particularly concerning behaviour and in the light of the diversity characterising bats as a group. In this thesis, I investigate further the responses and strategies that bats employ to cope with aridity, with a particular focus on the role of functional traits and movement. First, I model functional trait variation of bat assemblages to identify trends along the gradient of aridity globally. Bat assemblages inhabiting conditions of higher aridity display morphological and echolocation features more suitable to move in open habitats thanks to the greater speed and cost efficiency of flight. Additionally, larger body sizes appear to be favoured at these conditions, potentially as an advantage to reduce the exposure to cutaneous evaporative water loss by retaining a lower surface-to-volume ratio. Despite these general trends, bat communities in arid environments still retain functional diversity, with manoeuvrable species taking benefit from their ability to hunt in the vicinity of the vegetation. Therefore, I then investigate how a low-mobility species, Lavia frons, copes with seasonal changes in aridity and the associated reduction in resources by following its movement using miniaturised GPS devices across a rainy and a dry season. Despite the overall low mobility observed, L. frons appears to respond to seasonal increases in aridity by moving over larger areas and for extended periods of time, supporting the role of movement as a strategy to offset for low prey densities during harsh periods. Finally, due to the lack of synthesis on the topic of bat responses to aridity, I propose a narrative review integrating current available knowledge and thus providing an overview to facilitate future research. In my literature review, I cover both physiological and behavioural mechanism, pinpointing gaps in knowledge and the need of more direct studies on behaviour. Additionally, I discuss potential trade-offs among responses, focusing on the role of movement and roosting conditions in mediating the impact of environmental stressors. This thesis brings advances in the study of bat responses to aridity, targeting some of the knowledge gaps present in the literature and setting the ground for further research. My results also highlight the importance of taking into account the interactions between physiological and behavioural mechanisms, as well as environmental conditions, when approaching the study of bat responses to aridity.
  • Wang, Sheng Hua (Helsingin yliopisto, 2021)
    Neurophysiological dynamics of the brain, overt behaviours, and private experiences of the mind are co-emergent and co-evolving phenomena. An adult human brain contains ~100 billion neurons that are hierarchically organized into intricate networks of functional units comprised of interconnected neurons. It has been hypothesized that neurons within a functional unit communicate with each other or neurons from other units via synchronized activity. At any moment, cascades of synchronized activity from millions of neurons propagate through networks of all sizes, and the levels of synchronization wax and wane. How to understand cognitive functions or diseases from such rich dynamics poses a great challenge. The brain criticality hypothesis proposes that the brain, like many complex systems, optimize its performance by operating near a critical point of phase transition between disorder and order, which suggests complex brain dynamics be effectively studied by combining computational and empirical approaches. Hence, the brain criticality framework requires both classic reductionist and reconstructionist approaches. Reconstructionism in the current context refers to addressing the “Wholeness” of macro-level emergence due to fundamental mechanisms such as synchrony between neurons in the brain. This thesis includes five studies and aims to advance theory, empirical evidence, and methodology in the research of neuronal criticality and large-scale synchrony in the human brain. Study I: The classic criticality theory is based on the hypothesis that the brain operates near a continuous, second order phase transition between order and disorder in resource-conserving systems. This idea, however, cannot explain why the brain, a non-conserving system, often shows bistability, a hallmark of first order, discontinuous phase transition. We used computational modeling and found that bistability may occur exclusively within the critical regime so that the first-order phase transition emerged progressively with increasing local resource demands. We observed that in human resting-state brain activity, moderate α-band (11 Hz) bistability during rest predicts cognitive performance, but excessive resting-state bistability in fast (> 80 Hz) oscillations characterizes epileptogenic zones in patients’ brain. These findings expand the framework of brain criticality and show that near-critical neuronal dynamics involve both first- and second-order phase transitions in a frequency-, neuroanatomy-, and state-dependent manner. Study II: Long-range synchrony between cortical oscillations below ~100 Hz is pervasive in brain networks, whereas oscillations and broad-band activities above ~100 Hz have been considered to be strictly local phenomena. We showed with human intracerebral recordings that high-frequency oscillations (HFOs, 100−400 Hz) may be synchronized between brain regions separated by several centimeters. We discovered subject-specific frequency peaks of HFO synchrony and found the group-level HFO synchrony to exhibit laminar-specific connectivity and robust community structures. Importantly, the HFO synchrony was both transiently enhanced and suppressed in separate sub-bands during tasks. These findings showed that HFO synchrony constitutes a functionally significant form of neuronal spike-timing relationships in brain activity and thus a new mesoscopic indication of neuronal communication per se. Studies III: Signal linear mixing in magneto- (MEG) and electro-encephalography (EEG) artificially introduces linear correlations between sources and confounds the separability of cortical current estimates. This linear mixing effect in turn introduces false positives into synchrony estimates between MEG/EEG sources. Several connectivity metrics have been proposed to supress the linear mixing effects. We show that, although these metrics can remove false positives caused by instantaneous mixing effects, all of them discover false positive ghost interactions (SIs). We also presented major difficulties and technical concerns in mapping brain functional connectivity when using the most popular pairwise correlational metrics. Study IV and V: We developed a novel approach as a solution to the SIs problem. Our approach is to bundle observed raw edges, i.e., true interactions or SIs, into hyperedges by raw edges’ adjacency in signal mixing. We showed that this bundling approach yields hyperedges with optimal separability between true interactions while suffers little loss in the true positive rate. This bundling approach thus significantly decreases the noise in connectivity graphs by minimizing the false-positive to true-positive ratio. Furthermore, we demonstrated the advantage of hyperedge bundling in visualizing connectivity graphs derived from MEG experimental data. Hence, the hyperedges represent well the true cortical interactions that are detectable and dissociable in MEG/EEG sources. Taken together, these studies have advanced theory, empirical evidence, and methodology in the research of neuronal criticality and large-scale synchrony in the human brain. Study I provided modeling and empirical evidence for linking bistable criticality and the classic criticality hypothesis into a unified framework. Study II was the first to reveal HFO phase synchrony in large-scale neocortical networks, which was a fundamental discovery of long-range neuronal interactions on fast time-scale per se. Study III raised awareness of the ghost interaction (SI) problem for a critical view on reliable interpretation of MEG/EEG connectivity, and for the development of novel approaches to address the SI problem. Study IV offered a practical solution to the SI problem and opened a new avenue for mapping reliable MEG/EEG connectivity. Study V described the technical details of the hyperedge bundling approach, shared the source code and specified the simulation parameters used in Study IV.
  • Shrestha, Kul (Helsingin yliopisto, 2021)
    Mismatch repair (MMR) proteins are involved in maintaining genome integrity in somatic and germline cells. Defects in MMR leads to various abnormalities, such as tumorigenesis in Lynch syndrome (LS) and infertility. MLH1 (a central MMR protein) along with other MMR proteins are involved in repair of replication-induced errors arising due to inaccurate DNA polymerase. If unrepaired (due to defective MMR), these errors accumulate and give rise to a cellular phenotype known as microsatellite instability (MSI). MSI is a hallmark of tumors associated with LS and results from complete loss of MMR; LS patients have high incidence of colorectal cancer. It is still poorly understood why certain tissues in LS, in particular the gastrointestinal (GI) tract, are more vulnerable to MSI-associated tumors. Also, how heterozygosity of MMR genes impact the germline genomic integrity is not known. We hypothesized that certain tissues, in particular those with high proliferating rates, are vulnerable to MMR associated abnormalities compromising microsatellite stability (prior to complete loss of MMR function) in a tissue-specific manner before tumorigenesis. Our aim was to understand how MMR protein levels contribute to MSI in vivo. In the research presented here, we used Mlh1 heterozygous mice (Mlh1+/- mice) as model of LS to investigate how decreased MLH1 levels contribute to tissue-specific MSI, and whether MSI is detectable prior to loss of MMR function and to neoplastic growth. We tested MSI and measured MLH1 levels in primary cells derived from different organs, focusing on the comparison between highly proliferating small intestine and low proliferating spleen. Further, we tested MSI in sperm cells of Mlh1+/- mice. In addition, we studied the association of loss of heterozygosity (LOH) and Mlh1 promoter methylation to tissue-specific MLH1 expression and MSI. The studies were conducted at 4- and 12-month time point. We discovered that highly proliferating normal tissues (small intestine and sperm) of Mlh1+/- mice display MSI which increases with age, while low proliferating spleen was microsatellite stable. Further, Mlh1+/- small intestine showed sporadic decrease in MLH1 levels which associated with the observed MSI, while Mlh1+/- spleens showed expected MLH1 expression (i.e. approximately 50% of wildtype expression). We observed soma-wide Mlh1 promoter methylation in a subset of Mlh1+/- mice; these mice were the most vulnerable to MLH1 expression level decrease and to MSI in the small intestine, while MLH1 expression in other somatic tissues remained unaffected. In brief, we showed that normal small intestine of Mlh1+/- mice is particularly susceptible to MLH1 depletion giving rise to MSI long before neoplasia. Further, we demonstrated that Mlh1+/- sperm exhibit MSI which associates with germline Mlh1 promoter methylation.

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