Using molecular dynamics for the refinement of atomistic models of GPCRs by homology modeling

Despite GPCRs sharing a common seven helix bundle, analysis of the diverse crystallographic structures available reveal specific features that might be relevant for ligand design. Despite the number of crystallographic structures of GPCRs steadily increasing, there are still challenges that hamper the availability of new structures. In the absence of a crystallographic structure, homology modeling remains one of the important techniques for constructing 3D models of proteins. In the present study we investigated the use of molecular dynamics simulations for the refinement of GPCRs models constructed by homology modeling. Specifically, we investigated the relevance of template selection, ligand inclusion as well as the length of the simulation on the quality of the GPCRs models constructed. For this purpose we chose the crystallographic structure of the rat muscarinic M3 receptor as reference and constructed diverse atomistic models by homology modeling, using different templates. Specifically, templates used in the present work include the human muscarinic M2; the more distant human histamine H1 and the even more distant bovine rhodopsin as shown in the GPCRs phylogenetic tree. We also investigated the use or not of a ligand in the refinement process. Hence, we conducted the refinement process of the M3 model using the M2 muscarinic as template with tiotropium or NMS docked in the orthosteric site and compared with the results obtained with a model refined without any ligand bound.Peer ReviewedPostprint (author's final draft

Flavonoid allosteric modulation of mutated visual rhodopsin associated with retinitis pigmentosa

Dietary flavonoids exhibit many biologically-relevant functions and can potentially have beneficial effects in the treatment of pathological conditions. In spite of its well known antioxidant properties, scarce structural information is available on the interaction of flavonoids with membrane receptors. Advances in the structural biology of a specific class of membrane receptors, the G protein-coupled receptors, have significantly increased our understanding of drug action and paved the way for developing improved therapeutic approaches. We have analyzed the effect of the flavonoid quercetin on the conformation, stability and function of the G protein-coupled receptor rhodopsin, and the G90V mutant associated with the retinal degenerative disease retinitis pigmentosa. By using a combination of experimental and computational methods, we suggest that quercetin can act as an allosteric modulator of opsin regenerated with 9-cis-retinal and more importantly, that this binding has a positive effect on the stability and conformational properties of the G90V mutant associated with retinitis pigmentosa. These results open new possibilities to use quercetin and other flavonoids, in combination with specific retinoids like 9-cis-retinal, for the treatment of retinal degeneration associated with retinitis pigmentosa. Moreover, the use of flavonoids as allosteric modulators may also be applicable to other members of the G protein-coupled receptors superfamily.Peer ReviewedPostprint (author's final draft

한국의 죽은 소나무에서 공동 발생하는 목재부후균과 개미에 대한 고찰

학위논문(석사)--서울대학교 대학원 :자연과학대학 생명과학부,2019. 8. Lim, Young Woon.Interaction between fungi and insects such as ants, beetles, wasps and termites inhabiting dead pines has significant ecological implication in the forest as they can decompose wood debris and add nutrients to the soil; however, only scarce information is available regarding the interaction between wood-decaying fungi and ants. Wood-decaying fungi co-occurring with ants in dead pines of South Korea were investigated across 11 localities. A total of 57 pairs of wood-decaying fungi and ants were collected. 30 species of wood-decaying fungi and 14 species of ants were identified based on morphology and molecular analysis. Fungal species belonging to Trichaptum, Xylodon, Hyphodontia, and Ceriporia were dominant and co-occurred with common ant species of Lasius, Camponotus, Pristomyrmex, and Crematogaster across the multiple sampling sites. This study provides a new baseline in unravelling the complex interaction between wood-decaying fungi and ants in forest ecosystems.죽은 소나무에 서식하는 개미, 딱정벌레, 말벌, 흰개미와 같은 곤충과 균류의 상호작용은 목재 잔해를 분해하고 분해 산물을 토양으로 환원할 수 있기 때문에 숲에서 생태학적으로 중요한 의미를 갖는다. 그러나 목재부후균과 개미 사이의 상호작용에 관한 정보는 매우 부족하다. 이 연구에서는 국내의 죽은 소나무에서 개미와 함께 발견되는 목재부후균을 조사하였으며, 각기 다른 여러 지역에서 총 57쌍의 목재 부후균과 개미가 채집되었다. 형태 및 분자 동정에 근거하여 총 30종의 목재부후균과 14종의 개미가 확인되었다. Trichaptum속, Xylodon속, Hyphodontia속, Ceriporia속에 속한 균류가 우점하였으며, 여러 채집지에서 Lasius속, Camponotus속, Pristomyrmex속, Crematogaster속에 속한 비교적 흔한 개미와 함께 채집되었다. 이 연구는 산림 생태계에서 목재부후균과 개미 사이의 복잡한 상호작용을 이해하기 위한 새로운 단초를 제시하였다 .Abstract i List of contentsiii List of Figures iv List of Tables v 1. Introduction 1 1.1. Wood-decaying fungi 1 1.2. Wood-decaying fungi and insects interactions 1 1.3. Korean pine trees 3 1.4. Objective 4 2. Materials and methods 5 2.1. Sampling sites and specimen collection 5 2.1. Fungi collection and identification 8 2.3. Ants collection and identification 9 3. Results 13 3.1. Wood-decaying fungi inhabiting dead pinewoods 13 3.2. Ants nesting in dead pinewoods 21 3.3. Co-occurrence patterns of wood-decaying fungi and ants 28 4. Discussion 31 5. Conclusions 35 6. References 36 7. Abstract in Korean 45Maste

The conflict between attempts to green arid cities and urban livelihoods The case of Dodoma, Tanzania

One of the features that characterise the designated capital city of Dodoma is the limited green landscape element as a result of semiarid climatic conditions of the whole central region of Tanzania. Besides concerted efforts by the Dodoma urban authorities to develop greenery landscape within the city through the Capital City Development Programme, such efforts have fallen into conflict with people’s livelihood activities. In this paper, it is argued that the gap between identification of appropriate landscape features that are not consistent with people's lifestyles and the local conditions are the contributory factors to the observed conflicts between attempts to green the city and livelihoods of the residents. Borrowed planning concepts in the masterplans thatwere imposed on the contextof Dodoma do not reflectthe realityof thepeople's needs and priorities as regards their livelihoods. These concepts have to the greatest extent failed to integrate livelihood activities and greening initiatives. This paper underscores the need for developing locally based planning considerations that take cognisance of all stakeholders and the local context as a way towards harmonising greening initiatives while accommodating people's livelihood needs and activities. Key Words: greening initiatives, livelihood activities, semi-arid cities, urban planning, master plans, Dodoma, Tanzania

Geography of housing markets in spatio-temporal perspective: The case of Residential Land in Hawassa city, Ethiopia

The present study seeks to examine the geography of housing market dynamics in tem-poral and spatial dimensions in the rapidly urbanizing city-Hawassa-Ethiopia. Urban Rent Theory and Classical Models of Urban Land Use were employed to understand the epistemological and ontological milieu. The study employed a mixed research approach. The study reveals that residen-tial land values in the formal market remained skyrocketing to the extent of inducing income-based spatial exclusions over the years, including the peri-urban, as these locations became home to a mosaic of visible and invisible actors, including the government. The findings, conquer the central propositions of the Urban Rent Theory with polycentric CBDs signaling housing price hotspots

A Community-Randomized Evaluation of the Effect of Intermittent Preventive Treatment in Infants on Antimalarial Drug Resistance in Southern Tanzania

Background. Intermittent preventive treatment in infants (IPTi) is the administration of sulfadoxine-pyrimethamine (SP) at 2, 3, and 9 months of age to prevent malaria. We investigated the influence of IPTi on drug resistance. Methods. Twenty-four areas were randomly assigned to receive or not receive IPTi. Blood collected during representative household surveys at baseline and 15 and 27 months after implementation was tested for SP and resistance markers. Results. The frequency of SP in blood was similar in the IPTi and comparison areas at baseline and at 15 months. dhfr and dhps mutations were also similar at baseline and then increased similarly in both arms after 15 months of SP-IPTi. First-line treatment was switched from SP to artemether-lumefantrine before the final survey, when SP positivity fell among infants in comparison areas but increased in IPTi areas. This was accompanied by an increase in dhfr but not dhps mutations in IPTi areas (P = .004 and P = .18, respectively). Conclusions. IPTi did not increase drug pressure or the selection on dhfr and dhps mutants, when SP was the first-line malaria treatment. Introduction of artemether-lumefantrine was followed by an increase in dhfr mutations, consistent with weak selection attributable to SP-IPTi, but not by an increase in dhps mutations, suggesting a fitness cost of this mutatio

Elderly Perceptions Regarding Changes in the Parent-Child Relationship in the Modern Era: A Case of Coast Region, Tanzania

This study aimed at establishing elderly perceptions regarding changes in the parent-child relationship in the Coast region through crossectional design. Both probability and non-probability techniques were used to select the sample. The study managed to collect data from 394 respondents. Data was collected through a questionnaire survey, focus group discussions and key informant interviews. The study findings revealed that older people perceived changes in the parent-children relationship as negative and detrimental. This marks a contrasting difference in the parent-child relationship between the traditional and modern eras. Further, the elderly had a perception that the current generation of adult children has tremendously failed to keep and preserve values, norms, folklore and taboos that used to maintain the parent-child relationship in the past. This has led adult children to lack respect, proper consultation and regular communication with their elderly parents. Modernization and urbanization were perceived as the main causes of changing parent-child relationships in modern days. It is recommended that the government and the community should ensure that traditional norms and values which enforced children’s obedience towards their parents when are old are maintained. Further, the traditional communal parenting system whereby the whole community was responsible for the children's upbringing should be emphasized. Additionally, the community and the government at large should ensure that adult children are taught the importance of the elderly in the community, given their vast wisdom and experience. Moreover, there is a need for the government to collaborate with community leaders to ensure that modernization and urbanization do not alter the norms and values of most Tanzanian societies

Building Densification as a Strategy for Urban Spatial Sustainability: Analysis of Inner City Neighbourhoods of Dar Es Salaam, Tanzania

Building densification in developing countries is shaping the spatial patterns of the inner city neighbourhoods The densification processes are fuelled by higher land values and real estate market dynamics Due to increased land values new building forms uses and density are emerging Although densification is considered as a strategy to achieving compact development and city spatial sustainability the unguided nature of building redevelopment is increasingly posing threats in terms of diminishing spatial and liveability qualities in these neighbourhoods This paper examines the building densification processes in two neighbourhoods of Dar es Salaam City and the resulting effects in terms of plot coverage floor area ratio and overall spatial patterns are explored Observations measurements transect walks interview with officials and map analysis were the key methods employed in gathering data Results indicate that in one of the neighbourhoods building redevelopment was taking place without a proper redevelopment plan to guide the process In both cases several buildings were noted to have higher plot coverage and floor area ratio above the recommended guidelines This was compounded by the weak development control mechanism culminating into poor spatial and liveability qualities There is therefore a need for preparing plans that will guide the redevelopment processes instituting effective development control measures and revisiting the possibility of combining plots to facilitate flexibility in design and move towards urban spatial sustainabilit

Landscape Elements as Determinants of Pedestrian Movement in Urban Public Spaces: the Case of Dodoma, Tanzania

Provision of landscape elements to promote convenient pedestrian movement especially for cities in the tropics has constituted one of the key design elements. Although the majority of the inter-city trips in these cities are made through walking, basic landscape elements to support this mode of transport have been lacking. This paper attempts to evaluate the potentiality of landscape elements (pavements and shade trees) as key determinants in promoting pedestrian movement in urban centres. Two streets; One Way (with paved surface and pedestrian status) and Tembo (also paved but used by both pedestrians and vehicles) in Dodoma were picked for comparison purpose. Similarly, two sides of Arusha Road, one with and the other without shade trees were selected for comparison.  These streets were compared in terms of pedestrian volume based on results from pedestrian counts. The key method that was used to capture empirical evidence was pedestrian count along the lanes of the roads. Pedestrian count was carried out from 08.00 in the morning to 20.00 hours in the night. This was complemented with literature review, field observation, photographing and interview with road users. Findings show that roads which had adequate provisions of landscape elements (pavements or shade trees) accommodated twice as much as the number of pedestrians along roads with limited or no landscape elements. It is recommended that provision of more walking space, provision of continuous, paved and shaded walkways should be encouraged as a strategy of promoting walkability and livability in these cities

Efficacy of Agricultural Extensions and Environmental Conservation Awareness on the Sustainability of Urban Agricultural Practice: Case of Daraja Mbili and Lemala Wards in Arusha City, Tanzania

Urban agricultural activities can have a minimum or a substantial contribution to the livelihoods of people. They can either conserve or pollute the environment and degrade the land. The information about ensuring agricultural productivity with less effect on the environment is dynamic and the causes of dynamisms are not clear. The study was conducted to examine the cause of dynamisms in relation to changing institutional frameworks and political regimes. The study used qualitative research design and a case study strategy and 60 respondents were interviewed. We did content analysis to analyse qualitative data. The findings revealed that agricultural extension services and trainings, as well as environmental conservation awareness about good agricultural practice were provided to farmers and non-farmers, although the success was not promising. The uncoordinated agricultural activities were rhetorically managed and sometimes managed in uncoordinated ways. In tune with provision of agricultural extension services and awareness of conserving the environment to farmers, the mere conservation of the environment was not successful, unless it had a possibility of increasing agricultural productivity and helping farmers to get their livelihood needs