Refinement of the gonadotropin releasing hormone receptor I homology model by applying molecular dynamics

Sexual maturation of human cells in ovaries and prostate is linked to the biochemical cascade initiated by the activation of cell receptors through the binding of Gonadotropin Releasing Hormone (GnRH). The GnRH receptors (GnRHR) are part of the rhodopsin G-protein coupled receptor (GPCR) family and consist of seven trans–membrane helical domains connected via extra– and intra–cellular segments. The GnRH–GnRHR complex has been implicated in various forms of prostate and ovarian cancer. The lack of any structural data about the GnRH receptor impedes the design of antagonists for use in cancer treatment. The aim of the study is to devise a model of GnRHR to be used further for the design of improved peptide/non-peptide GnRH analogues and, to our knowledge provide new structural information regarding the extracellular loop 2 (ECL2) that acts a regulator of ligand entry to GnRHR. The common structural characteristics, of the members of the rhodopsin family of GPCRs, have been employed for the construction of a homology model for GnRHR. Structural information from the human β2–adrenergic receptor, as well as rhodopsins have been used in order to create a theoretical model for GnRHR. Furthermore, molecular dynamics (MD) simulations have been employed for the refinement of the model and to explore the impact of the bilayer membrane in GnRHR conformation

Theoretical modelling of epigenetically modified DNA sequences

We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts

Market research in the Finnish food industry

This study introduces the important factors of market research and its significancewhen aiming at new foreign markets. Understanding the cultural differences, the consumers and the market itself with the competitors’ actions among other factors, the organization has a better chance to succeed in entering new markets. The case company is a Belgian food industry company which is interested in the Finnish market environment with its consumers and competitors. Currently they are operating in Central European countries with a little market share. An interview was conducted in order to better understand their current situation and expectations on new markets. The company’s products are sold in specialty stores and in bigger hypermarkets due to their higher image which they would like to obtain in Finland. As a small country Finland can not offer big markets but this is no obstacle for the case company since they are not looking to challenge the market leader or even the followers. Instead they are looking for a small market share as in other countries that they already operate in. By using selective distribution focused on the biggest city areas the product availability is guaranteed to the majority of the Finnish population. The thesis emphasizes the different business chains - the different types of stores and their product variety as well as competitors and their product pricing. Among this, the importance of product visibility will be shown as the case company wishes to enter the markets with as little marketing as possible. Regulations on labelling are studied as well as there are little differences from organizations’ home markets. The study also introduces a Finnish importing company that could possibly cooperate with the customer when aiming at the Finnish markets.Tutkimus esittelee markkinatutkimuksen tärkeimmät osa-alueet sekä sen merkityksen tavoiteltaessa uusia markkinoita. Kulttuurillisten eroavaisuuksien, kuluttajien sekä itse markkinoiden ymmärtäminen kilpailijoineen edesauttaa yrityksen menestymistä uudella markkina-alueella. Asiakasyritys on Belgialainen elintarvikeyritys joka kiinnostui Suomen markkinaympäristöstä, kuluttajista sekä kilpailijoista. Tällä hetkellä he toimivat Keski-Euroopan markkinoilla pienin markkinaosuuksin. Haastattelu suoritettiin jotta saataisiin selville heidän nykytilanteensa sekä tulevaisuuden näkymät uusista markkinoista. Yrityksen tuotteet ovat myynnissä erikoisliikkeissä sekä suurimmissa marketeissa korkean imagon vuoksi ja näin he toivoisivat myös tapahtuvan Suomessa. Suomessa ei ole tarjolla suuria markkinoita jo pelkästään maan koon vuoksi. Tämä ei ole kuitenkaan este asiakasyritykselle sillä he eivät lähde haastamaan markkinajohtajaa tai seuraajia, vaan tyytyvät pieneen markkinaosuuteen aivan kuten muillakin markkinoilla. Selektiivisellä tuotejakelulla, keskittyen Suomen suurimpiin kaupunkialueisiin, taataan tuotteiden saatavuus suurimmalle osalle väestöstä. Tutkimus painottuu eri liikeketjuihin, Suomen kauppatyyppeihin ja niiden tuotevalikoiman suuruuteen sekä kilpailijoihin ja heidän tuotehinnoitteluun. Tämän lisäksi tuotteiden näkyvyyden tärkeys osoitetaan, sillä asiakasyritys toivoisi markkinoille tuloa vähäisin markkinointitoiminnoin. Pakkausmerkintäsäännökset tulevat myös esille sillä ne eroavat hieman yrityksen kotimarkkinoiden säännöksistä. Tutkimus esittelee myös suomalaisen maahantuontiyrityksen, joka voisi mahdollisesti toimia asiakasyrityksen yhteistyökumppanina Suomen markkinoille pyrittäessä

Tanzania's reptile biodiversity : Distribution, threats and climate change vulnerability

Assessments of biodiversity patterns and threats among African reptiles have lagged behind those of other vertebrate groups and regions. We report the first systematic assessment of the distribution, threat status, and climate change vulnerability for the reptiles of Tanzania. A total of 321 reptile species (including 90 Tanzanian endemics) were assessed using the global standard IUCN Red List methodology and 274 species were also assessed using the IUCN guidelines for climate change vulnerability. Patterns of species richness and threat assessment confirm the conservation importance of the Eastern Arc Mountains, as previously demonstrated for birds, mammals and amphibians. Lowland forests and savannah-woodland habitats also support important reptile assemblages. Protected area gap analysis shows that 116 species have less than 20% of their distribution ranges protected, among which 12 are unprotected, eight species are threatened and 54 are vulnerable to climate change. Tanzania's northern margins and drier central corridor support high numbers of climate vulnerable reptile species, together with the eastern African coastal forests and the region between Lake Victoria and Rwanda. This paper fills a major gap in our understanding of the distribution and threats facing Tanzania's reptiles, and demonstrates more broadly that the explicit integration of climate change vulnerability in Red Listing criteria may revise spatial priorities for conservation

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Iminium ion catalysis: tools and observations

In recent years the identification of new transformations and modes of reaction for iminium ion catalysis has attracted much interest, but the majority of reports have not looked at understanding the often complex processes taking place within the reaction flask. We have sought to understand these reactions and to test the validity of computational models. Iminium ion catalysts can be used to accelerate a variety of cycloaddn. and conjugate addn. processes. The accepted catalytic cycles do not help in explaining important observations, particularly regarding reaction medium. Through exptl. and theor. investigations we have focussed on three principle observations for the Diels-Alder cycloaddn.: - Water increases the rate of reactions. - Water increases the e.e. of the isolated products. - Theor. models for the conformations of the active species do not agree. We present evidence offering insights into the crucial roles of water within these transformations

Chemical and theoretical tools for understanding iminium ion catalysis

Recent reports have shown that the use of cyclic five membered nitrogen contg. heterocycles as catalysts for the iminium ion catalyzed Diels-Alder, [3+2] and [4+3]-cycloaddns., as well as Michael addns. of pyrroles, anilines, nitroalkanes, malonates and hydride have met with remarkable levels of asym. induction. We have become interested in developing new catalyst architectures to accelerate this class of transformation with the ultimate aim of providing more efficient systems than those reported. Our approach resides in gaining a fundamental mechanistic understanding of the reaction and applying this knowledge to improve catalytic efficiency. Utilizing a combination of mol. modeling, kinetic investigations and solid-state structural anal. we have probed the catalytic cycle of the iminium ion catalyzed Diels-Alder cycloaddn. reaction. This talk will describe our results in each of these areas and ongoing efforts in using these to develop a predictive tool for catalyst activity in this fascinating class of chem. transformation. [on SciFinder(R)

CCDC 607034: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 607032: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures