The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement. Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R)

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Utilizing BIM and GIS for Representation and Visualization of 3D Cadastre

The current three-dimensional (3D) property units are in most countries registered using two-dimensional (2D) documentation and textual descriptions. This approach has limitations of representing the actual extent of complicated 3D property units and also to provide an overview of the 3D cadastre in e.g. city centers. To improve the representation and visualization of the 3D cadastre we could utilize 3D digital models. To facilitate this several requirements needs to be considered such as organizations, legal rules, coordinate reference systems and height systems, data standards, geometry and users. In this study, we formulate these requirements and then develop a framework for integration of 3D cadastre and 3D digital models. The basic idea is that cadastral information (stored the in Land Administration Domain Model, LADM) are integrated with Building Information Modelling (BIM) on building level for accurate representation of legal boundaries and with Geographic Information System (GIS) on city level for visualization of 3D cadaster in urban environments. The framework is implemented and evaluated against the requirements in a practical case study in Sweden. The conclusion is that the integration of the cadastral information and BIM/GIS is possible on both conceptual level and data level which will facilitate that organizations dealing with cadastral information (cadastral units), BIM models (architecture, engineering and construction companies) and GIS (surveying units on e.g. municipality level) can exchange information; this facilitates better representation and visualization of 3D cadastral boundaries.Not duplicate with DiVA 1414202QC 20191022</p

Utilizing BIM and GIS for Representation and Visualization of 3D Cadastre

The current three-dimensional (3D) property units are in most countries registered using two-dimensional (2D) documentation and textual descriptions. This approach has limitations of representing the actual extent of complicated 3D property units and also to provide an overview of the 3D cadastre in e.g. city centers. To improve the representation and visualization of the 3D cadastre we could utilize 3D digital models. To facilitate this several requirements needs to be considered such as organizations, legal rules, coordinate reference systems and height systems, data standards, geometry and users. In this study, we formulate these requirements and then develop a framework for integration of 3D cadastre and 3D digital models. The basic idea is that cadastral information (stored the in Land Administration Domain Model, LADM) are integrated with Building Information Modelling (BIM) on building level for accurate representation of legal boundaries and with Geographic Information System (GIS) on city level for visualization of 3D cadaster in urban environments. The framework is implemented and evaluated against the requirements in a practical case study in Sweden. The conclusion is that the integration of the cadastral information and BIM/GIS is possible on both conceptual level and data level which will facilitate that organizations dealing with cadastral information (cadastral units), BIM models (architecture, engineering and construction companies) and GIS (surveying units on e.g. municipality level) can exchange information; this facilitates better representation and visualization of 3D cadastral boundaries.QC 20191022</p

Utilizing BIM and GIS for Representation and Visualization of 3D Cadastre

The current three-dimensional (3D) property units are in most countries registered using two-dimensional (2D) documentation and textual descriptions. This approach has limitations of representing the actual extent of complicated 3D property units and also to provide an overview of the 3D cadastre in e.g. city centers. To improve the representation and visualization of the 3D cadastre we could utilize 3D digital models. To facilitate this several requirements needs to be considered such as organizations, legal rules, coordinate reference systems and height systems, data standards, geometry and users. In this study, we formulate these requirements and then develop a framework for integration of 3D cadastre and 3D digital models. The basic idea is that cadastral information (stored the in Land Administration Domain Model, LADM) are integrated with Building Information Modelling (BIM) on building level for accurate representation of legal boundaries and with Geographic Information System (GIS) on city level for visualization of 3D cadaster in urban environments. The framework is implemented and evaluated against the requirements in a practical case study in Sweden. The conclusion is that the integration of the cadastral information and BIM/GIS is possible on both conceptual level and data level which will facilitate that organizations dealing with cadastral information (cadastral units), BIM models (architecture, engineering and construction companies) and GIS (surveying units on e.g. municipality level) can exchange information; this facilitates better representation and visualization of 3D cadastral boundaries.Not duplicate with DiVA 1414202QC 20191022</p

Label Placement Challenges in City Wayfinding Map Production - Identification and Possible Solutions

Map label placement is an important task in map production, which needs to be automated since it is tedious and requires a significant amount of manual work. In this paper, we identify five cartographic labeling situations that present challenges by causing intensive manual work in map production of city wayfinding maps, e.g., label placement in high density areas, utilizing true label geometries in automated methods, and creating a good relationship between text labels and icons. We evaluate these challenges in an open source map labeling tool (QGIS), provide results from a preliminary study, and discuss if there are other techniques that could be applicable to solving these challenges. These techniques are based on quantified cartographic rules or on machine learning. We focus on deep learning for which we provide several examples of techniques from other application domains that might have a potential in map label placement. The aim of the paper is to explore those techniques and to recommend future practical studies for each of the identified five challenges in map production. We believe that targeting the revealed challenges using the proposed solutions will significantly raise the automation level for producing city wayfinding maps, thus, having a real, measurable impact on production time and costs

EuroSDR GeoBIM Project a Study in Europe on how to use the Potentials of BIM and Geo Data in Practice

In both the Geo and BIM domains, it is widely acknowledged that the integration of geo-data and BIM-data is beneficial and a crucial step in facing the multi-disciplinary challenges of our built environment. The result of this integration – broadly termed as GeoBIM – has a range of potential uses from district study to road safety. However, from the data perspective, this integration raises the question of how to integrate very detailed design and construction data from the BIM domain with contextual geospatial data (both 2D and 3D) that model a very diverse range of aspects of the wider built and natural environment.This paper reports work carried out during the second phase of the EuroSDR GeoBIM project, which sets out to understand the general status of GeoBIM across Europe with particular focus from a National Mapping and Cadastral Agency perspective. The first phase of the project reviewed the current status of GeoBIM in participating countries and identified the need for specific detailed use cases to overcome both the lack of awareness and the lack of understanding of the potential of GeoBIM. We present both an update on the current status of GeoBIM, and additional details of one of the selected use cases relating to planning/development permits. For the latter, we have been able to develop a detailed workflow highlighting specific data exchange points within the process to issue a development permit, allowing a more in-depth identification of both the roles and data needs at each stage.Urban Data Scienc