Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identifica

Proteolytic activation is a unique feature of the epithelial sodium channel (ENaC). However, the underlying molecular mechanisms and the physiologically relevant proteases remain to be identified. The serine protease trypsin I can activate ENaC in vitro but is unlikely to be the physiologically relevant activating protease in ENaC-expressing tissues in vivo. Herein, we investigated whether human t

In a project to find novel neutral P1 fragments for the synthesis of thrombin inhibitors with improved pharmacokinetic properties, fragments containing a benzothiazole guanidine scaffold were identified as weak thrombin inhibitors. WaterLOGSY (Water-Ligand Observed via Gradient SpectroscopY) NMR was used to detect fragments binding to thrombin and these fragments were followed up by Biacore A100 a

The last two decades have seen remarkable progress and improvements in optical biosensor systems such that those are currently seen as an important and value-adding component of modern drug screening activities. In particular the introduction of microplate-based biosensor systems holds the promise to match the required throughput without compromising on data quality thus representing a sought-afte

A series of 1,6-naphthyridine-based compounds was synthesized as potent phosphodiesterase 10A (PDE10A) inhibitors. Structure-based chemical modifications of the discovered chemotype served to further improve potency and selectivity over DHODH, laying the foundation for future optimization efforts.

HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerfu

Acute pancreatitis is a life-threatening inflammatory disease characterized by abdominal pain of unknown etiology. Trypsin, a key mediator of pancreatitis, causes inflammation and pain by activating protease-activated receptor 2 (PAR(2)), but the isoforms of trypsin that cause pancreatitis and pancreatic pain are unknown. We hypothesized that human trypsin IV and rat P23, which activate PAR(2) and

Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMC

Using new and uniquely detailed data, we examine how construction workers' wages in Sweden developed between 1831 and 1900. Wages grew rapidly from the 1850s, and comparisons with Northwestern Europe show that Swedish workers benefited more from growth than workers elsewhere. Globalization forces, most notably overseas migration, in combination with flexible and well-integrated labor markets-signi

Objectives. To investigate if the pulmonary arterial hypertension (PAH) risk assessment tool presented in the 2015 ESC/ERS guidelines is valid for patients with chronic thromboembolic pulmonary hypertension (CTEPH) when taking pulmonary endarterectomy (PEA) into account. Design. Incident CTEPH patients registered in the Swedish PAH Registry (SPAHR) between 2008 and 2016 were included. Risk stratif

Purpose: An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake

Det svenska arbetet med att skapa en grön infrastruktur syftar till att bevara biologisk mångfald, gynna ekosystemtjänster och stärka ekosystemens resiliens mot exempelvis klimatförändringar. Inom det strategiska forskningsområdet BECC (Biodiversity and Ecosystem services in a Changing Climate) har vi undersökt de teoretiska förutsättningar och praktiska utmaningar som finns när det gäller att anv

Trycket på både skogs- och jordbruksmark ökar, bland annat som en följd av befolknings-ökningen, ändrade konsumtionsmönster och den pågående klimatförändringen. Detta leder till målkonflikter, där aktörer med olika intressen har olika syn på hur marken ska användas på bästa sätt. Dagens sektorsvisa planering, där beslut ofta tas på fastighetsnivå, gör det svårt att hitta lösningar på dessa målkonf

Swedish national breast cancer guidelines recommend that all women diagnosed with breast cancer (BC) at the age of 35 years or younger should be referred to their regional oncogenetic clinic for genetic counseling and testing, regardless of family history of cancer. The main objective of this study was to evaluate whether place of residence at BC diagnosis and treating hospital were associated wit

I denna andra upplagas fjorton kapitel – varav tretton publicerats tidigare som artiklar i årgångarna 218-223 (2014-2019) av Kungl Krigsvetenskapsakademiens Handlingar och Tidskrift – behandlas valda spörsmål rörande våldsanvändningens, den nukleära icke-spridningens, rustningskontrollens, underrättelseverksamhetens och cyberoperationers folkrätt, krigets lagar samt förhållandet mellan militär dokThis second edition’s fourteen chapters—thirteen of which have been published previously as articles in volumes 218–223 (2014–2019) of the “Proceedings and Journal of the Royal Swedish Academy of Military Sciences”—deal with selected international law issues concerning the use of force, nuclear nonproliferation, arms control, intelligence and cyber operations, armed conflicts as well as the relati

Background: There are limited data on population-wide assessment of cost in Crohn's disease (CD) and ulcerative colitis (UC). Aim: To estimate the societal cost of actively treated CD and UC in Sweden. Methods: We identified 10 117 prevalent CD and 19 762 prevalent UC patients, aged ≥18 years on 1 January 2014 and 4028 adult incident CD cases and 8659 adult incident UC cases (2010-2013) from Swedi

PURPOSE: To report the lifetime risk of visual impairment resulting from glaucoma in patients originally followed up in a 10-year prospective randomized study initiated in 1981 to assess patients with elevated intraocular pressure (IOP).DESIGN: Retrospective patient chart review.PARTICIPANTS: Data on deceased patients who initially were followed up prospectively in the randomized controlled study