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Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C

Cathepsin C (CatC)is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4)by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a

MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agoni

Discovery of three novel sesquiterpene synthases from Streptomyces chartreusis NRRL 3882 and crystal structure of an α-eudesmol synthase

With more than 50,000 members, terpenoids are one of the most important classes of natural products and show an enormous diversity. Due to their unique odors and specific bioactivities they already find wide application in the flavor, fragrance and pharma industries. Since most terpenoids can only be obtained by natural product extraction, the discovery of biosynthetic genes for the generation of

Transaminase-Catalyzed Racemization with Potential for Dynamic Kinetic Resolutions

Dynamic kinetic resolution (DKR) reactions in which a stereoselective enzyme and a racemization step are coupled in one pot would represent powerful tools for the production of enantiopure amines through enantioconvergence of racemates. The exploitation of DKR strategies is currently hampered by the lack of effective, enzyme-compatible and scalable racemization strategies for amines. In the presen

Synthesis of branched and linear 1,4-linked galactan oligosaccharides

We report the synthesis of linear and branched (1→4)-d-galactans. Four tetrasaccharides and one pentasaccharide were accessed by adopting a procedure of regioselective ring opening of a 4,6-O-naphthylidene protecting group followed by glycosylation using phenyl thioglycoside donors. The binding of the linear pentasaccharide with galectin-3 is also investigated by the determination of a co-crystal

Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus

CHANGES resulting in altered antigenic properties of viruses nearly always occur on their surface and have been attributed to the substitution of residues directly involved in binding antibody. To investigate the mechanism of antigenic variation in foot-and-mouth disease virus (FMDV), variants that escape neutralization by a monoclonal antibody have been compared crystallographically and serologic

Structure of a major immunogenic site on foot-and-mouth disease virus

ATTACHMENT of foot-and-mouth disease virus (FMDV) to its cellular receptor involves a long and highly antigenic loop containing the conserved sequence, Arg-Gly-Asp, a motif known to be a recognition element in many integrin-dependent cell adhesion processes1-7. In our original crystal structure of FMDV the Arg-Gly-Asp-containing loop ('the loop'), located between β-strands G and H of capsid protei

Saving the best for last? : Old age retirement among the Urban middle classes in Leiden and Regensburg (c. 1650- c. 1800)

In pre-industrial Europe, many thousands of ‘middle-class’ individuals retired by purchasing a corrody: a contract allowing them life-long food and lodging, usually by spending their remaining years in a hospital. Given that people usually struggle to prepare for the later stages of life, this article asks whether corrodies were priced in line with the market. We study institutions that specialize

Control Mechanisms Towards Project Success

This study, based on a systematic literature review, aims to identify and analyze selected control mechanisms when project success criteria operationalize. The main theoretical contribution of this study involves identifying the dimension of control mechanisms in success criteria operationalization. The most easily identified control mechanisms in the data material were output control mechanisms,

Value positions in the implementation of automated decision-making in social assistance

Automated decision-making (ADM) has been introduced into the public sector in many countries, including for decisions made regarding the provision of economic support to people in need. This article analyses the value positions (the ‘desired intentions’) for using ADM to determine such decisions in four Swedish municipalities. The value positions related to efficiency of the application process, i

Digitalisering i socialt arbete : Socialtjänstens utmaningar och möjligheter

I en tid då tekniska lösningar blir allt vanligare behövs en problematisering av vad digitalisering i socialtjänsten betyder och hur olika verksamheter påverkas. Digitaliseringen väcker reaktioner, både i form av rädslor för att det personliga mötet ska försvinna och förhoppningar om effektiva lösningar för ett mer ekonomiskt, rättvist och mer likriktat beslutsfattande och utförande. Kan digital t

Actors and Intentions in the Dissemination of Robotic Process Automation in Social Work

Automated decision-making is prevalent in numerous areas of the public sector. Based on the results of a qualitative, event-based study of how robotic process automation (RPA) is discussed and implemented in social work in Sweden, two questions are answered in this paper: What actors, intentions and network formations appear in the dissemination of RPA in the management of applications for social

Mostly Panel Econometrics : Essays on Asymptotic Analysis and Enhanced Inference

This thesis consists of five chapters which focus on panel data theory. Four of them analyze explicit panel data models and one chapter deals with time series forecasting model, where external panel data help us estimate unobserved explanatory variables. The broad topics discussed in the thesis include i) simplification of distribution of a statistical test under double asymptotics, ii) eliminatio

FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was signif

The continuous translation of the idea of integrated reporting (IR) : The travel of IR to a public sector entity

This study explores the travel of integrated reporting (IR) from a global private sector reporting idea into a local public sector entity. Drawing on the Scandinavian institutionalist notion of translation, a case study approach is adopted to analyse the continuous transformation of the idea of IR. The case study unfolds the process as IR became dis-embedded from the corporate reporting context, p

Infants hospitalised with acute respiratory tract infections. Mapping, description, and evaluation of physiotherapy treatment methods including frequent changes in body position and stimulation of physical activity.

The overall aim of this thesis was to increase knowledge about physiotherapy treatment for infants with lower respiratory tract infections, which is the most common reason for infant hospitalisation worldwide. Physiotherapy treatment for these infants is debated, and there is no clear consensus regarding the best treatment strategy.To examine current treatment and evaluation methods in Sweden, we

Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontract