Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Hemlösas upplevelser av sin livs- och karriärutveckling

Studiens problemområde är att antalet hemlösa i Sverige ökar, vilket därmed utgör ett tydligt samhällsproblem och det kräver ansvarstagande. Hemlöshet är ett komplext faktum som uppkommer med arbetslöshet, ökade boendekostnader och försämringar i välfärdssystemet. Syftet med denna studie är att undersöka hemlösas upplevelser av sin livs- och karriärutveckling, detta för att få en ökad förståelse av gruppens upplevda möjligheter utifrån valda teorier och tidigare forskning. Studiens frågeställningar lyder: Hur blev dessa personer hemlösa? Hur ser de hemlösas pågående livssituation ut? Hur upplever de hemlösa sina karriärmöjligheter? Jag har valt att använda kvalitativa metoder i studien för att få svar på intervjufrågor. Jag har intervjuat sex hemlösa i Skåne län, i områdena kring Malmö och Lund. I arbetet använder jag mig av delar av Bourdieus teorier och Hodkinson och Sparkes Careershipteori. Bourdieus teorier kan delas in i tre huvudbegrepp: fält, kapital och habitus. Hodkinson och Sparkes karriärteori är baserad på sociologiska och psykologiska utgångspunkter utifrån teoretiska begrepp från Bourdieus teori om habitus, kapital och fält. Ett huvudresultat visar att informanter blev hemlösa på grund av att de gick igenom en brytpunkt i form av att de fick avsluta sina dåvarande arbeten. Det resulteras även att alkoholmissbruk och psykisk ohälsa i form av depression påverkade deras övergång till hemlöshet. Huvudresultatet visar även att hemlösas tankar om karriärmöjligheter som studier och arbete är relativt låg.Study's problem area is that the number of homeless people in Sweden growths, thereby constituting a distinct social problem and it requires responsibility. Homelessness is a complex fact caused by unemployment, rising housing costs and deterioration in the welfare system. The purpose of this study is to investigate the homeless experiences of his life and career development, in order to get a better understanding of the group's perceived opportunities from selected theories and previous research. The study's questions are: How did these people homeless? How do the homeless current life situation like? How do the homeless their career prospects? I have chosen to use qualitative methods in the study to get answers to interview questions. I have interviewed six homeless in Skåne, in the areas around Malmö and Lund. I use parts of Bourdieu's theories and Hodkinson and Sparkes Career Ship Theory. Bourdieu's theories can be separated into three main concepts: field, capital and habitus. Hodkinson and Sparkes Career Ship Theory is based on sociological and psychological starting points based on theoretical concepts from Bourdieu's theories of habitus, capital and field. The main results show that the informants became homeless because they went through a breaking point as they had quit their former jobs. It resulted also that alcohol abuse and mental illness in the form of depression affected their change to homelessness. The main result also shows that homeless thoughts about the career opportunities of study and work is relatively low

Depression, the Devil & Transformation : A semiotic analysis of the devil as a visual metaphor for depression in the animated short film How Have You Been?

Uppsatsens syfte är att analysera hur djävulsgestalten används som visuell metafor för depression i den animerade kortfilmen How Have You Been? (2020) skapad av Polly Nor och Adam Baker. Detta med målet att skapa bredare förståelse för hur visuella metaforer kan användas inom visuell kommunikation för att gestalta känslor. Studien utförs med hjälp av en semiotisk analys samt metaforanalys med teoretisk utgångspunkt i semiotik och metaforteori. Uppsatsen resulterade i kunskap kring hur den visuella metaforen förstärks genom personifiering av depression samt en stark relation mellan protagonist o antagonist. Även förvandling av djävulsgestalten har stor betydelse för hur den visuella metaforen tolkas. Ytterligare framkom det att filmskaparna använder symboler samt ickeverbal kommunikation för att förstärka den visuella metaforen. The purpose of this thesis is to analyze how the devil figure is used as a visual metaphor for depression in the animated short film How Have You Been? (2020) made by Polly Nor and Adam Baker. This with the goal to create a wider understanding about how visual metaphor can be used in the field of visual communication to portray emotions. The study is carried out with the help of a semiotic analysis as well as a metaphor analysis with a theoretical basis in semiotics and metaphor theory. The thesis resulted in knowledge about how the visual metaphor is enhanced through the personification of depression and a strong relationship between the protagonist and the antagonist. The transformation of the devil figure is also of great importance for how the visual metaphor is interpreted. Furthermore, it became clear that the filmmakers use symbols and non-verbal communication to enhance the visual metaphor.

The possible role of Gly residues in prion octarepeat region in coordination of Cu2+ ions

Spectroscopic and potentiometric data have shown that insertion of tripeptides other than the Gly3 peptide fragment, Ala3 or Lys3, into the prion octarepeat region destabilizes the biologically relevant Cu2+ complex with the metal ion bound equatorially through the {Nimid,2N-} donor set. The other likely role of the high glycine content could be enforcement of the high flexibility of the N-terminal prion region resulting in the unstructured protein organization. However, the insertion of bulkier amino acid residues does not change the basic coordination mode at physiological pH which involves imidazole nitrogen and two amide nitrogen donors from the third and fourth residues

Atomic resolution crystal structure of HV-BBI protease inhibitor from amphibian skin in complex with bovine trypsin

Protease inhibitors of the Bowman-Birk (BBI) family are commonly found in plants and animals where they play a protective role against invading pathogens. Here, we report an atomic resolution (1Å) crystal structure of a peptide inhibitor isolated from a skin secretion of a Chinese bamboo odorous frog Huia versabilis (HV-BBI) in complex with trypsin. HV-BBI shares significant similarities in sequence with a previously described inhibitor from a diskless-fingered odorous frog Odorrana graham (ORB). However, the latter is characterized by more than a 16,000 fold higher K$_i$ against trypsin than HV-BBI. Comparative analysis of trypsin cocrystal structures of HV-BBI and ORB and additionally that of Sunflower Trypsin Inhibitor (SFTI-1) together with accessory information on the affinities of inhibitor variants allowed us to pinpoint the inhibitor moiety responsible for the observed large difference in activity and also to define the extent of modifications permissible within the common protease-binding loop scaffold of BBI inhibitors. We suggest that modifications outside of the inhibitory loop permit the evolution of specificity toward different enzymes characterized by trypsin-like specificity. Proteins 2015; 83:582–589. © 2014 Wiley Periodicals, Inc