The SNARE Protein SNAP23 and the SNARE-Interacting Protein Munc18c in Human Skeletal Muscle Are Implicated in Insulin Resistance/Type 2 Diabetes

OBJECTIVE-Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS-We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS-We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS-We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23. Diabetes 59: 1870-1878, 201

Bacterial cellulose-lactoferrin as an antimicrobial edible packaging

Bacterial cellulose (BC) films from two distinct sources (obtained by static culture with Gluconacetobacter xylinus ATCC 53582 (BC1) and from a commercial source (BC2)) were modified by bovine lactoferrin (bLF) adsorption. The functionalized films (BC+bLF) were assessed as edible antimicrobial packaging, for use in direct contact with highly perishable foods, specifically fresh sausage as a model of meat products. BC+bLF films and sausage casings were characterized regarding their water vapour permeability (WVP), mechanical properties, and bactericidal efficiency against two food pathogens, Escherichia coli and Staphylococcus aureus. Considering their edibility, an in vitro gastrointestinal tract model was used to study the changes occurring in the BC films during passage through the gastrointestinal tract. Moreover, the cytotoxicity of the BC films against 3T3 mouse embryo fibroblasts was evaluated. BC1 and BC2 showed equivalent density, WVP and maximum tensile strength. The percentage of bactericidal efficiency of BC1 and BC2 with adsorbed bLF (BC1+bLF and BC2+bLF, respectively) in the standalone films and in inoculated fresh sausages, was similar against E. coli (mean reduction 69 % in the films per se versus 94 % in the sausages) and S. aureus (mean reduction 97 % in the films per se versus 36 % in the case sausages). Moreover, the BC1+bLF and BC2+bLF films significantly hindered the specific growth rate of both bacteria. Finally, no relevant cytotoxicity against 3T3 fibroblasts was found for the films before and after the simulated digestion. BC films with adsorbed bLF may constitute an approach in the development of bio-based edible antimicrobial packaging systems.The authors would like to acknowledge Portuguese Foundation for Science and Technology (Fundação para a Ciência e Tecnologia) for the research grants: Jorge Padrão SFRH/BD/64901/2009, Sara Gonçalves SFRH/BD/63578/2009, João Pedro Silva SFRH/BPD/ 64958/2009, Ana Cristina Pinheiro SFRH/BPD/101181/2014. V. Sencadas thanks support from the COST Action MP1206: “Electrospun nano-fibres for bio inspired composite materials and innovative industrial applications” and MP1301: “New Generation Biomimetic and Customized Implants for Bone Engineering”. The authors would also like to thank the co-funded by the Programa Operacional Regional do Norte (ON.2 e O Novo Norte), QREN, FEDER Projects “BioHealth e Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124- FEDER-000027; “BioInd e Biotechnology and Bioengineering for improved Industrial and Agro-Food processes”, REF. NORTE-07- 0124-FEDER-000028; Strategic Project PEST-C/FIS/UI607/2014; Matepro eOptimizing Materials and Processes”, ref. NORTE-07- 0124-FEDER-000037; Strategic Project PEst-OE/EQB/LA0023/2013 and project ref. RECI/BBB-EBI/0179/2012 (project number FCOMP- 01-0124-FEDER-027462). Finally, the authors thank the Fundação para a Ciência e Tecnologia for the strategic funding from the UID/ BIO/04469/2013 unit

Stability of pencils of cubic surfaces P3

In this paper we study the classification of pencils of cubic surfaces in P3, up to projective equivalence. We obtain explicit vanishing criteria on the Plücker coordinates of a pencil for both stability and semi-stability; moreover, we give the equations defining pairs of generators for unstable and not properly stable pencils. Thus we extend the work of Miranda and Ballico [5, 1]. We give some geometric criteria for when a pencil is properly stable, and in particular, we give a characterization of smooth not properly stable pencils.Godkänd; 1999; 20070212 (evan)</p

Anti-infectious and anti-inflammatory activities of lactoferrin and fragments thereof

Lactoferrin (LF), a major protein present in milk, mucosal secretions and secondary granules of neutrophils, has been suggested to participate in host defense at mucosal surfaces and to mediate anti-inflammatory activities. A pepsin-derived fragment of LF has been shown to contain the antibacterial domain of the protein. Despite this proposed important dual capacity of LF at the mucosal membranes there are few in vivo studies to support these effects. Our aim was to investigate if anti-infectious or anti-inflammatory activities on mucosal surfaces could be mediated by perorally given LF or synthetic fragments of the antibacterial region of LF in experimental animal models, to gain insight into how LF mediates the anti-inflammatory activities in vitro, and to define the sequence in the antibacterial region of the LF molecule responsible for the antimicrobial activity. Experimental mouse models of urinary tract infection (UTI) induced by E.coli O6K5 and dextran sulphate (DX)-induced acute colitis were used. The number of E.coli present in the urinary tract and the urinary and systemic inflammatory response (urinary leukocytes, urinary and systemic IL-6 levels) in mice with UTI were reduced by the LF treatment compared to the control group. Mice treated with LF peptide fragments (HLD1 and 2) also showed reduced numbers of bacteria in the kidneys. The perorally given LF was found to pass over to the circulation and urine. HLD2 mediated significant bactericidal activity against E.coli when tested in vitro in mouse urine. The damaging effects induced by DX exposure (presence of blood in the faeces, colon shortening, IL-1b serum levels, crypt score) were delayed or reduced in mice treated with LF or the peptides. The number of inflammatory cells present in the colon after 7 days of DX exposure (F4/80 macrophages, CD4- and TNF-a- positive cells) was lower in the LF treated group compared to the control. LF also reduced shortening of the colon when given orally to animals with an already established inflammatory response as induced by two days of DX exposure. LF was shown to down-regulate the secretion of TNF-a, IL-1b, IL-6, IL-8 and IL-10 in monocytic cell lines (THP-1, Mono Mac 6) stimulated with LPS. The down regulation of the cytokines was reflected at the transcriptional level. Thus LPS-induced TNF-a-, IL-1b-, IL-6-, and IL-8 mRNA as shown by reversed transcription PCR were reduced as well. The known binding of LF to LPS could not explain the reduced cytokine mRNA expression and protein secretion since the effects were observed also when LF was added 30 min after the LPS to the cell assay. In addition, also IL-1b induced IL-6 secretion was down-regulated in the presence of LF. Moreover, LF was detected by immunocytochemistry in the cell nucleoli already after 30 min of incubation with the THP-1 cells and found by electromobility shift assay to decrease the binding of nuclear factor (NF)-kB to the TNF-a promoter. The antimicrobial activity against E.coli, S.aureus and C.albicans of synthetic peptides homologous to the surface exposed a-helix and b-sheet region from the N-terminal end of human LF showed that a short region comprising 12-15 a.a. corresponding to the major part of the helix region were optimal for the killing activity against all three microorganisms. In addition certain amino acids such as cystein, and hydrophobic and positively charged amino acids in the 12-amino acid long peptide were found to be important for the expression of antimicrobial activity. In summary, orally given LF can reduce infection and inflammation in a remote site such as the urinary tract, and mediates anti-inflammatory activities in the colon. This dual effect may partly reside in the antimicrobial region of the LF molecule, since synthetic fragments also provide similar activities. One possibly important mechanism of its anti-inflammatory effects is through the ability to down-regulate cytokine production via interference with the transcription factor NF-kB. The anti-infectious and anti-inflammatory activities of LF on mucosal surfaces is being utilized by the suckling child which obtains large amounts of LF via the maternal milk. However, therapeutic use of LF or its fragments may be possible in other fields of application

Det norske mistillitsinstituttet : en analytisk oversikt over mistillitsforslagene i perioden 1945 - 2004

Formålet med denne masteroppgaven, om det norske mistillitsinstituttet, er først og fremst å gi en bred deskriptiv og empirisk analyse av dette temaet. Jeg vil gi den første beskrivende analysen av samtlige mistillitsforslag som har vært oppe til votering i Stortinget mellom 4. desember 1945 og 1. oktober 2004. Jeg vil i tillegg se litt nærmere på ulike motiver som kan ligge bak et mistillitsforslag. For å besvare denne oppgaven har jeg sett nærmere på følgende fem forskningsspørsmål: - Hvor mange mistillitsforslag er det votert over i Stortinget i perioden 1945 2004? - Hvilke partier er det som fremmer flest mistillitsforslag? - Hvordan er ordlyden i mistillitsforslagene? - Hvilke regjeringer og fagområder blir utsatt for flest mistillitsforslag? - Hvilke motiver kan vi finne eksempler på som mulige årsaker til at mistillitsforslag har blitt fremmet etter 1945? Jeg mener disse fem spørsmålene til sammen vil gi en god helhetlig oversikt og beskrivelse av det norske mistillitsinstituttet. Når jeg skulle avgrense og definer begrepet mistillitsforslag brukte jeg teoriene til Per Stavang. Han deler mistillitsforslagene inn i tre grupper basert på ordlyden i forslagene. For det første har vi alle forslag som inneholder formuleringen Regjeringen har ikke Stortingets tillit . For det andre har vi alle forslag med formuleringen Stortinget beklager . For det tredje har vi alle andre forslag som inneholder en sterk kritikk mot regjeringen og som, etter en helhetsvurdering, blir tolket som mistillitsforslag. En slik helhetsvurdering inneholder momenter som formuleringen av forslaget, regjeringens og opposisjonens forståelse av forslaget, Presidentens forståelse av forslaget, voteringsmåten og registreringen i stortingsregisteret. I min deskriptive analyse fant jeg at Stortinget har votert over 49 mistillitsforslag, fordelt på 42 forskjellige saker, mellom 1945 og 2004. Det blir 0.833 mistillitsforslag per år, eller 3.2 per valgperiode. 19 av forslagene kom før 1. oktober 1973. De resterende 30 kom etter denne datoen. Så mange mistillitsforslag har de ulike partiene vært med på å fremme siden 1945: H:17, FRP:16, SP:12, SV:10, KRF:8, V:8, AP:5, NKP:2 og RV:1. Når vi tar hensyn til hvor mange år partiene har vært representert på Stortinget og antall år de har sittet i regjering, dvs. antall år i opposisjon, så fant jeg at FRP kom på første plass med 2.37 mistillitsforslag per valgperiode. H kom nærmest med 1.52 forslag. AP kom her på en tredje plass med 1.14 mistillitsforslag per valgperiode i opposisjon. Jeg fant også at fløypartiene har økt sin andel av mistillitsforslagene etter 1. oktober 1973. De har økt sin andel fra 21 % til 63 % Når det gjelder ordlyden i mistillitsforslagene så er ikke tillit varianten blitt brukt 14 ganger. Stortinget beklager varianten er brukt 21 ganger. Andre forslag er benyttet 14 ganger. Men her har det vært en utvikling der Stortinget beklager er blitt brukt stadig oftere, og hvor det i dag ser ut til å ha blitt en juridisk likestilling mellom ikke tillit og Stortinget beklager forslagene. Jeg har også funnet at ett-parti-regjeringer er mer utsatt for mistillitsforslag enn koalisjonsregjeringer, og at mindretallsregjeringer er mer utsatt enn flertallsregjeringer. Når det gjelder fagområdene er finansdepartementet mest utsatt ettersom de har fått 25 % av alle de 49 mistillitsforslagene mot seg. Det siste jeg så på var ulike motiver som kan ligge bak et mistillitsforslag. Jeg mener da at flere av forslagene må sees på som rene protestmarkeringer. Andre forslag har ønsket om å overta regjeringsmakten som motiv. Jeg fant også forslag som kan ha hatt som motiv å bygge opp et borgerlig regjeringsalternativ. Et annet motiv er det som går på rene kontrollsaker

QT-UNet: A Self-Querying All-Transformer U-Net for 2D and 3D Segmentation Augmented by Self-Supervised Learning

I 2017 revolusjonerte Transformer-modellen naturlig språkbehandling ved å tilgjengeliggjøre store modeller som var i stand til å forstå komplekse sammenhenger over store avstander i tekst med en håndterbar beregningskostnad. I 2021 brakte introduksjonen av Vision Transformere med seg en liknende revolusjon i bildebehandling, med liknende skaleringsfordeler. Utviklingen av effektive Vision Transformere med lineær tidskompleksitet som Swin Transformeren bidrog til ytteligere opptak i bruk av Vision Transformere, spesielt i felter som Autonomt Syn og Medisinsk Bildeanalyse. Modeller som VT-UNet smeltet sammen tradisjonelle UNet med Swin Transformere for å skape en ny sterk volumetrisk segmenteringsmodell for hjernesvulster, med et nyskapende Enkoder-Dekoder Cross-Attention konsept. Parallelt med disse revolusjonene opplevde Self-Supervised Learning en lignende revolusjon og økning i bruk innen flere datasynsdomener, spesielt domener der det er knapt med treningsdata. Swin-UNETR forhåndstrente en sterk Swin-basert koder med et stort CT-datasett og kontrast-, rekonstruksjons- og rotasjonsbaserte treningsoppgaver, og viste sterk nedstrøms ytelse i Medical Segmentation Decathlon (MSD) og Beyond The Cranial Vault (BTCV). Dette prosjektet smelter disse fremskrittene sammen med modellen Querying Transformer UNet (QT-UNet): Et all-Swin Transformer UNet med Enkoder-Dekoder Cross-Attention, forsterket med Self-Supervised Learning. QT-UNet testes med flere Medical Image Computing datasett for å evaluere modellens effektivitet som en generell volumetrisk segmenteringsmodell. Vi samler et stort datasett kalt CT-SSL med 3.597 CT-skanninger til pretrening. En 2D-versjon, QT-UNet-2D, spinnes ut av hovedmodellen for å evaluere effektiviteten til teknikkene i en 2D Autonomt synskontekst. Vår beste modell er konkurransedyktig med "state of the art" i BraTS2021 med 40% færre FLOPs enn vår baseline VT-UNet, med en gjennomsnittlig Dice score på 88,61 og Hausdorff Distance på 4,85 mm. Vi finner mindre gode resultater med BTCV og MSD, men demonstrer effektiviteten til både vår nye Cross-Attention mekanisme og vår SSL-pipeline ved pretrening på CT-SSL. Vi overfører også teknikkene til en 2D-kontekst med CityScapes, og finner at vår Cross-Attention mekanisme og SSL-pipeline er effektiv uten endringer