type I interferon

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Type I interferon stimulation of lymphocytes

Type I interferon stimulation of lymphocytes

Lymphopenia induced by infection with vesicular stomatitis virus (VSV) or treatment with the Toll-like receptor agonists poly(I:C) and R-848 was critically dependent on type I interferon receptor (IFNAR)-signalling. Using bone marrow-chimeric mice, radio-resistant cells, such as stroma and endothelium, could be excluded as type I interferon targets for the induction of lymphopenia. Instead, adoptive transfer experiments and studies in conditionally gene-targeted mice with a B or T cell-specific IFNAR deletion demonstrated that type I IFN exerted a direct effect on lymphocytes that was necessary and largely sufficient to induce lymphopenia. The investigation of the molecular mechanism revealed that lymphopenia was mainly independent of G protein-coupled receptors (GPCRs) and chemokines. Homing studies performed by FACS and laser scan microscopy showed that B cells, but not T cells, partially accumulated in spleen, but not in other organs.
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Molecular insight into the IRE1α-mediated type I interferon response induced by proteasome impairment in myeloid cells of the brain

Molecular insight into the IRE1α-mediated type I interferon response induced by proteasome impairment in myeloid cells of the brain

FIGURE 6 | Proposed inositol-requiring protein 1 alpha (IRE1α)-dependent mechanism of type I interferon induction upon proteasome impairment. Proteasome impairment due to pharmacological inhibition by bortezomib leads to accumulation of ubiquitinated proteins in cytosol and abrogated retro-translocation of defective proteins from endoplasmic reticulum (ER). As a consequence, misfolded or damaged proteins accumulate in ER causing dissociation of BIP from the ER stressors: IRE1α and protein kinase R like endoplasmic reticulum kinase (PERK) and activation of their downstream pathways. Upon induction, PERK oligomerizes and transphosphorylases itself and subsequently facilitates phosphorylation of eukaryotic initiation factor 2α (eIF2α), what globally diminishes protein translation. At the same time, messenger RNA (mRNA) of the transcription factor ATF4, which has an inhibitory upstream short open reading frame, is preferentially translated when eIF2α is phosphorylated and stimulates the production of C/EBP homologous protein 10 (CHOP). CHOP controls induction of proteins involved in autophagy and apoptosis but it is also involved in transcriptional regulation of Il-6 expression. ER-stress also leads to an induction of IRE1α, which then activates its kinase and endoribonuclease domains. The oligomerized protein cleaves a 26-bp long fragment in the Xbp1mRNA, which gives rise to a spliced form of XBP1 that translocates into the nucleus and activates transcription of its target genes, including Il-6. In addition to Xbp1 splicing, IRE1 non-specifically degrades mRNAs in a process named regulated IRE1-dependent decay of mRNA (RIDD). The small RNAs generated by the RIDD pathway may be recognized by the pattern recognition receptor RIG-I and trigger TBK1-IRF3-dependent induction of type I interferons.
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Analysis of SIGLEC1 as a surrogate marker for a type I interferon signature in autoimmune congenital heart block and primary Sjögren’s syndrome

Analysis of SIGLEC1 as a surrogate marker for a type I interferon signature in autoimmune congenital heart block and primary Sjögren’s syndrome

Within this study, we found that patients with pSS had an increased expression of SIGLEC1 compared to healthy controls, with levels comparable to those found in patients with SLE. Additionally, we found that the SIGLEC1 expression differed significantly between patients with a systemic disease manifestation and patients where the disease was restricted to the glandular organs. These findings contrast with those of a previous study by Maria et al., who did not find a correlation between SIGLEC1 expression and disease activity evaluated by ESSDAI score in pSS patients whose disease activity was inactive to mildly active.(17) We therefore hypothesize that a higher disease activity with a systemic disease manifestation is required for the production of type I interferons, leading to a subsequent upregulation of SIGLEC1. Maria et al. proposed MxA as a type I interferon-regulated biomarker in pSS, which was not assessed in our study. Future research should therefore compare the two biomarkers SIGLEC1 and MxA in pSS patients with a broader range of disease severity, also taking into account the clinical feasibility of each biomarker. Interestingly, SIGLEC1 correlated with IgM rheumatoid factor in the study by Maria et al., which is also reflected by our data. In summary, strong evidence exists that type I interferon-regulated biomarkers can be valuable clinical parameters in patients with pSS, and that an upregulation can be indicative of a more severe disease course, possibly requiring targeted (systemic) immunomodulatory therapy.
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Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

FIGURE 6 | Proposed inositol-requiring protein 1 alpha (IRE1α)-dependent mechanism of type I interferon induction upon proteasome impairment. Proteasome impairment due to pharmacological inhibition by bortezomib leads to accumulation of ubiquitinated proteins in cytosol and abrogated retro-translocation of defective proteins from endoplasmic reticulum (ER). As a consequence, misfolded or damaged proteins accumulate in ER causing dissociation of BIP from the ER stressors: IRE1α and protein kinase R like endoplasmic reticulum kinase (PERK) and activation of their downstream pathways. Upon induction, PERK oligomerizes and transphosphorylases itself and subsequently facilitates phosphorylation of eukaryotic initiation factor 2α (eIF2α), what globally diminishes protein translation. At the same time, messenger RNA (mRNA) of the transcription factor ATF4, which has an inhibitory upstream short open reading frame, is preferentially translated when eIF2α is phosphorylated and stimulates the production of C/EBP homologous protein 10 (CHOP). CHOP controls induction of proteins involved in autophagy and apoptosis but it is also involved in transcriptional regulation of Il-6 expression. ER-stress also leads to an induction of IRE1α, which then activates its kinase and endoribonuclease domains. The oligomerized protein cleaves a 26-bp long fragment in the Xbp1mRNA, which gives rise to a spliced form of XBP1 that translocates into the nucleus and activates transcription of its target genes, including Il-6. In addition to Xbp1 splicing, IRE1 non-specifically degrades mRNAs in a process named regulated IRE1-dependent decay of mRNA (RIDD). The small RNAs generated by the RIDD pathway may be recognized by the pattern recognition receptor RIG-I and trigger TBK1-IRF3-dependent induction of type I interferons.
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Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

Figure S5. Analysis of UPR and type I IFN response induction in BV-2 cells treated with ONX-0914. (A) Viability of BV-2 cells in response to different doses of ONX-0914. Cells were treated with the indicated doses of ONX-0914 for 6 hours and analyzed with the PreMix WST-1 Cell Proliferation Assay System. (B) Immunoblotting depicting expression of UPR drivers in response to indicated doses of ONX-0914. (D) Cytotoxicity test in response to 200 nM of ONX-0914. Cells were treated with the indicated dose of ONX-0914 up to 24 hours and analyzed with the PreMix WST-1 Cell Proliferation Assay System. (D) Expression of standard- and immunoproteasome catalytic subunits and as well as UPR proteins visualized by western blotting. (E) Examination of the XBP1s mRNA splicing, visualized by PCR. (F) Immunoblotting depicting expression of type I IFN response drivers in BV-2 cells treated with ONX-0914.
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Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function

Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function

Soluble inflammatory signals act mainly through cytokine re- ceptors ( Hotamisligil, 2017; Protzer et al., 2012; Racanelli and Rehermann, 2006 ). Type I interferons (IFN-Is) are central antiviral cytokines that signal through the ubiquitously expressed IFNAR receptor, which is composed of the two subunits IFNAR1 and IFNAR2. This induces the expression of a broad array of genes described as interferon-stimulated genes (ISGs). ISGs exert anti- viral functions by direct interference with viral replication and immunoregulatory properties ( McNab et al., 2015; Schoggins et al., 2011 ). More recently, IFN-Is are also recognized as modu- lators of metabolism, such as cellular lipid metabolism and redox homeostasis ( Bhattacharya et al., 2015; Pantel et al., 2014; Wu et al., 2016; York et al., 2015 ). Cytokine-induced regulation of liver metabolism is expected to result in altered metabolite turnover and release that impacts distal organs ( van den Berghe, 1991; Norata et al., 2015 ). Immune cells and in particular T cells critically depend on certain metabolites to efficiently perform their func- tions and are thus susceptible to altered metabolite availability ( Chang et al., 2015; Geiger et al., 2016; Johnson et al., 2018; Pearce et al., 2009 ). In line with this, a frequent immune evasion mechanism of cancer is the depletion of essential amino acids or glucose in the tumor microenvironment ( Buck et al., 2017; Chang et al., 2015; Ma et al., 2017; Murray, 2016 ).
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Type I interferon promotes alveolar epithelial type II cell survival during pulmonary inflammation / submitted by Barbara Maier

Type I interferon promotes alveolar epithelial type II cell survival during pulmonary inflammation / submitted by Barbara Maier

The homeostasis of several immune cell populations is dependent on constitutive low-level secretion of IFN-ß. IFNAR deficient mice, that are not able to process IFN-I signals, show decreased numbers of NK-cells and B-cells in the spleen and enhanced responsiveness of myeloid populations to Csf-1 [95,96]. Macrophage function is modulated by constitutive IFN-I signaling, indicated by the decreased phagocytic capacity of macrophages incapable of mounting IFN-I responses in response to LPS [97]. Also the bone resorption function of osteoclasts is impaired in the absence of IFNAR in mice [98]. Another important aspect of baseline IFN-I signaling is the modulation of expression levels of STAT proteins. In case the relative abundance between STAT proteins is shifted, hetero- or homodimer formation using specific forms of STAT is favored which in turn leads to a bias in signal transduction [99]. In steady state thymic epithelial cells show the highest detectable IFN-ß expression shown with a luciferase reporter mouse. Other IFN-ß expressing tissues are spleen, lymph nodes, liver, kidney and intestine [100].
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Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord

Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor path- ogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water chan- nel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from thera- pies involving type I interferons (I-IFN), NMO patients typically do not profit from such treat- ments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyeli- tis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.
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Der Einfluss von Typ-I-Interferonen auf Leukozyten-Subpopulationen im Blut: ein neuer diagnostischer Ansatz für die Verwendung der Interferon-Signatur als Biomarker beim systemischen Lupus erythematodes

Der Einfluss von Typ-I-Interferonen auf Leukozyten-Subpopulationen im Blut: ein neuer diagnostischer Ansatz für die Verwendung der Interferon-Signatur als Biomarker beim systemischen Lupus erythematodes

Interferon-regulated proteins and gene signatures are considered promising candidates for monitoring disease activity in systemic lupus erythematosus (SLE). The whole blood interferon signature (WBIFNS), defined by the simultaneous measurement of different interferon-induced transcripts in whole blood, is the most recent method for an indirect type I interferon assessment in SLE. Although the WBIFNS reflects the SLE disease activity in cross-sectional analyses, a long-term correlation has not yet been demon- strated. The aim of this study was to clarify the reasons for this paradox and, based on an optimized measurement procedure, further enhance the clinical diagnostic value of the type I interferon signature.
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Die Kinetik des viralen Core-Antigens und viraler Nukleinsäure unter kombinierter Therapie der chronischen Hepatitis C mit Peg-alpha-Interferon und alpha-Interferon

Die Kinetik des viralen Core-Antigens und viraler Nukleinsäure unter kombinierter Therapie der chronischen Hepatitis C mit Peg-alpha-Interferon und alpha-Interferon

Seit Zulassung und Empfehlung der European Association for the Study of the Liver (EASL) der Kombinationstherapie von Interferon und Ribavirin zur Behandlung der chronischen Hepatitis C im Jahre 1999, hat sich die Prognose von Patienten mit chronischer Hepatitis C entscheidend verbessert. Bei den Genotypen 2 und 3 konnten schon damals Sustained Response-Raten von etwa 65 % erreicht werden. Diese Erfolgsquote konnte durch die Einführung der pegylierten Interferone und der Kombinationstherapie aus pegyliertem Interferon plus Ribavirin auf 75-80% nochmals gesteigert werden. Ein Problem stellen jedoch nach wie vor die Genotypen 1 und 4 dar, welche bislang, trotz Einführung der pegylierten Interferone und Verlängerung der Therapiedauer auf zwölf Monate, noch immer dauerhafte Heilungsraten unter 50 % aufweisen. Da jedoch die Genotypen 1a und 1b in Europa die häufigsten Genotypen darstellen, gilt es, neue Therapieoptionen zur Verbesserung der Therapieprognose zu finden.
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Characterization of a type I-B CRISPR-Cas system of Clostridium thermocellum

Characterization of a type I-B CRISPR-Cas system of Clostridium thermocellum

6 conserved 26, 46, 47, 50-52 . The Cas6 homologues belong to the RAMP superfamily and share a common RRM motif, but their amino acid sequence was found to be very diverse and their protein structures vary. These divergences are thought to be responsible for the variability in recognition mechanisms of RNA substrates with different structures by different Cas6 homologues 26, 48, 51-53 . As an example, in type I-E and I-F systems, the respective Cas6 enzymes (Cas6f and Cas6e) bind repeat sequences that potentially form a hairpin structure. After Cas6 processing, the mature crRNAs are loaded into Cascade 45, 49 (fig 1.3 (5)). Cas6f and Cas6e are single-turnover enzymes that stay firmly associated with the repeat hairpin and form a stable Cascade subunit after crRNA delivery 11, 26, 51-56 . In contrast, other type-I variants are associated with repeat elements that are predicted to be unstructured and display mature crRNAs that harbor trimmed 3'-terminal ends. This suggests that the respective Cas6 variants are not a permanent subunit of Cascade, but function as stand-alone nucleases that only deliver the crRNAs to Cascade, which are then accessible for further enzymatic and/or chemical trimming 12, 43, 50 . The evolutionary basis for these mechanistic differences are not fully understood 57 . After associating with Cascade, mature crRNAs are used as guide molecules to target foreign DNA in case of a repeated infection via base complementaryty, which then results in the degradation of the viral DNA by a helicase/endonuclease called Cas3 (fig 1.3 (5), (6)). Experimental insights into type I-A, I-C, I-F and I-E Cascades have been published. These Cascades display similarities in the protein composition as they all share the three RAMP-containing Cas5, Cas6 and Cas7 variants, even though they differ in the subtype specific proteins that represent the large (and small) subunit of the complex (Cas8a and Csa5 for type I-A, Cas8c for type I-C, Cse1 and Cse2 for type I-E and Csy1 for type I-F, see fig 1.2). A major difference that can be observed between the Cascades is the composition of subunits that are permanently or temporarily associated components of the complexes (Cas6 and Cas3 variants) 21, 27, 43, 46, 48, 49, 55, 58, 59 . The type I-E Cascade was first described for E. coli and is the best studied Cascade in terms of structure and function 45, 54, 59, 60 . Its structure highlighted an uneven stoichiometry of: (Cse1) 1 -(Cse2) 2 -(Cas5) 1 -(Cas7) 6 -(Cas6) 1 49, 61 .
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Regional implementation of Multi-level Governance Type I - the European Cohesion Policy

Regional implementation of Multi-level Governance Type I - the European Cohesion Policy

Multi-level governance embodies the contrasting visions of the collective European decision-making. Type I is at the heart of democratic elections, party systems and sustains a class of politicians who mediate the preferences of citizens into law. It is best suited to political deliberation on basic value choices in a society: who gets what, when and how, such as the distribution of European funds. Type II is oriented towards problem solving and efficiency. Either way, European governance has the recognition of its binding decision-making. The enforcement of these binding legislative acts of the EU is mostly being accomplished by the subnational authorities. But in some cases, these subnational actors manage to be part of the decision-making process, which they will later implement. This participation is based on prepared and established interests of the actors involved. (Hooghe and Marks, 2010)
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The role of the degenerate nucleotide binding site in type I ABC exporters

The role of the degenerate nucleotide binding site in type I ABC exporters

With respect to the human transporters, these data could be interpreted in the following way: The motions of the NBDs of transporters with a degenerate NBS operate similar to a clamshell, while transporters with two canonical NBSs follow a seesaw motion of NBD rotation, but without a clear sequential order (Fig. 5). A transport cycle starts with an asymmetric inward- facing transporter that has one bound ATP, which remains from the previous transport cycle. This ATP resides in NBS1 in ABC exporters with a degenerate site, while it could be NBS1 or NBS2 in transporters with two canonical NBSs. Subsequently, ATP binds to the open and empty NBS, while substrate can bind to the TMDs. Subsequent motions lead to ATP occlusion and to a transition to the outward-facing state. It was biochemically shown that ATP occlusion is asymmetric in transporters with a degenerate NBS, but also in ABC transporters with two canonical NBSs (see section ‘Biochemical evidence for asymmetry’ for further details). Basal ATPase activity is associated with ATP occlusion and transition to the outward-facing state in the absences of substrate. Binding of substrate and of ATP contribute to the transition, cooperatively enhanc- ing the ATPase activity in most transporters. The outer gate opens in the outward-facing state to release sub- strate. While for some bacterial type I exporters widely separated wings were detected, this is unlikely for the majority of human ABC type I exporters that translo- cate hydrophobic substrates, including the lipid and multidrug resistance transporters. Such large motions are also not necessary, because typical substrates are small. These extensive TMD motions would be energeti- cally very expensive requiring that the TMDs push against the surrounding membrane, while exposing lar- ger hydrophobic surfaces to a water environment. The outward-facing state is most likely also asymmetric in the TMDs, as apparent for ABCC7, but also biochemi- cally shown for ABCB1. The hydrolysis of ATP leads to a high energy state [45] that promotes immediate separa- tion of that NBS. For transporters with a degenerate NBS, this process is inherently asymmetric as only NBS2 is hydrolysis competent. In all cases, under physi- ological conditions, the NBDs should only show rare, if any, complete separation of the NBDs, whereby some transporters might deviate, because of extra structural features, such as TmrAB.
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Identification and functions of type I signal peptidases of Bacillus amyloliquefaciens

Identification and functions of type I signal peptidases of Bacillus amyloliquefaciens

acid residues with others known Bacillus Sip-like proteins (Figure 16). Among Sip-like proteins, however, this distinct SipV protein shares highest sequence similarity within one branch of Sip proteins, which apparently form a cluster of closely related proteins. Most striking with respect to the multiplicity of Sip proteins in Bacillus, however, is the distinction of P- and ER-type SPases. These were only recently discovered after the SipW of B. subtilis was characterised (Tjalsma, et al., 1998, 2000). The cloning and sequence diversity of a SipW-like protein in B. amyloliquefaciens strengthen these conclusion as these proteins have similar characters of conserved sequence motifs in domains B and C (Table 5), as well as with respect to the exchange of the catalytic amino acid residue histidine for lysine within domain D (Table 5, Figure 17). The latter agreed to recent findings which indicated that P-type SPases make use of a serine-lysine catalytic dyad (Sung & Dalbey, 1992; Tschantz, et al., 1993; van Dijl et al., 1995; Dalbey, et al., 1997; Paetzel, et al., 1998), while the ER-type SPase of B. subtilis instead seems to employ a Ser-His-Asp triad or Ser-His catalytic dyad (Tjalsma, et al., 2000). The P-type and ER-type SPases also differ in the distance of the conserved domains (Dalbey, et al., 1997). As shown in Figure 12 the domains B and C of ER- type SPases are separated by only one and domain D and E by 10-11 residues, while these domains of P-type SPases are separated by 11 to 42 and 23 to 118 residues, respectively (Figure 16). While SipW-like SPases share significant sequence as well as domain similarity to P-type, the similarities are mostly limited to the conserved domains B, C, D and E (Table 5).
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Involution von Thymus und Peyer Plaques durch Interferon-α

Involution von Thymus und Peyer Plaques durch Interferon-α

4.1.5. Behandlung mit Interferon-α führt zur Thymusinvolution Poly(I:C) ist bekannt als starker Induktor einer Typ I Interferon Antwort. Vor allem Interferon-α wird durch die Poly(I:C) Bindung an und Aktivierung von MDA-5 und TLR3 in erhöhtem Maße gebildet. Auch VSV Infektionen führen bekanntlich zu erhöhten Interferonspiegeln. Nun sollte untersucht werden, ob eine alleinige Erhöhung des systemischen Interferon-α Spiegels oben beschriebene Veränderungen am Thymus hervorrufen kann, denn sowohl bei der Infizierung mit Poly(I:C) als auch mit VSV werden neben Interferon-α weitere Zytokine ausgeschüttet. Dazu wurde acht Wochen alten C57/BL6 Mäusen an sechs aufeinanderfolgenden Tagen im Abstand von 24 Stunden je 12 µg rekombinantes murines Interferon-α intraperitoneal verabreicht. 24 Stunden nach der letzten Applikation wurden die Organe analysiert. Wie in Abbildung 8
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Collagen Type I Conduits for the Regeneration of Nerve Defects

Collagen Type I Conduits for the Regeneration of Nerve Defects

Materials 2016, 9, 219 2 of 9 autografts are still considered the gold standard for peripheral nerve repair, disadvantages such as donor site morbidity, potential neuroma formation and mismatch in nerve quality and diameter have yielded novel approaches for the purpose of bridging nerve discontinuities [ 14 – 16 ]. Tubular nerve guidance conduits offer a straightforward option for surgical nerve repair that surmount the limitations of autologous nerve transplants. Nerve conduits are either obtainable as synthetic nerve guidance tubes from various biocompatible polymers or can be improvised as autologous transplants from ligated vessel segments [ 11 , 17 ]. Among the synthetic materials applied in human trials are collagen type I/III, acellular nerves, poly( D , L -lactide-caprolactone), polyglycolic acid and silicone [ 18 ]. The tubular space within the conduit, together with neurotrophic and neurotropic factors secreted by the nerve stumps, seem to provide a microenvironment that facilitates axonal sprouting and the formation of a glial sheath for sufficient nerve regeneration [ 11 , 17 ]. Recent studies using collagen conduits for the reconstruction of digital nerves present encouraging results [ 19 , 20 ]. Despite numerous experimental investigations, however, scarce clinical data exist to support the widespread use of guidance conduits, especially in the context of the enduring discussion as to whether or not large-diameter nerve reconstruction could be properly carried out using this approach [ 8 , 21 ]. In this study type I collagen conduits were implanted to bridge traumatic nerve discontinuities of less than 1.2 cm in lacerated nerves of the distal forearm region. The outcome was assessed by static two-point discrimination (S2PD), nerve conduction velocity relative to the uninjured limb, disability of arm shoulder and hand (DASH) outcome measure scoring, and patients’ perceived satisfaction.
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Interferon-α vermittelte Immuntherapie in der Friend Retrovirus Infektion

Interferon-α vermittelte Immuntherapie in der Friend Retrovirus Infektion

Die beiden unterschiedlichen Typen von Lymphozyten spiegeln zwei Hauptmechanismen der adaptiven Immunantwort wider, die humorale und die zelluläre Immunantwort. B-Zellen produzieren abhängig oder unabhängig von T- Zellen Antigen-spezifische Antikörper (Immunglobuline, Ig), die zur humoralen Immunantwort zählen. Menschen, die keine T-Zellen besitzen, weisen eine geringere Antikörperantwort auf (71). Dieses Phänomen beruht auf der Funktion einer Subpopulation von T-Zellen, die die Aktivität von Effektorzellen regulieren, so z.B. auch von B-Zellen. Daher bezeichnet man diese als T-Helferzellen (Th-Zellen). Auf ihrer Oberfläche exprimieren T-Zellen bestimmte Oberflächenmoleküle. Diese zellulären Proteine werden mit der Abkürzung CD (clusters of differentiation) und einer entsprechenden Zahl bezeichnet. CD4- und CD8-Moleküle sind Glykoproteine, die zur Ig-Superfamilie gehören und als Ko-Rezeptoren des T-Zellrezeptors (TCR) fungieren. Das CD4-Molekül findet sich üblicherweise auf T-Helferzellen. Es stellt einen Ko-Rezeptor für MHC-II restringente Antigen-induzierte T-Zellaktivierung dar. Zytotoxische T-Lymphozyten (CTL) hingegen sind durch die Expression des CD8- Ko-Rezeptors charakterisiert, welcher spezifisch an das MHC-I-Protein bindet (154).
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Characterization of DNA interference by a minimal Type I-F CRISPR-Cas system

Characterization of DNA interference by a minimal Type I-F CRISPR-Cas system

Type I CRISPR-Cas systems are most widespread in nature and the Cas protein composition of the employed Cascade interference complexes differs between seven subtypes (A-F,U) (K. S. Makarova et al., 2015). Most insights were obtained for the Type I-E Cascade complex from Escherichia coli and several crystal structures are available (Hayes et al., 2016; Jackson et al., 2014; Sabin Mulepati et al., 2014). The Type I-E Cascade crRNP consists of the five Cas proteins Cas5, Cas6, Cas7, Cse1 and Cse2 and a 61 nucleotide (nt) mature crRNA (Jackson et al., 2014; Sabin Mulepati et al., 2014; Wiedenheft et al., 2011). The crescent-shaped structure of this complex has a molecular mass of 405 kDa and displays an uneven stoichiometry: (Cse1)1-(Cse2)2-(Cas5)1- (Cas7)6-(Cas6e)1 (Semenova et al., 2011). The 61 nt mature crRNA contains a 32 nt spacer sequence that is flanked by a 8 nt long handle-region at the 5′-end and a 21 nt long repeat sequence with a terminal hairpin at 3′-end. The crRNA is generated by the RNA endonuclease Cas6. After processing, Cas6 stays tightly associated with the 3′- end, while Cas5 caps the crRNA’s 5′-terminal repeat tag (Niewoehner, Jinek, & Doudna, 2014; Semenova et al., 2011). The helical backbone of Type I-E Cascade is formed by six copies of Cas7, which generates a groove to bind and protect the crRNA. The large subunit, Cse1, is responsible for PAM recognition and is involved in recruitment of the target nuclease Cas3 (Hayes et al., 2016; Sashital, Wiedenheft, & Doudna, 2012; Semenova et al., 2011; Wiedenheft et al., 2011). A dimer of two small subunits, Cse2, stabilizes the formation of an R-loop structure and binds the displaced DNA strand (Jackson et al., 2014; Sabin Mulepati et al., 2014; Semenova et al., 2011). The general architecture of Cascade crRNPs appears to be conserved in Type I systems, even though their Cas protein composition can differ (Judith, James, & Malcolm, 2013).
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Functional studies of type I inositol hexakisphosphate kinase and its role in cell signaling

Functional studies of type I inositol hexakisphosphate kinase and its role in cell signaling

To further define a possible role for inositol pyrophosphates cell cycle inhibition, expression levels of different CDKIs in IP6K1 overexpressing cells can be determined.. Additionally,[r]

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Association of S-type and I-type granitoids in the Neoproterozoic Cameroon orogenic belt, Bafoussam area, West Cameroon - geology, geochemistry and petrogenesis

Association of S-type and I-type granitoids in the Neoproterozoic Cameroon orogenic belt, Bafoussam area, West Cameroon - geology, geochemistry and petrogenesis

The granitoids under study are genetically I-type granitoids (biotite granitoid, deformed biotite granitoid and mega feldspar granitoid) and one S-type granitoid (two-mica granitoid). The I-type granitoids are metaluminous (ASI: 0.70–1.00) or moderately peraluminous if highly fractionated (ASI: 1.01–1.06). The geochemistry and petrological features of these I-type granitoids argue for close genetic relationships and it is suggest that they originated from a single parent magma. The observed variability in mineralogy and major and trace element compositions in these granitoids are then the reflection of the fractional crystallization that evolved separation of plagioclase, biotite, K-feldspar and accessory minerals at the level of emplacement. The two- mica S-type granitoid is exclusively peraluminous (ASI: 1.07–1.25) and classified as a peraluminous leucocratic granitoid or leucogranite. It is marked in its CIPW normative composition by the permanent presence of corundum, ranging between 0.12 and 3.03.
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