Summary
Archaea are characterised by a complex metabolism with many unique enzymes that differ from their bacterial and eukaryotic counterparts. The thermoacidophilic archaeon Sulfolobus solfataricus ...is known for its metabolic versatility and is able to utilize a great variety of different carbon sources. However, the underlying degradation pathways and their regulation are often unknown. In this work, the growth on different carbon sources was analysed, using an integrated systems biology approach. The comparison of growth on L‐fucose and D‐glucose allows first insights into the genome‐wide changes in response to the two carbon sources and revealed a new pathway for L‐fucose degradation in S. solfataricus. During growth on L‐fucose major changes in the central carbon metabolic network, as well as an increased activity of the glyoxylate bypass and the 3‐hydroxypropionate/4‐hydroxybutyrate cycle were observed. Within the newly discovered pathway for L‐fucose degradation the following key reactions were identified: (i) L‐fucose oxidation to L‐fuconate via a dehydrogenase, (ii) dehydration to 2‐keto‐3‐deoxy‐L‐fuconate via dehydratase, (iii) 2‐keto‐3‐deoxy‐L‐fuconate cleavage to pyruvate and L‐lactaldehyde via aldolase and (iv) L‐lactaldehyde conversion to L‐lactate via aldehyde dehydrogenase. This pathway as well as L‐fucose transport shows interesting overlaps to the D‐arabinose pathway, representing another example for pathway promiscuity in Sulfolobus species.
Archaeal metabolism often differs from its bacterial and eukaryotic counterparts. Here, we investigate the global metabolic changes in response to growth on L‐fucose versus D‐glucose in the thermoacidophilic Crenarchaeon Sulfolobus solfataricus P2. A new pathway for L‐fucose degradation in this organism which is also the first description of L‐fucose metabolism in hyperthermophilic archaea was presented. Interestingly, L‐fucose degradation has shown to be promiscuous in S. solfataricus, partially using the enzymes involved in D‐arabinose degradation.
Abstract Background Caseous Lymphadenitis (CLA) is a contagious, infectious, chronic disease caused by Corynebacterium pseudotuberculosis , which affects mainly sheep and goats. The clinical ...prevalence of CLA in Brazil is 30%, resulting in decreased milk production, weight loss, and unusable meat and leather. Prophylaxis is based on vaccination; however, current vaccinations do not offer effective protection against the infection, which makes the development of a new vaccine essential to control this disease. Experimental approach Here, we developed a recombinant vaccine based on CP40 protein (rCP40) combined with an adjuvant (Freund's complete adjuvant or saponin) and evaluated its efficacy in a murine model of CLA. Female BALB/c mice were used in an immunization assay. Key results rCP40 induced high levels of IgG2a and IgG2b antibodies. After challenge with a virulent strain of C. pseudotuberculosis C57 (104 CFU/mL), the levels of IgG2a and IgG2b were sustained, indicating a Th1 response. The groups immunized with rCP40 protein (GES and GEF groups) showed 100% protection and was statistically significant in the GES and GEF groups ( p < 0.037 and p < 0.0952, respectively). Conclusions The results indicated the recombinant protein CP40 induced an specific immune response in mice that was able to afford protection after challenge, regardless the adjuvant used in the formulation.
Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due ...to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo
and Caspase-3 activity assays, we generated dose-response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.
Along the long service life of the approximately 65,000 bridges in Germany of more than 50 years, it requires the execution of many meetings under the participation of many different parties. These ...meetings are still location‐bound and run very manually using analog inventory documentation. For an optimization, further digitization as well as dissolution of the location dependency at the structure, immersive technologies can be used in connection with digital twins of bridge structures.
This article presents an approach for a location‐independent meeting at the bridge structure under the integration and possibility of interaction of all actors and linking of the digital and physical world. A digital building model of the bridge serves as the data basis and immersive technologies such as augmented and virtual reality as the output and interaction technology. In the first section, the status quo is elaborated based on a literature review. This is followed by the presentation of the theoretical concept. In the next step, the concept is implemented and validated by using a real bridge demonstrator. Finally, further development possibilities as well as still existing challenges are derived.
The result of the article shows a concept and the first feasibility of location‐independent meetings in the maintenance management of a bridge by merging the following elements.
Highlights • We used huge databases (covering 27 million Germans and 9 million Swedes). • We found elevated risk of SDPCs combined after 19 cancers in both countries. • Our data suggest common ...etiology of SDPCs after most of first primary cancers. • Our data suggest similar registration practices for most SDPCs in both countries. • Decreased risk after fatal cancers in Germany may be due to reporting practices.
We investigated if sleep deprivation (SD) and electroconvulsive therapy (ECT) affect striatal dopamine transporter (DAT) availability assessed by single-photon emission computed tomography (SPECT) ...and
123
I-FP-CIT, if dopamine transporter gene (
SLC6A3
;
DAT
) variation modifies aforementioned parameters, and if SD response or SD-induced DAT changes correlate with ECT response. Sixteen patients with major depression (MDD) referred for ECT and 12 matched controls were prospectively recruited for imaging and
SLC6A3
VNTR genotyping. After withdrawal from any psychiatric medication,
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I-FP-CIT-SPECT was acquired at baseline, after SD and after ECT series. Striatal DAT availability was assessed by volume-of-interest analysis of SPECT data. Eleven patients underwent combined treatment with SD and ECT (five ECT responders and six non-responders). Per-protocol analyses yielded no significant effect of SD or ECT on striatal DAT availability using repeated-measures ANOVA. However, intention-to-treat analysis indicated a significant decrease of striatal DAT availability due to SD (paired
t
test,
p
< 0.01). Stratification by
SLC6A3
VNTR genotype suggested the 9R allele to drive this effect. In an exploratory analysis, SD-induced change in DAT availability of the left caudate nucleus predicted ECT response. This study revealed a treatment effect of SD on striatal DAT availability—possibly depending on
SLC6A3
VNTR genotype. This and the observed association between SD-induced change of striatal DAT availability and response to ECT may help to identify treatment mechanisms and response predictors useful for precision medicine approaches in the treatment of MDD.
Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. ...Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.
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Anti-PM/Scl antibodies are present in sera from patients with polymyositis (PM), systemic sclerosis (SSc), and PM/SSc overlap syndromes. The prevalence of antibodies against the 75- and 100-kDa ...PM/Scl proteins and their clinical associations have not been studied in SSc patients in detail so far but could provide a valuable tool for risk assessment in these patients. Furthermore, it remains speculative whether commercially available test systems detecting only anti-PM/Scl-100 antibodies are sufficient in SSc patients.
Two hundred eighty sera from SSc patients, patients with other connective tissue diseases (n = 209), and healthy blood donors (n = 50) were analyzed for the presence of anti-PM/Scl-75 and anti-PM/Scl-100 antibodies by means of line immunoblot assay. For the SSc patients, possible associations between both subsets of anti-PM/Scl antibodies with clinical and laboratory findings were studied.
The determination of anti-PM/Scl reactivity revealed a diagnostic sensitivity of 12.5% and a specificity of 96.9% for SSc. Among anti-PM/Scl-positive SSc patients, 10.4% and 7.1% were positive for anti-PM/Scl-75 and anti-PM/Scl-100 antibodies, respectively. The highest prevalences of reactivity to PM/Scl were detected in diffuse SSc (19.8%) and overlap syndromes (17.6%). Patients with diffuse SSc showed mainly an anti-PM/Scl-75 response, whereas most cases of overlap syndromes were characterized by reactivity to both PM/Scl antigens. The presence of anti-PM/Scl-75/100 antibodies was associated with muscular and lung involvements as well as with digital ulcers; pulmonary arterial hypertension was found less frequently. Anti-PM/Scl-75 antibodies were detected more frequently in younger and more active patients with joint contractures. Anti-PM/Scl-100 antibodies were associated with creatine kinase elevation; however, gastrointestinal involvements were observed less frequently.
Anti-PM/Scl antibodies are common in distinct SSc subsets and are associated with several clinical symptoms. They are directed mainly to the PM/Scl-75 antigen. Consequently, the detection of anti-PM/Scl antibodies by tests based only on PM/Scl-100 as an antigen source may miss a relevant number of SSc patients positive for these antibodies.
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and ...recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. ...Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.
► Individuals carrying mutation in SIRT1 are susceptible to type 1 diabetes ► Human SIRT1 regulates the production of nitric oxide and cytokines ► SIRT1 regulates immune and metabolic function in humans
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