Search

Recent investigation has revealed the significant role of Cathelicidin antimicrobial peptide (CAMP) in infection defense and innate immunity processes in adipose tissue. Meanwhile, knowledge of its regulation and functions in metabolic contexts as an adipokine remains sparce. The present study investigated the postprandial regulation of circulating CAMP levels during oral glucose tolerance tests (OGTTs). Eighty-six metabolically healthy volunteers participated in a standardized 75 g-2 h-OGTT setting. The effects of exogenous glucose, insulin, and incretins on CAMP expression in human adipocyte culture (cell-line SGBS) were studied in vitro. CAMP concentrations in blood serum samples were measured by ELISA techniques and adipocyte gene expression levels were quantified by real-time PCR. Of note, base-line CAMP serum quantities were negatively correlated with HDL cholesterol levels as well as with the anti-inflammatory adipokine adiponectin. During the 2 h following glucose ingestion, a significant rise in circulating CAMP concentrations was observed in considerable contrast to reduced quantities of fatty acid binding proteins (FABP) 2 and 4 and dipeptidyl peptidase 4 (DPP4). In SGBS adipocytes, neither differing glucose levels nor insulin or incretin treatment significantly induced CAMP mRNA levels. According to our data, glucose represents a positive postprandial regulator of systemic CAMP. This effect apparently is not mediated by the regulatory impact of glucose metabolism on adipocyte CAMP expression.

Background: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2−) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2− breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. Methods: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women’s Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. Results: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2− tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2− breast cancer (TNBC). Of 2039 HER2− breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2− breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2− patients and 87 of 141 (61.7%) patients with TNBC). Conclusion: Approximately one in ten patients with HR+/HER2−, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

The aggregation of amyloid-β (Aβ) peptides, particularly of Aβ1−42, has been linked to the pathogenesis of Alzheimer’s disease. In this study, we focus on the conformational change of Aβ1−42 in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in Aβ by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in Aβ1−42 in solution to more compact states arising from stable β-hairpin formation when Aβ1−42 is in the vicinity of a GAG molecule, and even more compact states characterized by a α-helix or β-sheet structures when Aβ1−42 interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the Aβ1−42/GAG and Aβ1−42/POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of Aβ1−42, in the case of GAG there are hardly any intermolecular Aβ1−42–GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a β-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the Aβ peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils.

Introduction: Obesity and related diseases are among the main public health issues in the western world. They are thought to be caused by a state of chronic, low-grade inflammation. Cathelicidin antimicrobial peptide (CAMP) was recently discovered to be expressed and secreted by adipocytes. Representing a novel immunomodulatory adipokine, CAMP might play an important role in the complex interaction between metabolism and inflammation. Methods: In a cohort of 80 volunteers, serum samples were collected prior to, and 2 h, 4 h, and 6 h after, oral lipid ingestion. CAMP, fatty acid binding proteins 2 and 4 (FABP-2/-4), and dipeptidylpeptidase-4 (DPP-4) serum concentrations were measured via ELISA. Human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes were treated with free fatty acids, and gene expression levels of CAMP, FABP-4, and DPP-4 were quantified by RT-PCR. Results: The mean base-line CAMP serum concentration was 55.78 ± 29.26 ng/mL, with a range of 10.77–146.24 ng/mL. Interestingly, CAMP serum levels were positively correlated with LDL cholesterol, but negatively correlated with HDL cholesterol and adiponectin. Men exhibited higher CAMP serum concentrations than women, an effect apparently linked to oral contraception in the majority of female participants. In both genders, CAMP serum concentrations significantly decreased in a stepwise manner 4 h and 6 h after oral lipid ingestion. This decline was paralleled by a rise of serum bile acid and triglyceride levels upon lipid ingestion. In human SGBS adipocytes, treatment with free fatty acids did not affect CAMP gene expression, but increased FABP-4 gene expression. Conclusions: In conclusion, systemic levels of the antimicrobial peptide and novel adipokine CAMP are significantly decreased upon oral lipid ingestion. While this decline might be linked to the simultaneous increase in bile acids, the underlying mechanisms remain to be elucidated. Furthermore, CAMP might indicate a putative novel cardiovascular biomarker of both inflammatory and metabolic relevance in metaflammation and adipose inflammation.

Abstract The Si/SiGe heterosystem would be ideally suited for the realization of complementary metal-oxide-semiconductor (CMOS)-compatible integrated light sources, but the indirect band gap, exacerbated by a type-II band offset, makes it challenging to achieve efficient light emission. We address this problem by strain engineering in ordered arrays of vertically close-stacked SiGe quantum dot (QD) pairs. The strain induced by the respective lower QD creates a preferential nucleation site for the upper one and strains the upper QD as well as the Si cap above it. Electrons are confined in the strain pockets in the Si cap, which leads to an enhanced wave function overlap with the heavy holes near the upper QD’s apex. With a thickness of the Si spacer between the stacked QDs below 5 nm, we separated the functions of the two QDs: The role of the lower one is that of a pure stressor, whereas only the upper QD facilitates radiative recombination of QD-bound excitons. We report on the design and strain engineering of the QD pairs via strain-dependent Schrödinger-Poisson simulations, their implementation by molecular beam epitaxy, and a comprehensive study of their structural and optical properties in comparison with those of single-layer SiGe QD arrays. We find that the double QD arrangement shifts the thermal quenching of the photoluminescence signal at higher temperatures. Moreover, detrimental light emission from the QD-related wetting layers is suppressed in the double-QD configuration.

Abstract With increased application of DNA metabarcoding in biodiversity assessment, various laboratory protocols have been optimized, and their further evaluation is subject of current research. Homogenization of bulk samples and subsequent DNA extraction from a subsample of destructed tissue is a common first stage of the metabarcoding process. This can either be conducted using sample material soaked in a storage fixative, e.g., ethanol (here referred to as “wet” treatment) or from dried individuals (“dry”). However, it remains uncertain if perfect mixing and equal distribution of DNA within the tube is ensured during homogenization and to what extent incomplete mixing and resulting variations in tissue composition affect diversity assessments if only a fraction of the destructed sample is processed in the downstream metabarcoding workflow. Here we investigated the efficiency of homogenization under wet and dry conditions and tested how variations in destructed tissue composition might affect diversity assessments of complex arthropod samples. We considered five time intervals of Malaise trap bulk samples and process nine different subsamples of homogenized tissue (20 mg each) in both treatments. Results indicate a more consistent diversity assessment from dried material, but at the cost of a higher processing time. Both approaches detected comparable OTU diversity and revealed similar taxa compositions in a single tissue extraction. With an increased number of tissue subsamples during DNA extraction, OTU diversity increased for both approaches, especially for highly diverse samples obtained during the summer. Here, particularly the detection of small and low‐biomass taxa increased. The processing of multiple subsamples in the metabarcoding protocol can therefore be a helpful procedure to enhance diversity estimates and counteract taxonomic bias in biodiversity assessments. However, the process induces higher costs and time effort and the application in large‐scale biodiversity assessment, e.g., in monitoring schemes needs to be considered on project‐specific prospects.

In addition to the endocrine and paracrine systems, peripheral tissues such as gonads, skin, and adipose tissue are involved in the intracrine mechanisms responsible for the formation of sex steroids via the transformation of dehydroepiandrosterone and dehydroepiandrosterone sulfate (DHEA/DHEAS) into potent androgenic and estrogenic hormones. Numerous studies have examined the relationship between overweight, central obesity, and plasma levels of DHEA and DHEAS. The sodium-dependent organic anion transporter Soat (Slc10a6) is a plasma membrane uptake transporter for sulfated steroids. Significantly increased expression of Slc10a6 mRNA has been previously described in organs and tissues of lipopolysaccharide (LPS)-treated mice, including white adipose tissue. These findings suggest that Soat plays a role in the supply of steroids in peripheral target tissues. The present study aimed to investigate the expression of Soat in adipocytes and its role in adipogenesis. Soat expression was analyzed in mouse white intra-abdominal (WAT), subcutaneous (SAT), and brown (BAT) adipose tissue samples and in murine 3T3-L1 adipocytes. In addition, adipose tissue mass and size of the adipocytes were analyzed in wild-type and Slc10a6−/− knockout mice. Soat expression was detected in mouse WAT, SAT, and BAT using immunofluorescence. The expression of Slc10a6 mRNA was significantly higher in 3T3-L1 adipocytes than that of preadipocytes and was significantly upregulated by exposure to lipopolysaccharide (LPS). Slc10a6 mRNA levels were also upregulated in the adipose tissue of LPS-treated mice. In Slc10a6−/− knockout mice, adipocytes increased in size in the WAT and SAT of female mice and in the BAT of male mice, suggesting adipocyte hypertrophy. The serum levels of adiponectin, resistin, and leptin were comparable in wild-type and Slc10a6−/− knockout mice. The treatment of 3T3-L1 adipocytes with DHEA significantly reduced lipid accumulation, while DHEAS did not have a significant effect. However, following LPS-induced Soat upregulation, DHEAS also significantly inhibited lipid accumulation in adipocytes. In conclusion, Soat-mediated import of DHEAS and other sulfated steroids could contribute to the complex pathways of sex steroid intracrinology in adipose tissues. Although in cell cultures the Soat-mediated uptake of DHEAS appears to reduce lipid accumulation, in Slc10a6−/− knockout mice, the Soat deletion induced adipocyte hyperplasia through hitherto unknown mechanisms.

Mit DeepGreen wurde eine Infrastruktur aufgebaut und etabliert, die Zeitschriftenartikel von wissenschaftlichen Verlagen abholt und berechtigten Bibliotheken zur Veröffentlichung in ihren Repositorien sendet. DeepGreen unterstützt Bibliotheken als Dienstleister für Hochschulen, außeruniversitäre Einrichtungen und die dort tätigen Wissenschaftler*innen, Publikationen auf Open-Access-Repositorien frei zugänglich zu machen und fördert das Zusammenspiel von wissenschaftlichen Einrichtungen und Verlagen. DeepGreen wurde von Januar 2016 bis Juni 2021 von der Deutschen Forschungsgemeinschaft gefördert und wird nun vom Kooperativen Bibliotheksverbund Berlin-Brandenburg, von der Bayerischen Staatsbibliothek und von der Universitätsbibliothek Erlangen-Nürnberg in arbeitsteiliger Eigenleistung für zwei Jahre weiterbetrieben. Der vorliegende Beitrag beleuchtet vielfältige Aspekte bei der Realisierung von DeepGreen und geht auf die Perspektiven dieser zentralen Open-Access-Infrastruktur für deutsche Wissenschaftseinrichtungen ein.

Background & Aims: Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC. Methods: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice. Results: In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production. Conclusion: We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention.