| 1. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 6. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 7. |
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| 8. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Weng, Lu Chen, et al.
(författare)
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Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation : The AFGen Consortium
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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| 14. |
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| 15. |
- Bergström, Marcus, et al.
(författare)
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Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation
- 2021
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Ingår i: Transplant International. - : John Wiley & Sons. - 0934-0874 .- 1432-2277. ; 34:12, s. 2816-2823
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic islet transplantation in type 1 diabetes requires lifelong immunosuppression to prevent graft rejection. This medication can cause adverse effects and increases the susceptibility for infections and malignancies. Adoptive therapies with regulatory T cells (Tregs) have shown promise in reducing the need for immunosuppression in human transplantation settings but have previously not been evaluated in islet transplantation. In this study, five patients with type 1 diabetes undergoing intraportal allogeneic islet transplantation were co-infused with polyclonal autologous Tregs under a standard immunosuppressive regimen. Patients underwent leaukapheresis from which Tregs were purified by magnetic-activated cell sorting (MACS) and cryopreserved until transplantation. Dose ranges of 0.14–1.27 × 106 T cells per kilo bodyweight were transplanted. No negative effects were seen related to the Treg infusion, regardless of cell dose. Only minor complications related to the immunosuppressive drugs were reported. This first-in-man study of autologous Treg infusion in allogenic pancreatic islet transplantation shows that the treatment is safe and feasible. Based on these results, future efficacy studies will be developed under the label of advanced therapeutic medical products (ATMP), using modified or expanded Tregs with the aim of minimizing the need for chronic immunosuppressive medication in islet transplantation.
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| 16. |
- Bergström, Marcus, et al.
(författare)
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Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells
- 2019
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Ingår i: Cell Transplantation. - : SAGE PUBLICATIONS INC. - 0963-6897 .- 1555-3892. ; 28:12, s. 1603-1613
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Tidskriftsartikel (refereegranskat)abstract
- Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naive, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naive and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naive Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37 degrees C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.
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| 17. |
- Braungardt, Sibylle, et al.
(författare)
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Renewable heating and cooling pathways – Towards full decarbonisation by 2050 – Final report
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- With the adoption of the EU Climate Law in 2021, the EU has set itself a binding target to achieve climate neutrality by 2050 and to reduce greenhouse gas emissions by 55 percent compared to 1990 levels by 2030. To support the increased ambition, the EU Commission adopted proposals for revising the key directives and regulations addressing energy efficiency, renewable energies and greenhouse gas emissions in the Fit for 55 package.The heating and cooling (H&C) sector plays a key role for reaching the EU energy and climate targets. H&C accounts for about 50 percent of the final energy consumption in the EU, and the sector is largely based on fossil fuels. In 2021, the share of renewable energies in H&C reached 23%. The decarbonisation of heating and cooling is addressed across several directives and regulations at EU level.The aim of this study is to support the analytical basis for the development and implementation of policies to ensure a seamless pathway to the full decarbonisation of the heating and cooling sector by 2050 in buildings and industry.
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| 18. |
- Broman, Marcus Ewert, et al.
(författare)
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Malignant hyperthermia, a Scandinavian update.
- 2015
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 59:8, s. 951-961
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Forskningsöversikt (refereegranskat)abstract
- Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene.
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| 19. |
- Broman, Marcus, et al.
(författare)
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Next generation DNA sequencing of a Swedish Malignant Hyperthermia cohort.
- 2015
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 88:4, s. 381-385
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Tidskriftsartikel (refereegranskat)abstract
- Malignant Hyperthermia (MH) related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes.
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| 20. |
- Broman, Marcus, et al.
(författare)
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Screening of the ryanodine 1 gene for malignant hyperthermia causative mutations by high resolution melt curve analysis.
- 2011
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Ingår i: Anesthesia and Analgesia. - 1526-7598. ; 113:5, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- A diagnosis of malignant hyperthermia (MH) can be determined by performing an in vitro (muscle) contracture test (IVCT) or by identifying a known MH causative mutation in the ryanodine receptor 1 gene (RYR1). Genetic diagnosis has an advantage over IVCT because it is less invasive. Direct sequencing of the very large RYR1 coding region (15.117 bases) is a laborious and expensive task. In this study, we applied the High Resolution Melting (HRM) curve analysis as a tool to screen the entire coding region of the gene.
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| 21. |
- Bräunig, Jennifer, et al.
(författare)
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Time-dependent expression and activity of cytochrome P450 1s in early life-stages of the zebrafish (Danio rerio)
- 2015
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Ingår i: Environmental Science and Pollution Research. - : Springer. - 0944-1344 .- 1614-7499. ; 22:21, s. 16319-15328
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Tidskriftsartikel (refereegranskat)abstract
- Zebrafish embryos are being increasingly used as model organisms for the assessment of single substances and complex environmental samples for regulatory purposes.Thus, it is essential to fully understand the xenobiotic metabolism during the different life-stages of early development.The aim of the present study was to determine arylhydrocarbon receptor (AhR)-mediated activity during selected times of early development using qPCR, enzymatic activity through measurement of 7-ethoxyresorufin-Odeethylase(EROD) activity, and protein expression analysis. In the present study, gene expression of cyp1a, cyp1b1, cyp1c1, cyp1c2, and ahr2 as well as EROD activity were investigated up to 120 h postfertilization (hpf) after exposure to either β-naphthoflavone (BNF) or a polycyclic aromatichydrocarbons (PAH)-contaminated sediment extract from Vering Kanal in Hamburg (VK). Protein expression was measured at 72 hpf after exposure to 20 μg/L BNF. Altered proteins were identified by matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) peptide mass fingerprinting. Distinct patterns of basal messenger RNA (mRNA) expressionwere found for each of the cyp1 genes, suggesting specific roles during embryonic development. All transcripts were induced by BNF and VK. ahr2 mRNA expression was significantly upregulated after exposure toVK. All cyp1 genes investigated showed a temporal decline in expression at 72 hpf. The significant decline of Hsp 90β protein at 72 hpf after exposure to BNF may suggest an explanation for the decline of cyp1 genes at this time point as Hsp 90β is of major importance for the functioning of the Ah-receptor. EROD activity measured in embryos was significantly induced after 96 hpf of exposure to BNF or VK. Together, these results demonstrate distinct temporal patterns of cyp1 genes and protein activities in zebrafish embryos as well as show a need to investigate further the xenobiotic biotransformation system during early development of zebrafish.
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| 22. |
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| 23. |
- Czymzik, Markus, et al.
(författare)
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Synchronizing the Western Gotland Basin (Baltic Sea) and Lake Kälksjön (central Sweden) sediment records using common cosmogenic radionuclide production variations
- 2024
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Ingår i: Holocene. - 0959-6836.
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Tidskriftsartikel (refereegranskat)abstract
- Multi-archive studies of climate events and archive-specific response times require synchronous time scales. Aligning common variations in the cosmogenic radionuclide production rate via curve fitting methods provides a tool for the continuous synchronization of natural environmental archives down to decadal precision. Based on this approach, we synchronize 10Be records from Western Gotland Basin (WGB, Baltic Sea) and Lake Kälksjön (KKJ, central Sweden) sediments to the 14C production time series from the IntCal20 calibration curve during the Mid-Holocene period ~6400 to 5200 a BP. Before the synchronization, we assess and reduce non-production variability in the 10Be records by using 10Be/9Be ratios and removing common variability with the TOC record from KKJ sediments based on regression analysis. The synchronizations to the IntCal20 14C production time scale suggest decadal to multi-decadal refinements of the WGB and KKJ chronologies. These refinements reduce the previously centennial chronological uncertainties of both archives to about ± 20 (WGB) and ±40 (KKJ) years. Combining proxy time series from the synchronized archives enables us to interpret a period of ventilation in the deep central Baltic Sea basins from ~6250 to 6000 a BP as possibly caused by inter-annual cooling reducing vertical water temperature gradients allowing deep water formation during exceptionally cold winters.
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| 24. |
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| 25. |
- Eckhard, Andreas, et al.
(författare)
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Co-localisation of Kir4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K+ recycling routes
- 2012
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 0302-766X .- 1432-0878. ; 350:1, s. 27-43
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Tidskriftsartikel (refereegranskat)abstract
- Sensory transduction in the cochlea depends on perilymphatic-endolymphatic potassium (K+) recycling. It has been suggested that the epithelial supporting cells (SCs) of the cochlear duct may form the intracellular K+ recycling pathway. Thus, they must be endowed with molecular mechanisms that facilitate K+ uptake and release, along with concomitant osmotically driven water movements. As yet, no molecules have been described that would allow for volume-equilibrated transepithelial K+ fluxes across the SCs. This study describes the subcellular co-localisation of the Kir4.1 K+ channel (Kir4.1) and the aquaporin-4 water channel (AQP4) in SCs, on the basis of immunohistochemical double-labelling experiments in rat and human cochleae. The results of this study reveal the expression of Kir4.1 in the basal or basolateral membranes of the SCs in the sensory domain of the organ of Corti that are adjacent to hair cells and in the non-sensory domains of the inner and outer sulci that abut large extracellular fluid spaces. The SCs of the inner sulcus (interdental cells, inner sulcus cells) and the outer sulcus (Hensen’s cells, outer sulcus cells) display the co-localisation of Kir4.1 and AQP4 expression. However, the SCs in the sensory domain of the organ of Corti reveal a gap in the expression of AQP4. The outer pillar cell is devoid of both Kir4.1 and AQP4. The subcellular co-localisation of Kir4.1 and AQP4 in the SCs of the cochlea described in this study resembles that of the astroglia of the central nervous system and the glial Mueller cells in the retina.
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| 26. |
- Eckhard, Andreas, et al.
(författare)
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Water channel proteins in the inner ear and their link to hearing impairment and deafness
- 2012
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Ingår i: Molecular Aspects of Medicine. - : Elsevier BV. - 0098-2997 .- 1872-9452. ; 33:5-6, s. 612-637
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Tidskriftsartikel (refereegranskat)abstract
- The inner ear is a fluid-filled sensory organ that transforms mechanical stimuli into the senses of hearing and balance. These neurosensory functions depend on the strict regulation of the volume of the two major extracellular fluid domains of the inner ear, the perilymph and the endolymph. Water channel proteins, or aquaporins (AQPs), are molecular candidates for the precise regulation of perilymph and endolymph volume. Eight AQP subtypes have been identified in the membranous labyrinth of the inner ear. Similar AQP subtypes are also expressed in the kidney, where they function in whole-body water regulation. In the inner ear, AQP subtypes are ubiquitously expressed in distinct cell types, suggesting that AQPs have an important physiological role in the volume regulation of perilymph and endolymph. Furthermore, disturbed AQP function may have pathophysiological relevance and may turn AQPs into therapeutic targets for the treatment of inner ear diseases. In this review, we present the currently available knowledge regarding the expression and function of AQPs in the inner ear. We give special consideration to AQP subtypes AQP2, AQP4 and AQP5, which have been studied most extensively. The potential functions of AQP2 and AQP5 in the resorption and secretion of endolymph and of AQP4 in the equilibration of cell volume are described. The pathophysiological implications of these AQP subtypes for inner ear diseases, that appear to involve impaired fluid regulation, such as Menière's disease and Sjögren's syndrome, are discussed.
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| 27. |
- Fallahnejad, Mostafa, et al.
(författare)
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District heating potential in the EU-27 : Evaluating the impacts of heat demand reduction and market share growth
- 2024
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Ingår i: Applied Energy. - Oxford : Elsevier. - 0306-2619 .- 1872-9118. ; 353:Part B
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a novel approach to modeling the gradual reduction in heat demand and the evolving expansion of district heating (DH) grids for assessing the DH potential in EU member states (MS). It introduces new methodological elements for modeling the impact of connection rates below 100% on heat distribution costs in both dense and sparse areas. The projected heat demand in 2050 is derived from a decarbonization scenario published by the EU, which would lead to a reduction in demand from 3128 TWh in 2020 to 1709 TWh by 2050. The proposed approach yields information on economic DH areas, DH potential, and average heat distribution costs. The results confirm the need to expand DH grids to maintain supply levels in view of decreasing heat demand. The proportion of DH potential from the total demand in the EU-27 rises from 15% in 2020 to 31% in 2050. The analysis of DH areas shows that 39% of the DH potential is in areas with heat distribution costs above 35 EUR/MWh, but most MS have average heat distribution costs between 28 and 32 EUR/MWh. The study reveals that over 40% of the EU's heat demand is in regions with high potential for implementing DH. © 2023 The Author(s)
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| 28. |
- Fassnacht, Martin, et al.
(författare)
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Combination chemotherapy in advanced adrenocortical carcinoma
- 2012
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 366:23, s. 2189-2197
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.METHODS:We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.RESULTS:For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.CONCLUSIONS:Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival.
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| 29. |
- Frick, Claudia, et al.
(författare)
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Age-Dependency of Neurite Outgrowth in Postnatal Mouse Cochlear Spiral Ganglion Explants
- 2020
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Ingår i: Brain Sciences. - : MDPI. - 2076-3425. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs.Method: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions.Results: THF (7,8,3 '-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3).Conclusions: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF.
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| 30. |
- Frick, Claudia, et al.
(författare)
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Biofunctionalized peptide-based hydrogels provide permissive scaffolds to attract neurite outgrowth from spiral ganglion neurons
- 2017
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Ingår i: Colloids and Surfaces B. - : Elsevier BV. - 0927-7765 .- 1873-4367. ; 149, s. 105-114
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Tidskriftsartikel (refereegranskat)abstract
- Cochlear implants (CI) allow for hearing rehabilitation in patients with sensorineural hearing loss or deafness. Restricted CI performance results from the spatial gap between spiral ganglion neurons and the CI, causing current spread that limits spatially restricted stimulation and impairs frequency resolution. This may be substantially improved by guiding peripheral processes of spiral ganglion neurons towards and onto the CI electrode contacts. An injectable, peptide-based hydrogel was developed which may provide a permissive scaffold to facilitate neurite growth towards the CI. To test hydrogel capacity to attract spiral ganglion neurites, neurite outgrowth was quantified in an in vitro model using a custom-designed hydrogel scaffold and PuraMatrix(®). Neurite attachment to native hydrogels is poor, but significantly improved by incorporation of brain-derived neurotrophic factor (BDNF), covalent coupling of the bioactive laminin epitope IKVAV and the incorporation a full length laminin to hydrogel scaffolds. Incorporation of full length laminin protein into a novel custom-designed biofunctionalized hydrogel (IKVAV-GGG-SIINFEKL) allows for neurite outgrowth into the hydrogel scaffold. The study demonstrates that peptide-based hydrogels can be specifically biofunctionalized to provide a permissive scaffold to attract neurite outgrowth from spiral ganglion neurons. Such biomaterials appear suitable to bridge the spatial gap between neurons and the CI.
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| 31. |
- Gao, Yu, et al.
(författare)
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Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination
- 2022
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Ingår i: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 55:9, s. 1732-1746.e5
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Tidskriftsartikel (refereegranskat)abstract
- Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.
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| 32. |
- Hanschke, Lukas, et al.
(författare)
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Coherent scattering: either sub-natural linewidth or anti-bunched light
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Epitaxial quantum dots have emerged as one of the best single–photon sources, not only for applications in photonic quantum technologies but also for testing fundamental properties of quantum optics. One intriguing observation in this area is the emission of photons with subnatural–linewidth from a two-level system under resonant continuous wave excitation. In particular, an open question is whether these subnatural–linewidth photons exhibit simultaneously single–photon characteristics, i.e. show antibunching as a signature of single-photon emission. Here, we demonstrate that this simultaneous observation of subnatural–linewidth and single photoncharacter is not possible with simple resonant excitation. First, we independently confirm single–photon character and subnatural–linewidth by demonstrating antibunching in a Hanbury Brown and Twiss type setup and using high-resolution spectroscopy, respectively. However, when filtering the coherently scattered photons with filter bandwidths on the order of the homogeneous linewidth of the excited state of the two-level system, the antibunching dip vanishes in the correlation measurement. Our experimental work is consistent with recent theoretical findings, and can be explained by a fundamental model considering higher-order photon correlations.
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| 33. |
- Hanschke, Lukas, et al.
(författare)
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Origin of Antibunching in Resonance Fluorescence
- 2020
-
Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 125:17
-
Tidskriftsartikel (refereegranskat)abstract
- Resonance fluorescence has played a major role in quantum optics with predictions and later experimental confirmation of nonclassical features of its emitted light such as antibunching or squeezing. In the Rayleigh regime where most of the light originates from the scattering of photons with subnatural linewidth, antibunching would appear to coexist with sharp spectral lines. Here, we demonstrate that this simultaneous observation of subnatural linewidth and antibunching is not possible with simple resonant excitation. Using an epitaxial quantum dot for the two-level system, we independently confirm the single-photon character and subnatural linewidth by demonstrating antibunching in a Hanbury Brown and Twiss type setup and using high-resolution spectroscopy, respectively. However, when filtering the coherently scattered photons with filter bandwidths on the order of the homogeneous linewidth of the excited state of the two-level system, the antibunching dip vanishes in the correlation measurement. Our observation is explained by antibunching originating from photon-interferences between the coherent scattering and a weak incoherent signal in a skewed squeezed state. This prefigures schemes to achieve simultaneous subnatural linewidth and antibunched emission.
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| 34. |
- Hoshino, Yuichi, et al.
(författare)
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Quantitative evaluation of the pivot shift by image analysis using the iPad.
- 2013
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Ingår i: Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. - : Springer Science and Business Media LLC. - 1433-7347. ; 21:4, s. 975-80
-
Tidskriftsartikel (refereegranskat)abstract
- To enable comparison of test results, a widely available measurement system for the pivot shift test is needed. Simple image analysis of lateral knee joint translation is one such system that can be installed on a prevalent computer tablet (e.g. iPad). The purpose of this study was to test a novel iPad application to detect the pivot shift. It was hypothesized that the abnormal lateral translation in ACL deficient knees would be detected by the iPad application.
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| 35. |
- Ji, Xuemei, et al.
(författare)
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
- 2018
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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| 36. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 37. |
- Karlsson, Marcus, 1988-
(författare)
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Blind Massive MIMO Base Stations : Downlink Transmission and Jamming
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Massive MIMO (Multiple-Input--Multiple-Output) is a cellular-network technology in which the base station is equipped with a large number of antennas and aims to serve several different users simultaneously, on the same frequency resource through spatial multiplexing. This is made possible by employing efficient beamforming, based on channel estimates acquired from uplink reference signals, where the base station can transmit the signals in such a way that they add up constructively at the users and destructively elsewhere. The multiplexing together with the array gain from the beamforming can increase the spectral efficiency over contemporary systems.One challenge of practical importance is how to transmit data in the downlink when no channel state information is available. When a user initially joins the network, prior to transmitting uplink reference signals that enable beamforming, it needs system information---instructions on how to properly function within the network. It is transmission of system information that is the main focus of this thesis. In particular, the thesis analyzes how the reliability of the transmission of system information depends on the available amount of diversity. It is shown how downlink reference signals, space-time block codes, and power allocation can be used to improve the reliability of this transmission.In order to estimate the uplink and downlink channels from uplink reference signals, which is imperative to ensure scalability in the number of base station antennas, massive MIMO relies on channel reciprocity. This thesis shows that the principles of channel reciprocity can also be exploited by a jammer, a malicious transmitter, aiming to disrupt legitimate communication between two single-antenna devices. A heuristic scheme is proposed in which the jammer estimates the channel to a target device blindly, without any knowledge of the transmitted legitimate signals, and subsequently beamforms noise towards the target. Under the same power constraint, the proposed jammer can disrupt the legitimate link more effectively than a conventional omnidirectional jammer in many cases.
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| 38. |
- Kashani, Amir Hossein Navidi, et al.
(författare)
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Temporally-resolved decomposition of Ti0.12Al0.21B0.67 thin films at 1000°C
- 2024
-
Ingår i: Surface & Coatings Technology. - : Elsevier. - 0257-8972 .- 1879-3347. ; 487
-
Tidskriftsartikel (refereegranskat)abstract
- The thermal stability of stoichiometric Ti0.12Al0.21B0.67 thin films synthesized by magnetron sputtering was investigated by vacuum annealing at 1000°C for 1 and 3 h. The as-deposited and post-annealed films were compared regarding changes in chemical composition, phase formation, and morphology. X-ray diffraction (XRD) data indicate the formation of a single-phase solid solution in the as-deposited Ti0.12Al0.21B0.67 thin film. After annealing for 1 h, scanning transmission electron microscopy (STEM), energy-dispersive X-ray mapping (EDX), and atom probe tomography (APT) investigations reveal segregation into Al- and Ti-rich (Ti,Al)B2 domains, consistent with spinodal decomposition. Furthermore, the formation of AlB12 with a concomitant reduction in Al concentration from 20.9 to 16.8 at. %, likely by evaporation, indicate the decomposition of Al-rich (Ti,Al)B2 domains during annealing for 1 h. Analysis of the film after annealing for 3 h shows evidence for continued spinodal decomposition as well as for further decomposition of Al-rich (Ti,Al)B2 domains, leading besides the formation of AlB12 to a reduction in Al concentration to 12.5 at. % by Al evaporation. The observed phase formation trend during in situ transmission electron microscopy (TEM) studies at 1100 degrees C is consistent with the above discussed decomposition processes. The here identified thermal stability limit, revealed with spatially resolved structure and composition probes, confines the application temperature range of Ti0.12Al0.21B0.67 in vacuum to temperatures <1000°C and underlines that thermal stability investigations solely based on XRD data result in an overestimated thermal stability.
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| 39. |
- Laland, Kevin N, et al.
(författare)
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The extended evolutionary synthesis: its structure, assumptions and predictions.
- 2015
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Ingår i: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 282:1813
-
Forskningsöversikt (refereegranskat)abstract
- Scientific activities take place within the structured sets of ideas and assumptions that define a field and its practices. The conceptual framework of evolutionary biology emerged with the Modern Synthesis in the early twentieth century and has since expanded into a highly successful research program to explore the processes of diversification and adaptation. Nonetheless, the ability of that framework satisfactorily to accommodate the rapid advances in developmental biology, genomics and ecology has been questioned. We review some of these arguments, focusing on literatures (evo-devo, developmental plasticity, inclusive inheritance and niche construction) whose implications for evolution can be interpreted in two ways-one that preserves the internal structure of contemporary evolutionary theory and one that points towards an alternative conceptual framework. The latter, which we label the 'extended evolutionary synthesis' (EES), retains the fundaments of evolutionary theory, but differs in its emphasis on the role of constructive processes in development and evolution, and reciprocal portrayals of causation. In the EES, developmental processes, operating through developmental bias, inclusive inheritance and niche construction, share responsibility for the direction and rate of evolution, the origin of character variation and organism-environment complementarity. We spell out the structure, core assumptions and novel predictions of the EES, and show how it can be deployed to stimulate and advance research in those fields that study or use evolutionary biology.
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| 40. |
- Li, Yafang, et al.
(författare)
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Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
- 2019
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 10:19, s. 1760-1774
-
Tidskriftsartikel (refereegranskat)abstract
- The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
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| 41. |
- Li, Yafang, et al.
(författare)
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Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population
- 2018
-
Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 39:3, s. 336-346
-
Tidskriftsartikel (refereegranskat)abstract
- Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13 336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13 970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.
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| 42. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
-
Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 43. |
- Meier, Markus, et al.
(författare)
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Comparing reconstructed past variations and future projections of the Baltic sea ecosystem first results from multi model ensemble simulations
- 2012
-
Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 7:3, s. 034005-
-
Tidskriftsartikel (refereegranskat)abstract
- Multi-model ensemble simulations for the marine biogeochemistry and food web of the Baltic Sea were performed for the period 1850-2098, and projected changes in the future climate were compared with the past climate environment. For the past period 1850-2006, atmospheric, hydrological and nutrient forcings were reconstructed, based on historical measurements. For the future period 1961-2098, scenario simulations were driven by regionalized global general circulation model (GCM) data and forced by various future greenhouse gas emission and air-and riverborne nutrient load scenarios (ranging from a pessimistic 'business-as-usual' to the most optimistic case). To estimate uncertainties, different models for the various parts of the Earth system were applied. Assuming the IPCC greenhouse gas emission scenarios A1B or A2, we found that water temperatures at the end of this century may be higher and salinities and oxygen concentrations may be lower than ever measured since 1850. There is also a tendency of increased eutrophication in the future, depending on the nutrient load scenario. Although cod biomass is mainly controlled by fishing mortality, climate change together with eutrophication may result in a biomass decline during the latter part of this century, even when combined with lower fishing pressure. Despite considerable shortcomings of state-of-the-art models, this study suggests that the future Baltic Sea ecosystem may unprecedentedly change compared to the past 150 yr. As stakeholders today pay only little attention to adaptation and mitigation strategies, more information is needed to raise public awareness of the possible impacts of climate change on marine ecosystems.
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| 44. |
- Miethke, Marcus, et al.
(författare)
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Towards the sustainable discovery and development of new antibiotics
- 2021
-
Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
-
Forskningsöversikt (refereegranskat)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 45. |
- Mollenhauer, Jan, et al.
(författare)
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Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis.
- 2004
-
Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257. ; 39:3, s. 185-94
-
Tidskriftsartikel (refereegranskat)abstract
- Deleted in malignant brain tumors 1 (DMBT1) has been proposed as a candidate tumor suppressor for brain and epithelial cancer. Initial studies suggested loss of expression rather than mutation as the predominant mode of DMBT1 inactivation. However, in situ studies in lung cancer demonstrated highly sophisticated changes of DMBT1 expression and localization, pointing to a chronological order of events. Here we report on the investigation of DMBT1 in breast cancer in order to test whether these principles might also be attributable to other tumor types. Comprehensive mutational analyses did not uncover unambiguous inactivating DMBT1 mutations in breast cancer. Expression analyses in the human and mouse mammary glands pointed to the necessity of DMBT1 induction. While age-dependent and hormonal effects could be ruled out, 9 of 10 mice showed induction of Dmbt1 expression after administration of the carcinogen 7,12-dimethybenz(alpha)anthracene prior to the onset of tumorigenesis or other histopathological changes. DMBT1 displayed significant up-regulation in human tumor-flanking tissues compared to in normal breast tissues (P < 0.05). However, the breast tumor cells displayed a switch from lumenal secretion to secretion to the extracellular matrix and a significant down-regulation compared to that in matched normal flanking tissues (P < 0.01). We concluded that loss of expression also is the predominant mode of DMBT1 inactivation in breast cancer. The dynamic behavior of DMBT1 in lung carcinoma is fully reflected in breast cancer, which suggests that this behavior might be common to tumor types arising from monolayered epithelia.
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| 46. |
- Müller, Jens Daniel, et al.
(författare)
-
Cyanobacteria net community production in the Baltic Sea as inferred from profiling pCO2 measurements
- 2021
-
Ingår i: Biogeosciences. - : European Geosciences Union (EGU). - 1726-4170 .- 1726-4189. ; 18:17, s. 4889-4917
-
Tidskriftsartikel (refereegranskat)abstract
- Organic matter production by cyanobacteria blooms is a major environmental concern for the Baltic Sea, as it promotes the spread of anoxic zones. Partial pressure of carbon dioxide (pCO2) measurements carried out on Ships of Opportunity (SOOP) since 2003 have proven to be a powerful tool to resolve the carbon dynamics of the blooms in space and time. However, SOOP measurements lack the possibility to directly constrain depth-integrated net community production (NCP) in moles of carbon per surface area due to their restriction to the sea surface. This study tackles the knowledge gap through (1) providing an NCP best guess for an individual cyanobacteria bloom based on repeated profiling measurements of pCO2 and (2) establishing an algorithm to accurately reconstruct depth-integrated NCP from surface pCO2 observations in combination with modelled temperature profiles.Goal (1) was achieved by deploying state-of-the-art sensor technology from a small-scale sailing vessel. The low-cost and flexible platform enabled observations covering an entire bloom event that occurred in July–August 2018 in the Eastern Gotland Sea. For the biogeochemical interpretation, recorded pCO2 profiles were converted to C∗T, which is the dissolved inorganic carbon concentration normalised to alkalinity. We found that the investigated bloom event was dominated by Nodularia and had many biogeochemical characteristics in common with blooms in previous years. In particular, it lasted for about 3 weeks, caused a C∗T drawdown of 90 µmol kg−1, and was accompanied by a sea surface temperature increase of 10 ∘C. The novel finding of this study is the vertical extension of the C∗T drawdown up to the compensation depth located at around 12 m. Integration of the C∗T drawdown across this depth and correction for vertical fluxes leads to an NCP best guess of ∼1.2 mol m−2 over the productive period.Addressing goal (2), we combined modelled hydrographical profiles with surface pCO2 observations recorded by SOOP Finnmaid within the study area. Introducing the temperature penetration depth (TPD) as a new parameter to integrate SOOP observations across depth, we achieve an NCP reconstruction that agrees to the best guess within 10 %, which is considerably better than the reconstruction based on a classical mixed-layer depth constraint.Applying the TPD approach to almost 2 decades of surface pCO2 observations available for the Baltic Sea bears the potential to provide new insights into the control and long-term trends of cyanobacteria NCP. This understanding is key for an effective design and monitoring of conservation measures aiming at a Good Environmental Status of the Baltic Sea.
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| 47. |
- Müller, Thomas R., et al.
(författare)
-
Additive effects of booster mRNA vaccination and SARS-CoV-2 Omicron infection on T cell immunity across immunocompromised states
- 2023
-
Ingår i: Science Translational Medicine. - 1946-6234 .- 1946-6242. ; 15:704, s. eadg9452-
-
Tidskriftsartikel (refereegranskat)abstract
- Suboptimal immunity to SARS-CoV-2 mRNA vaccination has frequently been observed in individuals with various immunodeficiencies. Given the increased antibody evasion properties of emerging SARS-CoV-2 subvariants, it is necessary to assess whether other components of adaptive immunity generate resilient and protective responses against infection. We assessed T cell responses in 279 individuals, covering five different immunodeficiencies and healthy controls, before and after booster mRNA vaccination, as well as after Omicron infection in a subset of patients. We observed robust and persistent Omicron-reactive T cell responses that increased markedly upon booster vaccination and correlated directly with antibody titers across all patient groups. Poor vaccination responsiveness in immunocompromised or elderly individuals was effectively counteracted by the administration of additional vaccine doses. Functionally, Omicron-reactive T cell responses exhibited a pronounced cytotoxic profile and signs of longevity, characterized by CD45RA+ effector memory subpopulations with stem cell-like properties and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals appeared protected against severe disease and exhibited enhanced and diversified T cell responses against conserved and Omicron-specific epitopes. Our findings indicate that T cells retain the ability to generate highly functional responses against newly emerging variants, even after repeated antigen exposure and a robust immunological imprint from ancestral SARS-CoV-2 mRNA vaccination.
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| 48. |
- Müller, Thomas R., et al.
(författare)
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Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant
- 2024
-
Ingår i: Cell Host and Microbe. - : Elsevier. - 1931-3128 .- 1934-6069. ; 32:2, s. 156-161.e3
-
Tidskriftsartikel (refereegranskat)abstract
- T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory T cells can effectively cross-recognize new SARS-CoV-2 variants with a broad array of mutations, such as the emergent hypermutated BA.2.86 variant. Here, we report in two separate cohorts, including healthy controls and individuals with chronic lymphocytic leukemia, that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or vaccination demonstrate resilient immune recognition of BA.2.86. In both cohorts, we found largely preserved SARS-CoV-2 spike-specific CD4+ and CD8+ T cell magnitudes against mutated spike epitopes of BA.2.86. Functional analysis confirmed that both cytokine expression and proliferative capacity of SARS-CoV-2 spike-specific T cells to BA.2.86-mutated spike epitopes are similarly sustained. In summary, our findings indicate that memory CD4+ and CD8+ T cells continue to provide cell-mediated immune recognition to highly mutated emerging variants such as BA.2.86.
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| 49. |
- Nguyen, Hoang Long, et al.
(författare)
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The potential for a continuous 10Be record measured on ice chips from a borehole
- 2021
-
Ingår i: Results In Geochemistry. - : Elsevier BV. - 2666-2779. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Ice cores are excellent archives for obtaining long and continuous 10Be records. However, traditional ice core 10Be measurements required a lot of ice (0.5–1kg) and often needed to be connected to a large and costly ice core project. These reasons have been the factors limiting the number and variety of 10Be projects and data. In this paper, we show measurements of 10Be on small samples (∼45g) of continuous auger ice chips from a borehole at Little Dome C (LDC), East Antarctica. The sample preparation method for 10Be accelerator mass spectrometry (AMS) was tested and optimized using test samples (∼50g) including well-mixed surface ice chips from the LDC site, snow collected in Lund (Sweden) and frozen Milli-Q water. The results show that our small ice samples should be processed without ion exchange filtration of the melt water and cleaning the subsequent Be(OH)2 precipitate. In addition, co-precipitating Be with Fe led to more reproducible measurement currents and offer the potential for higher efficiency and precision via longer measurement time. We applied the established preparation method to measure 10Be on 76 samples of the auger ice chips. The resulting 10Be concentration record for the period from 1354 to 1950 CE agrees well with the 10Be concentration in a South Pole ice core and the global 14C production rate and thus reflects well the atmospheric production signal of 10Be. We also observed insignificant mixing among the ice chip samples during the process of drilling and retrieving the ice. Therefore, the new ice chip samples are promising for assessing the long-term changes in 10Be deposition at different ice core sites. A wide application of this novel ice chip samples will increase the variety of 10Be records which will help to improve the assessment of long-term solar and geomagnetic shielding of galactic cosmic rays.
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| 50. |
- Ouyang, Yingwei, 1995, et al.
(författare)
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Highly insulating thermoplastic blends comprising a styrenic copolymer for direct-current power cable insulation
- 2022
-
Ingår i: High Voltage. - : Institution of Engineering and Technology (IET). - 2397-7264. ; 7:2, s. 251-259
-
Tidskriftsartikel (refereegranskat)abstract
- The impact of the composition of blends comprising low-density polyethylene (LDPE), isotactic polypropylene (PP) and a styrenic copolymer additive on the thermomechanical properties as well as the direct-current (DC) electrical and thermal conductivity is investigated. The presence of 5 weight percent (wt%) of the styrenic copolymer strongly reduces the amount of PP that is needed to enhance the storage modulus above the melting temperature of LDPE from 40 to 24 wt%. At the same time, the copolymer improves the consistency of the thermomechanical properties of the resulting ternary blends. While both the DC electrical and thermal conductivity strongly decrease with PP content, the addition of the styrenic copolymer appears to have little influence on either property. Evidently, PP in combination with small amounts of a styrenic copolymer not only allows to reinforce LDPE at elevated temperatures but also functions as an electrical conductivity-reducing additive, which makes such thermoplastic ternary formulations possible candidates for the insulation of high-voltage power cables.
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