| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Kotmayer, L, et al.
(author)
-
Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax
- 2023
-
In: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 24:6
-
Journal article (peer-reviewed)abstract
- The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
|
|
| 7. |
- Zamora, Juan Carlos, et al.
(author)
-
Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
-
In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
-
Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
|
|
| 8. |
|
|
| 9. |
- Haak-Frendscho, M, et al.
(author)
-
Histidine decarboxylase expression in human melanoma.
- 2000
-
In: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 115:3, s. 345-52
-
Journal article (peer-reviewed)abstract
- Histamine has been implicated as one of the mediators involved in regulation of proliferation in both normal and neoplastic tissues. Histidine decarboxylase, the only enzyme that catalyzes the formation of histamine from L-histidine, is an essential regulator of histamine levels. In this study, we investigated the gene and protein expression of histidine decarboxylase in melanoma. Reverse transcriptase polymerase chain reaction and in situ hybridization studies of WM-35, WM-983/B, HT-168, and M1 human melanoma cell lines both resulted in positive signals for histidine decarboxylase messenger RNA. A polyclonal chicken antibody was developed against human histidine decarboxylase and protein expression was confirmed by western blot analysis of the cell lysates, revealing a predominant immunoreactive band at approximately 54 kDa corresponding to monomeric histidine decarboxylase. Protein expression of histidine decarboxylase was also shown by flow cytometric analysis and strong punctate cytoplasmic staining of melanoma cell lines. Moreover, both primary and metastatic human melanoma tissues were brightly stained for histidine decarboxylase. When compared with the very weak or no reactions on cultivated human melanocytes both western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells. These findings suggest that expression of histidine decarboxylase is elevated in human melanoma.
|
|
| 10. |
- Rozsas, Anita, et al.
(author)
-
Erythropoietin Receptor Expression Is a Potential Prognostic Factor in Human Lung Adenocarcinoma
- 2013
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
-
Journal article (peer-reviewed)abstract
- Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPO alpha were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPO alpha with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPO alpha treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPO alpha significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPO alpha treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.
|
|
| 11. |
|
|
| 12. |
- Schoch, Conrad L., et al.
(author)
-
Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi
- 2014
-
In: Database: The Journal of Biological Databases and Curation. - : Oxford University Press (OUP). - 1758-0463. ; 2014:bau061, s. 1-21
-
Journal article (peer-reviewed)abstract
- DNA phylogenetic comparisons have shown that morphology-based species recognition often underestimates fungal diversity. Therefore, the need for accurate DNA sequence data, tied to both correct taxonomic names and clearly annotated specimen data, has never been greater. Furthermore, the growing number of molecular ecology and microbiome projects using high-throughput sequencing require fast and effective methods for en masse species assignments. In this article, we focus on selecting and re-annotating a set of marker reference sequences that represent each currently accepted order of Fungi. The particular focus is on sequences from the internal transcribed spacer region in the nuclear ribosomal cistron, derived from type specimens and/or ex-type cultures. Re-annotated and verified sequences were deposited in a curated public database at the National Center for Biotechnology Information (NCBI), namely the RefSeq Targeted Loci (RTL) database, and will be visible during routine sequence similarity searches with NR_prefixed accession numbers. A set of standards and protocols is proposed to improve the data quality of new sequences, and we suggest how type and other reference sequences can be used to improve identification of Fungi.
|
|
| 13. |
- Woldmar, N., et al.
(author)
-
Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases
- 2023
-
In: ESMO Open. - : Elsevier BV. - 2059-7029. ; 8:1
-
Journal article (peer-reviewed)abstract
- Background: Brain metastases are associated with considerable negative effects on patients’ outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases. Materials and methods: Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259. Results: Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases. Conclusions: This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.
|
|
| 14. |
|
|
| 15. |
- Brasko, Csilla, et al.
(author)
-
Intelligent image-based in situ single-cell isolation
- 2018
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- Quantifying heterogeneities within cell populations is important for many fields including cancer research and neurobiology; however, techniques to isolate individual cells are limited. Here, we describe a high-throughput, non-disruptive, and cost-effective isolation method that is capable of capturing individually targeted cells using widely available techniques. Using high-resolution microscopy, laser microcapture microscopy, image analysis, and machine learning, our technology enables scalable molecular genetic analysis of single cells, targetable by morphology or location within the sample.
|
|
| 16. |
- Burri, Reto, et al.
(author)
-
Linked selection and recombination rate variation drive the evolution of the genomic landscape of differentiation across the speciation continuum of Ficedula flycatchers
- 2015
-
In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:11, s. 1656-1665
-
Journal article (peer-reviewed)abstract
- Speciation is a continuous process during which genetic changes gradually accumulate in the genomes of diverging species. Recent studies have documented highly heterogeneous differentiation landscapes, with distinct regions of elevated differentiation ("differentiation islands") widespread across genomes. However, it remains unclear which processes drive the evolution of differentiation islands; how the differentiation landscape evolves as speciation advances; and ultimately, how differentiation islands are related to speciation. Here, we addressed these questions based on population genetic analyses of 200 resequenced genomes from 10 populations of four Ficedula flycatcher sister species. We show that a heterogeneous differentiation landscape starts emerging among populations within species, and differentiation islands evolve recurrently in the very same genomic regions among independent lineages. Contrary to expectations from models that interpret differentiation islands as genomic regions involved in reproductive isolation that are shielded from gene flow, patterns of sequence divergence (d(XY) relative node depth) do not support a major role of gene flow in the evolution of the differentiation landscape in these species. Instead, as predicted by models of linked selection, genome-wide variation in diversity and differentiation can be explained by variation in recombination rate and the density of targets for selection. We thus conclude that the heterogeneous landscape of differentiation in Ficedula flycatchers evolves mainly as the result of background selection and selective sweeps in genomic regions of low recombination. Our results emphasize the necessity of incorporating linked selection as a null model to identify genome regions involved in adaptation and speciation.
|
|
| 17. |
- Damkjær, Jakob T, 1976-, et al.
(author)
-
The photosystem II light-harvesting protein Lhcb3 affects the macrostructure of photosystem II and the rate of state transitions in Arabidopsis
- 2009
-
In: The Plant Cell. - : Oxford University Press (OUP). - 1040-4651 .- 1532-298X. ; 21, s. 3245-3256
-
Journal article (peer-reviewed)abstract
- The main trimeric light-harvesting complex of higher plants (LHCII) consists of three different Lhcb proteins (Lhcb1-3). We show that Arabidopsis thaliana T-DNA knockout plants lacking Lhcb3 (koLhcb3) compensate for the lack of Lhcb3 by producing increased amounts of Lhcb1 and Lhcb2. As in wild-type plants, LHCII-photosystem II (PSII) supercomplexes were present in Lhcb3 knockout plants (koLhcb3), and preservation of the LHCII trimers (M trimers) indicates that the Lhcb3 in M trimers has been replaced by Lhcb1 and/or Lhcb2. However, the rotational position of the M LHCII trimer was altered, suggesting that the Lhcb3 subunit affects the macrostructural arrangement of the LHCII antenna. The absence of Lhcb3 did not result in any significant alteration in PSII efficiency or qE type of nonphotochemical quenching, but the rate of transition from State 1 to State 2 was increased in koLhcb3, although the final extent of state transition was unchanged. The level of phosphorylation of LHCII was increased in the koLhcb3 plants compared with wild-type plants in both State 1 and State 2. The relative increase in phosphorylation upon transition from State 1 to State 2 was also significantly higher in koLhcb3. It is suggested that the main function of Lhcb3 is to modulate the rate of state transitions.
|
|
| 18. |
- Gerencser, Laszlo, et al.
(author)
-
Randomization methods in optimization and adaptive control - Dedicated to Tyrone Duncan on occasion of his 60th birthday
- 2002
-
In: STOCHASTIC THEORY AND CONTROL. - : Springer-Verlag New York. - 3540437770 ; , s. 137-153
-
Book chapter (peer-reviewed)abstract
- We consider simultaneous perturbation stochastic approximation (SPSA) methods applied to noise-free problems in optimization and adaptive control. More generally, we consider discrete-time fixed gain stochastic approximation processes that are defined in terms of a random field that is identically zero at some point theta*. The boundedness of the estimator process is enforced by a resetting mechanism. Under appropriate technical conditions the estimator sequence converges to theta* with geometric rate almost surely. This result is in striking contrast to classical stochastic approximation theory where the typical convergence rate is n(-1/2). For the proof a discrete-time version of the ODE-method is used and the techniques of [10] are extended. A simple variant of noise free-SPSA is applied to extend a direct controller tuning method named Iterative Feedback Timing (IFT), see [16]. Using randomization, the number of experiments required to obtain an unbiased estimate of the gradient of the cost function can be reduced significantly for multi-input multi-output systems.
|
|
| 19. |
- Grosshans, H., et al.
(author)
-
Sensitivity of VOF simulations of the liquid jet breakup to physical and numerical parameters
- 2016
-
In: Computers & Fluids. - : Elsevier. - 0045-7930 .- 1879-0747. ; 136, s. 312-323
-
Journal article (peer-reviewed)abstract
- In this paper the characteristics of the primary breakup of a liquid jet is analyzed numerically. We applied the Volumes of Fluids (VOF) approach utilizing the Direction Averaged Curvature (DAC) model, to estimate the interface curvature, and the Direction Averaged Normal (DAN) model, to propagate the interface. While being used for the first time to predict liquid atomization, this methodology showed a high accuracy. The influence of varying the fluid properties, namely liquid-gas density and viscosity ratio, and injection conditions is discussed related to the required grid resolution. Resulting droplet sizes are compared to distributions obtained through the One-Dimensional Turbulence (ODT) model.
|
|
| 20. |
|
|
| 21. |
- Lambrechts, Marcel M., et al.
(author)
-
The design of artificial nestboxes for the study of secondary hole-nesting birds: a review of methodological inconsistencies and potential biases
- 2010
-
In: Acta Ornithologica. - 0001-6454 .- 1734-8471. ; 45:1, s. 1-26
-
Journal article (peer-reviewed)abstract
- The widespread use of artificial nestboxes has led to significant advances in our knowledge of the ecology, behaviour and physiology of cavity nesting birds, especially small passerines Nestboxes have made it easier to perform routine monitoring and experimental manipulation of eggs or nestlings, and also repeatedly to capture, identify and manipulate the parents However, when comparing results across study sites the use of nestboxes may also Introduce a potentially significant confounding variable in the form of differences in nestbox design amongst studies, such as their physical dimensions, placement height, and the way in which they are constructed and maintained However, the use of nestboxes may also introduce an unconsidered and potentially significant confounding variable clue to differences in nestbox design amongst studies, such as their physical dimensions, placement height, and the way in which they are constructed and maintained Here we review to what extent the characteristics of artificial nestboxes (e g size, shape, construction material, colour) are documented in the 'methods' sections of publications involving hole-nesting passerine birds using natural or excavated cavities or artificial nestboxes for reproduction and roosting Despite explicit previous recommendations that authors describe in detail the characteristics of the nestboxes used, we found that the description of nestbox characteristics in most recent publications remains poor and insufficient We therefore list the types of descriptive data that should be included in the methods sections of relevant manuscripts and justify this by discussing how variation in nestbox characteristics can affect or confound conclusions from nestbox studies We also propose several recommendations to improve the reliability and usefulness of research based on long-term studies of any secondary hole-nesting species using artificial nestboxes for breeding or roosting.
|
|
| 22. |
- Mattsson, Niklas, 1979, et al.
(author)
-
The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
-
In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
-
Journal article (peer-reviewed)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
|
|
| 23. |
- Senar, Juan Carlos, et al.
(author)
-
Urban Great Tits (Parus major) Show Higher Distress Calling and Pecking Rates than Rural Birds across Europe
- 2017
-
In: Frontiers in Ecology and Evolution. - : Frontiers Media SA. - 2296-701X. ; 5
-
Journal article (peer-reviewed)abstract
- Environmental change associated with urbanization is considered one of the major threats to biodiversity. Some species nevertheless seem to thrive in the urban areas, probably associated with selection for phenotypes that match urban habitats. Previous research defined different “copying styles” in distress behavior during the handling of birds. These behaviors vary along a continuum from “proactive” to “reactive” copers. By studying avian distress behaviors we aimed to broaden our understanding of the relationship between coping styles and urbanization. Using a large-scale comparative study of seven paired rural and urban sites across Europe, we assayed distress behaviors during handling of urban and rural-dwelling populations of the great tit Parus major. We detected no consistent pairwise differences in breath rate between urban and rural habitats. However, urban great tits displayed more distress calling (fear screams) and higher pecking rate (handling aggression) than rural birds. These findings suggest that urban great tits have a more proactive coping strategy when dealing with stressful conditions. This finding is in line with previous studies implying that urban great tits are more explorative, less neophobic and display shorter flight distances than their rural counterparts, representing further aspects of the same “proactive”, coping strategy. Future research should investigate whether reported differences in distress behavior are due to local adaption caused by natural selection or due to phenotypic plasticity.
|
|
| 24. |
- Smeds, Linnea, et al.
(author)
-
Evolutionary analysis of the female-specific avian W chromosome
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- The typically repetitive nature of the sex-limited chromosome means that it is often excluded from or poorly covered in genome assemblies, hindering studies of evolutionary and population genomic processes in non-recombining chromosomes. Here, we present a draft assembly of the non-recombining region of the collared flycatcher W chromosome, containing 46 genes without evidence of female-specific functional differentiation. Survival of genes during W chromosome degeneration has been highly non-random and expression data suggest that this can be attributed to selection for maintaining gene dose and ancestral expression levels of essential genes. Re-sequencing of large population samples revealed dramatically reduced levels of within-species diversity and elevated rates of between-species differentiation (lineage sorting), consistent with low effective population size. Concordance between W chromosome and mitochondrial DNA phylogenetic trees demonstrates evolutionary stable matrilineal inheritance of this nuclear-cytonuclear pair of chromosomes. Our results show both commonalities and differences between W chromosome and Y chromosome evolution.
|
|
| 25. |
- Zuntini, Alexandre R., et al.
(author)
-
Phylogenomics and the rise of the angiosperms
- 2024
-
In: NATURE. - 0028-0836 .- 1476-4687. ; 629, s. 843-850
-
Journal article (peer-reviewed)abstract
- Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods(1,2). A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome(3,4). Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins(5-7). However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes(8). This 15-fold increase in genus-level sampling relative to comparable nuclear studies(9) provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade.
|
|
