| 71. |
- Zhang, Jingjing, 1986, et al.
(författare)
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The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer susceptibility gene II (BRCA2) is central in homologous recombination (HR). In meiosis, BRCA2 binds to MEILB2 to localize to DNA double-strand breaks (DSBs). Here, we identify BRCA2 and MEILB2-associating protein 1 (BRME1), which functions as a stabilizer of MEILB2 by binding to an α-helical N-terminus of MEILB2 and preventing MEILB2 self-association. BRCA2 binds to the C-terminus of MEILB2, resulting in the formation of the BRCA2-MEILB2-BRME1 ternary complex. In Brme1 knockout (Brme1-/-) mice, the BRCA2-MEILB2 complex is destabilized, leading to defects in DSB repair, homolog synapsis, and crossover formation. Persistent DSBs in Brme1-/- reactivate the somatic-like DNA-damage response, which repairs DSBs but cannot complement the crossover formation defects. Further, MEILB2-BRME1 is activated in many human cancers, and somatically expressed MEILB2-BRME1 impairs mitotic HR. Thus, the meiotic BRCA2 complex is central in meiotic HR, and its misregulation is implicated in cancer development.
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| 72. |
- Abadikhah, Marie, 1992, et al.
(författare)
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Evidence of competition between electrogens shaping electroactive microbial communities in microbial electrolysis cells
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- In single-chamber microbial electrolysis cells (MECs), organic compounds are oxidized at the anode, liberating electrons that are used for hydrogen evolution at the cathode. Microbial communities on the anode and cathode surfaces and in the bulk liquid determine the function of the MEC. The communities are complex, and their assembly processes are poorly understood. We investigated MEC performance and community composition in nine MECs with a carbon cloth anode and a cathode of carbon nanoparticles, titanium, or stainless steel. Differences in lag time during the startup of replicate MECs suggested that the initial colonization by electrogenic bacteria was stochastic. A network analysis revealed negative correlations between different putatively electrogenic Deltaproteobacteria on the anode. Proximity to the conductive anode surface is important for electrogens, so the competition for space could explain the observed negative correlations. The cathode communities were dominated by hydrogen-utilizing taxa such as Methanobacterium and had a much lower proportion of negative correlations than the anodes. This could be explained by the diffusion of hydrogen throughout the cathode biofilms, reducing the need to compete for space.
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| 73. |
- Abdalaal, Hind, et al.
(författare)
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Collateral toxicity limits the evolution of bacterial Release Factor 2 towards total omnipotence
- 2020
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 37:10, s. 2918-2930
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Tidskriftsartikel (refereegranskat)abstract
- When new genes evolve through modification of existing genes, there are often trade-offs between the new and original functions, making gene duplication and amplification necessary to buffer deleterious effects on the original function. We have used experimental evolution of a bacterial strain lacking peptide release factor 1 (RF1) in order to study how peptide release factor 2 (RF2) evolves to compensate the loss of RF1. As expected, amplification of the RF2-encoding gene prfB to high copy number was a rapid initial response, followed by the appearance of mutations in RF2 and other components of the translation machinery. Characterization of the evolved RF2 variants by their effects on bacterial growth rate, reporter gene expression, and in vitro translation termination reveals a complex picture of reduced discrimination between the cognate and near cognate stop codons and highlight a functional trade-off that we term “collateral toxicity”. We suggest that this type of trade-off may be a more serious obstacle in new gene evolution than the more commonly discussed evolutionary trade-offs between “old” and “new” functions of a gene, as it cannot be overcome by gene copy number changes. Further, we suggest a model for how RF2 autoregulation responds not only to alterations in the demand for RF2 activity, but also for RF1 activity.
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| 74. |
- Ahi, Ehsan Pashay, et al.
(författare)
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Appetite regulating genes in zebrafish gut; a gene expression study
- 2022
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- The underlying molecular pathophysiology of feeding disorders, particularly in peripheral organs, is still largely unknown. A range of molecular factors encoded by appetite-regulating genes are already described to control feeding behaviour in the brain. However, the important role of the gastrointestinal tract in the regulation of appetite and feeding in connection to the brain has gained more attention in the recent years. An example of such inter-organ connection can be the signals mediated by leptin, a key regulator of body weight, food intake and metabolism, with conserved anorexigenic effects in vertebrates. Leptin signals functions through its receptor (lepr) in multiple organs, including the brain and the gastrointestinal tract. So far, the regulatory connections between leptin signal and other appetite-regulating genes remain unclear, particularly in the gastrointestinal system. In this study, we used a zebrafish mutant with impaired function of leptin receptor to explore gut expression patterns of appetite-regulating genes, under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-hours refeeding). We provide evidence that most appetite-regulating genes are expressed in the zebrafish gut. On one hand, we did not observed significant differences in the expression of orexigenic genes (except for hcrt) after changes in the feeding condition. On the other hand, we found 8 anorexigenic genes in wild-types (cart2, cart3, dbi, oxt, nmu, nucb2a, pacap and pomc), as well as 4 genes in lepr mutants (cart3, kiss1, kiss1r and nucb2a), to be differentially expressed in the zebrafish gut after changes in feeding conditions. Most of these genes also showed significant differences in their expression between wild-type and lepr mutant. Finally, we observed that impaired leptin signalling influences potential regulatory connections between anorexigenic genes in zebrafish gut. Altogether, these transcriptional changes propose a potential role of leptin signal in the regulation of feeding through changes in expression of certain anorexigenic genes in the gastrointestinal tract of zebrafish.
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| 75. |
- Akkuratov, Evgeny E.
(författare)
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The Biophysics of Na+,K+-ATPase in neuronal health and disease
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Na+,K+-ATPase is one of the most important proteins in the mammalian cell. It creates sodium and potassium gradients which are fundamental for the membrane potential and sodium-dependent secondary active transport. It has a second role in the cell as a receptor that by binding chemicals from the cardiotonic steroids family, the most knowledgeable of them is ouabain, triggers various signaling pathways in the cell which regulate gene activation, proliferation, apoptosis, etc. It has been shown that several severe neurological diseases are associated with mutations in the Na+,K+-ATPase encoding genes. Although Na+,K+-ATPase was discovered already in 1957 by the Danish scientist Jens Skou, the knowledge about the function of this enzyme is still not complete. In the studies included in the thesis, we have learned more about the function of Na+,K+-ATPase in different aspects of health and disease. In study I we showed a mechanism of ouabain-dependent regulation of the NMDA receptor, one of the most important receptors in the nervous system, via binding with Na+,K+-ATPase. This allows us to look at the Na+,K+-ATPase as regulator via protein-protein interaction. In study II we investigated a different aspect of Na+,K+-ATPase functioning – to look at how binding of ouabain to Na+,K+-ATPase activates a number of signaling cascades by looking at the phosphoproteome status of the cells. This allows us to see the whole picture of ouabain-mediated cascades and further characterize them. In study III we focused on the role of Na+,K+-ATPase in severe epileptic encephalopathy caused by a mutation in the ATP1A1 gene. We performed a molecular and cellular study to describe how mutations affects protein structure and function and found that this mutation converts the ion pump to a nonspecific leak channel. In study IV we performed a translational study of the most common mutation for rapid-onset dystonia-parkinsonism. We studied how this mutation affects the nervous system on the protein-, cellular-, and organism level and found that the complete absence of ultraslow afterhyperpolarization (usAHP) could explain gait disturbances found in patients. In the on-going study we showed that Na+,K+-ATPase can oligomerize and that this effect is triggered by ouabain binding to the Na+,K+-ATPase. In this study, we utilized a novel fluorescence labelling approach and used biophysical techniques with single molecule sensitivity to track Na+,K+-ATPase interactions. In summary, we applied biophysical and molecular methods to study different aspects of the function of Na+,K+-ATPase, and gained insights that could be helpful not only for answering fundamental questions about Na+,K+-ATPase but also to find a treatment for patients with diseases associated with mutations in this protein.
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| 76. |
- Akula, Srinivas, et al.
(författare)
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The Evolutionary History of the Chymase Locus -a Locus Encoding Several of the Major Hematopoietic Serine Proteases
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:20
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Forskningsöversikt (refereegranskat)abstract
- Several hematopoietic cells of the immune system store large amounts of proteases in cytoplasmic granules. The absolute majority of these proteases belong to the large family of chymotrypsin-related serine proteases. The chymase locus is one of four loci encoding these granule-associated serine proteases in mammals. The chymase locus encodes only four genes in primates, (1) the gene for a mast-cell-specific chymotryptic enzyme, the chymase; (2) a T-cell-expressed asp-ase, granzyme B; (3) a neutrophil-expressed chymotryptic enzyme, cathepsin G; and (4) a T-cell-expressed chymotryptic enzyme named granzyme H. Interestingly, this locus has experienced a number of quite dramatic expansions during mammalian evolution. This is illustrated by the very large number of functional protease genes found in the chymase locus of mice (15 genes) and rats (18 genes). A separate expansion has also occurred in ruminants, where we find a new class of protease genes, the duodenases, which are expressed in the intestinal region. In contrast, the opossum has only two functional genes in this locus, the mast cell (MC) chymase and granzyme B. This low number of genes may be the result of an inversion, which may have hindered unequal crossing over, a mechanism which may have been a major factor in the expansion within the rodent lineage. The chymase locus can be traced back to early tetrapods as genes that cluster with the mammalian genes in phylogenetic trees can be found in frogs, alligators and turtles, but appear to have been lost in birds. We here present the collected data concerning the evolution of this rapidly evolving locus, and how these changes in gene numbers and specificities may have affected the immune functions in the various tetrapod species.
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| 77. |
- Alm Rosenblad, Magnus, 1957, et al.
(författare)
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Genomic Characterization of the Barnacle Balanus improvisus Reveals Extreme Nucleotide Diversity in Coding Regions
- 2021
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Ingår i: Marine Biotechnology. - : Springer Science and Business Media LLC. - 1436-2228 .- 1436-2236. ; 23, s. 402-416
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Tidskriftsartikel (refereegranskat)abstract
- Barnacles are key marine crustaceans in several habitats, and they constitute a common practical problem by causing biofouling on man-made marine constructions and ships. Despite causing considerable ecological and economic impacts, there is a surprising void of basic genomic knowledge, and a barnacle reference genome is lacking. We here set out to characterize the genome of the baybarnacle Balanus improvisus (= Amphibalanus improvisus) based on short-read whole-genome sequencing and experimental genome size estimation. We show both experimentally (DNA staining and flow cytometry) and computationally (k-mer analysis) that B. improvisus has a haploid genome size of ~ 740 Mbp. A pilot genome assembly rendered a total assembly size of ~ 600 Mbp and was highly fragmented with an N50 of only 2.2 kbp. Further assembly-based and assembly-free analyses revealed that the very limited assembly contiguity is due to the B. improvisus genome having an extremely high nucleotide diversity (π) in coding regions (average π ≈ 5% and average π in fourfold degenerate sites ≈ 20%), and an overall high repeat content (at least 40%). We also report on high variation in the α-octopamine receptor OctA (average π = 3.6%), which might increase the risk that barnacle populations evolve resistance toward antifouling agents. The genomic features described here can help in planning for a future high-quality reference genome, which is urgently needed to properly explore and understand proteins of interest in barnacle biology and marine biotechnology and for developing better antifouling strategies. © 2021, The Author(s).
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| 78. |
- Ament-Velásquez, Sandra Lorena, Ph.D. 1988-, et al.
(författare)
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The plot thickens : haploid and triploid-like thalli, hybridization, and biased mating type ratios in Letharia
- 2021
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Ingår i: Frontiers in Fungal Biology. - : Frontiers Media S.A.. - 2673-6128. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- The study of the reproductive biology of lichen fungal symbionts has been traditionally challenging due to their complex lifestyles. Against the common belief of haploidy, a recent genomic study found a triploid-like signal in Letharia. Here, we infer the genome organization and reproduction in Letharia by analyzing genomic data from a pure culture and from thalli, and performing a PCR survey of the MAT locus in natural populations. We found that the read count variation in the four Letharia specimens, including the pure culture derived from a single sexual spore of L. lupina, is consistent with haploidy. By contrast, the L. lupina read counts from a thallus’ metagenome are triploid-like. Characterization of the mating-type locus revealed a conserved heterothallic configuration across the genus, along with auxiliary genes that we identified. We found that the mating-type distributions are balanced in North America for L. vulpina and L. lupina, suggesting widespread sexual reproduction, but highly skewed in Europe for L. vulpina, consistent with predominant asexuality. Taken together, we propose that Letharia fungi are heterothallic and typically haploid, and provide evidence that triploid-like individuals are hybrids between L. lupina and an unknown Letharia lineage, reconciling classic systematic and genetic studies with recent genomic observations.
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| 79. |
- Augstein, Frauke
(författare)
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Mechanisms of plant root xylem developmental plasticity in response to water deficiency and salt
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Plants may be exposed to a variety of different environmental conditions including water deficiency and salt, both affecting the uptake of water into the plant. Water is taken up from the soil by the roots and distributed throughout the plant via the water conducting tissue, the xylem. Plants are remarkably plastic and have evolved different mechanisms to sense the environment and adjust their development accordingly. However, how xylem development may respond to water availability is not clear. In this thesis, I show how water deficiency and salt affect xylem development and how the observed phenotypic alterations are regulated on a molecular level. We found that upon water deficiency additional protoxylem strands were formed along with an early differentiation of the inner metaxylem. These phenotypes were regulated both by non-cell autonomous and cell autonomous signaling via the hormone abscisic acid (ABA). The expression of microRNA165 was induced by ABA signaling in the endodermis leading to downregulation of homeo domain leucine zipper class III (HD-ZIP III) transcription factors in the stele. This caused a shift in xylem identity from meta- to protoxylem and the formation of additional protoxylem strands. At the same time, cell autonomous ABA signaling upregulated several VASCULAR RELATED NAC DOMAIN (VND) transcription factors including VND7, which promoted the shift in xylem identity as well as VND2 and VND3, which promoted early differentiation of the inner metaxylem. In contrast, during an initial phase of salt stress, we observed the formation of protoxylem gaps specifically in response to ionic stress and distinct from ABA-signaling. We identified that protoxylem gaps were caused by lowered levels and signaling of the growth regulator gibberellin (GA). Downstream of GA-signaling, protoxylem gap formation upon salt was controlled by genes involved in secondary cell wall formation including the xylem master regulator VND6 and factors involved in cell wall modification. Salt tolerance assays suggested that protoxylem gaps may contribute to salt tolerance and the phenotypes that we observed upon water deficiency have been suggested to confer drought tolerance. We observed similar effects on xylem developmental plasticity in response to water deficiency and salt in various different dicot species indicating an evolutionary conservation. Thus, xylem development is of high relevance for breeding programs to generate plant varieties better adapted to a changing climate.
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| 80. |
- Bahram, Mohammad, et al.
(författare)
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Metagenomic assessment of the global diversity and distribution of bacteria and fungi
- 2021
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Ingår i: Environmental Microbiology. - : Wiley. - 1462-2912 .- 1462-2920. ; 23, s. 316-326
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria and fungi are of uttermost importance in determining environmental and host functioning. Despite close interactions between animals, plants, their associated microbiomes, and the environment they inhabit, the distribution and role of bacteria and especially fungi across host and environments as well as the cross‐habitat determinants of their community compositions remain little investigated. Using a uniquely broad global dataset of 13 483 metagenomes, we analysed the microbiome structure and function of 25 host‐associated and environmental habitats, focusing on potential interactions between bacteria and fungi. We found that the metagenomic relative abundance ratio of bacteria‐to‐fungi is a distinctive microbial feature of habitats. Compared with fungi, the cross‐habitat distribution pattern of bacteria was more strongly driven by habitat type. Fungal diversity was depleted in host‐associated communities compared with those in the environment, particularly terrestrial habitats, whereas this diversity pattern was less pronounced for bacteria. The relative gene functional potential of bacteria or fungi reflected their diversity patterns and appeared to depend on a balance between substrate availability and biotic interactions. Alongside helping to identify hotspots and sources of microbial diversity, our study provides support for differences in assembly patterns and processes between bacterial and fungal communities across different habitats.
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