| 1. |
- Olszewski, Pawel K., et al.
(författare)
-
Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans
- 2012
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002568-
-
Tidskriftsartikel (refereegranskat)abstract
- Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.
|
|
| 2. |
- Soliveres, Santiago, et al.
(författare)
-
Biodiversity at multiple trophic levels is needed for ecosystem multifunctionality
- 2016
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7617, s. 456-459
-
Tidskriftsartikel (refereegranskat)abstract
- Many experiments have shown that loss of biodiversity reduces the capacity of ecosystems to provide the multiple services on which humans depend. However, experiments necessarily simplify the complexity of natural ecosystems and will normally control for other important drivers of ecosystem functioning, such as the environment or land use. In addition, existing studies typically focus on the diversity of single trophic groups, neglecting the fact that biodiversity loss occurs across many taxa and that the functional effects of any trophic group may depend on the abundance and diversity of others. Here we report analysis of the relationships between the species richness and abundance of nine trophic groups, including 4,600 above- and below-ground taxa, and 14 ecosystem services and functions and with their simultaneous provision (or multifunctionality) in 150 grasslands. We show that high species richness in multiple trophic groups (multitrophic richness) had stronger positive effects on ecosystem services than richness in any individual trophic group; this includes plant species richness, the most widely used measure of biodiversity. On average, three trophic groups influenced each ecosystem service, with each trophic group influencing at least one service. Multitrophic richness was particularly beneficial for 'regulating' and 'cultural' services, and for multifunctionality, whereas a change in the total abundance of species or biomass in multiple trophic groups (the multitrophic abundance) positively affected supporting services. Multitrophic richness and abundance drove ecosystem functioning as strongly as abiotic conditions and land-use intensity, extending previous experimental results to real-world ecosystems. Primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services. Our results show that multitrophic richness and abundance support ecosystem functioning, and demonstrate that a focus on single groups has led to researchers to greatly underestimate the functional importance of biodiversity.
|
|
| 3. |
- Soliveres, Santiago, et al.
(författare)
-
Locally rare species influence grassland ecosystem multifunctionality
- 2016
-
Ingår i: Philosophical Transactions of the Royal Society B: Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 371:1694
-
Tidskriftsartikel (refereegranskat)abstract
- Species diversity promotes the delivery of multiple ecosystem functions (multifunctionality). However, the relative functional importance of rare and common species in driving the biodiversity-multifunctionality relationship remains unknown. We studied the relationship between the diversity of rare and common species (according to their local abundances and across nine different trophic groups), and multifunctionality indices derived from 14 ecosystem functions on 150 grasslands across a land-use intensity (LUI) gradient. The diversity of above-and below-ground rare species had opposite effects, with rare above-ground species being associated with high levels of multifunctionality, probably because their effects on different functions did not trade off against each other. Conversely, common species were only related to average, not high, levels of multifunctionality, and their functional effects declined with LUI. Apart from the community-level effects of diversity, we found significant positive associations between the abundance of individual species and multifunctionality in 6% of the species tested. Species-specific functional effects were best predicted by their response to LUI: species that declined in abundance with land use intensification were those associated with higher levels of multifunctionality. Our results highlight the importance of rare species for ecosystem multifunctionality and help guiding future conservation priorities.
|
|
| 4. |
- Andreasson, Claes, et al.
(författare)
-
Direct Cloning of Isogenic Murine DNA in Yeast and Relevance of Isogenicity for Targeting in Embryonic Stem Cells
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9, s. e74207-
-
Tidskriftsartikel (refereegranskat)abstract
- Efficient gene targeting in embryonic stem cells requires that modifying DNA sequences are identical to those in the targeted chromosomal locus. Yet, there is a paucity of isogenic genomic clones for human cell lines and PCR amplification cannot be used in many mutation-sensitive applications. Here, we describe a novel method for the direct cloning of genomic DNA into a targeting vector, pRTVIR, using oligonucleotide-directed homologous recombination in yeast. We demonstrate the applicability of the method by constructing functional targeting vectors for mammalian genes Uhrf1 and Gfap. Whereas the isogenic targeting of the gene Uhrf1 showed a substantial increase in targeting efficiency compared to non-isogenic DNA in mouse E14 cells, E14-derived DNA performed better than the isogenic DNA in JM8 cells for both Uhrf1 and Gfap. Analysis of 70 C57BL/6-derived targeting vectors electroporated in JM8 and E14 cell lines in parallel showed a clear dependence on isogenicity for targeting, but for three genes isogenic DNA was found to be inhibitory. In summary, this study provides a straightforward methodological approach for the direct generation of isogenic gene targeting vectors.
|
|
| 5. |
- Birkhofer, Klaus, et al.
(författare)
-
Land-use type and intensity differentially filter traits in above- and below-ground arthropod communities
- 2017
-
Ingår i: Journal of Animal Ecology. - : Wiley. - 0021-8790 .- 1365-2656. ; 86:3, s. 511-520
-
Tidskriftsartikel (refereegranskat)abstract
- Along with the global decline of species richness goes a loss of ecological traits. Associated biotic homogenization of animal communities and narrowing of trait diversity threaten ecosystem functioning and human well-being. High management intensity is regarded as an important ecological filter, eliminating species that lack suitable adaptations. Below-ground arthropods are assumed to be less sensitive to such effects than above-ground arthropods. Here, we compared the impact of management intensity between (grassland vs. forest) and within land-use types (local management intensity) on the trait diversity and composition in below- and above-ground arthropod communities. We used data on 722 arthropod species living above-ground (Auchenorrhyncha and Heteroptera), primarily in soil (Chilopoda and Oribatida) or at the interface (Araneae and Carabidae). Our results show that trait diversity of arthropod communities is not primarily reduced by intense local land use, but is rather affected by differences between land-use types. Communities of Auchenorrhyncha and Chilopoda had significantly lower trait diversity in grassland habitats as compared to forests. Carabidae showed the opposite pattern with higher trait diversity in grasslands. Grasslands had a lower proportion of large Auchenorrhyncha and Carabidae individuals, whereas Chilopoda and Heteroptera individuals were larger in grasslands. Body size decreased with land-use intensity across taxa, but only in grasslands. The proportion of individuals with low mobility declined with land-use intensity in Araneae and Auchenorrhyncha, but increased in Chilopoda and grassland Heteroptera. The proportion of carnivorous individuals increased with land-use intensity in Heteroptera in forests and in Oribatida and Carabidae in grasslands. Our results suggest that gradients in management intensity across land-use types will not generally reduce trait diversity in multiple taxa, but will exert strong trait filtering within individual taxa. The observed patterns for trait filtering in individual taxa are not related to major classifications into above- and below-ground species. Instead, ecologically different taxa resembled each other in their trait diversity and compositional responses to land-use differences. These previously undescribed patterns offer an opportunity to develop management strategies for the conservation of trait diversity across taxonomic groups in permanent grassland and forest habitats.
|
|
| 6. |
- Kip, Miriam Julia, et al.
(författare)
-
The usefulness of direct ethanol metabolites in assessing alcohol intake in nonintoxicated male patients in an emergency room setting
- 2008
-
Ingår i: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 32:7, s. 1284-1291
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A major part of medical pathology in internal medicine is associated with chronic alcoholism. The aim of the current study was to investigate whether screening for Alcohol Use Disorders (AUD) can be improved through determination of direct ethanol metabolites compared to traditional biological state markers, the Alcohol Use Disorders Identification Test (AUDIT) and additional self-reports beyond the detection time period of a positive blood alcohol concentration (BAC). Methods: A total of 74 blood alcohol negative male patients who presented at the emergency room with either thoracic or gastrointestinal complaints were included. Phosphatidylethanol (PEth) was determined in whole blood, and ethyl glucuronide (EtG) in serum and urine samples. Traditional biological state markers [carbohydrate deficient transferrin (%CDT), gamma glutamyl transpeptidase (GGT), mean corpuscular volume (MCV)] were determined. The AUDIT was obtained and furthermore, all patients completed an additional self-report of alcohol consumption. Patients were divided into two (2) groups: AUDIT scores < 8 and AUDIT scores >= 8. Results: After assessment of the AUDIT, patients were allocated to one of the following groups: patients with AUDIT scores < 8 (n = 52) and with AUDIT scores >= 8 (n = 22). Twenty-five percent of the patients with AUDIT scores below the cut-off (n = 13/52) were tested positive for both PEth and UEtG. Of the patients who declared to be sober during the past 12 months, 38.5% were tested positive for PEth and UEtG. PEth discriminated similarly as %CDT for AUDIT scores >= 8 (AUC: 0.672; 95%CI 0.524 to 0.821). Self-reports of alcohol consumption were unreliable. Conclusion: Determination of direct ethanol metabolites such as PEth and UEtG provides additional evidence in screening for AUD in an ER setting. Determination of PEth might be considered complementary with or alternatively to %CDT.
|
|
| 7. |
- Refojo, Damian, et al.
(författare)
-
Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1
- 2011
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 333:6051, s. 1903-1907
-
Tidskriftsartikel (refereegranskat)abstract
- The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.
|
|
| 8. |
- Russo, Gianluca L., et al.
(författare)
-
CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boosts Direct Glia-to-Neuron Conversion
- 2021
-
Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 28:3, s. 524-534
-
Tidskriftsartikel (refereegranskat)abstract
- Astrocyte-to-neuron conversion is a promising avenue for neuronal replacement therapy. Neurons are particularly dependent on mitochondrial function, but how well mitochondria adapt to the new fate is unknown. Here, we determined the comprehensive mitochondrial proteome of cortical astrocytes and neurons, identifying about 150 significantly enriched mitochondrial proteins for each cell type, including transporters, metabolic enzymes, and cell-type-specific antioxidants. Monitoring their transition during reprogramming revealed late and only partial adaptation to the neuronal identity. Early dCas9-mediated activation of genes encoding mitochondrial proteins significantly improved conversion efficiency, particularly for neuron-enriched but not astrocyte-enriched antioxidant proteins. For example, Sod1 not only improves the survival of the converted neurons but also elicits a faster conversion pace, indicating that mitochondrial proteins act as enablers and drivers in this process. Transcriptional engineering of mitochondrial proteins with other functions improved reprogramming as well, demonstrating a broader role of mitochondrial proteins during fate conversion.
|
|
| 9. |
- Schmidt, Sebastian, et al.
(författare)
-
A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease
- 2023
-
Ingår i: Nature Communications. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the alpha-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD. Mitochondrial dysfunction is a contributing factor in Parkinson's disease. Here the authors carry out a multilayered omics analysis of Parkinson's disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by alpha-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients.
|
|
| 10. |
- Schriever, Sonja C., et al.
(författare)
-
Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
- 2020
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 130:11, s. 6093-6108
-
Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron–specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
|
|
