| 1. |
- Casewell, Nicholas R, et al.
(författare)
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Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals.
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:51, s. 25745-25755
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Tidskriftsartikel (refereegranskat)abstract
- Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.
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| 2. |
- Whiffin, N, et al.
(författare)
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The effect of LRRK2 loss-of-function variants in humans
- 2020
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:6, s. 869-877
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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| 3. |
- Wiklund, Tobias, 1986-
(författare)
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Insomnia Symptoms in Chronic Pain : Clinical presentation, risk and treatment
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, chronic and recurrent pain have gained interest as distinct conditions interacting both with peripheral and central parts of the nervous system as well as with the immune system. The risk of getting affected by abnormal pain modulation i.e., chronic pain is not equally distributed in the population and the search for risk factors is therefore of interest. One potential risk factor for chronic pain is insomnia symptoms i.e., difficulties falling asleep or maintaining sleep. In turn, insomnia symptoms are overrepresented in persons with chronic pain. Common current pain treatments lead to limited improvement of insomnia symptoms calling for treatments specifically directed to improve sleep. The overall aim of this thesis is therefore to investigate the distribution of insomnia severity in patients seeking specialized care for chronic pain, to investigate the role of insomnia severity as a risk factor for spreading of pre-existing pain, and to evaluate potential treatments for insomnia symptoms comorbid to chronic pain.Study I highlighted the high prevalence rates of insomnia symptoms in patients with chronic pain conditions. Roughly, insomnia was six times more common in our sample compared to the general population. We also showed that there were weak connections between insomnia symptoms and other variables (primarily psychological symptoms and pain intensity). In Study II physical exercise was more efficacious than Acceptance and Commitment Therapy-based stress management and the active control group in reducing insomnia symptoms and pain intensity short term. Improvements in physical exercise were largely maintained after twelve months but pain intensity had then also declined in the control group. No improvements in the Acceptance and Commitment Therapy-based stress management remain significant when an intention to treat principles were applied. In Study III, a dose-dependent increase in risk for spreading of pain was confirmed in subjects reporting moderate and severe insomnia symptoms. Though, there was no increase in the risk of pain spreading in subjects reporting sub-threshold insomnia symptoms (according to Insomnia Severity Index). In Study IV patients in the Internet-delivered Cognitive Behavioural Therapy for insomnia group, showed a more rapid improvement in insomnia symptoms than patients in the internet-delivered applied relaxation. The effect of Cognitive Behavioural Therapy for insomnia had declined slightly after six months and the Applied Relaxation group had continued to improve, leading to a comparable outcome on the Insomnia Severity Index at six-month follow-up.In conclusion, insomnia symptoms are common in patients seeking specialized pain care. High levels of insomnia symptoms increase the risk of spreading of pre-existing pain and this in a dose-dependent manner. Physical exercise has significant, but not clinically meaningful effects on pain intensity and insomnia symptoms. Internet-delivered Cognitive Behavioral Therapy for insomnia leads to a more rapid reduction of insomnia symptoms compared to applied relaxation, although long-term effects are uncertain
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| 4. |
- Wiklund, Tobias, et al.
(författare)
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Is sleep disturbance in patients with chronic pain affected by physical exercise or ACT-based stress management? : A randomized controlled study
- 2018
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Ingår i: BMC Musculoskeletal Disorders. - : BioMed Central. - 1471-2474. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Most people suffering chronic pain are plagued by sleeping difficulties. Cognitive behaviour therapy has produced promising results for insomnia comorbid with chronic pain, but the access to such treatment is often limited. Over the last ten years, interventions aiming to increase cognitive flexibility and physical activity have been assumed to be effective treatments for a variety of conditions, including insomnia and chronic pain. If proven effective, these treatments could constitute the first steps in a stepped care model for chronic pain and insomnia.METHODS: Two hundred ninety-nine chronic pain subjects were randomized to Exercise, ACT-based stress management (ACT-bsm), or an active control group. Two hundred thirty-two participants (78%) received their allocated intervention at least to some extent. These participants were evaluated using mixed model analyses for changes in sleep (Insomnia Severity Index, ISI), pain intensity, depression, and anxiety immediately after treatment, six months and twelve months after treatment.RESULTS: The mixed model analyses revealed that Exercise had a positive effect on insomnia compared with the control group and the effect remained after 12 months. No clear effect (i.e., both for completers and for completers together with treatment non-completers) upon ISI was found for the ACT-bsm. Pain intensity decreased significantly both in the exercise group and in the control group. For the two psychological variables (i.e., symptoms of anxiety and depression) were found significant improvements over time but no group differences. The treatment effects for ISI and pain intensity did not reach clinical significance per definitions presented in other relevant studies.CONCLUSIONS: Beneficial significant effects on insomnia was confirmed in the exercise condition. However, these changes were probably not clinically important. For pain intensity a general decrease was found in the Exercise condition and in the control condition, while no change occurred in ACT-bsm. No group differences were found for the two psychological variables.
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| 5. |
- Wucher, Valentin, et al.
(författare)
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FEELnc : a tool for long non-coding RNA annotation and its application to the dog transcriptome
- 2017
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 45:8
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Tidskriftsartikel (refereegranskat)abstract
- Whole transcriptome sequencing (RNA-seq) has become a standard for cataloguing and monitoring RNA populations. One of the main bottlenecks, however, is to correctly identify the different classes of RNAs among the plethora of reconstructed transcripts, particularly those that will be translated (mRNAs) from the class of long non-coding RNAs (lncRNAs). Here, we present FEELnc (FlExible Extraction of LncRNAs), an alignment-free program that accurately annotates lncRNAs based on a Random Forest model trained with general features such as multi k-mer frequencies and relaxed open reading frames. Benchmarking versus five state-of-the-art tools shows that FEELnc achieves similar or better classification performance on GENCODE and NONCODE data sets. The program also provides specific modules that enable the user to fine-tune classification accuracy, to formalize the annotation of lncRNA classes and to identify lncRNAs even in the absence of a training set of non-coding RNAs. We used FEELnc on a real data set comprising 20 canine RNA-seq samples produced by the European LUPA consortium to substantially expand the canine genome annotation to include 10 374 novel lncRNAs and 58 640 mRNA transcripts. FEELnc moves beyond conventional coding potential classifiers by providing a standardized and complete solution for annotating lncRNAs and is freely available at https://github.com/tderrien/FEELnc.
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