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- Jin, S. C., et al.
(författare)
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Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:10
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Tidskriftsartikel (refereegranskat)abstract
- Whole-exome sequencing of 250 parent-offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder. In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1AandCTNNB1) met genome-wide significance. We identified two novel monogenic etiologies,FBXO31andRHOB, and showed that theRHOBmutation enhances active-state Rho effector binding while theFBXO31mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in aDrosophilareverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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- Arama, Charles, et al.
(författare)
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Ethnic differences in susceptibility to malaria : What have we learned from immuno-epidemiological studies in West Africa?
- 2015
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Ingår i: Acta Tropica. - : Elsevier BV. - 0001-706X .- 1873-6254. ; 146, s. 152-156
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Forskningsöversikt (refereegranskat)abstract
- There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host.
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- Arama, Charles, et al.
(författare)
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Genetic Resistance to Malaria Is Associated With Greater Enhancement of Immunoglobulin (Ig)M Than IgG Responses to a Broad Array of Plasmodium falciparum Antigens
- 2015
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Ingår i: Open forum infectious diseases. - : Oxford University Press (OUP). - 2328-8957. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Background. People of the Fulani ethnic group are more resistant to malaria compared with genetically distinct ethnic groups, such as the Dogon people, in West Africa, and studies suggest that this resistance is mediated by enhanced antibody responses to Plasmodium falciparum antigens. However, prior studies measured antibody responses to < 0.1% of P falciparum proteins, so whether the Fulani mount an enhanced and broadly reactive immunoglobulin (Ig) M and IgG response to P falciparum remains unknown. In general, little is known about the extent to which host genetics influence the overall antigen specificity of IgM and IgG responses to natural infections. Methods. In a cross-sectional study in Mali, we collected plasma from asymptomatic, age-matched Fulani (n = 24) and Dogon (n = 22) adults with or without concurrent P falciparum infection. We probed plasma against a protein microarray containing 1087 P falciparum antigens and compared IgM and IgG profiles by ethnicity. Results. We found that the breadth and magnitude of P falciparum-specific IgM and IgG responses were significantly higher in the malaria-resistant Fulani versus the malaria-susceptible Dogon, and, unexpectedly, P falciparum-specific IgM responses more strongly distinguished the 2 ethnic groups. Conclusions. These findings point to an underappreciated role for IgM in protection from malaria, and they suggest that host genetics may influence the antigen specificity of IgM and IgG responses to infection.
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| 10. |
- Dunstan, R. H., et al.
(författare)
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Sweat facilitated amino acid losses in male athletes during exercise at 32-34°C
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Sweat contains amino acids and electrolytes derived from plasma and athletes can lose 1-2L of sweat per hour during exercise. Sweat may also contain contributions of amino acids as well as urea, sodium and potassium from the natural moisturizing factors (NMF) produced in the stratum corneum. In preliminary experiments, one participant was tested on three separate occasions to compare sweat composition with surface water washings from the same area of skin to assess contributions from NMF. Two participants performed a 40 minute self-paced cycle session with sweat collected from cleansed skin at regular intervals to assess the contributions to the sweat load from NMF over the period of exercise. The main study investigated sweat amino acid composition collected from nineteen male athletes following standardised endurance exercise regimes at 32-34°C and 20-30% RH. Plasma was also collected from ten of the athletes to compare sweat and plasma composition of amino acids. The amino acid profiles of the skin washings were similar to the sweat, suggesting that the NMF could contribute certain amino acids into sweat. Since the sweat collected from athletes contained some amino acid contributions from the skin, this fluid was subsequently referred to as "faux" sweat. Samples taken over 40 minutes of exercise showed that these contributions diminished over time and were minimal at 35 minutes. In the main study, the faux sweat samples collected from the athletes with minimal NMF contributions, were characterised by relatively high levels of serine, histidine, ornithine, glycine and alanine compared with the corresponding levels measured in the plasma. Aspartic acid was detected in faux sweat but not in the plasma. Glutamine and proline were lower in the faux sweat than plasma in all the athletes. Three phenotypic groups of athletes were defined based on faux sweat volumes and composition profiles of amino acids with varying relative abundances of histidine, serine, glycine and ornithine. It was concluded that for some individuals, faux sweat resulting from exercise at 32-34°C and 20-30% RH posed a potentially significant source of amino acid loss. © 2016 Dunstan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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- Dunstan, R. H., et al.
(författare)
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Sweat facilitated losses of amino acids in Standardbred horses and the application of supplementation strategies to maintain condition during training
- 2015
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Ingår i: Comparative Exercise Physiology. - : Wageningen Academic Publishers. - 1755-2540 .- 1755-2559. ; 11:4, s. 201-212
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the amino acid composition of horse sweat, but significant fluid losses can occur during exercise with the potential to facilitate substantial nutrient losses. Sweat and plasma amino acid compositions for Standardbred horses were assessed to determine losses during a standardised training regime. Two cohorts of horses 2013 (n=5) and 2014 (n=6) were assessed to determine baseline levels of plasma and sweat amino acids. An amino acid supplement designed to counter losses in sweat during exercise was provided after morning exercise daily for 5 weeks (2013, n=5; 2014, n=4). After the supplementation period, blood and sweat samples were collected to assess amino acid composition changes. From baseline assessments of sweat in both cohorts, it was found that serine, glutamic acid, histidine and phenylalanine were present at up to 9 times the corresponding plasma concentrations and aspartic acid at 0-2.2 mu mol/l in plasma was measured at 154-262 mu mol/l in sweat. In contrast, glutamine, asparagine, methionine and cystine were conserved in the plasma by having lower concentrations in the sweat. The predominant plasma amino acids were glycine, glutamine, alanine, valine, serine, lysine and leucine. As the sweat amino acid profile did not simply reflect plasma composition, it was proposed that mechanisms exist to generate high concentrations of certain amino acids in sweat whilst selectively preventing the loss of others. The estimated amino acid load in 16 l of circulating plasma was 3.8-4.3 g and the calculated loss via sweat during high intensity exercise was 1.6-3.0 g. Following supplementation, total plasma amino acid levels from both cohorts increased from initial levels of 2,293 and 2,044 mu mol/l to post-supplementation levels of 2,674 and 2,663 mu mol/l respectively (P<0.05). It was concluded that the strategy of providing free amino acids immediately after exercise resulted in raising resting plasma amino acid levels.
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- Portugal, Silvia, et al.
(författare)
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B cell analysis of ethnic groups in Mali with differential susceptibility to malaria
- 2012
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 11, s. 162-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized. Methods: In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n = 25) and Dogon (n = 25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U. S. (n = 8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 36% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs). Results: The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P = 0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U. S. adults (U. S.: 3.0% [95% CI: -0.21 - 6.164]; P < 0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P = 0.011), but not Dogon adults. Conclusion: These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani.
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