| 1. |
- Helbig, K. L., et al.
(författare)
-
De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
|
|
| 2. |
|
|
| 3. |
- Liu, Z. G., et al.
(författare)
-
Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features
- 2023
-
Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:20, s. 2981-2995
-
Tidskriftsartikel (refereegranskat)abstract
- Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
|
|
| 4. |
|
|
| 5. |
- Wyrick, J., et al.
(författare)
-
Do Two-Dimensional "Noble Gas Atoms" Produce Molecular Honeycombs at a Metal Surface?
- 2011
-
Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 11:7, s. 2944-2948
-
Tidskriftsartikel (refereegranskat)abstract
- Anthraquinone self-assembles on Cu(111) into a giant honeycomb network with exactly three molecules on each side. Here we propose that the exceptional degree of order achieved in this system can be explained as a consequence of the confinement of substrate electrons in the pores, with the pore size tailored so that the confined electrons can adopt a noble-gas-like two-dimensional quasi-atom configuration with two filled shells. Formation of identical pores in a related adsorption system (at different overall periodicity due to the different molecule size) corroborates this concept. A combination of photoemission spectroscopy with density functional theory computations (including van der Waals interactions) of adsorbate-substrate interactions allows quantum mechanical modeling of the spectra of the resultant quasi-atoms and their energetics.
|
|
| 6. |
- Garbulsky, Martin F., et al.
(författare)
-
Patterns and controls of the variability of radiation use efficiency and primary productivity across terrestrial ecosystems
- 2010
-
Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-8238 .- 1466-822X. ; 19:2, s. 253-267
-
Tidskriftsartikel (refereegranskat)abstract
- Aim The controls of gross radiation use efficiency (RUE), the ratio between gross primary productivity (GPP) and the radiation intercepted by terrestrial vegetation, and its spatial and temporal variation are not yet fully understood. Our objectives were to analyse and synthesize the spatial variability of GPP and the spatial and temporal variability of RUE and its climatic controls for a wide range of vegetation types. Location A global range of sites from tundra to rain forest. Methods We analysed a global dataset on photosynthetic uptake and climatic variables from 35 eddy covariance (EC) flux sites spanning between 100 and 2200 mm mean annual rainfall and between -13 and 26 degrees C mean annual temperature. RUE was calculated from the data provided by EC flux sites and remote sensing (MODIS). Results Rainfall and actual evapotranspiration (AET) positively influenced the spatial variation of annual GPP, whereas temperature only influenced the GPP of forests. Annual and maximum RUE were also positively controlled primarily by annual rainfall. The main control parameters of the growth season variation of gross RUE varied for each ecosystem type. Overall, the ratio between actual and potential evapotranspiration and a surrogate for the energy balance explained a greater proportion of the seasonal variation of RUE than the vapour pressure deficit (VPD), AET and precipitation. Temperature was important for determining the intra-annual variability of the RUE at the coldest energy-limited sites. Main conclusions Our analysis supports the idea that the annual functioning of vegetation that is adapted to its local environment is more constrained by water availability than by temperature. The spatial variability of annual and maximum RUE can be largely explained by annual precipitation, more than by vegetation type. The intra-annual variation of RUE was mainly linked to the energy balance and water availability along the climatic gradient. Furthermore, we showed that intra-annual variation of gross RUE is only weakly influenced by VPD and temperature, contrary to what is frequently assumed. Our results provide a better understanding of the spatial and temporal controls of the RUE and thus could lead to a better estimation of ecosystem carbon fixation and better modelling.
|
|
| 7. |
- Harter Griep, R, et al.
(författare)
-
Beyond simple approaches to studying the association between work characteristics and absenteeism : Combining the DCS and ERI models
- 2010
-
Ingår i: Work & Stress. - : Informa UK Limited. - 0267-8373 .- 1464-5335. ; 24:2, s. 179-195
-
Tidskriftsartikel (refereegranskat)abstract
- The Demand-Control-Support (DCS) and the Effort-Reward Imbalance (ERI) models assess different psychosocial factors. This study investigates whether a combination of these models increases their ability to predict sickness absence, as compared to results based on each model separately. A cross-sectional study with nursing personnel (N = 1307) in Brazil was performed. Regression analyses were conducted in three stages: analysis of each scale of the models and sickness absences; assessment of the independent association of each model with sickness absences; assessment of the associations of three combinations of models/scales with sickness absences: DC and social support (SS), ERI and overcommitment, and DC and ERI. As regards comparisons between the stress models, ERI was shown to be independently associated with short (up to 9 days) and long (10 days or more) spells of absenteeism. The same result held true for low social support. The combinations DC-ERI and DC-SS were better predictors for short spells than each model/scale separately, whereas for long spells, the combination DC-SS was the best predictor. ERI seems to be a good instrument for predicting absenteeism if used alone, whereas DC performed better when combined with ERI or SS. An improved risk estimation of sickness absences by combining information from the two models was observed.
|
|
| 8. |
- Lowden, Arne, et al.
(författare)
-
Does Work after Retirement Matter? Sleep Features among Workers in the Brazilian Longitudinal Study of Adult Health
- 2021
-
Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:8
-
Tidskriftsartikel (refereegranskat)abstract
- A growing number of people keep working after retirement, a phenomenon known as bridge employment. Sleep features, which are related to morbidity and mortality outcomes, are expected to be influenced by bridge employment or permanent retirement. The objective of this study was to analyze sleep duration and quality of bridge employees and permanent retirees compared to nonretired, i.e., active workers, from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants (second wave of ELSA-Brasil, 2012-2014) comprised permanently retired (n = 2348), career bridge workers (n = 694), bridge workers in a different place (n = 760), and active workers (n = 6271). The associations of all studied retirement schemes and self-reported sleep quality and duration were estimated through logistic and linear regression analysis. Workers from all studied retirement schemes showed better sleep patterns than active workers. In comparison to active workers, bridge workers who had changed workplace also showed a reduced chance of difficulty falling asleep and too-early awakenings, which were not found among career bridge workers. Bridge employment and permanent retirement were associated with a reduced chance of reporting sleep deficit. Bridge work at a different place rather than staying at the same workplace seems to be favorable for sleep. Further study is needed to explain mechanisms.
|
|
