Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune ...diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Knowledge of aerosol size and composition is important for determining radiative forcing effects of aerosols, identifying aerosol sources and improving aerosol satellite retrieval algorithms. The ...ability to extrapolate aerosol size and composition, or type, from intensive aerosol optical properties can help expand the current knowledge of spatiotemporal variability in aerosol type globally, particularly where chemical composition measurements do not exist concurrently with optical property measurements. This study uses medians of the scattering Ångström exponent (SAE), absorption Ångström exponent (AAE) and single scattering albedo (SSA) from 24 stations within the NOAA/ESRL Federated Aerosol Monitoring Network to infer aerosol type using previously published aerosol classification schemes.Three methods are implemented to obtain a best estimate of dominant aerosol type at each station using aerosol optical properties. The first method plots station medians into an AAE vs. SAE plot space, so that a unique combination of intensive properties corresponds with an aerosol type. The second typing method expands on the first by introducing a multivariate cluster analysis, which aims to group stations with similar optical characteristics and thus similar dominant aerosol type. The third and final classification method pairs 3-day backward air mass trajectories with median aerosol optical properties to explore the relationship between trajectory origin (proxy for likely aerosol type) and aerosol intensive parameters, while allowing for multiple dominant aerosol types at each station.The three aerosol classification methods have some common, and thus robust, results. In general, estimating dominant aerosol type using optical properties is best suited for site locations with a stable and homogenous aerosol population, particularly continental polluted (carbonaceous aerosol), marine polluted (carbonaceous aerosol mixed with sea salt) and continental dust/biomass sites (dust and carbonaceous aerosol); however, current classification schemes perform poorly when predicting dominant aerosol type at remote marine and Arctic sites and at stations with more complex locations and topography where variable aerosol populations are not well represented by median optical properties. Although the aerosol classification methods presented here provide new ways to reduce ambiguity in typing schemes, there is more work needed to find aerosol typing methods that are useful for a larger range of geographic locations and aerosol populations.
The classical GLUT-1 deficiency syndrome (GLUT-1 DS, De Vivo disease) was described over 2 decades ago as a metabolic encephalopathy characterized by developmental delay, secondary microcephaly ...paroxysmal neurological symptoms (epilepsy) and movement disorders. The biochemical parameters of this disease, used in diagnosis, are low levels of glucose in the cerebrospinal fluid, normal level of glucose in the blood and consequent low ratio of cerebrospinal fluid vs. blood glucose levels (<40-45%). So far, more than 200 cases of the classical GLUT-1 DS have been described in the literature. Genetic research demonstrated that this disease is caused by mutations in SLC2A1 gene coding for GLUT-1, a transporter of glucose across the blood brain barrier. Over the last few years the clinical spectrum of GLUT-1 deficiencywas expanded to include other rare diseases such as paroxysmal exertional dyskinesia and early-onset absence epilepsy, but also some more common diseases such as idiopathic generalised epilepsy (1-2%). GLUT-1 deficiency is an important pathophysiological basis of these diseases as early diagnosis (aided by DNA mutation testing) and treatment (ketogenic diet) could lead to improved disease outcomes.
Objective:
We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).
Methods:
The IGEs are common, heritable epilepsies that usually follow ...complex inheritance; currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood–brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced.
Results:
Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect; 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE.
Interpretation:
SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders. ANN NEUROL 2012;72:807–815
The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and ...environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.
This study reveals the effect of aerosols and water vapor on downward longwave radiation in the high mountain region of Musala peak, Bulgaria. The investigated period is 01/01/2017 (Jan. 1st 2017) - ...30/09/2019 (Sep. 30th 2019). Statistical methods are the main tool for discovering the relationships between the different elements. The results indicate that air temperature is the leading factor for downward longwave radiation, specific humidity, and amount of aerosols in the air. That is why, in order to reveal the pure relationship between downward longwave radiation, specific humidity and amount of aerosols in the atmosphere, the air temperature was cleared from the data series. After this procedure, the results show that specific humidity has a significant influence on the downward longwave radiation flux, and an increase of 1% of the specific humidity results in an increase of about 12-15% in the values of the downward longwave radiation. At air temperatures around 0ºC the influence of water vapor on the downward longwave flux is highest, which is due to the phase transitions of the water - a process during which release/absorption of radiation in the longwave spectrum occurs. The amount of aerosols in the atmosphere also has a significant effect on this type of radiation, and an increase of 1% of the amount of aerosols in the air at air temperatures above -5.5°C results in an increase of the downward longwave radiation of about 2-4%. The findings of this study show that coarser and opaque aerosol particles have a stronger effect on downward longwave radiation. In the area of Musala peak, as the air temperature rises, there is an increase in the amount of aerosols in the air, a decrease in their size, and a transition from transparent to opaque aerosols. The combination of these different tendencies causes the influence of aerosols on downward longwave radiation to be strongest in the middle temperature interval - air temperatures between -5.5°C and +5.5°C. Due to the increased total amount of aerosols and increased amount of opaque aerosols, their influence on downward longwave radiation is significant also at air temperatures above 5.5°C.
Summary
Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a ...cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike‐waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in‐frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of ...Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
Background & Aims
Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high‐fat(HF) diet. To establish whether diabetes or obesity is more closely associated with ...NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non‐diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways.
Methods
Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways.
Results
All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF‐fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF‐α, IL‐12, IL‐4, IL‐10 was increased (but not IFN‐γ, IL‐1β, IL‐17A), and IL‐4:IFN‐γ ratio (indicating Th‐2 predominance) was higher in HF‐fed foz/foz C57BL6/J than BALB/c mice. In livers of HF‐fed foz/foz C57BL6/J mice, TGF‐β was unaltered but PDGFα and CTGF were increased in association with enhanced α‐SMA, CD147and MMP activity.
Conclusions
In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes‐mediated CTGF‐regulation of MMPs as well as cytokines/growth factors (Th‐2 cytokine predominant, PDGFα, not TGF‐β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis.
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