The biochemical differences between simple steatosis, a benign liver disease, and non-alcoholic steatohepatitis, which leads to cirrhosis, are unclear. Fat aussie is an obese mouse strain with a ...truncating mutation (
foz) in the
Alms1 gene. Chow-fed female
foz/
foz mice develop obesity, diabetes, and simple steatosis. We fed
foz/
foz and
wildtype mice a high-fat diet.
Foz/
foz mice developed serum ALT elevation and severe steatohepatitis with hepatocyte ballooning, inflammation, and fibrosis;
wildtype mice showed simple steatosis. Biochemical pathways favoring hepatocellular lipid accumulation (fatty acid uptake; lipogenesis) and lipid disposal (fatty acid β-oxidation; triglyceride egress) were both induced by high-fat feeding in
wildtype but not
foz/
foz mice. The resulting extremely high hepatic triglyceride levels were associated with induction of mitochondrial uncoupling protein-2 and adipocyte-specific fatty acid binding protein-2, but not cytochrome P4502e1 or lipid peroxidation. In this model of metabolic syndrome, transition of steatosis to steatohepatitis was associated with hypoadiponectinemia, a mediator of hepatic fatty acid disposal pathways.
Resistance to thyroid hormones is a very rare condition, which is often misdiagnosed and mistreated. The cases where there is a concomitant autoimmune thyroid disorder are ultra-rare and particularly ...challenging to treat. Diagnostic and research-based genomic testing can sometimes identify pathogenic variants unrelated to the primary reason for testing (incidental findings).
We present a patient with thyroid resistance associated with hypothyroid Hashimoto thyroiditis. The long diagnostic odyssey spanning over 20-years included repeated misdiagnoses and mistreatments and was concluded by a research-based genomic testing, identifying a "de novo"
pathogenic variant. The varying sensitivity of various tissues to thyroid hormones accompanied by hypothyroid Hashimoto thyroiditis continues to pose a significant treatment challenge.
Thyroid hormone resistance continues to be an un(der)- and misdiagnosed thyroid condition whose management is particularly challenging when associated with autoimmune thyroid disease. Whole exome sequencing has the potential to identify
pathogenic variants as incidental findings. Reporting such secondary findings from genomic testing may be particularly important in the context of the rarity of the condition and the potential clinical consequences of misdiagnosis and mistreatment.
The aim of this study is to reveal the direct radiative effect of aerosols on global solar shortwave radiation in the region of peak Musala, which has specific climatic and environmental conditions. ...Correlations between the measured global solar shortwave radiation and the total aerosol content, Ångström exponent in the visible spectrum, absorption of radiation by aerosols, scattering of radiation by aerosols, Single Scattering Albedo (SSA) of aerosols are calculated using statistical methods. The results show that the underlying surface through its albedo plays a significant role in terms of the radiative effect of aerosols. At low albedo values, the higher aerosol amounts exert, at surface level, a negative radiative effect and vice versa. However, at high albedo values, the higher aerosol amounts exert, at surface level, a positive radiative effect and vice versa. This is due to the fact that a higher albedo leads to larger amounts of reflected and scattered shortwave radiation, especially close to the earth's surface, which at higher aerosol amounts result in an increase in the amount of scattered shortwave radiation, which also increases the global solar shortwave radiation. The relationships between global solar shortwave radiation and aerosols are, in most cases, non-linear, which is due to the statistical distributions of the studied parameters, which are not normal. Disclosed dependencies should be taken into account when modeling the impact of aerosols on climate change.
•Surface albedo plays a significant role in terms of radiative effect of aerosols.•High albedo leads to a positive radiative effect of aerosols at surface level.•Higher albedo causes larger amounts of reflected and scattered shortwave radiation.•DRE of aerosols at peak Musala changes its sign at albedo values of about 0.4
OBJECTIVE: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. DESIGN: Genetic analysis. SETTING: Ambulatory and ...hospitalized care. PATIENTS: Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. MAIN OUTCOME MEASURE: Any SLC2A1 mutations. RESULTS: Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. CONCLUSIONS: Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.
Bronchial asthma is a multifactorial disease whereby both environmental and genetic factors contribute to its aetiology and/or clinical severity. The aim of this study was to examine the association ...of 22 cytokine gene polymorphism in the Macedonian population with bronchial asthma (BA). The sample of the population comprised of 301 normal unrelated individuals and 74 patients with BA. Cytokine genotyping was performed by PCR. Susceptible cytokine polymorphisms for BA for ten genotypes (IL-4 -1098/T:T, TNF-alpha -238/A:G, IL-4 -590/C:C, IL-2 +166/T:T, IL-2 -330/T:T, IL-10 -1082/G:G, IFNgamma utr5644/T:T, IL-10 -1082/A:A, IL-1beta +3962/T:T, IL-6 -174/G:G), six diplotypes, four haplotypes, and two alleles were found. Protective cytokine polymorphisms for BA for seven cytokine genotypes (IL-4 -1098/G:T, TNF- alpha -238/G:G, IL-2 -330/G:T, IL-4 -590/C:T, IFNgamma utr5644/A:T, IL-1beta +3962/C:T, IL-10 -1082/A:G), six cytokine diplotypes, four cytokine haplotypes, and four cytokine alleles were found. We concluded that several cytokine polymorphisms are protective, or susceptible associated with BA in population of Macedonians.
Abstract
Solar UV/visible monitoring has increased its importance in the recent years due to the global warming, unexpected atmospheric anomalies and storms, and the increasing needs for additional ...human protection. In mountain areas with high elevation the interest to UV irradiation measurements is expected to increase due to atmospheric transparency, however frequent events of lightning and risk of equipment failures has to be taken into account. The cost of the UV measurement systems can be greatly reduced by employing low-cost integrated inexpensive digital sensors with on-chip signal conditioning as detectors which are more convenient for field deployment and outdoor measurements. Thus, a compact portable UV/visible sensor equipment is in great demand for annual solar irradiation monitoring and seasonal all-day measurement campaigns. In this work, we report on the development of an in-house portable UV sensor system based on digital sensors with I
2
C communication, open-source hardware and software. The developed equipment is based on integrated digital sensors (VEML 6075, TSL 2591). It has been developed by employing Wi-Fi ESP 32 microcontroller, ODROID microcomputer and open-source software (InfluxDB and Grafana visualization tool). We investigate the system performance by measuring daily profiles of UV-B/UV-A irradiation in different locations and under different atmospheric conditions in order to evaluate its feasibility for prevention of humans from UV overexposure during outdoor operations. On-field tests are performed for 2 years in 7 different locations in Bulgaria. Interestingly, in downtown during particular days with high traffic an increased UV scattering and absorption due to urban pollution has been observed.
In order to assess the evolution of aerosol parameters affecting climate change, a long-term trend analysis of aerosol optical properties was performed on time series from 52 stations situated across ...five continents. The time series of measured scattering, backscattering and absorption coefficients as well as the derived single scattering albedo, backscattering fraction, scattering and absorption Ångström exponents covered at least 10 years and up to 40 years for some stations. The non-parametric seasonal Mann–Kendall (MK) statistical test associated with several pre-whitening methods and with Sen's slope was used as the main trend analysis method. Comparisons with general least mean square associated with autoregressive bootstrap (GLS/ARB) and with standard least mean square analysis (LMS) enabled confirmation of the detected MK statistically significant trends and the assessment of advantages and limitations of each method. Currently, scattering and backscattering coefficient trends are mostly decreasing in Europe and North America and are not statistically significant in Asia, while polar stations exhibit a mix of increasing and decreasing trends. A few increasing trends are also found at some stations in North America and Australia. Absorption coefficient time series also exhibit primarily decreasing trends. For single scattering albedo, 52 % of the sites exhibit statistically significant positive trends, mostly in Asia, eastern/northern Europe and the Arctic, 22 % of sites exhibit statistically significant negative trends, mostly in central Europe and central North America, while the remaining 26 % of sites have trends which are not statistically significant. In addition to evaluating trends for the overall time series, the evolution of the trends in sequential 10-year segments was also analyzed. For scattering and backscattering, statistically significant increasing 10-year trends are primarily found for earlier periods (10-year trends ending in 2010–2015) for polar stations and Mauna Loa. For most of the stations, the present-day statistically significant decreasing 10-year trends of the single scattering albedo were preceded by not statistically significant and statistically significant increasing 10-year trends. The effect of air pollution abatement policies in continental North America is very obvious in the 10-year trends of the scattering coefficient – there is a shift to statistically significant negative trends in 2009–2012 for all stations in the eastern and central USA. This long-term trend analysis of aerosol radiative properties with a broad spatial coverage provides insight into potential aerosol effects on climate changes.
Objective
Increased Toll‐like receptor 7 (TLR‐7) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase ...C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR‐7/TLR‐9–mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo PACSIN1 missense variant identified in a child with SLE.
Methods
PACSIN1 Q59K de novo and null variants were introduced into a human plasmacytoid dendritic cell line and into mice using CRISPR/Cas9 editing. The effects of the variants on TLR‐7/TLR‐9 signaling in human and mouse cells, as well as PACSIN1 messenger RNA and IFN signature in SLE patients, were assessed using real‐time polymerase chain reaction and flow cytometry. Mechanisms were investigated using luciferase reporter assays, RNA interference, coimmunoprecipitation, and immunofluorescence.
Results
We established that PACSIN1 forms a trimolecular complex with tumor necrosis factor receptor–associated factor 4 (TRAF4) and TRAF6 that is important for the regulation of type I IFN. The Q59K mutation in PACSIN1 augments binding to neural Wiskott‐Aldrich syndrome protein while it decreases binding to TRAF4, leading to unrestrained TRAF6‐mediated activation of type I IFN. Intriguingly, PACSIN1 Q59K increased TLR‐7 but not TLR‐9 signaling in human cells, leading to elevated expression of IFNβ and IFN‐inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with IFN‐related genes. Introduction of the Pacsin1 Q59K mutation into mice caused increased surface TLR‐7 and TRAIL expression in B cells.
Conclusion
PACSIN1 Q59K increases IFNβ activity through the impairment of TRAF4‐mediated inhibition of TLR‐7 signaling, possibly contributing to SLE risk.
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