We estimated autism spectrum disorder (ASD) prevalence in 7–9 year-old children in 2015 using data from three nationwide health registry systems (Denmark, Finland, Iceland) and two French ...population-based regional registries. Prevalence ranged from 0.48% in South-East France to 3.13% in Iceland (South-West France: 0.73%, Finland: 0.77%, Denmark: 1.26%). Male/female ratios ranged from 3.3 in Finland to 5.4 in South-West France. Between 12% (Denmark) and 39% (South-West France) of cases were diagnosed with intellectual disability. The variations in population-based ASD prevalence across four European countries with universal health care practices likely reflect variation in detection, referral and diagnosis practices and autism awareness across these areas. Using established population-based data systems is an efficient approach to monitor ASD prevalence trends over time.
This study conducted a questionnaire-led survey to explore the financial feasibility and socio-environmental impacts of stand-alone solar home systems (SHS) through stratified random sampling. Based ...on the above consideration, fifteen cases of studies of various watt peak (Wp) capacities have been investigated to evaluate the economic viability of solar home systems. The results revealed that most of the cases have positive net present value (NPV) and low payback periods, with an internal rate of return (IRR) value ranging from 16% to 131%, which signifies a high rate of investment exchange. Solar home systems are economically profitable for micro-enterprises and households with low-income generation activities as opposed to the households using it only for lighting. The study found that solar home systems with a capacity above 30 Wp are the most economically viable option, which can also avoid 6.15 to 7.34 tonnes of CO2 emissions during the 20 years of life-cycle, while providing different applications including lighting, recreation, information, health, and economic benefits.
Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for ...such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood. We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Gαi1 coupling being sensitive to AT1 activation, as well as apparent enhanced β-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In persons who had received the BNT162b2 vaccine in Qatar, the incidence of infection with the omicron variant after 35 days of observation was 2.4% among those who had received three doses and 4.5% ...among those who were vaccinated but not boosted; among those who had received the mRNA-1273 vaccine, the incidence was 1.0% with a boost and 1.9% without.
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The type 1 angiotensin II (AngII) receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR), which leads to pathological remodeling of heart, blood vessels and ...kidney. End-point assays are used as surrogates of EGFR activation, however these downstream readouts are not applicable to live cells, in real-time. Herein, we report the use of a bioluminescence resonance energy transfer (BRET)-based assay to assess recruitment of the EGFR adaptor protein, growth factor receptor-bound protein 2 (Grb2), to the EGFR. In a variety of cell lines, both epidermal growth factor (EGF) and AngII stimulated Grb2 recruitment to EGFR. The BRET assay was used to screen a panel of 9 G protein-coupled receptors (GPCRs) and further developed for other EGFR family members (HER2 and HER3); the AT1R was able to transactivate HER2, but not HER3. Mechanistically, AT1R-mediated ERK1/2 activation was dependent on Gq/11 and EGFR tyrosine kinase activity, whereas the recruitment of Grb2 to the EGFR was independent of Gq/11 and only partially dependent on EGFR tyrosine kinase activity. This Gq/11 independence of EGFR transactivation was confirmed using AT1R mutants and in CRISPR cell lines lacking Gq/11. EGFR transactivation was also apparently independent of β-arrestins. Finally, we used additional BRET-based assays and confocal microscopy to provide evidence that both AngII- and EGF-stimulation promoted AT1R-EGFR heteromerization. In summary, we report an alternative approach to monitoring AT1R-EGFR transactivation in live cells, which provides a more direct and proximal view of this process, including the potential for complexes between the AT1R and EGFR.
Hemorphins are known for their role in the control of blood pressure. Recently, we revealed the positive modulation of the angiotensin II (AngII) type 1 receptor (AT1R) by LVV-hemorphin-7 (LVV-H7) in ...human embryonic kidney (HEK293) cells. Here, we examined the molecular binding behavior of LVV-H7 on AT1R and its effect on AngII binding using a nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay in HEK293FT cells, as well as molecular docking and molecular dynamics (MD) studies. Saturation and real-time kinetics supported the positive effect of LVV-H7 on the binding of AngII. While the competitive antagonist olmesartan competed with AngII binding, LVV-H7 slightly, but significantly, decreased AngII's k
by 2.6 fold with no effect on its B
. Molecular docking and MD simulations indicated that the binding of LVV-H7 in the intracellular region of AT1R allosterically potentiates AngII binding. LVV-H7 targets residues on intracellular loops 2 and 3 of AT1R, which are known binding sites of allosteric modulators in other GPCRs. Our data demonstrate the allosteric effect of LVV-H7 on AngII binding, which is consistent with the positive modulation of AT1R activity and signaling previously reported. This further supports the pharmacological targeting of AT1R by hemorphins, with implications in vascular and renal physiology.
The dipole–dipole interaction model is employed to investigate the angular dependence of the levitation and lateral forces acting on a small magnet in an anti-symmetric magnet/superconducting sphere ...system. Breaking the symmetry of the system enables us to study the lateral force which is important in the stability of the magnet above a superconducting sphere in the Meissner state. Under the assumption that the lateral displacement of the magnet is small compared to the physical dimensions of our proposed system, analytical expressions are obtained for the levitation and lateral forces as a function of the geometrical parameters of the superconductor as well as the height, the lateral displacement, and the orientation of the magnetic moment of the magnet. The dependence of the levitation force on the height of the levitating magnet is similar to that in the symmetric magnet/superconducting sphere system within the range of proposed lateral displacements. It is found that the levitation force is linearly dependent on the lateral displacement whereas the lateral force is independent of this displacement. A sinusoidal variation of both forces as a function of the polar and azimuthal angles specifying the orientation of the magnetic moment is observed. The relationship between the stability and the orientation of the magnetic moment is discussed for different orientations.
The angiotensin type 2 (AT
2
) receptor and the bradykinin type 2 (B
2
) receptor are G protein-coupled receptors (GPCRs) that have major roles in the cardiovascular system. The two receptors are ...known to functionally interact at various levels, and there is some evidence that the observed crosstalk may occur as a result of heteromerization. We investigated evidence for heteromerization of the AT
2
receptor and the B
2
receptor in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)-proximity based assays, including the Receptor Heteromer Investigation Technology (Receptor-HIT) and the NanoBRET ligand-binding assay. The Receptor-HIT assay showed that Gα
q
, GRK2 and β-arrestin2 recruitment proximal to AT
2
receptors only occurred upon B
2
receptor coexpression and activation, all of which is indicative of AT
2
-B
2
receptor heteromerization. Additionally, we also observed specific coupling of the B
2
receptor with the Gα
z
protein, and this was found only in cells coexpressing both receptors and stimulated with bradykinin. The recruitment of Gα
z
, Gα
q
, GRK2 and β-arrestin2 was inhibited by B
2
receptor but not AT
2
receptor antagonism, indicating the importance of B
2
receptor activation within AT
2
-B
2
heteromers. The close proximity between the AT
2
receptor and B
2
receptor at the cell surface was also demonstrated with the NanoBRET ligand-binding assay. Together, our data demonstrate functional interaction between the AT
2
receptor and B
2
receptor in HEK293FT cells, resulting in novel pharmacology for both receptors with regard to Gα
q
/GRK2/β-arrestin2 recruitment (AT
2
receptor) and Gα
z
protein coupling (B
2
receptor). Our study has revealed a new mechanism for the enigmatic and poorly characterized AT
2
receptor to be functionally active within cells, further illustrating the role of heteromerization in the diversity of GPCR pharmacology and signaling.
Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific ...subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor-immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.
The purpose of this study is to measure the incidence of recurrence of discrete subaortic stenosis (DSS) after primary resection in two major cardiac centers in Saudi Arabia and to identify risk ...factors associated with recurrence.
Data on 234 patients who were diagnosed with DSS and underwent surgical resection between 1999 and 2018 were retrospectively reviewed. Patient demographics as well as echocardiographic, surgical, and pathological data were compared between patients with recurrence and non-recurrence.
The overall recurrence incidence after primary resection was 44.87% (N = 105). Most patients were male (59%). The median age at the 1
operation was 60 months (range 3 months to 133 months). The presence of aortic stenosis at the time of diagnosis was significantly associated with recurrence (p-value = 0.002). The overall median peak gradient in which the primary resection was indicated is 60 mmHg (range 11 to 152 mmHg). The median peak gradient pre-operation and post-operation were significantly higher for the recurrence group (p-value=0.018 and p<0.001, respectively). We used univariate and multivariate analysis and controlled for the follow-up time, but there were no significant independent predictors of recurrence.
The recurrence rate of DSS after the primary resection is relatively high in this study. Further prospective studies are needed to draw a definite conclusion on risk factors for recurrence after primary resection.
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