STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Three new Cu (II), Pd (II) and Ag (I) complexes of bidentate Schiff base ligand 2-[(4-chlorobenzylidene)amino] phenol (HL) were synthesized. The stoichiometric ratios and physicochemical properties of these complexes were determined using elemental analyses, magnetic measurements, infrared and UVvisible spectra, molar conductivity measurements and thermal analyses. The results revealed that the metal ions coordinated with through azomethine nitrogen and phenolic oxygen atoms. AgL and PdL complexes are present in a 1:1 molar ratio with square planar and tetrahedral geometry, respectively, while CuL 2 complex is present in a 1:2 molar ratio with octahedral geometry. The electronic structure and nonlinear optical parameters of HL and the studied 1:1 and 1:2 complexes were investigated theoretically at the DFT-B3LYP/6-311G** level of theory. The compounds were screened against various strains of bacteria and fungi. They displayed good results for inhibition against the studied pathogenic microorganisms. Absorption spectroscopic, viscosity and gel electrophoresis measurements were used for studying the interaction of the prepared complexes with calf thymus DNA (CT-DNA). The studied complexes showed a good interaction with CT-DNA via intercalation and groove modes. Moreover, molecular docking of these complexes was studied to understand the drug-DNA interactions and calculate the potential binding mode and energy. The anticancer effects of HL and its complexes, on selected human carcinoma cell lines, were determined. The cytotoxicity results showed that the prepared complexes are more potent than the Schiff base ligand.

Herein, we report facile procedures for synthesis of a new Schiff base ligand (H2L,5-Diethylamino-2-({2-[(2-hydroxy-benzylidene)-amino]-phenylimino}-methyl)-phenol) and its Ag(I), Pd(II) and Cu(II) complexes. The structure of the H2L ligand as well as its metal complexes was deduced based on wide range of analytical, structural and spectroscopic tools, along with theoretical evidence via density functional theory (DFT) calculations. The obtained results indicated that the Schiff base (H2L) ligand acts as a tetradentate N2O2 donor with two azomethine nitrogen’s (N1, N2) and two deprotonated phenolic oxygens (O1, O2) atoms. A distorted octahedral structure is assigned to [CuL(OH2)2]·3/2H2O complex and square planar structure for PdL and AgL complexes. The electronic structure and non-linear optical (NLO) property of the prepared compounds were discussed theoretically by the B3LYP/GENECP program. Results revealed that all complexes have non-planner geometries as indicated from the dihedral angles. The charge transfer occurs within the synthesized complexes as indicated from the calculated energy gap between HOMO and LUMO energies. The H2L ligand and its complexes are excellent candidates for NLO materials as implied from their hyperpolarizabilities and polarizabilities values. The biological activities of the prepared complexes against selected microorganisms and cancer cell lines gave good growth inhibitory effect. The biocidal potencies of the ligand and its complexes can be arranged as follows: AgL > CuL > PdL > H2L, as compared to the used standard drugs. The antiproliferative activity of the studied complexes against different carcinoma cell lines such as liver (Hep-G2), breast (MCF-7) and colon (HCT-116) followed the order H2L < AgL< PdL < CuL < vinblastine. Probing the binding interactions of prepared complexes with calf thymus (CT)-DNA using electronic absorption, gel electrophoresis and viscosity measurements revealed strong interaction via intercalation modes, as also evidenced by their molecular docking study.

Background Sensitization to common environmental aeroallergens plays a significant role in the pathogenesis and severity of respiratory allergic disorders, specifically asthma and allergic rhinitis. Understanding sensitization patterns helps clinicians tailor care more effectively. This study examines patterns of sensitization to aeroallergens in subjects suspected of having an allergic disease in Edmonton and catchment area. Methods Retrospective chart review of skin prick test (SPT) results to 11 environmental aeroallergens performed between January 1st and June 30th 2014 at a University-based clinic, where patients are referred for SPT by allergists, respirologists, otolaryngologists, internists and general practitioners. Potential differences in aeroallergen sensitization patterns were evaluated. Results A total of 623 patients (36.9% males; 63.1% females), aged 4–84 years (mean age 38.6 years) had SPT done, of which 438 (70.3%) had a positive test for at least one aeroallergen (atopy). There were no significant sex differences in the frequency of atopy (males: 71.3% versus females: 69.7%; p = 0.373). The frequency of sensitivity to particular allergens among atopic subjects was: cat (53.1%), house dust mites (50.3%), grass (39.2%), birch (23.7%), alternaria (23.7%), dog (17.3%), poplar (12.1%), cedar (9.6%), aspergillus (9.6%), hormodendrum (8%), and penicillium (6.2%). Of 438 atopic patients, 110 (25.1%) were mono sensitized, 199 (45.4%) oligosensitized (2–3 allergens), and 129 (29.5%) polysensitized (≥ 4 allergens). There were no significant differences between males and females in the odds of being oligo-sensitized (OR: 0.95; 95% CI 0.58, 1.57). Polysensitization was significantly more frequent in males 37.2% than in females 24.8%; (OR: 0.95; 95% CI 0.58, 1.57). Conclusion Cat is the most frequent perennial allergen and timothy grass pollen the most frequent seasonal allergen in Edmonton and catchment area. There was no significant difference in the frequency of atopy between males and females. However, males were more likely to be polysensitized compared to females.

STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. STAT6 mediates the biological effects of IL-4, a cytokine necessary for type 2 differentiation of T cells and B cell survival, proliferation and class switching to IgE. We have identificated two unrelated patients with a phenotype notable for their early-life onset of profound allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic esophagitis, elevated serum IgE, IgE-mediated food allergies, and vascular anomalies of the brain. Both patients harbored heterozygous de novo missense variants in the DNA binding domain of STAT6 (c.1144G>C, p.E382Q; and c.1256A>G, p.D419G). Functional studies established that both variants caused a gain-of-function (GOF) phenotype associated with enhanced phosphorylation and transcriptional activity of STAT6, in addition to increased transcript abundance of known STAT6 target genes and other genes implicated in allergic disease. JAK inhibitors decreased the enhanced STAT6 responses associated with both these STAT6 GOF variants. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of the first humans with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.