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Auricular vagus nerve stimulation (aVNS) has emerged as a noninvasive neuromodulatory strategy with the potential to modulate central sensitization and inflammatory pathways. However, its role in fibromyalgia (FM) remains insufficiently explored. To investigate whether stimulation laterality (left vs. right auricular branch of the vagus nerve, ABVN) differentially influences clinical and biological outcomes in women with FM. In this randomized, double-blind, sham-controlled trial, 51 women with FM were allocated to sham stimulation, right-sided aVNS (aVNS-R), or left-sided aVNS (aVNS-L). Participants underwent weekly sessions for four weeks and were followed for 12 weeks. Pain intensity was the primary outcome. Secondary outcomes included psychological symptoms, sleep, functional status, quality of life, and circulating biomarkers (pro- and anti-inflammatory cytokines, brain-derived neurotrophic factor [BDNF]). While no significant between-group differences were observed in pain intensity, left-sided stimulation (aVNS-L) was associated with a modest but significant reduction in global symptom severity. Importantly, aVNS-L produced consistent immunomodulatory effects, including decreased IL-1β and TNF-α levels, and increased IL-4, IL-10, and BDNF concentrations. This exploratory trial suggests that stimulation laterality may shape the biological response to aVNS in FM. Although clinical pain relief was not superior to sham, left-sided stimulation promoted an anti-inflammatory profile and enhanced neuroplasticity markers. These findings support further investigation of aVNS laterality as a targeted neuromodulatory approach for FM. Brazilian Clinical Trials Registry RBR-10d3crcf. Show less

The authors report the clinical and genetic investigation of a family with hypertrophic cardiomyopathy (HCM). The individuals described are three affected first-degree relatives (father, daughter and son), one affected niece and unaffected nephew and niece. Those affected all share a very similar phenotype consisting of asymmetric HCM, with hypertrophy particularly affecting the septum and the anterior wall, and similar electrocardiographic features, including a short PR interval. Case 1 (proband) presented with obstructive HCM and had undergone myectomy and mitral valve replacement. Case 2 (oldest offspring of Case 1) had non-obstructive HCM with exertional angina and NYHA II heart failure (HF) symptoms; she developed non-sustained ventricular tachycardia during follow-up and received a single-chamber ICD for primary prevention of sudden cardiac death. Case 3 (son of case 1) presented with asymptomatic non-obstructive HCM and developed NYHA II HF symptoms during follow-up. Case 4 had non-obstructive HCM, mainly with NYHA II HF symptoms. Testing of the proband for sarcomeric mutations and phenocopies was initially negative. After eight years of clinical follow-up, the suspicion of an undiscovered pathogenic gene mutation shared among the members of this family led us to enroll the proband in a whole-genome sequencing research project, which revealed a heterozygous pathogenic intronic MYBPC3 variant (c.1227-13G>A [rs397515893]), cosegregating with the phenotype. Show less

Excess fat content in chickens has a negative impact on poultry production. The discovery of QTL associated with fat deposition in the carcass allows the identification of positional candidate genes (PCGs) that might regulate fat deposition and be useful for selection against excess fat content in chicken's carcass. This study aimed to estimate genomic heritability coefficients and to identify QTLs and PCGs for abdominal fat (ABF) and skin (SKIN) traits in a broiler chicken population, originated from the White Plymouth Rock and White Cornish breeds. ABF and SKIN are moderately heritable traits in our broiler population with estimates ranging from 0.23 to 0.33. Using a high density SNP panel (355,027 informative SNPs), we detected nine unique QTLs that were associated with these fat traits. Among these, four QTL were novel, while five have been previously reported in the literature. Thirteen PCGs were identified that might regulate fat deposition in these QTL regions: JDP2, PLCG1, HNF4A, FITM2, ADIPOR1, PTPN11, MVK, APOA1, APOA4, APOA5, ENSGALG00000000477, ENSGALG00000000483, and ENSGALG00000005043. We used sequence information from founder animals to detect 4843 SNPs in the 13 PCGs. Among those, two were classified as potentially deleterious and two as high impact SNPs. This study generated novel results that can contribute to a better understanding of fat deposition in chickens. The use of high density array of SNPs increases genome coverage and improves QTL resolution than would have been achieved with low density. The identified PCGs were involved in many biological processes that regulate lipid storage. The SNPs identified in the PCGs, especially those predicted as potentially deleterious and high impact, may affect fat deposition. Validation should be undertaken before using these SNPs for selection against carcass fat accumulation and to improve feed efficiency in broiler chicken production. Show less

Glucose-dependent insulinotropic polypeptide (GIP), a gut peptide released in response to food intake brings about secretion of insulin in a glucose-dependent manner upon binding to its receptor, GIPR. GIP-GIPR has emerged as a new vista for anti-diabetic drug discovery and their interaction is being probed at the atomic level to aid rational drug design. In order to probe this interaction on cells, the current study attempts towards expressing Show less

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, or GIP), a 42-amino acid incretin hormone, modulates insulin secretion in a glucose-concentration-dependent manner. Its insulinotropic action is highly dependent on glucose concentration that surmounts the hypoglycemia side effects associated with current therapy. In order to develop a GIP-based anti-diabetic therapy, it is essential to establish the 3D structure of the peptide and study its interaction with the GIP receptor (GIPR) in detail. This will give an insight into the GIP-mediated insulin release process. In this article, we report the solution structure of GIP(1-42, human)NH(2) deduced by NMR and the interaction of the peptide with the N-terminus of GIPR using molecular modelling methods. The structure of GIP(1-42, human)NH(2) in H(2)O has been investigated using 2D-NMR (DQF-COSY, TOCSY, NOESY, (1)H-(13)C HSQC) experiments, and its conformation was built by constrained MD simulations with the NMR data as constraints. The peptide in H(2)O exhibits an alpha-helical structure between residues Ser8 and Asn39 with some discontinuity at residues Gln29 to Asp35; the helix is bent at Gln29. This bent gives the peptide an 'L' shape that becomes more pronounced upon binding to the receptor. The interaction of GIP with the N-terminus of GIPR was modelled by allowing GIP to interact with the N-terminus of GIPR under a series of decreasing constraints in a molecular dynamics simulation, culminating with energy minimization without application of any constraints on the system. The canonical ensemble obtained from the simulation was subjected to a detailed energy analysis to identify the peptide-protein interaction patterns at the individual residue level. These interaction energies shed some light on the binding of GIP with the GIPR N-terminus in a quantitative manner. Show less

Gastric inhibitory polypeptide (GIP, or glucose-dependent insulinotropic polypeptide) is a 42-amino acid incretin hormone moderating glucose-induced insulin secretion. Antidiabetic therapy based on GIP holds great promise because of the fact that its insulinotropic action is highly dependent on the level of glucose, overcoming the sideeffects of hypoglycemia associated with the current therapy of Type 2 diabetes. The truncated peptide, GIP(1-30)NH2, has the same activity as the full length native peptide. We have studied the structure of GIP(1-30)NH2 and built a model of its G-protein coupled receptor (GPCR). The structure of GIP(1-30)NH2 in DMSO-d6 and H2O has been studied using 2D NMR (total correlation spectroscopy (TOCSY), nuclear overhauser effect spectroscopy (NOESY), double quantum filtered-COSY (DQF-COSY), 13C-heteronuclear single quantum correlation (HSQC) experiments, and its conformation built by MD simulations with the NMR data as constraints. The peptide in DMSO-d6 exhibits an alpha-helix between residues Ile12 and Lys30 with a discontinuity at residues Gln19 and Gln20. In H2O, the alpha-helix starts at Ile7, breaks off at Gln19, and then continues right through to Lys30. GIP(1-30)NH2 has all the structural features of peptides belonging to family B1 GPCRs, which are characterized by a coil at the N-terminal and a long C-terminal alpha-helix with or without a break. A model of the seven transmembrane (TM) helices of the GIP receptor (GIPR) has been built on the principles of comparative protein modeling, using the crystal structure of bovine rhodopsin as a template. The N-terminal domain of GIPR has been constructed from the NMR structure of the N-terminal of corticoptropin releasing factor receptor (CRFR), a family B1 GCPR. The intra and extra cellular loops and the C-terminal have been modeled from fragments retrieved from the PDB. On the basis of the experimental data available for some members of family B1 GPCRs, four pairs of constraints between GIP(1-30)NH2 and its receptor were used in the FTDOCK program, to build the complete model of the GIP(1-30)NH2:GIPR complex. The model can rationalize the various experimental observations including the potency of the truncated GIP peptide. This work is the first complete model at the atomic level of GIP(1-30)NH2 and of the complex with its GPCR. Show less

Zebrafish embryos homozygous for the masterblind (mbl) mutation exhibit a striking phenotype in which the eyes and telencephalon are reduced or absent and diencephalic fates expand to the front of the brain. Here we show that mbl(-/-) embryos carry an amino-acid change at a conserved site in the Wnt pathway scaffolding protein, Axin1. The amino-acid substitution present in the mbl allele abolishes the binding of Axin to Gsk3 and affects Tcf-dependent transcription. Therefore, Gsk3 activity may be decreased in mbl(-/-) embryos and in support of this possibility, overexpression of either wild-type Axin1 or Gsk3beta can restore eye and telencephalic fates to mbl(-/-) embryos. Our data reveal a crucial role for Axin1-dependent inhibition of the Wnt pathway in the early regional subdivision of the anterior neural plate into telencephalic, diencephalic, and eye-forming territories. Show less