Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice

Aims. We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods. Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 μl/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results. r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p<0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p<0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p<0.05). Conclusion. r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke

A Comprehensive Family-Based Replication Study of Schizophrenia Genes

Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Meta-analyses of genome-wide association studies for postpartum depression

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)–based heritability (), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone)

Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer's disease

Background: Although insulin-like growth factor-I (IGF-I) is of importance for the adult function of the central nervous system (CNS), little is known of the significance of IGF-I in cerebrospinal fluid (CSF) in relation to Alzheimer's disease (AD). Methods: A cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-I, IGF-binding protein-3 (IGFBP-3), and insulin were measured in serum and CSF. Results: Serum IGF-I level was increased in AD patients and in patients with other dementias compared to healthy controls (P = 0.01 and P < 0.05, respectively). Serum IGFBP-3 concentration was increased in AD and SMCI patients compared to controls (P = 0.001 and P < 0.05, respectively). CSF levels of IGF-I and IGFBP-3 as well as serum and CSF levels of insulin were similar in all study groups. In the total study population (n = 80), serum levels of IGF-I and IGFBP-3 correlated negatively with CSF beta-amyloid(1-42) (A beta(1-42)) level (r = -0.29, P = 0.01 and r = -0.27, P = 0.02, respectively) and in the AD patients (n = 32), the increased CSF/serum IGF-I ratio correlated positively with the CSF level of phosphorylated tau protein (P-tau; r = 0.42, P = 0.02). Conclusion: Patients with AD as well as other dementias had high levels of IGF-I in serum but not in CSF. In AD patients, the IGF-I system was associated with biomarkers of AD disease status. (C) 2013 Elsevier Ltd. All rights reserved

Structure of the N -linked glycan present on multiple glycoproteins in the gram-negative bacterium, Campylobacter jejuni: J.Biol.Chem.

Mass spectrometry investigations of partially purified C. jejuni protein PEB3 showed it to be partially modified with an Asn-linked glycan of mass 1406 Da and comprised of one hexose, five HexNAc and a species of mass 228 Da, consistent with a trideoxydiacetamidohexose. By means of soybean lectin affinity chromatography, a mixture of glycoproteins was obtained from a glycine extract, and 2D-gel proteomics analysis led to the identification of at least 22 glycoproteins, predominantly annotated as periplasmic proteins. Glycopeptides were prepared from the glycoprotein mixture by pronase digestion and gel-filtration. The structure of the glycan was determined by using nano-NMR techniques to be GalNAc-a1,4-GalNAc-a1,4-GalNAc-a1,4-[Glcb1,3-]GalNAc-a1,4-GalNAc-a1,3-Bac- b1,N-Asn-Xaa, where Bac is bacillosamine, 2,4-diacetamido-2,4,6-trideoxyglucopyranose. Protein glycosylation was abolished when the pglB gene was mutated, providing further evidence that the enzyme encoded by this gene is responsible for formation of the glycopeptide N-linkage. Comparison of the pgl locus with that of Neisseria meningitidis suggested that most of the homologous genes are probably involved in the biosynthesis of bacillosamineNRC publication: Ye

Growth hormone deficiency is associated with worse cardiac function, physical performance, and outcome in chronic heart failure: Insights from the T.O.S.CA. GHD study

Background Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. Methods One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6 +/- 1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6 +/- 1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. Results GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p=.008 and -24%, p=.015, respectively), lower LV end-systolic wall stress (-21%, p=.03), higher RV performance (+18% in RV area change, p=.03), lower estimated systolic pulmonary artery pressure (-11%, p=.04), higher peak VO2 (+20%, p=.001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p=.002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (beta = -1.92, SE = 1.67, p=.03), VE/VCO2 slope (beta = 2.23, SE = 1.20, p=.02) and NT-proBNP (beta = 2.48, SE = 1.02, p=.016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p<.001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. Conclusions GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality