Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions

Serum Procalcitonin Levels in Newly Diagnosed Hodgkin Lymphoma: Correlation with Other Inflammatory Biomarkers

Background and Objectives: Procalcitonin (PCT) is a useful biomarker for the diagnosis of sepsis. Inflammatory markers are elevated in patients with Hodgkin lymphoma (HL), and yet ongoing infection rarely coexists at diagnosis. PCT levels might be helpful in differentiating bacterial from disease-related inflammation. Materials and Methods: We evaluated serum PCT levels and other inflammation markers in newly diagnosed HL patients. Values < 0.50 ng/mL were considered normal (0.10–0.50 ng/mL: detectable, <0.10 ng/mL: undetectable), while values ≥ 0.50 ng/L were considered elevated. Results: Among 137 patients, 55 had B symptoms (40%), 77/130 (59%) had elevated Erythrocyte Sedimentation Rate (ESR) and 116 (85%) had elevated C-Reactive Protein (CRP) (median 38.1 mg/L (range; 2.97–328)). PCT levels were normal in most patients (undetectable 94/137 (68.5%) and detectable 41/137(30%)) with median value < 0.10 ng/mL (range; <0.10–15.90). Elevated PCT was recorded in only two patients (1.5%). Patients with PCT < 0.10 ng/mL had significantly lower median CRP (25.75; range (2.97–203.0)) compared to patients with PCT ≥ 0.1 ng/mL (median CRP 92.50 mg/L; range (3.34–328.0)). Almost all patients (40/41, 97.6%) with detectable PCT had elevated CRP. Conclusions: This is the first study showing that the inflammation characterizing HL is not associated with PCT elevations, although CRP levels are elevated in 85% of the patients. Normal PCT levels may rule out the possibility of occult infection, thus preventing extensive evaluation, which may delay treatment initiation

Serum ferritin levels in previously untreated classical Hodgkin lymphoma: correlations and prognostic significance

Serum ferritin (SF) is frequently elevated in classical Hodgkin lymphoma (cHL). We report on its prognostic significance in an unselected series of 529 cHL patients treated with state-of-the-art therapy. Higher baseline levels correlated with markers of advanced/aggressive disease. SF levels were significantly higher in male and older patients, those with high body mass index and mixed cellularity histology. The strongest correlation was recorded between SF and complement reactive protein (CRP) levels. Gender-specific SF cutoffs which provided the best discrimination in terms of freedom from progression (FFP) were identified. In multivariate analysis elevated SF levels, advanced stage and high lactate dehydrogenase (LDH) were independent prognostic factors of inferior FFP. SF also appears to retain independent prognostic significance for progression-free survival (PFS) but not for overall survival (OS). In conclusion, SF levels in cHL reflect disease activity and are associated with adverse patient outcomes

SynGO : An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org)

SynGO : An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org)

SynGO: an evidence-based, expert-curated knowledge base for the synapse

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org). The SynGO consortium presents a framework to annotate synaptic protein locations and functions and annotations for 1,112 synaptic genes based on published experimental evidence. SynGO reports exceptional features and disease associations for synaptic genes and provides an online data analysis platform.</p