BA11 FKBP5 expression levels correlate with dendritic spine density in postmortem PTSD and controls

AbstractGenetic variants of the immunophilin FKBP5 have been implicated in susceptibility to post-traumatic stress disorder (PTSD) and other stress-related disorders. We examined the relationship between mushroom, stubby, thin and filopodial spine densities measured with Golgi staining and FKBP5 gene expression in the medial orbitofrontal cortex (BA11) in individuals diagnosed with PTSD and normal controls (n = 8/8). ANCOVA revealed PTSD cases had a significantly elevated density of stubby spines (29%, P < 0.037) and a trend for a reduction in mushroom spine density (25%, p < 0.082). Levels of FKBP5 mRNA were marginally elevated in the PTSD cases (z = 1.94, p = 0.053) and levels correlated inversely with mushroom (Spearman's rho = −0.83, p < 0.001) and overall spine density (rho = −0.75, p < 0.002) and directly with stubby spine density (rho = 0.55, p < 0.027). These data suggest that FKBP5 may participate in a cellular pathway modulating neuronal spine density changes in the brain, and that this pathway may be dysregulated in PTSD

Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity

This is the published version. Copyright 2014 Oxford University PressCatechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically, low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms. One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT) and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals and schizophrenia patients is yet to be determined

The enzymatic activities of brain COMT and methionine sulfoxide reductase are correlated in a COMT Val/Met allele-dependent fashion

This is the peer reviewed version of the following article: J. Moskovitz, C. Walss-Bass, D. A. Cruz, P. M. Thompson, J. Hairston and M. Bortolato (2015) Neuropathology and Applied Neurobiology The enzymatic activities of brain catechol-O-methyltransferase (COMT) and methionine sulphoxide reductase are correlated in a COMT Val/Met allele-dependent fashion, which has been published in final form at http://doi.org/10.1111/nan.12219. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.AIMS: The enzyme catechol-O-methyl transferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best-characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulfoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion. METHODS: COMT and MSR activities were measured from post-mortem samples of prefrontal cortices, striata and cerebella of 32 subjects, by using catechol and dabsyl-Met sulfoxide as substrates, respectively. Allelic discrimination of COMT Val108/185Met SNP was performed using the Taqman 5’nuclease assay. RESULTS: Our studies revealed that, in homozygous carriers of Met, but not Val alleles, the activity of COMT and MSR were significantly correlated throughout all tested brain regions. DISCUSSION: These results suggest that the reduced enzymatic activity of Met-containing COMT may be secondary to Met sulfoxidation, and point to MSR as a key molecular determinant for the modulation of COMT activity

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P \u3c 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman\u27s rank correlations between PBMCs and the brain regions are all highly significant (r s = 0.47-0.57; P \u3c 2.2 × 10-16), although pairwise correlations among the brain regions are markedly stronger (r s = 0.86-0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (\u3e70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P &lt; 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T&gt;C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P &lt; .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

The evaluation of animal bite treatment centers in the Philippines from a patient perspective

BACKGROUND: The Philippines has built an extensive decentralised network of Animal Bite Treatment Centers (ABTCs) to help bite victims receive timely rabies post-exposure prophylaxis (PEP) at little cost. This study surveyed patients in the community and at ABTCs of three provinces to assess animal bite/scratch incidence, health-seeking behaviour and PEP-related out-of pocket expenses (OOPE). METHODOLOGY AND PRINCIPAL FINDINGS: During community surveys in 90 barangays (neighbourhoods), 53% of households reported at least one animal bite /scratch injury over the past 3 years, similar across urban and rural barangays. Overall bite/scratch incidences in 2016-17 were 67.3, 41.9 and 48.8 per 1,000 population per year for Nueva Vizcaya, Palawan and Tarlac respectively. Incidences were around 50% higher amongst those under 15 years of age, compared to -those older than 15. Household awareness of the nearest ABTCs was generally over 80%, but only 44.9% sought proper medical treatment and traditional remedies were still frequently used. The proportion of patients seeking PEP was not related to the distance or travel time to the nearest ABTC. For those that did not seek medical treatment, most cited a lack of awareness or insufficient funds and almost a third visited a traditional healer. No deaths from bite/scratch injuries were reported. A cohort of 1,105 patients were interviewed at six ABTCs in early 2017. OOPE varied across the ABTCs, from 5.53 USD to 37.83 USD per patient, primarily dependent on the need to pay for immunization if government supplies had run out. Overall, 78% of patients completed the recommended course, and the main reason for non-completion was a lack of time, followed by insufficient funds. Dog observation data revealed that 85% of patients were not truly exposed to rabies, and education in bite prevention might reduce provoked bites and demand for PEP. An accompanying paper details the ABTC network from the health provider's perspective.S1 Checklist. STROBE checklist. https://doi.org/10.1371/journal.pone.0200873.s001S1 Fig. Locations of ABTCs in (A) Nueva Vizcaya, (B) Palawan, and (C) Tarlac. https://doi.org/10.1371/journal.pone.0200873.s002S1 Table. Number of animal bites and scratches recorded by community surveys by province and by year. https://doi.org/10.1371/journal.pone.0200873.s003S2 Table. Additional reasons given in the community survey for not seeking medical treatment for wounds. https://doi.org/10.1371/journal.pone.0200873.s004S3 Table. Reasons for patients not completing the PEP series. https://doi.org/10.1371/journal.pone.0200873.s005S4 Table. Total Out-of-Pocket Expenses, ABTC patient survey, 2017. https://doi.org/10.1371/journal.pone.0200873.s006S5 Table. Biting animal status at day 28 follow-up. https://doi.org/10.1371/journal.pone.0200873.s007S6 Table. PEP completion status of patients bitten by animals that died or were of unknown status. https://doi.org/10.1371/journal.pone.0200873.s008GlaxoSmithKline Biologicals SA (Belgium)http://www.plosone.orgVeterinary Tropical Disease

Differential Neuregulin 1 Cleavage in the Prefrontal Cortex and Hippocampus in Schizophrenia and Bipolar Disorder: Preliminary Findings

Neuregulin 1 (NRG1) is a key candidate susceptibility gene for both schizophrenia (SCZ) and bipolar disorder (BPD). The function of the NRG1 transmembrane proteins is regulated by cleavage. Alteration of membrane bound-NRG1 cleavage has been previously shown to be associated with behavioral impairments in mouse models lacking expression of NRG1-cleavage enzymes such as BACE1 and gamma secretase. We sought to determine whether alterations in NRG1 cleavage and associated enzymes occur in patients with SCZ and BPD.Using human postmortem brain, we evaluated protein expression of NRG1 cleavage products and enzymes that cleave at the external (BACE1, ADAM17, ADAM19) and internal (PS1-gamma secretase) sides of the cell membrane. We used three different cohorts (Controls, SCZ and BPD) and two distinct brain regions: BA9-prefrontal cortex (Controls (n = 6), SCZ (n = 6) and BPD (n = 6)) and hippocampus (Controls (n = 5), SCZ (n = 6) and BPD (n = 6)). In BA9, the ratio of the NRG1 N-terminal fragment relative to full length was significantly upregulated in the SCZ cohort (Bonferroni test, p = 0.011). ADAM17 was negatively correlated with full length NRG1 levels in the SCZ cohort (r = -0.926, p = 0.008). In the hippocampus we found significantly lower levels of a soluble 50 kDa NRG1 fragment in the two affected groups compared the control cohort (Bonferroni test, p = 0.0018). We also examined the relationship of specific symptomatology criteria with measures of NRG1 cleavage using the Bipolar Inventory of Signs and Symptoms Scale (BISS) and the Montgomery Åsberg Depression Rating Scale (MADRS). Our results showed a positive correlation between ADAM19 and psychosis (r = 0.595 p = 0.019); PS1 and mania (r = 0.535, p = 0.040); PS1 and depression (r = 0.567, p = 0.027) in BA9, and BACE1 with anxiety (r = 0.608, p = 0.03) in the hippocampus.Our preliminary findings suggest region-specific alterations in NRG1 cleavage in SCZ and BPD patients. These changes may be associated with specific symptoms in these psychiatric disorders

Lutzomyia Sand Fly Diversity and Rates of Infection by Wolbachia and an Exotic Leishmania Species on Barro Colorado Island, Panama

Certain sand fly species living inside or on the edge of tropical forests are well known to transmit a protozoan to humans, which in lowland Panama develops into a cutaneous form of leishmaniasis; open, itching sores on the face and extremities requiring aggressive treatment with antimonial compounds. Morphological characters and DNA sequence from mitochondrial and nuclear gene fragments permitted us to identify and then establish historical relationships among 20 common sand fly species occurring in the understory of Barro Colorado Island, a forested preserve in the middle of the Panama Canal. Individuals in three of these sand fly species were found to be 26–43% infected by Leishmania naiffi, a species hitherto known only from the Amazonian region and the Caribbean. We then screened the same 20 sand fly species for the cytoplasmically transmitted bacteria Wolbachia pipientis, finding three infected at high rates, each by a distinct strain. Lutzomyia trapidoi, the most likely transmitter of Leishmania to humans in Panama, was among the Wolbachia-infected species, thus marking it as a possible high-value target for future biocontrol studies using the bacteria either to induce mating incompatabilities or to drive selected genes into the population

Frontal Lobe Circuitry in Posttraumatic Stress Disorder

Symptoms of posttraumatic stress disorder include hyperarousal, avoidance of trauma-related stimuli, re-experiencing of trauma, and mood changes. This review focuses on the frontal cortical areas that form crucial links in circuitry pertinent to posttraumatic stress disorder symptomatology: (1) the conditioned fear extinction circuit, (2) the salience circuit, and (3) the mood circuit. These frontal areas include the ventromedial prefrontal cortex (conditioned fear extinction), the dorsal anterior cingulate and insular cortices (salience), and the lateral orbitofrontal and subgenual cingulate cortices (mood). Frontal lobe structural abnormalities in posttraumatic stress disorder, including volumetric reductions in the cingulate cortices, impact all three circuits. Functional analyses of frontal cortices in posttraumatic stress disorder show abnormal activation in all three according to task demand and emotional valence. Network analyses reveal altered amygdalo-frontal connectivity and failure to suppress the default mode network during cognitive engagement. Spine shape alterations also have been detected in the medial orbitofrontal cortex in posttraumatic stress disorder postmortem brains, suggesting reduced synaptic plasticity. Importantly, frontal lobe abnormalities in posttraumatic stress disorder extend beyond emotion-related circuits to include the lateral prefrontal cortices that mediate executive functions. In conclusion, widespread frontal lobe dysfunction in posttraumatic stress disorder provides a neurobiologic basis for the core symptomatology of the disorder, as well as for executive function impairment