UFGI publication round-up week 3/27/17
Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study.
Author information: Miller JL1, Tamura R2, Butler MG3, Kimonis V4, Sulsona C1, Gold JA5, Driscoll DJ1,6.
Date of e-pub: March 2017
Abstract: Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale – Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P < 0.05) between groups at Day 6. The drug effect appeared to be diminished at Day 14. There was no evidence of a difference between oxytocin and placebo in safety lab parameters, 60 min post dose vital signs, weight, or diet parameters. The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further, long-term studies with a larger population of participants are necessary to confirm these findings. The results of this study are encouraging that oxytocin may be a safe and effective treatment for many of the issues that negatively impact individuals with PWS.
Why do phylogenomic data sets yield conflicting trees? Data type influences the avian tree of life more than taxon sampling.
Author information: Reddy S1, Kimball RT2, Pandey A2, Hosner PA2,3, Braun MJ4,5, Hackett SJ6, Han KL2, Harshman J7, Huddleston CJ8, Kingston S4,5,9, Marks BD6, Miglia KJ8, Moore WS8, Sheldon FH10, Witt CC11, Yuri T2,12, Braun EL2,13.
Date of e-pub: March 2017
Abstract: Phylogenomics, the use of large-scale data matrices in phylogenetic analyses, has been viewed as the ultimate solution to the problem of resolving difficult nodes in the tree of life. However, it has become clear that analyses of these large genomic datasets can also result in conflicting estimates of phylogeny. Here we use the early divergences in Neoaves, the largest clade of extant birds, as a ‘model system’ to understand the basis for incongruence among phylogenomic trees. We were motivated by the observation that trees from two recent avian phylogenomic studies exhibit conflicts. Those studies used different strategies: 1) collecting many characters [∼42 mega base pairs (Mbp) of sequence data] from 48 birds, sometimes including only one taxon for each major clade; and 2) collecting fewer characters (∼0.4 Mbp) from 198 birds, selected to subdivide long branches. However, the studies also used different data types: the taxon-poor data matrix comprised 68% non-coding sequences whereas coding exons dominated the taxon-rich data matrix. This difference raises the question of whether the primary reason for incongruence is the number of sites, the number of taxa, or the data type. To test among these alternative hypotheses we assembled a novel, large-scale data matrix comprising 90% non-coding sequences from 235 bird species. Although increased taxon sampling appeared to have a positive impact on phylogenetic analyses the most important variable was data type. Indeed, by analyzing different subsets of the taxa in our data matrix we found that increased taxon sampling actually resulted in increased congruence with the tree from the previous taxon-poor study (which had a majority of non-coding data) instead of the taxon-rich study (which largely used coding data). We suggest that the observed differences in the estimates of topology for these studies reflect data-type effects due to violations of the models used in phylogenetic analyses, some of which may be difficult to detect. If incongruence among trees estimated using phylogenomic methods largely reflects problems with model fit developing more ‘biologically-realistic’ models is likely to be critical for efforts to reconstruct the tree of life.
New developments in RAN translation: insights from multiple diseases.
Author information: Cleary JD1, Ranum LP2.
Date of e-pub: March 2017
Abstract: Since the discovery of repeat-associated non-ATG (RAN) translation, and more recently its association with amyotrophic lateral sclerosis/frontotemporal dementia, there has been an intense focus to understand how this process works and the downstream effects of these novel proteins. RAN translation across several different types of repeat expansions mutations (CAG, CTG, CCG, GGGGCC, GGCCCC) results in the production of proteins in all three reading frames without an ATG initiation codon. The combination of bidirectional transcription and RAN translation has been shown to result in the accumulation of up to six mutant expansion proteins in a growing number of diseases. This process is complex mechanistically and also complex from the perspective of the downstream consequences in disease. Here we review recent developments in RAN translation and their implications on our basic understanding of neurodegenerative disease and gene expression.
Dynamic Gene Regulatory Networks of Human Myeloid Differentiation.
Author information: Ramirez RN1, El-Ali NC1, Mager MA1, Wyman D2, Conesa A3, Mortazavi A4.
Date of e-pub: March 2017
Abstract: The reconstruction of gene regulatory networks underlying cell differentiation from high-throughput gene expression and chromatin data remains a challenge. Here, we derive dynamic gene regulatory networks for human myeloid differentiation using a 5-day time series of RNA-seq and ATAC-seq data. We profile HL-60 promyelocytes differentiating into macrophages, neutrophils, monocytes, and monocyte-derived macrophages. We find a rapid response in the expression of key transcription factors and lineage markers that only regulate a subset of their targets at a given time, which is followed by chromatin accessibility changes that occur later along with further gene expression changes. We observe differences between promyelocyte- and monocyte-derived macrophages at both the transcriptional and chromatin landscape level, despite using the same differentiation stimulus, which suggest that the path taken by cells in the differentiation landscape defines their end cell state. More generally, our approach of combining neighboring time points and replicates to achieve greater sequencing depth can efficiently infer footprint-based regulatory networks from long series data.
Alpha1-antitrypsin-deficient Macrophages Have Increased Matriptase-mediated Proteolytic Activity.
Author information: Krotova K1, Marek GW2, Wang RL3, Aslanidi G4, Hoffman BE5, Khodayari N6, Rouhani FN7, Brantly ML8.
Date of e-pub: March 2017
Abstract: Alpha1-antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels by augmentation therapy only slows disease progression; the absence of full recovery indicates a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation is called Z) compromise Mɸ function and contribute to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology; in this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of mutant AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mɸ. Importantly, compared with normal Mɸ, the membrane-bound serine protease matriptase is present in Z-Mɸ at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified MMP-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-Mɸ both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mɸ confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AATD-associated emphysema.
Type 1 diabetes mellitus.
Author information: Katsarou A1, Gudbjörnsdottir S2,3, Rawshani A2,3, Dabelea D4, Bonifacio E5, Anderson BJ6, Jacobsen LM7, Schatz DA7, Lernmark Å1.
Date of e-pub: March 2017
Abstract: Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 – all of which are proteins associated with secretory granules in β-cells – are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.
Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).
Author information: Magvanjav O1, McDonough CW1, Gong Y1, McClure LA1, Talbert RL1, Horenstein RB1, Shuldiner AR1, Benavente OR1, Mitchell BD1, Johnson JA2.
Date of e-pub: March 2017
Abstract: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke.
Nine hundred and twenty-six participants of the SPS3 trial’s (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network).
MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, β-blocker-treated Gly49 carriers had increased MACE versus non-β-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism.
Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among β-blocker-treated individuals. Further research is needed to define β-blocker benefit among ischemic stroke patients by ADRB1 genotype.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.
Is Universal HLA-B*15:02 Screening a Cost-Effective Option in an Ethnically-Diverse Population? A Case Study of Malaysia.
Author information: Chong HY1, Mohamed Z2, Tan LL3, Wu DB1, Shabaruddin FH4, Dahlui M5, Apalasamy YD2, Snyder SR6, Williams MS7, Hao J6, Cavallari LH8, Chaiyakunapruk N1,9,10,11.
Date of e-pub: March 2017
Abstract: Strong association was documented between human leukocyte antigen (HLA)-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Beyond Asia, the HLA testing is potentially valuable in many countries with increasingly diverse communities of Asian ancestry, to facilitate an early recognition of patient susceptibility to SCARs.
To determine the cost-effectiveness of universal HLA-B*15:02 screening in preventing carbamazepine-induced Stevens-Johnson syndrome/ toxic epidermal necrolysis in an ethnically-diverse Malaysian population.
A hybrid model of a decision tree and Markov model was developed to evaluate three strategies for treating newly-diagnosed epilepsy among adults – (i) carbamazepine initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to carbamazepine initiation; and (iii) alternative treatment [sodium valproate (VPA)] prescribing without HLA-B*15:02 screening. From a societal perspective, base-case analysis and sensitivity analyses were performed over lifetime time horizon. Incremental cost-effectiveness ratios were calculated.
In the base-case analysis, both universal HLA-B*15:02 screening and VPA prescribing were dominated by current practice. Compared to current practice, universal HLA-B*15:02 screening resulted in 0.0255 quality-adjusted life years (QALYs) loss at an additional cost of USD707, while VPA prescribing resulted in 0.2622 QALYs loss at an additional cost of USD4,127, due to estimated differences in antiepileptic treatment efficacy.
This study suggests that universal HLA-B*15:02 screening is unlikely to be a cost-effective intervention in Malaysia compared to current practice. However, with the emergence of an ethnically-diverse population in many other countries, this may render HLA-B*15:02 screening a potentially viable intervention when an increasing proportion of the population is at risk and an equally effective yet safer antiepileptic drug is available. This article is protected by copyright. All rights reserved.
Institutional profile: University of Florida Health Personalized Medicine Program.
Author information: Cavallari LH1,2,3, Weitzel KW1,2,3, Elsey AR1,3, Liu X4, Mosley SA1,2, Smith DM1,2, Staley BJ4,5, Winterstein AG4,6, Mathews CA7, Franchi F8, Rollini F8, Angiolillo DJ8, Starostik P9, Clare-Salzler MJ3,9, Nelson DR2,10, Johnson JA1,2,3,10.
Date of e-pub: April 2017
Abstract: The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.
Parental Psychopathology and Tourette Syndrome/Chronic Tic Disorder in Offspring: A Nationwide Case-Control Study.
Author information: Leivonen S1, Scharf JM2, Mathews CA3, Chudal R4, Gyllenberg D4, Sucksdorff D4, Suominen A4, Voutilainen A5, Brown AS6, Sourander A7.
Date of e-pub: April 2017
Abstract: To determine the associations between maternal and paternal psychiatric diagnoses and Tourette syndrome (TS)/chronic tic disorder (CT) in a nationwide study.
This nested case-control study linked data derived from three national registers. All singletons born and diagnosed with TS/CT in Finland between January 1991 and December 2010 were identified (n = 1,120) and matched to four controls (n = 4,299). Conditional logistic regression was used to examine the associations between parental psychopathology and TS/CT.
Altogether, 24.9% of patients with TS/CT and 12.0% of controls had a mother with a psychiatric diagnosis. Similarly, 17.9% and 12.9% had a father with a psychiatric diagnosis. Any maternal and any paternal psychiatric diagnosis was associated with offspring TS/CT (odds ratio [OR] 2.3; 95% CI 1.9-2.7 and OR 1.2; 95% CI 1.01-1.5, respectively). The association between maternal psychiatric diagnosis and TS/CT was stronger than that between paternal psychiatric diagnosis and TS/CT (p < .001). Maternal personality disorders (OR 3.1, 95% CI 1.9-5.1), anxiety disorders (OR 2.6, 95% CI 1.9-3.5), affective disorders (OR 2.3, 95% CI 1.8-2.9), psychotic disorders (OR 2.0, 95% CI 1.2-3.3), and addiction disorders (OR 1.8, 95% CI 1.1-2.8) were associated with TS/CT. Paternal OCD (OR 6.5, 95% CI 1.1-39.5) and anxiety disorders (OR 1.5, 95% CI 1.1-2.3) were associated with TS/CT.
Parental psychiatric diagnoses (especially in the mother) are associated with diagnosed offspring TS/CT. Further studies are required before the results can be generalized to all children with TS/CT. The associations between maternal psychiatric disorders and TS may reflect both maternal specific environmental and/or genetic influences.
Fluorescence Resonance Energy Transfer-Based DNA Tetrahedron Nanotweezer for Highly Reliable Detection of Tumor-Related mRNA in Living Cells.
Author information: He L1, Lu DQ1, Liang H1, Xie S1, Luo C1, Hu M1, Xu L1, Zhang X1, Tan W1,2.
Date of e-pub: March 2017
Abstract: Accurate detection and imaging of tumor-related mRNA in living cells hold great promise for early cancer detection. However, currently, most probes designed to image intracellular mRNA confront intrinsic interferences arising from complex biological matrices and resulting in inevitable false-positive signals. To circumvent this problem, an intracellular DNA nanoprobe, termed DNA tetrahedron nanotweezer (DTNT), was developed to reliably image tumor-related mRNA in living cells based on the FRET (fluorescence resonance energy transfer) “off” to “on” signal readout mode. DTNT was self-assembled from four single-stranded DNAs. In the absence of target mRNA, the respectively labeled donor and acceptor fluorophores are separated, thus inducing low FRET efficiency. However, in the presence of target mRNA, DTNT alters its structure from the open to closed state, thus bringing the dual fluorophores into close proximity for high FRET efficiency. The DTNT exhibited high cellular permeability, fast response and excellent biocompatibility. Moreover, intracellular imaging experiments showed that DTNT could effectively distinguish cancer cells from normal cells and, moreover, distinguish among changes of mRNA expression levels in living cells. The DTNT nanoprobe also exhibits minimal effect of probe concentration, distribution and laser power as other ratiometric probe. More importantly, as a result of the FRET “off” to “on” signal readout mode, the DTNT nanoprobe almost entirely avoids false-positive signals due to intrinsic interferences, such as nuclease digestion, protein binding and thermodynamic fluctuations in complex biological matrices. This design blueprint can be applied to the development of powerful DNA nanomachines for biomedical research and clinical early diagnosis.
Evaluation of genetic components in traits related to superovulation, in vitro fertilization, and embryo transfer in Holstein cattle.
Author information: Parker Gaddis KL1, Dikmen S2, Null DJ3, Cole JB3, Hansen PJ4.
Date of e-pub: April 2017
Abstract: The objectives of this study were to estimate variance components and identify regions of the genome associated with traits related to embryo transfer in Holsteins. Reproductive technologies are used in the dairy industry to increase the reproductive rate of superior females. A drawback of these methods remains the variability of animal responses to the procedures. If some variability can be explained genetically, selection can be used to improve animal response. Data collected from a Holstein dairy farm in Florida from 2008 to 2015 included 926 superovulation records (number of structures recovered and number of good embryos), 628 in vitro fertilization records (number of oocytes collected, number of cleaved embryos, number of high- and low-quality embryos, and number of transferrable embryos), and 12,089 embryo transfer records (pregnancy success). Two methods of transformation (logarithmic and Anscombe) were applied to count variables and results were compared. Univariate animal models were fitted for each trait with the exception of pregnancy success after embryo transfer. Due to the binary nature of the latter trait, a threshold liability model was fitted that accounted for the genetic effect of both the recipient and the embryo. Both transformation methods produced similar results. Single-step genomic BLUP analyses were performed and SNP effects estimated for traits with a significant genetic component. Heritability of number of structures recovered and number of good embryos when log-transformed were 0.27 ± 0.08 and 0.15 ± 0.07, respectively. Heritability estimates from the in vitro fertilization data ranged from 0.01 ± 0.08 to 0.21 ± 0.15, but were not significantly different from zero. Recipient and embryo heritability (standard deviation) of pregnancy success after embryo transfer was 0.03 (0.01) and 0.02 (0.01), respectively. The 10-SNP window explaining the largest proportion of variance (0.37%) for total structures collected was located on chromosome 8 beginning at 55,663,248 bp. Similar regions were identified for number of good embryos, with the largest proportion of variance (0.43%) explained by a 10-SNP window on chromosome 14 beginning at 26,713,734 bp. Results indicate that there is a genetic component for some traits related to superovulation and that selection should be possible. Moreover, the genetic component for superovulation traits involves some genomic regions that are similar to those for other fertility traits currently evaluated.
Heritability of tic disorders: a twin-family study.
Author information: Zilhão NR1, Olthof MC2, Smit DJ1, Cath DC3, Ligthart L1, Mathews CA4, Delucchi K5, Boomsma DI1, Dolan CV1.
Date of e-pub: April 2017
Abstract: Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample.
In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria.
Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects.
Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.
Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.
Author information: Darrow SM1, Hirschtritt ME1, Davis LK1, Illmann C1, Osiecki L1, Grados M1, Sandor P1, Dion Y1, King R1, Pauls D1, Budman CL1, Cath DC1, Greenberg E1, Lyon GJ1, Yu D1, McGrath LM1, McMahon WM1, Lee PC1, Delucchi KL1, Scharf JM1, Mathews CA1; Tourette Syndrome Association International Consortium for Genetics1.
Date of e-pub: April 2017
Abstract: Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts.
Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated.
The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not.
The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.
A surfactant-based wound dressing can reduce bacterial biofilms in a porcine skin explant model.
Author information: Yang Q1, Larose C1, Della Porta AC1, Schultz GS1, Gibson DJ1.
Date of e-pub: April 2017
Abstract: Bacterial biofilms have been found in many, if not all, chronic wounds. Their excessive extracellular matrix secretion and the metabolic changes that they undergo render them highly tolerant of many antibiotic and antimicrobial treatments. Physical removal and/or disruption are a common approach to treating wounds suspected of having bacterial biofilms. While many of these techniques use mechanical energy as the primary means of removal, we have begun to investigate if surfactants could facilitate the removal of bacterial biofilms, or if they might sensitise the biofilms to antimicrobial interventions. We tested a new surfactant-based wound gel on an ex vivo porcine skin explant model infected with a functionally tolerant 3-day biofilm. The wounds were dressed with a surfactant-based gel directly on the wound or with moistened gauze. The wounds were then wiped daily with moistened gauze, and the gel or gauze was re-applied. Each day, an explant from each group was harvested and tested for total viable bacteria counts and viable biofilm-protected bacteria counts. The results show that daily wiping with moistened gauze led to an initial decrease of bacteria, but by day 3, the biofilm had been fully re-established to the same level prior to the beginning of treatment. For the surfactant-based treatment, there was no detectable functional biofilm after the first treatment. The gauze control, which was also subjected to daily wiping, still contained functional biofilms, indicating that this result was not due to wiping alone. The total bacteria in the surfactant-treated explants steadily decreased through day 3, when there were no detectable bacteria, while the wiping-only control bacteria counts remained steady. The use of a moist gauze to wipe the visually apparent slime off of a wound appears to be insufficient to reduce biofilm over a 3-day period. Daily application of the surfactant gel dressing and wiping reduced the biofilm to undetectable levels within 3 days in a skin explant model. A 3-day regimen of dressing the wound model with a surfactant gel followed by gentle removal of the gel by wiping with a moistened gauze appears to be a simple and adequate approach to removing a bacterial biofilm infection in an ex vivo model. Additional clinical evidence is needed to determine if this promising approach can perform the same in clinically infected chronic wounds.
Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease.
Author information: Foster TC1, Kyritsopoulos C2, Kumar A3.
Date of e-pub: March 2017
Abstract: Increased human longevity has magnified the negative impact that aging can have on cognitive integrity of older individuals experiencing some decline in cognitive function. Approximately 30% of the elderly will have cognitive problems that influence their independence. Impaired executive function and memory performance are observed in normal aging and yet can be an early sign of a progressive cognitive impairment of Alzheimer’s disease (AD), the most common form of dementia. Brain regions that are vulnerable to aging exhibit the earliest pathology of AD. Senescent synaptic function is observed as a shift in Ca2+-dependent synaptic plasticity and similar mechanisms are thought to contribute to the early cognitive deficits associated with AD. In the case of aging, intracellular redox state mediates a shift in Ca2+ regulation including N-methyl-d-aspartate (NMDA) receptor hypofunction and increased Ca2+ release from intracellular stores to alter synaptic plasticity. AD can interact with these aging processes such that molecules linked to AD, β-amyloid (Aβ) and mutated presenilin 1 (PS1), can also degrade NMDA receptor function, promote Ca2+ release from intracellular stores, and may increase oxidative stress. Thus, age is one of the most important predictors of AD and brain aging likely contributes to the onset of AD. The focus of this review article is to provide an update on mechanisms that contribute to the senescent synapse and possible interactions with AD-related molecules, with special emphasis on regulation of NMDA receptors.
The Role of Regional Conferences in Research Resident Career Development: The California Psychiatry Research Resident Retreat.
Author information: Besterman AD1, Williams JK1, Reus VI1, Pato MT2, Voglmaier SM1, Mathews CA3.
Date of e-pub: April 2017
Abstract: For psychiatry research resident career development, there is a recognized need for improved cross-institutional mentoring and networking opportunities. One method to address this need is via regional conferences, open to current and recently graduated research residents and their mentors. With this in mind, we developed the biennial California Psychiatry Research Resident Retreat (CPRRR) and collected feedback from participants to 1) Assess resident satisfaction, 2) Determine the utility of the retreat as a networking and mentorship tool, and 3) Identify areas for improvement.
We gathered survey data from resident attendees at the two first CPRRRs. We analyzed the data to look for trends in satisfaction as well as areas that need improvement.
Thirty-two residents from five California training programs attended the CPRRR in 2013 while 33 attended from six programs in 2015. The residents were from all years of training, but concentrated in their second and third years. Approximately 41% and 49% of the attendees were female and 53% and 39% had an MD/PhD in 2013 and 2015, respectively. Twenty-four and 32 residents provided anonymous feedback in 2013 and 2015, respectively. Mean feedback scores were very high (> 4/5) for overall satisfaction, peer- and faculty-networking, the keynote speaker and the flash talks for both years. Mean feedback scores for the ethics debates and mentoring sessions were somewhat lower (≤ 4/5), however, both showed significant improvement from 2013 to 2015.
The CPRRRs appear to be an effective mechanism for providing psychiatry research residents with a meaningful cross-institutional opportunity for networking and mentorship. Feedback-driven changes to the CPRRRs improved participant satisfaction for several components of the conference. Future efforts will be aimed at broadening mentorship and networking opportunities, optimizing teaching approaches for research ethics, and considering different feedback-gathering approaches to allow for improved longitudinal follow-up and subgroup analysis.
Molecular characterization of XopAG effector AvrGf2 from Xanthomonas fuscans ssp. aurantifolii in grapefruit.
Author information: Gochez AM1,2, Shantharaj D2, Potnis N2, Zhou X3, Minsavage GV2, White FF2, Wang N3, Hurlbert JC4, Jones JB2.
Date of e-pub: April 2017
Abstract: Xanthomonas fuscans ssp. aurantifolii group C strains exhibit host specificity on different citrus species. The strains possess a type III effector, AvrGf2, belonging to the XopAG effector gene family, which restricts host range on citrus. We dissected the modular nature and mode of action of AvrGf2 in grapefruit resistance. XopAG effectors possess characteristic features, such as a chloroplast localization signal, a cyclophilin-binding domain characteristic amino acid sequence motif (GPLL) and a C-terminal domain-containing CLNAxYD. Mutation of GPLL to AASL in AvrGf2 abolished the elicitation of the hypersensitive response (HR), whereas mutation of only the first amino acid to SPLL delayed the HR in grapefruit. Yeast two-hybrid experiments showed strong interaction of AvrGf2 with grapefruit cyclophilin (GfCyp), whereas AvrGf2-SPLL and AvrGf2-AASL mutants showed weak and no interaction, respectively. Molecular modelling and in silico docking studies for the cyclophilin-AvrGf2 interaction predicted the binding of citrus cyclophilins (CsCyp, GfCyp) to hexameric peptides spanning the cyclophilin-binding domain of AvrGf2 and AvrGf2 mutants (VAGPLL, VASPLL and VAAASL) with affinities equivalent to or better than a positive control peptide (YSPSA) previously demonstrated to bind CsCyp. In addition, the C-terminal domain of XopAG family effectors contains a highly conserved motif, CLNAxYD, which was identified to be crucial for the induction of HR based on site-directed mutagenesis (CLNAxYD to CASAxYD). Our results suggest a model in which grapefruit cyclophilin promotes a conformational change in AvrGf2, thereby triggering the resistance response.
NOTE: These abstracts were retrieved from the U.S. National Library of Medicine website managed in collaboration with the U.S. National Library of Medicine