Gene expression is a heritable cellular phenotype that defines the function of a cell and can lead to diseases in case of misregulation. In order to detect genetic variations affecting gene ...expression, we performed association analysis of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with gene expression measured in 869 lymphoblastoid cell lines of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in cis and in trans. We discovered that 3,534 genes (false discovery rate (FDR) = 5%) are affected by an expression quantitative trait locus (eQTL) in cis and 48 genes are affected in trans. We observed that CNVs are more likely to be eQTLs than SNPs. In addition, we found that variants associated to complex traits and diseases are enriched for trans-eQTLs and that trans-eQTLs are enriched for cis-eQTLs. As a variant affecting both a gene in cis and in trans suggests that the cis gene is functionally linked to the trans gene expression, we looked specifically for trans effects of cis-eQTLs. We discovered that 26 cis-eQTLs are associated to 92 genes in trans with the cis-eQTLs of the transcriptions factors BATF3 and HMX2 affecting the most genes. We then explored if the variation of the level of expression of the cis genes were causally affecting the level of expression of the trans genes and discovered several causal relationships between variation in the level of expression of the cis gene and variation of the level of expression of the trans gene. This analysis shows that a large sample size allows the discovery of secondary effects of human variations on gene expression that can be used to construct short directed gene regulatory networks.
Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). ...Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment.
Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.
Calcification in prosthetic vascular conduits is a major challenge in cardiac and vascular surgery that compromises the long‐term performance of these devices. Significant research efforts have been ...made to understand the etiology of calcification in the cardiovascular system and to combat calcification in various cardiovascular devices. Novel biomaterial design and tissue engineering strategies have shown promise in preventing or delaying calcification in prosthetic vascular grafts. In this review, we highlight recent advancements in the development of acellular prosthetic vascular grafts with preclinical success in attenuating calcification through advanced biomaterial design. We also discuss the mechanisms of action involved in the designs that will contribute to the further understanding of cardiovascular calcification. Lastly, recent insights into the etiology of vascular calcification will guide the design of future prosthetic vascular grafts with greater potential for translational success.
Negative symptoms are complex psychopathology. Although evidence generally supported the NIMH five consensus domains, research seldom examined measurement invariance of this model, and ...domain-specific correspondence across multiple scales. This study aimed to examine the interrelationship between negative symptom domains captured by different rating scales, and to examine the domain-specific correspondence across multiple scales. We administered the Brief Negative Symptom Scale (BNSS), the Self-evaluation of Negative Symptoms (SNS), and the Scale for Assessment of Negative Symptoms (SANS) to 204 individuals with schizophrenia. We used network analysis to examine the interrelationship between negative symptom domains. Besides regularized partial correlation network, we estimated bridge centrality indices to investigate domain-specific correspondence, while taking each scale as an independent community. The regularized partial correlation network showed that the SNS nodes clustered together, whereas the SANS and the BNSS nodes intermingled together. The SANS attention domain lied at the periphery of the network according to the Fruchterman–Reingold algorithm. The SANS anhedonia–asociality (strength = 1.48; EI = 1.48) and the SANS affective flattening (strength = 1.06; EI = 1.06) had the highest node strength and EI. Moreover, the five nodes of the BNSS bridged the nodes of the SANS and the SNS. BNSS blunted affect (strength = 0.76; EI = 0.76) and SANS anhedonia–asociality (strength = 0.76; EI = 0.74) showed the highest bridge strength and bridge EI. The BNSS captures negative symptoms and bridges the symptom domains measured by the SANS and the SNS. The three scales showed domain-specific correspondence.
Abstract Background Theory of mind (ToM) impairment has been consistently demonstrated in patients with schizophrenia, but whether ToM impairments exist in unaffected siblings of patients with ...schizophrenia remains unclear. Few studies have examined the affective and cognitive components of ToM in schizophrenia. This study aimed to examine whether ToM impairments exist in patients with first-episode schizophrenia and their unaffected siblings, and whether there is any dissociation between the affective and cognitive components of ToM. Method We adopted a family-based case-control design. Participants were 41 patients with first-episode schizophrenia, 43 unaffected siblings, and 42 healthy controls. The Yoni Task which measures the participants’ ability to understand first- and second-order affective versus cognitive ToM and the Faux Pas Task which taps into integration of the affective and cognitive components of ToM were administered. Multivariate and univariate ANCOVAs were used to examine the group differences in ToM, while controlling for other neurocognitive functions. Results Compared with controls, patients with schizophrenia and their unaffected siblings performed poorer on the Faux Pas Task ( p < 0.001), with siblings having intermediate performance between patients and controls. Patients with schizophrenia performed worse than controls on second-order affective condition of the Yoni Task ( p = 0.004), but their unaffected siblings did not ( p = 0.063). We did not find any significant Group-by-Condition interaction in the Yoni Task ( p = 0.358). Conclusion Patients with first-episode schizophrenia and their unaffected siblings exhibit ToM impairments, but no dissociation between affective and cognitive component of ToM was found. Our findings support the notion that ToM deficit may be a trait marker of schizophrenia.
Exposure to pain management curriculum in medical school is currently variable. This paper reports on formal prescribing education, self-perceived prescribing readiness, and prescribing practices ...among incoming surgical residents before and after a pain management training session.
Pre-residency survey of thirty surgical interns at a single urban medical center, followed by a repeat survey after an educational session on prescription writing and opioid abuse.
Thirty-three percent of respondents had formal education on prescription writing in medical school. Median subjective preparedness to write an opioid prescription was 1.5 (range 1–10) on a 1–10 Likert scale. Ranges of morphine milligram equivalents (MME) prescribed varied from 420-2700 MME for 8 mock surgical scenarios. Post-training, median subjective preparedness increased to 3.5 (range 1–6) and prescription accuracy (the inclusion of a medication, dose, frequency, and duration) improved from 75% to 97% (p < 0.001). Overall, 90% of interns found the training session useful.
Most surgical interns were not trained in prescribing narcotics in medical school. Improved pain management curriculum is necessary to assure safe and consistent opioid prescriptions.
•33% (N = 18) of residents had exposure to opioid prescribing education in medical school.•Incoming surgical residents reported a median readiness of 1.5 (range 1–10) to write opioid prescriptions.•Ranges of morphine milligram equivalents (MME) prescribed varied from 420-2700 MME for 8 mock surgical scenarios.•Overall, 90% of interns found the training session useful.
In-stent restenosis is a pervasive challenge to the durability of stenting for the treatment of lower extremity ischemia. There is considerable controversy about the criteria for diagnosis, ...indications for treatment, and preferred algorithm for addressing in-stent restenosis. This evidence summary seeks to review existing information on strategies for the treatment of this difficult problem.
Tekscan pressure sensors are used in biomechanics research to measure joint contact loads. While the overall accuracy of these sensors has been reported previously, the effects of different ...calibration algorithms on sensor accuracy have not been compared. The objectives of this validation study were to determine the most appropriate calibration method supplied in the Tekscan program software and to compare its accuracy to the accuracy obtained with two user-defined calibration protocols. We evaluated the calibration accuracies for test loads within the low range, high range, and full range of the sensor. Our experimental setup used materials representing those found in standard prosthetic joints, i.e., metal against plastic. The Tekscan power calibration was the most accurate of the algorithms provided with the system software, with an overall rms error of 2.7% of the tested sensor range, whereas the linear calibrations resulted in an overall rms error of up to 24% of the tested range. The user-defined ten-point cubic calibration was almost five times more accurate, on average, than the power calibration over the full range, with an overall rms error of 0.6% of the tested range. The user-defined three-point quadratic calibration was almost twice as accurate as the Tekscan power calibration, but was sensitive to the calibration loads used. We recommend that investigators design their own calibration curves not only to improve accuracy but also to understand the range(s) of highest error and to choose the optimal points within the expected sensing range for calibration. Since output and sensor nonlinearity depend on the experimental protocol (sensor type, interface shape and materials, sensor range in use, loading method, etc.), sensor behavior should be investigated for each different application.
The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. ...Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age.
We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution.
DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.
Prospective memory (PM) refers to the ability to remember to carry out a delayed intention in the future. Evidence suggests that emotionally salient cues can enhance PM functions in healthy ...population, but whether the benefit exists in schizophrenia and bipolar patients remains unclear. This study aimed to examine and compare the potential enhancement effect of emotional PM cues in schizophrenia patients and bipolar patients. Twenty-eight clinically stable schizophrenia participants, 26 euthymic bipolar participants and 29 controls completed a computerized PM task involving PM cues with different types of valences (i.e., positive, neutral and negative). All the three groups showed better PM performance when negative PM cues were presented compared with positive and neutral PM cues. The sizes of the enhancement effects of negative PM cues were large (all Cohen’s
d
≥ 1.00) and comparable across three groups. Our findings suggested that patients with schizophrenia and bipolar disorders could benefit from negative PM cues to an extent similar to healthy individuals, thus extended the notion of psychosis continuum to the important area of emotion-cognition interaction.
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