Defining Transcriptomic Heterogeneity between Left and Right Ventricle-Derived Cardiac Fibroblasts.

Cardiac fibrosis is a key aspect of heart failure, leading to reduced ventricular compliance and impaired electrical conduction in the myocardium. Various pathophysiologic conditions can lead to fibrosis in the left ventricle (LV) and/or right ventricle (RV). Despite growing evidence to support the transcriptomic heterogeneity of cardiac fibroblasts (CFs) in healthy and diseased states, there have been no direct comparisons of CFs in the LV and RV. Given the distinct natures of the ventricles, we hypothesized that LV- and RV-derived CFs would display baseline transcriptomic differences that influence their proliferation and differentiation following injury. Bulk RNA sequencing of CFs isolated from healthy murine left and right ventricles indicated that LV-derived CFs may be further along the myofibroblast transdifferentiation trajectory than cells isolated from the RV. Single-cell RNA-sequencing analysis of the two populations confirmed that Postn+ CFs were more enriched in the LV, whereas Igfbp3+ CFs were enriched in the RV at baseline. Notably, following pressure overload injury, the LV developed a larger subpopulation of pro-fibrotic Thbs4+/Cthrc1+ injury-induced CFs, while the RV showed a unique expansion of two less-well-characterized CF subpopulations (Igfbp3+ and Inmt+). These findings demonstrate that LV- and RV-derived CFs display baseline subpopulation differences that may dictate their diverging responses to pressure overload injury. Further study of these subpopulations will elucidate their role in the development of fibrosis and inform on whether LV and RV fibrosis require distinct treatments.

Myocardial Infarction Induces Cardiac Fibroblast Transformation within Injured and Noninjured Regions of the Mouse Heart.

Heart failure (HF) is associated with pathological remodeling of the myocardium, including the initiation of fibrosis and scar formation by activated cardiac fibroblasts (CFs). Although early CF-dependent scar formation helps prevent cardiac rupture by maintaining the heart's structural integrity, ongoing deposition of the extracellular matrix in the remote and infarct regions can reduce tissue compliance, impair cardiac function, and accelerate progression to HF. In our study, we conducted mass spectrometry (MS) analysis to identify differentially altered proteins and signaling pathways between CFs isolated from 7 day sham and infarcted murine hearts. Surprisingly, CFs from both the remote and infarct regions of injured hearts had a wide number of similarly altered proteins and signaling pathways that were consistent with fibrosis and activation into pathological myofibroblasts. Specifically, proteins enriched in CFs isolated from MI hearts were involved in pathways pertaining to cell-cell and cell-matrix adhesion, chaperone-mediated protein folding, and collagen fibril organization. These results, together with principal component analyses, provided evidence of global CF activation postinjury. Interestingly, however, direct comparisons between CFs from the remote and infarct regions of injured hearts identified 15 differentially expressed proteins between MI remote and MI infarct CFs. Eleven of these proteins (Gpc1, Cthrc1, Vmac, Nexn, Znf185, Sprr1a, Specc1, Emb, Limd2, Pawr, and Mcam) were higher in MI infarct CFs, whereas four proteins (Gstt1, Gstm1, Tceal3, and Inmt) were higher in MI remote CFs. Collectively, our study shows that MI injury induced global changes to the CF proteome, with the magnitude of change reflecting their relative proximity to the site of injury.

Acute changes of left ventricular function during surgical revascularization by 3D speckle tracking.

BACKGROUND: Detecting early impact of coronary artery bypass grafting (CABG) on left ventricular (LV) function is important because such measures may contribute to meaningful improvement in clinical outcomes. We aimed to gain knowledge about acute changes of LV performance during surgical revascularization using three-dimensional speckle tracking echocardiography (3D STE). METHODS: Thirty-five patients scheduled for CABG surgery who underwent intraoperative transesophageal echocardiography (TEE) were enrolled (mean age 68.9 ± 7.3 years). TEE was performed before and after surgery, as well as before and after grafting. 3D LV ejection fraction (LVEF), tissue motion annular displacement (TMAD) of the mitral valves, 3D global longitudinal strain (GLS), global circumferential strain (GCS), twist, and torsion were quantified. Regional longitudinal strain (LS) was calculated based on coronary perfusion territories in a 16-segment LV model. RESULTS: Despite the absence of change in TMAD and 3D LVEF, 3D GLS (-18.6 ± 4.3% at baseline vs -16.0 ± 4.0% after surgery, P = .01) was significantly decreased, followed with no significant effect on GCS, twist, and torsion during surgery. 3D GLS correlated significantly with 3D LVEF (r between -0.34 and -0.51, P < .05 for all) under the whole operation. Territorial LS did not increase immediately after surgery. CONCLUSION: 3D speckle tracking imaging allows for detailed and direct evaluation of myocardial deformation, though impaired LV longitudinal function is still apparent immediately after surgery. GLS is more sensitive to an acute reduction in LV function than conventional parameters, which can be potentially useful for serial monitoring of functional recovery.

Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury.

OBJECTIVES: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. DESIGN: Experimental animal study. SETTING: Research laboratory. SUBJECTS: Adult male mice and hippocampal brain slices. INTERVENTIONS: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). MEASUREMENTS AND MAIN RESULTS: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. CONCLUSIONS: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury-induced persistent cognitive deficits.

Cognitive and functional status predictors of delirium and delirium severity after coronary artery bypass graft surgery: an interim analysis of the Neuropsychiatric Outcomes After Heart Surgery study.

BACKGROUND: Cognitive and functional impairment increase risk for post-coronary artery bypass graft (CABG) surgery delirium (PCD), but how much impairment is necessary to increase PCD risk remains unclear. METHODS: The Neuropsychiatric Outcomes After Heart Surgery (NOAHS) study is a prospective, observational cohort study of participants undergoing elective CABG surgery. Pre-operative cognitive and functional status based on Clinical Dementia Rating (CDR) scale and neuropsychological battery are assessed. We defined mild cognitive impairment (MCI) based on either (1) CDR global score 0.5 (CDR-MCI) or (2) performance 1.5 SD below population means on any cognitive domain on neurocognitive battery (MCI-NC). Delirium was assessed daily post-operative day 2 through discharge using the confusion assessment method (CAM) and delirium index (DI). We investigate whether MCI - either definition - predicts delirium or delirium severity. RESULTS: So far we have assessed 102 participants (mean age 65.1 ± 9; male: 75%) for PCD. Twenty six participants (25%) have MCI-CDR; 38 (62% of those completing neurocognitive testing) met MCI-NC criteria. Fourteen participants (14%) developed PCD. After adjusting for age, sex, comorbidity, and education, MCI-CDR, MMSE, and Lawton IADL score predicted PCD on logistic regression (OR: 5.6, 0.6, and 1.5, respectively); MCI-NC did not (OR [95% CI]: 11.8 [0.9, 151.4]). Using similarly adjusted linear regression, MCI-CDR, MCI-NC, CDR sum of boxes, MMSE, and Lawton IADL score predicted delirium severity (adjusted R(2): 0.26, 0.13, 0.21, 0.18, and 0.32, respectively). CONCLUSIONS: MCI predicts post-operative delirium and delirium severity, but MCI definition alters these relationships. Cognitive and functional impairment independently predict post-operative delirium and delirium severity.

Tracing the trajectory of skill learning with a very large sample of online game players.

In the present study, we analyzed data from a very large sample (N = 854,064) of players of an online game involving rapid perception, decision making, and motor responding. Use of game data allowed us to connect, for the first time, rich details of training history with measures of performance from participants engaged for a sustained amount of time in effortful practice. We showed that lawful relations exist between practice amount and subsequent performance, and between practice spacing and subsequent performance. Our methodology allowed an in situ confirmation of results long established in the experimental literature on skill acquisition. Additionally, we showed that greater initial variation in performance is linked to higher subsequent performance, a result we link to the exploration/exploitation trade-off from the computational framework of reinforcement learning. We discuss the benefits and opportunities of behavioral data sets with very large sample sizes and suggest that this approach could be particularly fecund for studies of skill acquisition.

Point process modelling of the Afghan War Diary.

Modern conflicts are characterized by an ever increasing use of information and sensing technology, resulting in vast amounts of high resolution data. Modelling and prediction of conflict, however, remain challenging tasks due to the heterogeneous and dynamic nature of the data typically available. Here we propose the use of dynamic spatiotemporal modelling tools for the identification of complex underlying processes in conflict, such as diffusion, relocation, heterogeneous escalation, and volatility. Using ideas from statistics, signal processing, and ecology, we provide a predictive framework able to assimilate data and give confidence estimates on the predictions. We demonstrate our methods on the WikiLeaks Afghan War Diary. Our results show that the approach allows deeper insights into conflict dynamics and allows a strikingly statistically accurate forward prediction of armed opposition group activity in 2010, based solely on data from previous years.

Identifying hosts of families of viruses: a machine learning approach.

Identifying emerging viral pathogens and characterizing their transmission is essential to developing effective public health measures in response to an epidemic. Phylogenetics, though currently the most popular tool used to characterize the likely host of a virus, can be ambiguous when studying species very distant to known species and when there is very little reliable sequence information available in the early stages of the outbreak of disease. Motivated by an existing framework for representing biological sequence information, we learn sparse, tree-structured models, built from decision rules based on subsequences, to predict viral hosts from protein sequence data using popular discriminative machine learning tools. Furthermore, the predictive motifs robustly selected by the learning algorithm are found to show strong host-specificity and occur in highly conserved regions of the viral proteome.

Parameter estimation and inference for stochastic reaction-diffusion systems: application to morphogenesis in D. melanogaster.

BACKGROUND: Reaction-diffusion systems are frequently used in systems biology to model developmental and signalling processes. In many applications, count numbers of the diffusing molecular species are very low, leading to the need to explicitly model the inherent variability using stochastic methods. Despite their importance and frequent use, parameter estimation for both deterministic and stochastic reaction-diffusion systems is still a challenging problem. RESULTS: We present a Bayesian inference approach to solve both the parameter and state estimation problem for stochastic reaction-diffusion systems. This allows a determination of the full posterior distribution of the parameters (expected values and uncertainty). We benchmark the method by illustrating it on a simple synthetic experiment. We then test the method on real data about the diffusion of the morphogen Bicoid in Drosophila melanogaster. The results show how the precision with which parameters can be inferred varies dramatically, indicating that the ability to infer full posterior distributions on the parameters can have important experimental design consequences. CONCLUSIONS: The results obtained demonstrate the feasibility and potential advantages of applying a Bayesian approach to parameter estimation in stochastic reaction-diffusion systems. In particular, the ability to estimate credibility intervals associated with parameter estimates can be precious for experimental design. Further work, however, will be needed to ensure the method can scale up to larger problems.

Cardiac surgery in a patient with heparin-induced thrombocytopenia--cautions with use of the direct thrombin inhibitor, argatroban.

Heparin-induced thrombocytopenia (HIT) is being recognized in an increasing number of patients referred for cardiac surgery, as a result of previous exposure to heparin. We present a case of a patient with HIT scheduled for aortic valve replacement and coronary bypass graft surgery, who was managed with the direct thrombin inhibitor, argatroban for anticoagulation during cardiopulmonary bypass (CPB). The patient sustained continued bleeding in excess of the acknowledged half-life of the drug and required a substantial number of blood products to restore coagulation following CPB. Pertinent reports using argatroban for cardiac surgery with CPB are reviewed in the context of the present case report. The pharmacologic basis, cost analysis and resource utilization of heparin substitutes are discussed for the patient with HIT requiring CPB.

An improved set of mndo parameters for sulfur.

The MNDO parameters for sulfur have been reoptimized. Calculations for a number of sulfur compounds indicate a very significant improvement. Inclusion of d AOs failed to correct the errors for compounds of sulfur in its higher valence states. Since d AOs are not included, the calculations are still confined to compounds of divalent sulfur.