Atherosclerosis is a multifactorial disease that preferentially occurs in arterial regions exposed to d-flow can be used to indicate disturbed flow or disturbed blood flow. The mechanisms by which d-flow induces atherosclerosis involve changes in the transcriptome, methylome, proteome, and metabolome of multiple vascular cells, especially endothelial cells. Initially, we begin with the pathogenesis of atherosclerosis and the changes that occur at multiple levels owing to d-flow, especially in the endothelium. Also, there are a variety of strategies used for the global profiling of the genome, transcriptome, miRNA-ome, DNA methylome, and metabolome that are important to define the biological and pathophysiological mechanisms of endothelial dysfunction and atherosclerosis. Finally, systems biology can be used to integrate these ‘omics’ datasets, especially those that derive data based on a single animal model, in order to better understand the pathophysiology of atherosclerosis development in a holistic manner and how this integrative approach could be used to identify novel molecular diagnostics and therapeutic targets to prevent or treat atherosclerosis. WIREs Syst Biol Med 2016, 8:378–401. doi: 10.1002/wsbm.1344. For further resources related to this article, please visit the WIREs website.
Purpose: This study tested the hypothesis that encapsulation of influenza vaccine in microneedle patches increases vaccine stability during storage at elevated temperature. Methods: Whole inactivated influenza virus vaccine (A/Puerto Rico/8/34) was formulated into dissolving microneedle patches and vaccine stability was evaluated by in vitro and in vivo assays of antigenicity and immunogenicity after storage for up to 3 months at 4, 25, 37 and 45°C. Results: While liquid vaccine completely lost potency as determined by hemagglutination (HA) activity within 1-2 weeks outside of refrigeration, vaccine in microneedle patches lost 40-50% HA activity during or shortly after fabrication, but then had no significant additional loss of activity over 3 months of storage, independent of temperature. This level of stability required reduced humidity by packaging with desiccant, but was not affected by presence of oxygen. This finding was consistent with additional stability assays, including antigenicity of the vaccine measured by ELISA, virus particle morphological structure captured by transmission electron microscopy and protective immune responses by immunization of mice in vivo. Conclusions: These data show that inactivated influenza vaccine encapsulated in dissolving microneedle patches has enhanced stability during extended storage at elevated temperatures.
Optogenetic techniques provide an unprecedented ability to precisely manipulate neural activity in the context of complex neural circuitry. Although the toolbox of optogenetic probes continues to expand at a rapid pace with more efficient and responsive reagents, hardware-based light delivery is still a major hurdle that limits its practical use in vivo. We have bypassed the challenges of external light delivery by directly coupling a bioluminescent light source (a genetically encoded luciferase) to an inhibitory opsin, which we term an inhibitory luminopsin (iLMO). iLMO was shown to suppress action potential firing and synchronous bursting activity in vitro in response to both external light and luciferase substrate. iLMO was further shown to suppress single-unit firing rate and local field potentials in the hippocampus of anesthetized rats. Finally, expression of iLMO was scaled up to multiple structures of the basal ganglia to modulate rotational behavior of freely moving animals in a hardware-independent fashion. This novel class of optogenetic probes demonstrates how non-invasive inhibition of neural activity can be achieved, which adds to the versatility, scalability, and practicality of optogenetic applications in freely behaving animals.
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Adolfo Ramirez-Zamora;
James J. Giordano;
Aysegul Gunduz;
Peter Brown;
Justin C. Sanchez;
Kelly D. Foote;
Leonardo Almeida;
Philip A. Starr;
Helen M. Bronte-Stewart;
Wei Hu;
Cameron McIntyre;
Wayne Goodman;
Doe Kumsa;
Warren M. Grill;
Harrison C. Walker;
Matthew D. Johnson;
Jerrold L. Vitek;
David Greene;
Daniel S. Rizzuto;
Dong Song;
Theodore W. Berger;
Robert E. Hampson;
Sam A. Deadwyler;
Leigh R. Hochberg;
Nicholas D. Schiff;
Paul Stypulkowski;
Greg Worrell;
Vineet Tiruvadi;
Helen S Mayberg;
Joohi Jimenez-Shahed;
Pranav Nanda;
Sameer A. Sheth;
Robert Gross;
Scott F. Lempka;
Luming Li;
Wissam Deeb;
Michael S. Okun
The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.
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Elmar W. Tobi;
Roderick C. Slieker;
Rene Luijk;
Koen F. Dekkers;
Aryeh Stein;
Kate M. Xu;
P. Eline Slagboom;
Erik W. Van Zwet;
L.H. Lumey;
Bastiaan T. Heijmans
Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342, 596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formalmediation analysis.DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing b cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-termmetabolic health. The specific mechanism awaits elucidation.
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Michal T. Berry;
Brent M. Kremen;
Vaclav Miller;
Laura Miller Khadjevand;
Fatemeh Ezzyat;
Youssef Stein;
Joel Wanda;
Paul Sperling;
Michael R. Gorniak;
Richard Davis;
Kathryn Jobst;
Barbara Gross;
Michal T. Kucewicz;
Bradley Lega;
S. Matt Stead;
Daniel S. Rizzuto;
Michael J. Kahana;
Gregory A. Worrell
Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with “poor” memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation.
The development and application of high-throughput genomics technologies has resulted in massive quantities of diverse omics data that continue to accumulate rapidly. These rich datasets offer unprecedented and exciting opportunities to address long standing questions in biomedical research. However, our ability to explore and query the content of diverse omics data is very limited. Existing dataset search tools rely almost exclusively on the metadata. A text-based query for gene name(s) does not work well on datasets wherein the vast majority of their content is numeric. To overcome this barrier, we have developed Omicseq, a novel web-based platform that facilitates the easy interrogation of omics datasets holistically to improve â € findability' of relevant data. The core component of Omicseq is trackRank, a novel algorithm for ranking omics datasets that fully uses the numerical content of the dataset to determine relevance to the query entity. The Omicseq system is supported by a scalable and elastic, NoSQL database that hosts a large collection of processed omics datasets. In the front end, a simple, web-based interface allows users to enter queries and instantly receive search results as a list of ranked datasets deemed to be the most relevant.
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Stella Iurato;
Tania Carrillo-Roa;
Janine Arloth;
Darina Czamara;
Laura Diener-Hoelzl;
Jennifer Lange;
Muller-Myhsok Mueller-Myhsok;
Elisabeth B. Binder;
Angelika Erhardt
Panic disorder (PD) affects about four million Europeans, with women affected twice as likely as men, causing substantial suffering and high economic costs. The etiopathogenesis of PD remains largely unknown, but both genetic and environmental factors contribute to risk. An epigenome-wide association study (EWAS) was conducted to compare medication-free PD patients (n = 89) with healthy controls (n = 76) stratified by gender. Replication was sought in an independent sample (131 cases, 169 controls) and functional analyses were conducted in a third sample (N = 71). DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. One genome-wide association surviving FDR of 5% (cg07308824, P = 1.094 × 10-7, P-adj = 0.046) was identified in female PD patients (N = 49) compared to controls (N = 48). The same locus, located in an enhancer region of the HECA gene, was also hypermethylated in female PD patients in the replication sample (P = 0.035) and the significance of the association improved in the meta-analysis (P-adj = 0.004). Methylation at this CpG site was associated with HECA mRNA expression in another independent female sample (N = 71) both at baseline (P = 0.046) and after induction by dexamethasone (P = 0.029). Of 15 candidates, 5 previously reported as associated with PD or anxiety traits also showed differences in DNA methylation after gene-wise correction and included SGK1, FHIT, ADCYAP1, HTR1A, HTR2A. Our study examines epigenome-wide differences in peripheral blood for PD patients. Our results point to possible sex-specific methylation changes in the HECA gene for PD but overall highlight that this disorder is not associated with extensive changes in DNA methylation in peripheral blood.
Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused. Case presentation: A 42year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma. Conclusion: Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma.