Making sense: dopamine activates conscious self-monitoring through medial prefrontal cortex

When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self-awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self-awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self-awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self-awareness. In a separate experiment with extended self-awareness dopamine improved the retrieval accuracy of memories of self-judgment (autonoetic, i.e., explicitly self-conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self-awareness, this explains the specific effect of dopamine on explicit self-awareness and autonoetic metacognition

Ballroom Music Spillover into a Beluga Whale Aquarium Exhibit

It is not uncommon for modern aquaria to be built with special entertainment areas. There are no known measurements of sound spillover from such entertainment areas into underwater animal exhibits. Entertainment organizations typically prefer to play music for events at 95 and 100 dBA in a ballroom at Georgia Aquarium. Concern over the potential effects of the music and noise on animals in adjacent exhibits inspired an initial project to monitor and compare sound levels in the adjacent underwater exhibits against the typical in-air sound levels of the ballroom. Measured underwater noise levels were compared to modeled levels based on finite element analysis and plane wave transmission loss calculations through the acrylic viewing window. Results were compared with the model to determine how, if at all, the ambient noise level in the Cold Water Quest exhibit changed as a result of music played in the ballroom

The transcriptional profile of coronary arteritis in Kawasaki disease.

BACKGROUND: Kawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment. METHODS: Deep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD. RESULTS: T lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis. CONCLUSIONS: The immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies

Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis

BACKGROUND: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). OBJECTIVE: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. METHODS: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. RESULTS: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca CONCLUSIONS: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice

Thermodynamics of Heat Shock Response

Production of heat shock proteins are induced when a living cell is exposed to a rise in temperature. The heat shock response of protein DnaK synthesis in E.coli for temperature shifts from temperature T to T plus 7 degrees, respectively to T minus 7 degrees is measured as function of the initial temperature T. We observe a reversed heat shock at low T. The magnitude of the shock increases when one increase the distance to the temperature $T_0 \approx 23^o$, thereby mimicking the non monotous stability of proteins at low temperature. Further we found that the variation of the heat shock with T quantitatively follows the thermodynamic stability of proteins with temperature. This suggest that stability related to hot as well as cold unfolding of proteins is directly implemented in the biological control of protein folding. We demonstrate that such an implementation is possible in a minimalistic chemical network.Comment: To be published in Physical Review Letter

The transcriptional profile of coronary arteritis in Kawasaki disease

BackgroundKawasaki Disease (KD) can cause potentially life-threatening coronary arteritis in young children, and has a likely infectious etiology. Transcriptome profiling is a powerful approach to investigate gene expression in diseased tissues. RNA sequencing of KD coronary arteries could elucidate the etiology and the host response, with the potential to improve KD diagnosis and/or treatment.MethodsDeep RNA sequencing was performed on KD (n = 8) and childhood control (n = 7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Non-human RNA sequences were subjected to a microbial discovery bioinformatics platform, and microbial sequences were analyzed by Metastats for association with KD.ResultsT lymphocyte activation, antigen presentation, immunoglobulin production, and type I interferon response were significantly upregulated in KD arteritis, while the tumor necrosis factor α pathway was not differentially expressed. Transcripts from known infectious agents were not specifically associated with KD coronary arteritis.ConclusionsThe immune transcriptional profile in KD coronary artery tissues has features of an antiviral immune response such as activated cytotoxic T lymphocyte and type I interferon-induced gene upregulation. These results provide new insights into the pathogenesis of KD arteritis that can guide selection of new immunomodulatory therapies for high-risk KD patients, and provide direction for future etiologic studies

Interleukin 1β and Prostaglandin E2 Affect Expression of DNA Methylating and Demethylating Enzymes in Human Gingival Fibroblasts

Periodontitis is a common chronic inflammatory condition that results in increased levels of inflammatory cytokines and inflammatory mediators. In addition to oral disease and tooth loss, it also causes low-grade systemic inflammation that contributes to development of systemic conditions including cardiovascular disease, pre-term birth, diabetes and cancer. Chronic inflammation is associated with epigenetic change, and it has been suggested that such changes can alter cell phenotypes in ways that contribute to both ongoing inflammation and development of associated pathologies. Here we show that exposure of human gingival fibroblasts to IL-1β increases expression of maintenance methyltransferase DNMT1 but decreases expression of de novo methyltransferase DNMT3a and the demethylating enzyme TET1, while exposure to PGE2 decreases expression of all three enzymes. IL-1β and PGE2 both affect global levels of DNA methylation and hydroxymethylation, as well as methylation of some specific CpG in inflammation-associated genes. The effects of IL-1β are independent of its ability to induce production of PGE2, and the effects of PGE2 on DNMT3a expression are mediated by the EP4 receptor. The finding that exposure of fibroblasts to IL-1β and PGE2 can result in altered expression of DNA methylating/demethylating enzymes and in changing patterns of DNA methylation suggests a mechanism through which inflammatory mediators might contribute to the increased risk of carcinogenesis associated with inflammation

Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT

BACKGROUND: Cryopreservation of PBMC and/or overnight shipping of samples are required for many clinical trials, despite their potentially adverse effects upon immune monitoring assays such as MHC-peptide tetramer staining, cytokine flow cytometry (CFC), and ELISPOT. In this study, we compared the performance of these assays on leukapheresed PBMC shipped overnight in medium versus cryopreserved PBMC from matched donors. RESULTS: Using CMV pp65 peptide pool stimulation or pp65 HLA-A2 tetramer staining, there was significant correlation between shipped and cryopreserved samples for each assay (p ≤ 0.001). The differences in response magnitude between cryopreserved and shipped PBMC specimens were not significant for most antigens and assays. There was significant correlation between CFC and ELISPOT assay using pp65 peptide pool stimulation, in both shipped and cryopreserved samples (p ≤ 0.001). Strong correlation was observed between CFC (using HLA-A2-restricted pp65 peptide stimulation) and tetramer staining (p < 0.001). Roughly similar sensitivity and specificity were observed between the three assays and between shipped and cryopreserved samples for each assay. CONCLUSION: We conclude that all three assays show concordant results on shipped versus cryopreserved specimens, when using a peptide-based readout. The assays are also concordant with each other in pair wise comparisons using equivalent antigen systems

PARP inhibitors and the treatment of breast cancer: beyond BRCA1/2?

Poly(ADP-ribose) polymerase (PARP) inhibitors have been explored as therapeutic agents for the treatment of hereditary breast and ovarian cancers harboring mutations in BRCA1 or BRCA2. In a new study, Inbar-Rozensal and colleagues show that phenanthridine-derived PARP inhibitors promote cell cycle arrest and cell death in breast cancer cells lacking BRCA1 and BRCA2 mutations and prevent the growth of tumors from xenografts of these cells in immunocompromised mice. These results suggest a potential broader utility of PARP-1 inhibitors in the treatment of breast cancer, although further mechanistic studies are needed