Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND & AIMS: A greater understanding of cholestatic disease is necessary to advance diagnostic tools and therapeutic options for conditions such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The purpose of this study was to determine and compare the serum metabolomes of patients with PBC (n = 18) or PSC (n = 21) and healthy controls (n = 10) and to identify metabolites that may differentiate these two cholestatic diseases. METHODS AND RESULTS: Using a mass spectrometry-based, non-targeted biochemical profiling approach, we identified 420 serum metabolites, 101 that differed significantly (P ≤ 0.05) between PBC and control groups, 115 that differed significantly between PSC and control groups, and 56 that differed significantly between PSC and PBC groups. Random forest classification analysis was able to distinguish patients with PBC or PSC with 95% accuracy with selected biochemicals reflective of protein and amino acid metabolism identified as the major contributors. Metabolites related to bile acid metabolism, lipid metabolism, inflammation, and oxidative stress/lipid peroxidation were also identified as differing significantly when comparing the disease groups and controls, with some of these pathways differentially affected in the PBC and PSC groups. CONCLUSION: In this study, we identified novel metabolic changes associated with cholestatic disease that were both consistent and different between PBC and PSC. Validation studies in larger patient cohorts are required to determine the utility of these biochemical markers for diagnosis and therapeutic monitoring of patients with PBC and PSC

Emotion Regulation in Consumption: Antecedents and Consequences

While people often feel “ruled by their passions,” individuals can and do exert substantial control over their emotional experiences. A growing body of literature in psychology suggests that the various ways emotions are regulated can have considerable impact on both the emotional experience and other psychological processes. Over three essays, this work examines how individuals regulate their emotions, when they are motivated to do so, and why these concepts are important for consumer behavior. In the first essay, I investigate how emotions are managed by looking at one specific emotion regulation strategy: attention deployment. Using experimental methods, I determine that individuals naturally use attention deployment to regulate their emotions, but the effectiveness varies with the emotion being regulated. After establishing attention deployment as a viable emotion regulation strategy, the second essay asks when individuals are motivated to change their emotions. I propose that identities are associated with discrete emotions, and that these associations give rise to emotion profiles that describe appropriate emotional experiences for individuals with that active identity. The studies reported in the second essay establish that social identities have associations to specific emotions, these associations differ between identities, and the emotion-identity relationships lead to outcomes in cognition, affect, motivation, and regulation. Additional experiments demonstrate that individuals engage in emotion regulation to reduce (enhance) their experience of emotions which are inconsistent (consistent) with the identity’s emotion profile. In the third and final essay, I connect emotion regulation and emotion profiles to marketing and consumer outcomes. Four studies show that experiencing emotions consistent with the identity’s emotion profile enhances persuasion, product choice, and consumption—even for identity-unrelated products and advertisements. Ultimately, consequences for the framing and positioning of identity-relevant products are drawn. Across the three essays, I investigate how, when and why emotion regulation processes influence consumer outcomes. From identifying a specific emotion regulation strategy, to introducing the concept of emotion profiles, new insights into the emotion regulation process are provided. These findings suggest that emotion regulation has widespread impact on consumer outcomes, and represents a new viewpoint on how the emotion experience varies by individual

Hubungan antara kepuasan hubungan romantis dengan intensi berselingkuh pada mahasiswa

<p>[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref007" target="_blank">7</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref010" target="_blank">10</a>]DrmMS did not retain many of the DrmMS contact sites with DrmMS-R2, consistent with SAR data that indicate the analog is inactive in heart and gut. Thus, taken together, these data indicated [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref007" target="_blank">7</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref010" target="_blank">10</a>]DrmMS, one less N-terminal residue than [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref006" target="_blank">6</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120492#pone.0120492.ref010" target="_blank">10</a>]DrmMS, the active core in heart, did not activate DrmMS-R2, in line with this receptor transducing the DrmMS-R2 signal.</p

Blockade of Mast Cell Activation Reduces Cutaneous Scar Formation

Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1a, IL-1b, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase b1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound

TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Cardiac contractility structure-activity relationship and ligand-receptor interactions; the discovery of unique and novel molecular switches in myosuppressin signaling

Peptidergic signaling regulates cardiac contractility; thus, identifying molecular switches, ligand-receptor contacts, and antagonists aids in exploring the underlying mechanisms to influence health. Myosuppressin (MS), a decapeptide, diminishes cardiac contractility and gut motility. Myosuppressin binds to G protein-coupled receptor (GPCR) proteins. Two Drosophila melanogaster myosuppressin receptors (DrmMS-Rs) exist; however, no mechanism underlying MS-R activation is reported. We predicted DrmMS-Rs contained molecular switches that resembled those of Rhodopsin. Additionally, we believed DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 interactions would reflect our structure-activity relationship (SAR) data. We hypothesized agonist- and antagonist-receptor contacts would differ from one another depending on activity. Lastly, we expected our study to apply to other species; we tested this hypothesis in Rhodnius prolixus , the Chagas disease vector. Searching DrmMS-Rs for molecular switches led to the discovery of a unique ionic lock and a novel 3-6 lock, as well as transmission and tyrosine toggle switches. The DrmMS-DrmMS-R1 and DrmMS-DrmMS-R2 contacts suggested tissue-specific signaling existed, which was in line with our SAR data. We identified R. prolixus (Rhp)MS-R and discovered it, too, contained the unique myosuppressin ionic lock and novel 3-6 lock found in DrmMS-Rs as well as transmission and tyrosine toggle switches. Further, these motifs were present in red flour beetle, common water flea, honey bee, domestic silkworm, and termite MS-Rs. RhpMS and DrmMS decreased R. prolixus cardiac contractility dose dependently with EC50 values of 140 nM and 50 nM. Based on ligand-receptor contacts, we designed RhpMS analogs believed to be an active core and antagonist; testing on heart confirmed these predictions. The active core docking mimicked RhpMS, however, the antagonist did not. Together, these data were consistent with the unique ionic lock, novel 3-6 lock, transmission switch, and tyrosine toggle switch being involved in mechanisms underlying TM movement and MS-R activation, and the ability of MS agonists and antagonists to influence physiology.Fil: Leander, Megan. University of Michigan; Estados UnidosFil: Bass, Chloe. University of Michigan; Estados UnidosFil: Marchetti, Kathryn. University of Michigan; Estados UnidosFil: Maynard, Benjamin F.. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wulff, Juan Pedro. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ons, Sheila. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; ArgentinaFil: Nichols, Ruthann. University of Michigan; Estados Unido

Materials

Qualtrics material

Code

Rmarkdown Code and Outpu

Social Decisions Study

This OSF project documents three studies we replicated directly in April 2018 in a graduate course on rigorous and reproducible research practices at Tufts University (PSY 262)