13 research outputs found
A solid-state device for eliminating electrical noise and biopotentials in electromyographic (EMG) recordings
Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins
Opioid therapeutics are excellent
analgesics, whose utility is
compromised by dependence. Morphine (<b>1</b>) and its clinically
relevant derivatives such as OxyContin (<b>2</b>), Vicodin (<b>3</b>), and Dilaudid (<b>4</b>) are “biased”
agonists at the μ opioid receptor (OR), wherein they engage
G protein signaling but poorly engage β-arrestin and the endocytic
machinery. In contrast, endorphins, the endogenous peptide agonists
for ORs, are potent analgesics, show reduced liability for tolerance
and dependence, and engage both G protein and β-arrestin pathways
as “balanced” agonists. We set out to determine if marine-derived
alkaloids could serve as novel OR agonist chemotypes with a signaling
profile distinct from morphine and more similar to the endorphins.
Screening of 96 sponge-derived extracts followed by LC-MS-based purification
to pinpoint the active compounds and subsequent evaluation of a mini
library of related alkaloids identified two structural classes that
modulate the ORs. These included the following: aaptamine (<b>10</b>), 9-demethyl aaptamine (<b>11</b>), demethyl (oxy)–aaptamine
(<b>12</b>) with activity at the δ-OR (EC<sub>50</sub>: 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (<b>17</b>), and 10-bromo fascaplysin (<b>18</b>) with activity at the
μ-OR (EC<sub>50</sub>: 6.3, 4.2 μM respectively). An <i>in vivo</i> evaluation of <b>10</b> using δ-KO mice indicated
its previously reported antidepressant-like effects are dependent
on the δ-OR. Importantly, <b>17</b> functioned as a balanced
agonist promoting both G protein signaling and β-arrestin recruitment
along with receptor endocytosis similar to the endorphins. Collectively
these results demonstrate the burgeoning potential for marine natural
products to serve as novel lead compounds for therapeutic targets
in neuroscience research
Identification of the First Marine-Derived Opioid Receptor Balanced Agonist with a Signaling Profile That Resembles the Endorphins
Comparison of Healthcare Experiences in Autistic and Non-Autistic Adults: A Cross-Sectional Online Survey Facilitated by an Academic-Community Partnership
BACKGROUND: Little is known about the healthcare experiences of adults on the autism spectrum. Moreover, autistic adults have rarely been included as partners in autism research. OBJECTIVE: To compare the healthcare experiences of autistic and non-autistic adults via an online survey. METHODS: We used a community-based participatory research (CBPR) approach to adapt survey instruments to be accessible to autistic adults and to conduct an online cross-sectional survey. We assessed preliminary psychometric data on the adapted scales. We used multivariate analyses to compare healthcare experiences of autistic and non-autistic participants. RESULTS: Four hundred and thirty-seven participants completed the survey (209 autistic, 228 non-autistic). All adapted scales had good to excellent internal consistency reliability (alpha 0.82–0.92) and strong construct validity. In multivariate analyses, after adjustment for demographic characteristics, health insurance, and overall health status, autistic adults reported lower satisfaction with patient-provider communication (beta coefficient −1.9, CI −2.9 to −0.9), general healthcare self-efficacy (beta coefficient −11.9, CI −14.0 to −8.6), and chronic condition self-efficacy (beta coefficient −4.5, CI −7.5 to −1.6); higher odds of unmet healthcare needs related to physical health (OR 1.9 CI 1.1–3.4), mental health (OR 2.2, CI 1.3–3.7), and prescription medications (OR 2.8, CI 2.2–7.5); lower self-reported rates of tetanus vaccination (OR 0.5, CI 0.3–0.9) and Papanicolaou smears (OR 0.5, CI 0.2–0.9); and greater odds of using the emergency department (OR 2.1, CI 1.8–3.8). CONCLUSION: A CBPR approach may facilitate the inclusion of people with disabilities in research by increasing researchers’ ability to create accessible data collection instruments. Autistic adults who use the Internet report experiencing significant healthcare disparities. Efforts are needed to improve the healthcare of autistic individuals, including individuals who may be potentially perceived as having fewer disability-related needs
Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides
Sampling of California nearshore
sediments resulted in the isolation
of a Gram-negative bacterium, <i>Photobacterium halotolerans</i>, capable of producing unusual biosynthetic products. Liquid culture
in artificial seawater-based media provided cyclic depsipeptides including
four known compounds, kailuins B–E (<b>2</b>–<b>5</b>), and two new analogues, kailuins G and H (<b>7</b> and <b>8</b>). The structures of the new and known compounds
were confirmed through extensive spectroscopic and Marfey’s
analyses. During the course of these studies, a correction was made
to the previously reported double-bond geometry of kailuin D (<b>4</b>). Additionally, through the application of a combination
of derivatization with Mosher’s reagent and extensive <sup>13</sup>C NMR shift analysis, the previously unassigned chiral center
at position C-3 of the β-acyloxy group of all compounds was
determined. To evaluate bioactivity and structure–activity
relationships, the kailuin core (<b>13</b>) and kailuin lactam
(<b>14</b>) were prepared by chiral synthesis using an Fmoc
solid-phase peptide strategy followed by solution-phase cyclization.
All isolated compounds and synthetic cores were assayed for solid
tumor cell cytotoxicity and showed only minimal activity, contrary
to other published reports. Additional phenotypic screenings were
done on <b>4</b> and <b>5</b>, with little evidence of
activity