Tremorgenic indole alkaloids produce neurological disorders (e.g., staggers syndromes) in ruminants. The mode of action of these fungal mycotoxins is not understood but may be related to their known effects on neurotransmitter release. To determine whether these effects could be due to inhibition of K+ channels, the interaction of various indole diterpenes with high-conductance Ca(2+)-activated K+ (maxi-K) channels was examined. Paspalitrem A, paspalitrem C, aflatrem, penitrem A, and paspalinine inhibit binding of [125I]charybdotoxin (ChTX) to maxi-K channels in bovine aortic smooth muscle sarcolemmal membranes. In contrast, three structurally related compounds, paxilline, verruculogen, and paspalicine, enhanced toxin binding. As predicted from the binding studies, covalent incorporation of [125I]ChTX into the 31-kDa subunit of the maxi-K channel was blocked by compounds that inhibit [125I]ChTX binding and enhanced by compounds that stimulate [125I]ChTX binding. Modulation of [125I]ChTX binding was due to allosteric mechanisms. Despite their different effects on binding of [125I]ChTX to maxi-K channels, all compounds potently inhibited maxi-K channels in electrophysiological experiments. Other types of voltage-dependent or Ca(2+)-activated K+ channels examined were not affected. Chemical modifications of paxilline indicate a defined structure-activity relationship for channel inhibition. Paspalicine, a deshydroxy analog of paspalinine lacking tremorgenic activity, also potently blocked maxi-K channels. Taken together, these data suggest that indole diterpenes are the most potent nonpeptidyl inhibitors of maxi-K channels identified to date. Some of their pharmacological properties could be explained by inhibition of maxi-K channels, although tremorgenicity may be unrelated to channel block.

Fibrinogen, D-dimer, PAI-1 activity, and factor VIIc each has potential to increase the prediction of coronary disease/ischemic stroke in middle-aged men, in addition to conventional risk factors.

Background and purposeEffective mentorship is critical to the success of early stage investigators, and has been linked to enhanced mentee productivity, self-efficacy, and career satisfaction. The mission of the National Research Mentoring Network (NRMN) is to provide all trainees across the biomedical, behavioral, clinical, and social sciences with evidence-based mentorship and professional development programming that emphasizes the benefits and challenges of diversity, inclusivity, and culture within mentoring relationships, and more broadly the research workforce. The purpose of this paper is to describe the structure and activities of NRMN.Key highlightsNRMN serves as a national training hub for mentors and mentees striving to improve their relationships by better aligning expectations, promoting professional development, maintaining effective communication, addressing equity and inclusion, assessing understanding, fostering independence, and cultivating ethical behavior. Training is offered in-person at institutions, regional training, or national meetings, as well as via synchronous and asynchronous platforms; the growing training demand is being met by a cadre of NRMN Master Facilitators. NRMN offers career stage-focused coaching models for grant writing, and other professional development programs. NRMN partners with diverse stakeholders from the NIH-sponsored Diversity Program Consortium (DPC), as well as organizations outside the DPC to work synergistically towards common diversity goals. NRMN offers a virtual portal to the Network and all NRMN program offerings for mentees and mentors across career development stages. NRMNet provides access to a wide array of mentoring experiences and resources including MyNRMN, Guided Virtual Mentorship Program, news, training calendar, videos, and workshops. National scale and sustainability are being addressed by NRMN “Coaches-in-Training” offerings for more senior researchers to implement coaching models across the nation. “Shark Tanks” provide intensive review and coaching for early career health disparities investigators, focusing on grant writing for graduate students, postdoctoral trainees, and junior faculty.ImplicationsPartners from diverse perspectives are building the national capacity and sparking the institutional changes necessary to truly diversify and transform the biomedical research workforce. NRMN works to leverage resources towards the goals of sustainability, scalability, and expanded reach.

A tailored intervention can be efficacious in promoting tobacco use cessation and increased fruit and vegetable consumption among construction laborers, a high-risk, mobile workforce.

Neurotransmitter release from preganglionic parasympathetic neurons is resistant to inhibition by selective antagonists of L-, N-, P/Q-, R-, and T-type calcium channels. In this study, the effects of different -conotoxins from genus Conus were investigated on current flow-through cloned voltage-sensitive calcium channels expressed in Xenopus oocytes and nerve-evoked transmitter release from the intact preganglionic cholinergic nerves innervating the rat submandibular ganglia. Our results indicate that -conotoxin CVID from Conus catus inhibits a pharmacologically distinct voltage-sensitive calcium channel involved in neurotransmitter release, whereas -conotoxin MVIIA had no effect. Venom of the predatory marine gastropods of the genus Conus (cone snails) contain a unique array of peptides whose pharmaceutical potential remains largely unexploited (1). These peptides have been classified based on their pharmacological target and structure (2, 3). One important class, the -conotoxins, utilizes a four-loop framework to selectively inhibit "Ntype" voltage-sensitive calcium channels (VSCCs) 1 found in the central and peripheral nervous systems of vertebrates (4).Neurotransmitter release from preganglionic parasympathetic neurons has been found to be resistant to inhibition by a range of selective calcium channel antagonists of L-, N-, P/Q-, R-, and T-type calcium channels (5-8). A recently discovered -conotoxin from Conus catus (CVID) is highly selective for N-type over P/Q-type VSCCs (9) and shows potent analgesic activity in rats (10). In this study, we investigated the effects of CVID on autonomic neurotransmission using conventional intracellular microelectrode recording techniques. -Conotoxin CVID was found to be a potent inhibitor of neurally evoked transmitter release from the intact preganglionic cholinergic nerves innervating the rat submandibular ganglia, whereas -conotoxin MVIIA had no effect.The orientation and nature of the residues in loop 2 of -conotoxins have been shown to be crucial for selective binding to the N-type VSCC (11-15). Since the only sequence difference in loop 2 between CVID and MVIIA is at position 10, we investigated the importance of this position for -conotoxin structure and ability to block neurotransmitter release from preganglionic parasympathetic neurons. The inhibition of preganglionic transmitter release was favored in -conotoxins with a Lys at position 10.

1. Intracellular and focal extracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea‐pig isolated vas deferens. 2. High concentrations of the selective N‐type calcium channel blocker omega‐conotoxin GVIA abolished the release of the neurotransmitter ATP evoked by trains of low‐frequency stimuli. However, in the presence of high concentrations of the blocker, a ‘residual release’ persisted at higher frequencies. 3. Residual release was dependent on calcium entry through a pharmacologically distinct voltage‐dependent calcium channel. 4. Residual release was inhibited by ryanodine in a use‐ and time‐dependent manner and this inhibitory effect was potentiated by caffeine. The inhibitory effect of ryanodine on residual release was reversed by 4‐aminopyridine. 5. These findings indicate that calcium‐induced calcium released from intraneuronal stores plays an important role in action potential‐evoked neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals.

In patients undergoing LEB, LOS is primarily associated with the occurrence of postoperative complications, whereas 30-day readmission is largely explained by underlying patient illness. Additionally, increased LOS is an independent risk factor for readmission. These findings suggest that efforts to reduce both LOS and readmission will be complementary. Furthermore, they support the notion that both LOS and 30-day readmission rates should be risk-adjusted.

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