Search

The fine tuning of biological electrical signaling is mediated by variations in the rates of opening and closing of gates that control ion flux through different ion channels. Human ether-a-go-go related gene (HERG) potassium channels have uniquely rapid inactivation kinetics which are critical to the role they play in regulating cardiac electrical activity. Here, we exploit the K + sensitivity of HERG inactivation to determine structures of both a conductive and non-conductive selectivity filter structure of HERG. The conductive state has a canonical cylindrical shaped selectivity filter. The non-conductive state is characterized by flipping of the selectivity filter valine backbone carbonyls to point away from the central axis. The side chain of S620 on the pore helix plays a central role in this process, by coordinating distinct sets of interactions in the conductive, non-conductive, and transition states. Our model represents a distinct mechanism by which ion channels fine tune their activity and could explain the uniquely rapid inactivation kinetics of HERG., (© 2024. The Author(s).)

Introduction: Bronchoscopy is a useful diagnostic tool capable of performing core biopsy, forceps biopsy, bronchoalveolar lavage, and bronchial brushing. This study compares the cellularity of bronchial cytology including pre- and post-biopsy lavage by digital image analysis, aiming to increase diagnostic and tumor yield by optimizing the sequence and combination of bronchial biopsy and cytology., Methods: Alveolar macrophage, bronchial epithelium, and tumor cell cellularity from liquid-based cytology preparations of bronchial brushing and pre-biopsy and post-biopsy bronchoalveolar lavage were annotated on digitized whole-slide images and compared. Secondary analysis on the relationship of tumor cell and non-lesional cell yield was performed., Results: Overall, 118 cytology specimens from 43 patients were retrieved in total. Bronchial epithelium count was higher in pre-biopsy than post-biopsy lavage (p < 0.01) but not for alveolar macrophages nor tumor cell (p > 0.05). Tumor cell count was higher for bronchial brushing cytology samples than lavage (p = 0.018). The alveolar macrophage count was higher in post-biopsy lavage than bronchial brushing (p = 0.033); otherwise, brushing showed consistently higher bronchial epithelium and tumor cell counts. There were 33 false negative (tumor cell absent) specimens, and the combination of bronchial brushing and pre-biopsy lavage yielded the lowest false negative cases. Correlation between bronchial epithelium and alveolar macrophage counts with tumor cell count was weak (correlation coefficient = -0.168-0.203) except for post-biopsy lavage (correlation coefficient = 0.412-0.479, p < 0.05)., Conclusion: Bronchial brushing yields a greater amount of tumor cell than lavage, and timing lavage before or after core biopsy does not affect tumor cell yield. Combining bronchial brushing and pre-biopsy lavage results in the lowest false negative rate., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Voltage-sensor domains (VSDs) are modular transmembrane domains of voltage-gated ion channels that respond to changes in membrane potential by undergoing conformational changes that are coupled to gating of the ion-conducting pore. Most spider-venom peptides function as gating modifiers by binding to the VSDs of voltage-gated channels and trapping them in a closed or open state. To understand the molecular basis underlying this mode of action, we used nuclear magnetic resonance to delineate the atomic details of the interaction between the VSD of the voltage-gated potassium channel KvAP and the spider-venom peptide VSTx1. Our data reveal that the toxin interacts with residues in an aqueous cleft formed between the extracellular S1-S2 and S3-S4 loops of the VSD whilst maintaining lipid interactions in the gaps formed between the S1-S4 and S2-S3 helices. The resulting network of interactions increases the energetic barrier to the conformational changes required for channel gating, and we propose that this is the mechanism by which gating modifier toxins inhibit voltage-gated ion channels.

Available systematic reviews showed uncertainty on the effectiveness of using acupuncture and related therapies for palliative cancer care. The aim of this systematic review and meta-analysis was to summarize current best evidence on acupuncture and related therapies for palliative cancer care. Five international and 3 Chinese databases were searched. Randomized controlled trials (RCTs) comparing acupuncture and related therapies with conventional or sham treatments were considered. Primary outcomes included fatigue, paresthesia and dysesthesias, chronic pain, anorexia, insomnia, limb edema, constipation, and health-related quality of life, of which effective conventional interventions are limited. Thirteen RCTs were included. Compared with conventional interventions, meta-analysis demonstrated that acupuncture and related therapies significantly reduced pain (2 studies, n = 175, pooled weighted mean difference: -0.76, 95% confidence interval: -0.14 to -0.39) among patients with liver or gastric cancer. Combined use of acupuncture and related therapies and Chinese herbal medicine improved quality of life in patients with gastrointestinal cancer (2 studies, n = 111, pooled standard mean difference: 0.75, 95% confidence interval: 0.36-1.13). Acupressure showed significant efficacy in reducing fatigue in lung cancer patients when compared with sham acupressure. Adverse events for acupuncture and related therapies were infrequent and mild. Acupuncture and related therapies are effective in reducing pain, fatigue, and in improving quality of life when compared with conventional intervention alone among cancer patients. Limitations on current evidence body imply that they should be used as a complement, rather than an alternative, to conventional care. Effectiveness of acupuncture and related therapies for managing anorexia, reducing constipation, paresthesia and dysesthesia, insomnia, and limb edema in cancer patients is uncertain, warranting future RCTs in these areas.