The functional diversity of large conductance Ca 2؉ -and voltage-dependent K ؉ (BK) channels arises mainly from co-assembly of the pore-forming mSlo ␣ subunits with four tissueenriched auxiliary ␤ subunits. The structural basis of the interaction between ␣ subunits with ␤ subunits is not well understood. Using computational and experimental methods, we demonstrated that four mSlo turrets decentralized distally from the channel pore to provide a wide open conformation and that the mSlo and h␤4 subunits together formed a "helmet" containing three basic residues (Lys-120, Arg-121, and Lys-125), which impeded the entry of charybdotoxin (ChTX) by both the electrostatic interaction and limited space. In addition, the tyrosine insert mutant (in100Y) showed 56% inhibition, with a K d ‫؍‬ 17 nM, suggesting that the h␤4 lacks an external ChTX-binding site (Tyr-100). We also found that mSlo had an internal binding site (Tyr-294) in the ␣ subunits that could "permanently" block 15% of mSlo؉h␤4 currents in the presence of 100 nM ChTX. These findings provide a better understanding of the diverse interactions between ␣ and ␤ subunits and will improve the design of channel inhibitors.It is well known that functional diversity of large conductance Ca 2ϩ -and voltage-dependent potassium (BK) channels arises mainly from co-expression of the pore-forming ␣ subunits with the tissue-enriched auxiliary ␤ subunits (1-10). Four mammalian ␤ genes (␤1-␤4) are responsible for a variety of the kinetic and pharmacological characteristics of BK channels in native tissues, even though they share sequence homology. For instance, the brain-enriched h␤4 subunits not only alter the conductance-voltage curve of mSlo channels but also slow both the activation and deactivation time courses, suggesting that ␤4 plays a critical role in the regulation of neuronal excitability and neurotransmitter release (9). Furthermore, results from experiments with a ␤4 knock-out showed reduced dentate gyrus excitability and protection against temporal lobe seizures (11).Natural venomous peptides have been used widely to probe the pore conformation of potassium channels. One particular scorpion toxin, charybdotoxin (ChTX), 4 was used to probe the pore structure of BK channels. It is known that the ␣ϩh␤1 has a K d for ChTX similar to that of mSlo channels (4). However, BK channels associating with the ␤2 or ␤3 subunits usually have about 30-fold lower sensitivity to ChTX in equilibrium (3, 4), whereas the ␣ϩh␤4 channel has about 1000-fold slower association with the toxin (7). Is there a common mechanism working for all of four ␤ genes?To explore the toxin resistance mechanism of h␤4 subunits, Jin et al. (12) investigated how the N-linked glycosylation of the h␤4 subunit modulated the toxin sensitivity of hSloϩh␤4 channels. They confirmed that the double glycosylation site mutated in h␤4 showed reduced protection of the channel against toxin blockade as compared with the hSlo channel co-expressed with the wild type h␤4 subunits. Another study is in regard to the remo...

Key points• Repeated, but not single, in vivo cocaine exposure leads to an experience-dependent potentiation of glutamatergic synapses on hypocretin-producing neurons (hypocretin neurons) in mice.• The locus of synaptic potentiation is at the postsynaptic site of glutamatergic synapses on hypocretin neurons and the up-regulation of AMPA-type glutamate receptors may be involved.• Cocaine-induced synaptic potentiation is long-lasting and exists during the abstinence of cocaine.• The expression of tetanus-induced long-term potentiation is facilitated in hypocretin neurons in cocaine-treated mice.• These results may help us better understand the role of the hypocretin system in behavioural changes related to cocaine addiction in animals and humans.Abstract Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centred on hypocretin-producing neurons (hypocretin neurons) is modified by drugs of abuse and how changes in this circuit might alter behaviours related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long-lasting, experience-dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine-conditioned place preference (CPP) protocol. The synaptic potentiation occurs postsynaptically and probably involves up-regulation of AMPA-type glutamate receptors on hypocretin neurons. Phosphorylation of cAMP response element-binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine-treated animals, suggesting that CREB-mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long-term potentiation (LTP) triggered by a high-frequency stimulation is facilitated in hypocretin neurons in cocaine-treated mice, suggesting that long-lasting changes in synapses onto hypocretin neurons would probably be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience-dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support

Background Lung cancer survivors need more options to improve quality of life (QoL). It is unclear to what extent patients with advanced stage disease are willing to participate in home-based physical activity (PA) and if these interventions improve QoL. The goal of our study was to determine interest in participating in our 3-month home-based walking regimen in patients with advanced stage lung cancer. We used a randomized design to evaluate for potential benefit in PA and patient-reported outcomes. Methods We performed an open-label, 1:1 randomized trial in 40 patients with stage III/IV non-small cell lung cancer (NSCLC) evaluating enrollment rate, PA, QoL, dyspnea, depression, and biomarkers. Compared to usual care (UC), the intervention group (IG) received an accelerometer, in-person teaching session, and gain-framed text messages for 12 weeks. Results We enrolled 56% (40/71) of eligible patients. Participants were on average 65 years and enrolled 1.9 years from diagnosis. Most patients were women (75%), and receiving treatment (85%) for stage IV (73%) adenocarcinoma (83%). A minority of patients were employed part-time or full time (38%). Both groups reported low baseline PA (IG mean 37 (Standard deviation (SD) 46) vs UC 59 (SD 56) minutes/week; p = 0.25). The IG increased PA more than UC (mean change IG + 123 (SD 212) vs UC + 35 (SD 103) minutes/week; p = 0.051)). Step count in the IG was not statistically different between baseline (4707 step/day), week 6 (5605; p = 0.16), and week 12 (4606 steps/day; p = 0.87). The intervention improved EORTC role functioning domain (17 points; p = 0.022) with borderline improvement in dyspnea (− 13 points; p = 0.051) compared to UC. In patients with two blood samples (25%), we observed a significant increase in soluble PD-1 (219.8 (SD 54.5) pg/mL; p < 0.001). Conclusions Our pilot trial using a 3-month, home-based, mobile health intervention enrolled over half of eligible patients with stage III and IV NSCLC. The intervention increased PA, and may improve several aspects of QoL. We also identified potential biomarker changes relevant to lung cancer biology. Future research should use a larger sample to examine the effect of exercise on cancer biomarkers, which may mediate the association between PA and QoL. Clinical trial registration Clinicaltrials.gov (NCT03352245).

MicroAbstract The goal of the present study was to evaluate a novel prospective influenza vaccination strategy in patients with plasma cell disorders. Fifty-one patients were treated with a two dose series of high-dose inactivated trivalent influenza vaccine. This vaccination strategy was well tolerated led to very high rates of seroprotection against influenza. Background Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population despite routine administration of seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of less than 20% following standard influenza vaccination in MM. Methods Patients with plasma cell dyscrasia (N=51) were treated with a two dose series of high-dose inactivated trivalent influenza vaccine over the 2014–2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination inhibition (HAI) titer assays, and logistic regression models were used to identify clinical correlates of HAI serologic responses. Findings Influenza vaccine was well tolerated without any vaccine-related ≥grade two adverse events. Only three patients (6%) experienced laboratory-confirmed influenza. Rates of HAI seroprotection against all three vaccine strains (influenza B, H1N1, and H3N2) increased from 4% at baseline to 49% and 65% following one and two doses, respectively. Risk factors associated with lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, disease response assessment < partial response, or active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with proteasome inhibitor was associated with a higher likelihood of HAI serologic response. Conclusions These data demonstrate that in contrast to historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this to standard vaccination strategy.

No abstract