25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Robustness of Significant Dichotomous Outcomes in Randomized Controlled Trials in the Treatment of Patients with COVID-19: A Systematic Analysis

Abstract Purpose Significant results of randomized controlled trials (RCTs) should be properly weighed. This study adopted fragility index (FI) to evaluate the robustness of significant dichotomous outcomes from RCTs on coronavirus disease 2019 (COVID-19) treatment. Materials and methods ClinicalTrials.gov and PubMed were searched from inception to July 31, 2021. FIs were calculated and their distribution was depicted. FI’s categorical influential factors were analyzed. Spearman correlation coefficient (r s) was reported for the relationship between FI and the continuous characteristics of RCTs. Results Fifty RCTs with 120 outcomes in 7869 patients were included. The FI distribution was abnormal with median 3 (interquartile range 1–7, P = 0.0001). The FIs and robustness were affected by the outcomes of interest, various patient populations, and interventions (T = 18.215,16.667, 23.107; P = 0.02,0.0001, 0.001, respectively). A cubic relationship between the FIs and absolute difference of events between groups with R square of 0.848 (T = 215.828, P = 0.0001, R square = 0.865) was observed. A strong negative logarithmic relationship existed between FI and the P value with R square = – 0.834. Conclusion The robustness of significant dichotomous outcomes of COVID-19 treatments was fragile and affected by the outcomes of interest, patients, interventions, P value, and absolute difference of events between the groups. FI was an useful quantitative metric for the binary significant outcomes on COVID-19 treatments. Registration PROSPERO (CRD42021272455)

The Impacts of COVID-19 on Distance Education with the Application of Traditional and Digital Appliances: Evidence from 60 Developing Countries

Educational disruptions from the COVID-19 pandemic during school closures have become a remarkable social issue, particularly among the developing countries. Ample literature has verified the adverse effects of the long-lasing epidemic on school education. However, rare studies seek to understand the association between the severity of COVID-19 and distance learning, an alternative education pattern, and foster policy designs to promote educational transition, particularly targeting the post-crisis phase of the COVID-19. By combining four data surveys, this article empirically examines the impacts of COVID-19 on children’s distance education with the application of various appliances across 60 developing countries. The results suggest that, after controlling socio-economic, geographic, and demographic variables, a higher level of mortality rate of COVID-19 contributes to more households participating in distance education. In particular, this positive term is larger for distance education by using TVs and radios compared with the usage of digital appliances. To explore the potential channel of the above linkage, this article argues that the positive association between mortality rate and the use of traditional appliances is weakened through higher levels of stringency in lockdown measures. Timely policies are, therefore, recommended to guide towards distance learning with economic and technological supports to guarantee a wave of inclusive educational recovery in the ongoing post-COVID-19 era

Theoretical study of terahertz active transmission line oscillator based on RTD-gated HEMT

In this paper, a new kind of terahertz oscillator is presented using plasma wave excitation in a resonant tunnel diode (RTD) gated high electron mobility transistor (HEMT). The plasma wave arising from the RTD-gated HEMT is equivalent to active transmission lines and induces negative differential conductance (NDC) of the oscillator. The proposed RTD-gated HEMT oscillator is more compact and has higher oscillation frequency than the transmission line loaded traditional RTD oscillator duo to plasma wave effect. This paper analyses and calculates the oscillation conditions, the relationships between device structures, oscillation frequency and the output power of the oscillator. The presented work may provide a new concept for fabricating terahertz oscillator

BYL719 reverses gefitinib-resistance induced by PI3K/AKT activation in non-small cell lung cancer cells

Abstract Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation often obtain de novo resistance or develop secondary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), which restricts the clinical benefit for the patients. The activation of phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway is one of the most important mechanisms for the EGFR-TKIs resistance beyond T790M mutation. There are currently no drugs simultaneously targeting EGFR and PI3K signal pathways, and combination of these two pathway inhibitors may be a possible strategy to reverse theses resistances. To test whether this combinational strategy works, we investigated the therapeutic effects and mechanisms of combining BYL719, a PI3Kα inhibitor, with gefitinib, an EGFR-TKI inhibitor in EGFR-TKIs resistance NSCLC models induced by PI3K/AKT activation. Our results demonstrated that PIK3CA mutated cells showed increased growth rate and less sensitive or even resistant to gefitinib, associated with increased PI3K/AKT expression. The combination of BYL719 and gefitinib resulted in synergistic effect compared with the single agents alone in EGFR-mutated NSCLC cells with PI3K/AKT activation. The inhibition of AKT phosphorylation by BYL719 increased the antitumor efficacy of gefitinib in these cell lines. Moreover, the combined effect and mechanism of gefitinib and BYL719 were also confirmed in the NSCLC cells and patient-derived organoids under 3D culture condition, as well as in vivo. Taken together, the data indicate that PIK3CA mutation induces more aggressive growth and gefitinib resistance in NSCLC cells, and the combination treatment with gefitinib and BYL719 is a promising therapeutic approach to overcoming EGFR-TKIs resistance induced by PI3K/AKT activation

Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers

The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is amplified in human breast cancer specimens, and the CSN6 protein is upregulated in human breast and thyroid tumors. CSN6 expression positively correlated with expression of murine double minute 2 (MDM2), a potent negative regulator of the p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis (E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic development (E10.5), which suggests that loss of p53 could partially rescue the effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to γ-irradiation–induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to γ-irradiation–induced tumorigenesis. These results suggest that loss of CSN6 enhances p53-mediated tumor suppression in vivo and that CSN6 plays an important role in regulating DNA damage–associated apoptosis and tumorigenesis through control of the MDM2-p53 signaling pathway