The COP9 signalosome stabilized MALT1 promotes Non-Small Cell Lung Cancer progression through activation of NF-κB pathway.

MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.

P/N-Heteroleptic Cu(I)-Photosensitizer-Catalyzed [3 + 2] Regiospecific Annulation of Aminocyclopropanes and Functionalized Alkynes.

We report here a regiospecific [3 + 2] annulation between aminocyclopropanes and various functionalized alkynes enabled by a P/N-heteroleptic Cu(I) photosensitizer under photoredox catalysis conditions. Thus, a divergent construction of 3-aminocyclopentene derivatives including methylsulfonyl-, arylsulfonyl-, chloro-, ester-, and trifluoromethyl-functionalized aminocyclopentenes could be achieved with advantages of high regioselectivity, broad substrate compatibility, and mild and environmentally benign reaction conditions.

Forward Electric Stimulation-Induced Interference in Intracochlear Electrocochleography of Acoustic Stimulation in the Cochlea of Guinea Pigs.

Electric-acoustic stimulation (EAS) uses amplified sound by a hearing aid to stimulate an apical low-frequency region of the cochlea and electrical current from a cochlear implant (CI) to stimulate the basal high-frequency region. EAS recipients had significantly improved speech perception, music appreciation, and hearing function in noise compared to those relying on CI electrical stimulation (ES) alone. However, the interaction between basal ES and apical acoustic stimulation (AS) in the cochlea potentially affects EAS advantages. To investigate ES-AS interaction, we designed a system that recorded the electrically evoked compound action potential (ECAP) and the auditory evoked potential (AEP). We used an intracochlear electrode array to deliver ES at the basal cochlea and detect intracochlear electrocochleography (iECochG) generated from apical AS. Within iECochG, 3 or 6 dB (double or quadruple intensity of ECAP threshold) electric stimulation, 1 ms-forward ES significantly increased CAP amplitudes of 4 kHz/20 dB AS compared to 0 dB ES. Notably, 1 ms-forward 3 dB ES significantly increased CAP amplitudes of 4 kHz/20 dB AS, while 3 or 5 ms-forward ES did not change the CAP amplitudes. The elevation in CAP amplitude of 40 dB/4 kHz AS induced by 1 ms-forward 3 dB ES was significantly lower than that in 20 dB/4 kHz AS. With 1 ms-forward 3 dB ES, AS frequency and stimulating electrode location have no significant impact on relative CAP amplitudes of 20 dB AS. These results suggest that the basal forward ES and the following apical AS could produce a cumulative effect on the auditory nerve response.

Founders' Creativity, Business Model Innovation, and Business Growth.

Given the existing studies on the role of different founders' personalities in the growth of new ventures, we take the digital technology start-ups as the research object and focus on the role of founders' creativity. In this study, we assess the relationship between founders' creativity and business growth. According to the framework of upper echelons theory, we propose several hypotheses. Based on the investigation of 153 new ventures in China's transition economy, we find that: (1) founders' creativity has a positive impact on the growth of enterprises; (2) business model innovation positively mediates the relationship between founders' creativity and enterprise growth; (3) work experience is found to be a moderator of the relationship between founders' creativity and business model innovation. The conclusion of our analysis not only helps to further deepen the research on the growth process of start-ups but also helps to further expand the important role of business model innovation and founders' work experience in the growth of new firms.

Kinectin1 depletion promotes EGFR degradation via the ubiquitin-proteosome system in cutaneous squamous cell carcinoma.

Depletion of kinectin1 (KTN1) provides a potential strategy for inhibiting tumorigenesis of cutaneous squamous cell carcinoma (cSCC) via reduction of epidermal growth factor receptor (EGFR) protein levels. Yet, the underlying mechanisms of KTN1 remain obscure. In this study, we demonstrate that KTN1 knockdown induces EGFR degradation in cSCC cells by promoting the ubiquitin-proteasome system, and that this effect is tumor cell-specific. KTN1 knockdown increases the expression of CCDC40, PSMA1, and ADRM1 to mediate tumor suppressor functions in vivo and in vitro. Mechanistically, c-Myc directly binds to the promoter region of CCDC40 to trigger the CCDC40-ADRM1-UCH37 axis and promote EGFR deubiquitination. Furthermore, KTN1 depletion accelerates EGFR degradation by strengthening the competitive interaction between PSMA1 and ADRM1 to inhibit KTN1/ADRM1 interaction at residues Met1-Ala252. These results are supported by studies in mouse xenografts and human patient samples. Collectively, our findings provide novel mechanistic insight into KTN1 regulation of EGFR degradation in cSCC.

The first complete mitochondrial genome of Macalpinomyces bursus (Ustilaginales: Ustilaginaceae) and insights into its phylogeny.

In the present study, the complete mitochondrial genome of Macalpinomyces bursus (Berk.) Vanky 2002 was sequenced and assembled. The complete mitochondrial genome of M. bursus was 49,024 bp in length, with the GC content of 30.4%. The M. bursus mitochondrial genome contained 27 protein-coding genes, 2 ribosomal RNA (rRNA) genes, and 22 transfer RNA (tRNA) genes. Phylogenetic analysis based on combined mitochondrial gene dataset indicated that the M. bursus exhibited a close relationship with species from the genera Ustilago, Sporisorium, and Anthracocystis.

The role of oxidative stress in the susceptibility of noise-impaired cochleae to synaptic loss induced by intracochlear electrical stimulation.

Intracochlear electrical stimulation (ES) generated by cochlear implants (CIs) is used to activate auditory nerves to restore hearing perception in deaf subjects and those with residual hearing who use electroacoustic stimulation (EAS) technology. Approximately 1/3 of EAS recipients experience loss of residual hearing a few months after ES activation, but the underlying mechanism is unknown. Clinical evidence indicates that the loss is related to the previous history of noise-induced hearing loss (NIHL). In this report, we investigated the impact of intracochlear ES on oxidative stress levels and synaptic counts in inner hair cells (IHCs) of the apical, middle and basal regions of guinea pigs with normal hearing (NH) and NIHL. Our results demonstrated that intracochlear ES with an intensity of 6 dB above the thresholds of electrically evoked compound action potentials (ECAPs) could induce the elevation of oxidative stress levels, resulting in a loss of IHC synapses near the electrodes in the basal and middle regions of the NH cochleae. Furthermore, the apical region of cochleae with NIHL were more susceptible to synaptic loss induced by relatively low-intensity ES than that of NH cochleae, resulting from the additional elevation of oxidative stress levels and the reduced antioxidant capability throughout the whole cochlea.

Psychometric Assessment of the Chinese Version of the Indian Vision Functioning Questionnaire Based on the Method of Successive Dichotomizations.

Purpose: The purpose of this study was to assess whether a Chinese translated version of the 33-item Indian Vision Function Questionnaire (IND-VFQ-33) forms a valid measurement scale and to evaluate its psychometric properties based on the method of successive dichotomizations (MSD). Methods: The English version of the IND-VFQ-33 was translated, back translated, and cross-culturally adapted for use in China. It was interviewer administered to patients with cataracts. MSD, a polytomous Rasch model that estimates ordered thresholds, was used to assess and optimize psychometric properties of the overall scale and three subscales separately. Results: One hundred and seventy-nine patients provided complete responses. After the removal of 2 misfitting items, a revised 31-item overall scale demonstrated adequate precision (person reliability [PR] = 0.92) and no misfitting items. The general functioning subscale fit the MSD model well after removing two misfitting items. The psychosocial impact subscale and the visual symptoms subscale were not considered further due to poor measurement precision. After addressing psychometric deficiencies, a 31-item overall scale (IND-VFQ-31-CN) and a 19-item general functioning subscale (IND-VFQ-GF-19-CN) were developed. Conclusions: The original IND-VFQ-33 required re-engineering to form valid measures for use in China. The revised overall scale and general functioning subscale demonstrated adequate MSD based psychometric properties. Translational Relevance: The revised IND-VFQ-33 is a valid patient-reported outcome assessment for Chinese patients with cataract based on MSD analysis.

Opposite Roles of NT-3 and BDNF in Synaptic Remodeling of the Inner Ear Induced by Electrical Stimulation.

With the development of neural prostheses, neural plasticity including synaptic remodeling under electrical stimulation is drawing more and more attention. Indeed, intracochlear electrical stimulation used to restore hearing in deaf can induce the loss of residual hearing and synapses of the inner hair cells (IHCs). However, the mechanism under this process is largely unknown. Considering that the guinea pig is always a suitable and convenient choice for the animal model of cochlea implant (CI), in the present study, normal-hearing guinea pigs were implanted with CIs. Four-hour electrical stimulation with the intensity of 6 dB above electrically evoked compound action potential (ECAP) threshold (which can decrease the quantity of IHC synapses and the excitability of the auditory nerve) resulted in the upregulation of Bdnf (p < 0.0001) and downregulation of Nt-3 (p < 0.05). Intracochlear perfusion of exogenous NT-3 or TrkC/Fc (which blocks NT-3) can, respectively, resist or aggravate the synaptic loss induced by electrical stimulation. In contrast, local delivery of exogenous BDNF or TrkB/Fc (which blocks BDNF) to the cochlea, respectively, exacerbated or protected against the synaptic loss caused by electrical stimulation. Notably, the synaptic changes were only observed in the basal and middle halves of the cochlea. All the findings above suggested that NT-3 and BDNF may play opposite roles in the remodeling of IHC synapses induced by intracochlear electrical stimulation, i.e. NT-3 and BDNF promoted the regeneration and degeneration of IHC synapses, respectively.

Aerobic Cu-catalyzed oxidative 1 : 2 coupling of benzynes with terminal alkynes.

Cu-Catalyzed oxidative 1 : 2 couplings of arynes with nucleophilic terminal alkynes under aerobic conditions are described herein. A mechanistic investigation revealed a plausible involvement of an aryl-Cu(iii)-generating pathway. By this method, ubiquitous arenediynes can be efficiently assembled in a single step under mild conditions.

The sensitivity of different methods for detecting abnormalities in auditory nerve function.

BACKGROUND: Cochlear implants (CIs) have become important for the treatment of severe-to-profound sensorineural hearing loss (SNHL). Meanwhile, electrically evoked compound action potentials (ECAPs) and electrically evoked auditory brainstem responses (EABRs), which can be examined and evaluated with minimal patient cooperation, have become more reliable for tone measurement and speech recognition postoperatively. However, few studies have compared the electrophysiological characteristics of the auditory nerve using ECAPs and EABRs under different functional states of the auditory nerve (FSANs). We used guinea pig models in which six electrodes were implanted unilaterally with continuous electrical stimulation (ES) for 4 h. The amplitude growth functions (AGFs) of the alternating polarity ECAP (AP-ECAP) and forward-masking subtraction ECAP (FM-ECAP), as well as the EABR waves under "normal" and "abnormal" FSANs, were obtained. RESULTS: Both the AP-ECAP and FM-ECAP thresholds were significantly higher than those measured by EABR under both "normal" FSAN and "abnormal" FSANs (p < 0.05). There was a significant difference in the slope values between electrodes 1 and 2 and electrodes 3 and 4 in terms of the AP-ECAP under the "abnormal" FSAN (p < 0.05). The threshold gaps between the AP-ECAP and FM-ECAP were significantly larger under the "abnormal" FSAN than under the "normal" FSAN (p < 0.05). CONCLUSIONS: Both of the ECAP thresholds were higher than the EABR thresholds. The AP-ECAP was more sensitive than the FM-ECAP under the "abnormal" FSAN.

The impact of auditory nerve functional states on the correlations between human and computer decisions for electrically evoked compound action potential threshold.

OBJECTIVES: The electrically evoked compound action potential (ECAP) is widely used in clinical to reflect the functional states of the auditory nerve in cochlear implant (CI) recipients, especially in pediatric CI users. Currently, the software can automatically provide the ECAP threshold, which is convenient and not affected by the subjective judgement of the clinicians. However, it remains unclear whether the correlations between human and computer decisions for ECAP threshold can be affected by auditory nerve functional states, which is also the main purpose of our present study. METHODS: Intracochlear electrical stimulation, which can decrease the excitability of the auditory nerve, was used to change the auditory nerve functional states of guinea pigs. Ten normal-hearing guinea pigs were implanted with CIs unilaterally. ECAPs were recorded both before and after the electrical stimulation, representing different functional states of the auditory nerve. Forward masking (FwdMsk) and alternating polarity (AltPol), two most commonly-used artifact-reduction methods, were applied to the measurements. All measurements recorded by the software were saved for computer and human analysis with linear regression and visual detection methods. RESULTS: The correlations between human and computer performance in the peak-picking process were not affected by auditory nerve states and artifact-reduction methods. However, complicated findings were observed for ECAP threshold. With FwdMsk utilized, weaker correlations between human and computer performance were observed in abnormal state compared to those in normal state. Regardless of the functional states of the auditory nerve, the results revealed stronger correlations in AltPol than those in FwdMsk. Furthermore, when compared with human decision, computer linear-regression threshold (C-LRT) was always less accurate than computer visual-detection threshold (C-VDT), which was not affected by auditory nerve states. CONCLUSIONS: (1) the functional states of the auditory nerve can definitely affect the correlations between human and computer decisions for ECAP threshold, but the impact is limited to the FwdMsk method; (2) AltPol can produce stronger correlations compared with FwdMsk, which is not affected by auditory nerve states; and (3) regardless of the auditory nerve states, C-VDT can always show higher consistency with human decision, while C-LRT reveals more variability.

Electrical stimulation induces synaptic changes in the peripheral auditory system.

Since a rapidly increasing number of neurostimulation devices are used clinically to modulate specific neural functions, the impact of electrical stimulation on targeted neural structure and function has become a key issue. In particular, the specific effect of electrical stimulation via a cochlear implant (CI) on inner hair cell (IHC) synapses remains unclear. Importantly, CI candidacy has recently expanded to include patients with partial hearing loss. Unfortunately, some CI recipients experience progressive hearing loss after activation of electrical stimulation. The mechanism(s) accounting for loss of residual hearing following electrical stimulation is unknown. Here normal-hearing guinea pigs were implanted with customized CIs. Intracochlear electrical stimulation with an intensity equal to or above electrically evoked compound action potential (ECAP) threshold decreased the excitability of auditory nerve. Furthermore, the number of synapses between IHCs and the afferent spiral ganglion neurons (SGNs) also decreased after electrical stimulation with higher intensities. However, no significant change was observed in the packing density and perikaryal area of SGNs as well as the quantity of hair cells. These results carry important implications for use of CIs in patients with residual hearing and for an increasing number of patients treated with other neurostimulation devices. Notably, the results were based on acute electrical stimulation. Considering the complex interaction between CIs and targeted tissues, it is urgent to conduct further research to clarify whether the similar changes could be induced by chronic electrical stimulation.