Comprehensive Urinary Proteome Profiling Analysis Identifies Diagnosis and Relapse Surveillance Biomarkers for Bladder Cancer.

Bladder cancer (BCa) is the predominant malignancy of the urinary system. Herein, a comprehensive urine proteomic feature was initially established for the noninvasive diagnosis and recurrence monitoring of bladder cancer. 279 cases (63 primary BCa, 87 nontumor controls (NT), 73 relapsed BCa (BCR), and 56 nonrelapsed BCa (BCNR)) were collected to screen urinary protein biomarkers. 4761 and 3668 proteins were qualified and quantified by DDA and sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis in two discovery sets, respectively. Upregulated proteins were validated by multiple reaction monitoring (MRM) in two independent combined sets. Using the multi-support vector machine-recursive feature elimination (mSVM-RFE) algorithm, a model comprising 13 proteins exhibited good performance between BCa and NT with an AUC of 0.821 (95% CI: 0.675-0.967), 90.9% sensitivity (95% CI: 72.7-100%), and 73.3% specificity (95% CI: 53.3-93.3%) in the diagnosis test set. Meanwhile, an 11-marker classifier significantly distinguished BCR from BCNR with 75.0% sensitivity (95% CI: 50.0-100%), 81.8% specificity (95% CI: 54.5-100%), and an AUC of 0.784 (95% CI: 0.609-0.959) in the test cohort for relapse surveillance. Notably, six proteins (SPR, AK1, CD2AP, ADGRF1, GMPS, and C8A) of 24 markers were newly reported. This paper reveals novel urinary protein biomarkers for BCa and offers new theoretical insights into the pathogenesis of bladder cancer (data identifier PXD044896).

Charge Exchange and Transfer between Water and van der Waals Monolayers Under Tensile Strains.

Charge exchange and transfer between water and low-dimensional materials are critical for water-related nanogenerators to harvest electricity from water. By first-principles calculations and molecular dynamics simulations, the interface interaction and charge transfer between ion-containing or pure water and two-dimensional (2D) van der Waals monolayers including transition metal dichalcogenides, hexagonal boron nitride, and graphene have been systematically investigated. Applying uniaxial tensile strain or the introduction of defects on 2D monolayers could significantly enhance the interface interaction and charge transfer from 2D monolayers to water molecules, as the tensile strain or defect weakens the bonds of 2D monolayers and changes the hydrogen bond networks in the interfacial water layer. In contrast, the presence of ions in water suppresses the charge transfer from 2D monolayers to water molecules and reduces interfacial adhesion because of the formation of hydrated ions and stronger charge exchange between ions and water molecules. These results reveal the role of strain, defect, and ion in dominating the charge exchange and transfer between water and 2D monolayers.

Triglyceride-glucose index in early pregnancy predicts the risk of gestational diabetes: a prospective cohort study.

OBJECTIVE: This study aimed to investigate the association between the triglyceride-glucose (TyG) index in early pregnancy and the development of gestational diabetes mellitus (GDM) in the second trimester. The primary objectives were to evaluate the predictive potential of the TyG index for GDM, determine the optimal threshold value of the TyG index for GDM assessment, and compare the predictive performance of the TyG index alone versus its combination with maternal age and pre-pregnancy body mass index on GDM. Moreover, the study explored the association between the TyG index in early pregnancy and the risk of other pregnancy-related complications (PRCs), such as placental abruption and gestational hypertension. PATIENTS AND METHODS: This prospective cohort study recruited 1,624 pregnant women who underwent early pregnancy antenatal counseling and comprehensive assessments with continuous monitoring until delivery. To calculate the TyG index, health indicators, including maternal triglycerides and fasting plasma glucose, were measured in early pregnancy (< 14 weeks of gestation). The predictive power of the TyG index for evaluating GDM in Chinese pregnant women was determined using multifactorial logistic regression to derive the odds ratios and 95% confidence interval (CI). Subgroup analyses were conducted, and the efficacy of the TyG index in predicting PRCs was assessed via receiver operating characteristic (ROC) curve analysis and restricted cubic spline, with the optimal cutoff value calculated. RESULTS: Logistic regression analyses revealed a 2.10-fold increase in the GDM risk for every 1-unit increase in the TyG index, after adjusting for covariates. The highest GDM risk was observed in the group with the highest TyG index compared with the lowest quintile group (odds ratios: 3.25; 95% CI: 2.23-4.75). Subgroup analyses indicated that exceeding the recommended range of gestational weight gain and an increased GDM risk were significantly associated (P = 0.001). Regarding predictive performance, the TyG index exhibited the highest area under the curve (AUC) value in the ROC curve for GDM (AUC: 0.641, 95% CI: 0.61-0.671). The optimal cutoff value was 8.890, with both sensitivity and specificity of 0.617.The combination of the TyG index, maternal age, and pre-pregnancy body mass index proved to be a superior predictor of GDM than the TyG index alone (AUC: 0.672 vs. 0.641, P < 0.01). After adjusting for multiple factors, the analyses indicated that the TyG index was associated with an increased risk of gestational hypertension. However, no significant association was noted between the TyG index and the risk of preeclampsia, placental abruption, intrauterine distress, or premature rupture of membranes. CONCLUSION: The TyG index can effectively identify the occurrence of GDM in the second trimester, aligning with previous research. Incorporating the TyG index into routine clinical assessments of maternal health holds significant practical implications. Early identification of high-risk groups enables healthcare providers to implement timely interventions, such as increased monitoring frequency for high-risk pregnant women and personalized nutritional counseling and health education. These measures can help prevent or alleviate potential maternal and infant complications, thereby enhancing the overall health outcomes for both mothers and babies.

Self-powered solar-blind detector array based on ε-Ga2O3 Schottky photodiodes for dual-mode binary UV communication.

In this work, a solar-blind UV metal-semiconductor Schottky photodiode array is constructed by using metalorganic chemical vapor deposition grown ε-Ga2O3 thin film, possessing high-performance and self-powered characteristics, toward dual-mode (self-powered and biased modes) binary light communication. For the array unit, the responsivity, specific detectivity, and external quantum efficiency are 30.8 A/W/6.3 × 10-2 A/W, 1.51 × 104%/30.9%, 1.28 × 1014/5.4 × 1012 Jones for biased (-10 V)/self-powered operation. The rise and decay time are 0.19 and 7.96 ms at biased modes, respectively, suggesting an ability to trace fast light signal. As an array, the deviation of photocurrent is only 4.3%, highlighting the importance of accurate information communication. Through certain definition of "1/0" binary digital information, the "NY" and "IC" characters are communicated to illustrate the self-powered and biased modes by right of ASCII codes, based on the prepared ε-Ga2O3 solar-blind UV Schottky photodiode array. This work made dual-mode binary deep-UV light communication come true and may well guide the development of UV optoelectronics.

Field-Induced Hydration Shell Reorganization Enables Electro-osmotic Flow in Nanochannels.

Electro-osmotic flow is the motion of fluid driven by an applied electric field, for which an electric double layer near a charged surface is deemed essential. Here, we find that electro-osmotic flow can occur in electrically neutral nanochannels in the absence of definable electric double layers through extensive molecular dynamics simulations. An applied electric field is shown to cause an intrinsic channel selectivity between cations and anions, by reorienting the hydration shells of these confined ions. The ion selectivity then results in a net charge density in the channel that induces the unconventional electro-osmotic flow. The flow direction is amenable to manipulation by the field strength and the channel size, which will inform ongoing efforts to develop highly integrated nanofluidic systems capable of complex flow control.

Diameter-Optimum Spreading for the Impinging of Water Nanodroplets on Solid Surfaces.

The impinging of water nanodroplets on solid surfaces is crucial to many nanotechnologies. Through large-scale molecular dynamics simulations, the size effect on the spreading of water nanodroplets after impinging on hydrophilic, graphite, and hydrophobic surfaces under low impinging velocities has been systematically studied. The spreading rates of nanodroplets first increase and then decrease and gradually become constant with the increase of nanodroplet diameter. The nanodroplets with the diameters of 17-19 nm possess the highest spreading rates because of the combined effect of the strongest interfacial interaction and the strongest surface interaction within water molecules. The highest water molecule densities, hydrogen bond numbers, and dielectric constants of interface and surface layers mainly contribute to the lowest interface work of adhesion and surface tension values at optimal diameters. These results unveil the nonmonotonic characteristics of spreading velocity, interface work of adhesion and surface tension with nanodroplet diameter for nanodroplets on solid surfaces.

Metabolic engineering of fast-growing Vibrio natriegens for efficient pyruvate production.

BACKGROUND: Pyruvate is a widely used value-added chemical which also serves as a hub of various metabolic pathways. The fastest-growing bacterium Vibrio natriegens is a promising chassis for synthetic biology applications with high substrate uptake rates. The aim of this study was to investigate if the high substrate uptake rates of V. natriegens enable pyruvate production at high productivities. RESULTS: Two prophage gene clusters and several essential genes for the biosynthesis of byproducts were first deleted. In order to promote pyruvate accumulation, the key gene aceE encoding pyruvate dehydrogenase complex E1 component was down-regulated to reduce the carbon flux into the tricarboxylic acid cycle. Afterwards, the expression of ppc gene encoding phosphoenolpyruvate carboxylase was fine-tuned to balance the cell growth and pyruvate synthesis. The resulting strain PYR32 was able to produce 54.22 g/L pyruvate from glucose within 16 h, with a yield of 1.17 mol/mol and an average productivity of 3.39 g/L/h. In addition, this strain was also able to efficiently convert sucrose or gluconate into pyruvate at high titers. CONCLUSION: A novel strain of V. natriegens was engineered which was capable to provide higher productivity in pyruvate synthesis. This study lays the foundation for the biosynthesis of pyruvate and its derivatives in fast-growing V. natriegens.

Bibliometric analysis of Helicobacter pylori resistance-from 2002 to 2022.

BACKGROUND: Drug resistance in Helicobacter pylori severely affects the efficacy of eradication therapy, and a number of studies have been conducted on this issue. The aim of this study was to assess the progress in this field using a bibliometric approach. MATERIALS AND METHODS: Publications related to H. pylori resistance from 2002 to 2022 were retrieved from the Web of Science database. Relevant information including titles, authors, countries, and keywords was extracted, and the data were processed using Excel, VOSviewer, and CiteSpace software for co-authorship, co-citation, and co-occurrence analysis. RESULTS: From 2002 to 2022 (as of 09/24/2022), the field of H. pylori-resistance research produced a total of 2677 publications with a total of 75217 citations, with an overall upward trend in the annual number of articles published, reaching a peak of 204 in 2019. Articles were mainly published in Q1 or Q2 journals, with Helicobacter (TP = 261) publishing the most literature, Baylor College of Medicine (TP = 68) and Deng-chyang wu (TP = 38) being the most prolific institutions and authors, respectively. China and the United States were the locations of most of the articles, accounting for 35.08% of the global publication volume. Keyword co-occurrence analysis divided H. pylori-resistance research into four clusters: "Therapeutic Strategies," "Diseases," "Mechanism Research and Epidemiology," and "Drug Research." "Drug research" and burst detection indicate that the current research hotspot involves the selection and analysis of treatment strategies. CONCLUSIONS: H. pylori-resistance research has become a popular research field, and although there are significant contributions from Europe, the United States, and East Asia, there are significant imbalances between regions that cannot be ignored. In addition, the exploration of treatment strategies remains a key issue for research at the current stage.

Multi-pixels gallium oxide UV detector array and optoelectronic applications.

With the continuous advancement of deep-ultraviolet (DUV) communication and optoelectronic detection, research in this field has become a significant focal point in the scientific community. For more accurate information collection and transport, the photodetector array of many pixels is the key of the UV imaging and commnication systems, and its photoelectric performance seriously depends on semiconductor material and array layout. Gallium oxide (Ga2O3) is an emerging wide bandgap semicondutor material which has been widely used in DUV dectection. Therefore, this paper mainly focuses on Ga2O3semiconductor detector array which has gained widespread attention in the field of DUV technique, from the perspective of individual device to array and its optoelectonic integration, for reviewing and discussing the research progress in design, fabrication, and application of Ga2O3arrays in recent years. It includes the structure design and material selection of array units, units growth and array layout, response to solar blind light, the method of imaging and image recognition. Morever, the future development trend of the photodetector array has been analyzed and reflected, aiming to provide some useful suggestions for the optimizing array structure, improving patterned growth technology and material growth quality. As well as Ga2O3optoelectronic devices and their applications are discussed in view of device physics and photophysics in detector.

Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis.

BACKGROUND: Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis. METHODS: In this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483. RESULTS: Induction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01-81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65-11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%). CONCLUSION: Our network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.

Tunable Ga2O3solar-blind photosensing performance via thermal reorder engineering and energy-band modulation.

As an ultra-wide bandgap semiconductor, gallium oxide (Ga2O3) has been extensively applied in solar-blind photodetectors (PDs) owing to the absorbance cut-off wavelength of shorter than 280 nm, and the optimized technologies of detection performance is seriously essential for its further usages. Herein, a feasible thermal reorder engineering method was performed through annealing Ga2O3films in vacuum, O2and oxygen plasma atmospheres, realizing to tune solar-blind photosensing performance of Ga2O3PDs. Thermal treatment, in fact a crystal reorder process, significantly suppressed the noise in Ga2O3-based PDs and enhanced the photo-sensitivity, with the dark current decreasing from 154.63 pA to 269 fA and photo-to-dark current ratio magically raising from 288 to 2.85 × 104. This achievement is dependent of energy-band modulation in Ga2O3semiconductor, that is certified by first-principles calculation. Additionally, annealing in oxygen atmospheres notably reduces the concentration of oxygen vacancies in the surface of films, thereby improving the performance of the PDs; the oxygen vacancy is extremely concerned in oxide semiconductors in the view of physics of surface defects. In all, this work could display a promising guidance for modulating the performance of PDs based on wide bandgap oxide semiconductor, especially for hot Ga2O3issue.

Highly sensitive vibration sensor based on the dispersion turning point microfiber Mach-Zehnder interferometer.

In the present work, we introduced a highly sensitive vibration sensor, which is based on the dispersion turning point (DTP) microfiber Mach-Zehnder interferometer. The axial strain and vibration sensing characteristics of the microfiber Mach-Zehnder interferometer were investigated. First, we theoretically analyzed the spectrum evolution characteristics of the microfiber Mach-Zehnder interferometer caused by axial strain. Second, the microfiber with different diameters was fabricated using the electrode discharge and fused taper method, and the axial strain experiments were conducted; the maximum sensitivity of the DTP microfiber with a diameter of ∼2.2 µm reached -45.55 pm/µÉ› at ∼1550 nm. Finally, based on the axial strain principle of the microfiber, we designed a highly sensitive vibration sensor using a DTP microfiber integrated into a rectangular through-hole cantilever beam. The 30-3500 Hz vibration signal monitoring could be realized, the maximum signal-to-noise ratio (SNR) was ∼75 dB at 52 Hz, and the acceleration sensitivity reached as high as 0.764 V/g at 45Hz. These results suggested the high performance of the microfiber in axial strain and micro-vibration sensing fields.

Humidity effect on peeling of monolayer graphene and hexagonal boron nitride.

Ambient humidity introduces water adsorption and intercalation at the surfaces and interfaces of low-dimensional materials. Our extensive molecular dynamics (MD) simulations reveal the completely opposite contributions of interfacial water to the peeling of monolayer graphene and hexagonal boron nitride (h-BN) sheets from graphite and BN substrates. For graphene, interfacial water decreases the peeling force, due to lower adhesion at the graphene/water interface. The peeling force of h-BN increases with an increase in the thickness of interfacial water, owing to stronger adhesion at the h-BN/water interface and the detachment of the water layer from the substrates. In this work, a theoretical model considering graphene/water and water/substrate interfacial adhesion energies is established, to predict the peeling forces of graphene and h-BN, which coincides well with the peeling forces predicted by the MD simulations. Our results should provide a deeper insight into the effect of interfacial water, induced by ambient humidity, on mechanical exfoliation and the transfer of two-dimensional van der Waals crystals.

Screening effect of monolayer van der Waals crystals on surface deicing: a molecular simulation study.

Our extensive molecular dynamics simulations reveal a significant screening effect of monolayer graphene and hexagonal boron nitride (h-BN) on surface deicing of substrates with different degrees of hydrophilicity, including superhydrophilic (SHP) and superhydrophobic (SHB) substrates. Compared with bare surfaces, graphene and h-BN reduce the interfacial shear strength and the normal detaching strength of ice on an SHP substrate but increase the shear and detaching strengths on hydrophobic and SHB substrates. However, the shear and detaching strengths of ice become approximately unified on all of the surfaces, when interface ice layers melt into liquid water, demonstrating the screening capability from graphene and h-BN that weakens the influence of substrates on ice adhesion. Graphene and h-BN coatings suppress ice premelting on the SHP surface and change the dielectric constant of interface ice or water. This work could deepen our understanding of the role of van der Waals crystals in deicing coating.

Genomic, transcriptomic, and metabolic characterizations of Escherichia coli adapted to branched-chain higher alcohol tolerance.

Microbial-produced branched-chain higher alcohols (BCHAs), such as isopropanol, isobutanol, and isopentanol in Escherichia coli, have emerged as promising alternative biofuels under development. Elucidating and improving the tolerance of E. coli to BCHAs are important issues for microbial production of BCHAs due to their physiological inhibitory effect. Previous works aimed at understanding the genetic basis of E. coli tolerance to BCHAs with a comparative genome, reverse engineering, or transcriptome approach have gained some important insights into the mechanism of tolerance. However, investigation on BCHA tolerance from the whole-genomic, transcriptomic, and metabolic levels via a systematic approach has not yet been completely elucidated. Here, in this study, genomic, transcriptomic, and 13C-metabolic flux analyses (13C-MFA) of an evolved E. coli strain adapted to BCHA tolerance were conducted. Genome mutation of negative regulation factor (rssB, acrB, and clpX) of RpoS level suggested upregulation of RpoS activity in BCHA tolerance of E. coli. From a more detailed perspective, enhanced energy metabolism was observed to be the main characteristic of E. coli strain tolerant to BCHAs. Enhanced energy metabolism has been achieved through several routes, which included redistribution of the central carbon metabolism, upregulation of the energy generation machinery, and facilitating the operation of electron transferring chain. Evidence of multiple solutions of genotype modification toward BCHA tolerance was also revealed through comparative analysis of previous works from different groups.

Hyperbaric oxygen therapy may be effective to improve hypoxemia in patients with severe COVID-2019 pneumonia: two case reports.

Objectives: To determine whether hyperbaric oxygen (HBO2) therapy be effective to improve hypoxemia for severe COVID-19 pneumonia patients. Methods: Two male patients ages 57 and 64 years old were treated. Each met at least one of the following criteria: shortness of breath; respiratory rate (RR) ≥30 breaths/minute; finger pulse oxygen saturation (SpO2) ≤93% at rest; and oxygen index (P/F ratio: PaO2/FiO2 ≤300 mmHg). Each case excluded any combination with pneumothorax, pulmonary bullae or other absolute contraindications to HBO2. Patients were treated with 1.5 atmospheres absolute HBO2 with an oxygen concentration of more than 95% for 60 minutes per treatment, once a day for one week. Patients' self-reported symptoms, daily mean SpO2 (SO2), arterial blood gas analysis, D-dimer, lymphocyte, cholinesterase (che) and chest CT were conducted and measured. Results: For both patients, dyspnea and shortness of breath were immediately alleviated after the first HBO2 treatment and remarkably relieved after seven days of HBO2 therapy. The RR also decreased daily. Neither patient became critically ill. The decreasing trend of SO2 and P/F ratio was immediately reversed and increased day by day. The lymphocyte count and ratio corresponding to immune function gradually recovered. D-dimer corresponding to peripheral circulation disorders and serum cholinesterase, reflecting liver function had improved. Follow-up chest CT showed that the pulmonary inflammation had clearly subsided. Conclusion: Our preliminary uncontrolled case reports suggest that HBO2 therapy may promptly improve the progressive hypoxemia of patients with COVID-2019 pneumonia. However, the limited sample size and study design preclude a definitive statement about the potential effectiveness of HBO2 therapy to COVID-2019 pneumonia. It requires evaluation in randomized clinical trials in future.

Development and genomic elucidation of hybrid yeast with improved glucose-xylose co-fermentation at high temperature.

Enhanced capability of co-fermenting glucose and xylose at high temperature is highly desirable for yeast application in second-generation bioethanol production. Here, we obtained hybrid strains with improved glucose-xylose co-fermentation properties at high temperature by combining genome shuffling and adaptive evolution. Genome resequencing of these strains suggested predominantly inherited genetic information from one parental strain Spathaspora passalidarum SP rather than the other parental strain Saccharomyces cerevisiae ScY01, possibly due to that the CUG codon system of S. passalidarum might have systematically eliminated most of the functional proteins from S. cerevisiae through misfolding. Compared to SP, one-copy loss of a 146-kb fragment was found in the hybrid strain and regained after being evolved for a while, whereas one-copy loss of an 11-kb fragment was only found after being evolved for a longer time. Besides, the genes affected by nonsynonymous variants were also identified, especially the mutation S540F in the endoplasmic reticulum chaperon Kar2. Structural prediction indicated that S540F might change the substrate binding activity of Kar2, and thus play a role in preventing protein aggregation in yeast at high temperature. Our results illustrated genomic alterations during this process and revealed some genomic factors that might be involved to determine yeast thermotolerance.

Distinct Proteome Remodeling of Industrial Saccharomyces cerevisiae in Response to Prolonged Thermal Stress or Transient Heat Shock.

To gain a deep understanding of yeast-cell response to heat stress, multiple laboratory strains have been intensively studied via genome-wide expression analysis for the mechanistic dissection of classical heat-shock response (HSR). However, robust industrial strains of Saccharomyces cerevisiae have hardly been explored in global analysis for elucidation of the mechanism of thermotolerant response (TR) during fermentation. Herein, we employed data-independent acquisition and sequential window acquisition of all theoretical mass spectra based proteomic workflows to characterize proteome remodeling of an industrial strain, ScY01, responding to prolonged thermal stress or transient heat shock. By comparing the proteomic signatures of ScY01 in TR versus HSR as well as the HSR of the industrial strain versus a laboratory strain, our study revealed disparate response mechanisms of ScY01 during thermotolerant growth or under heat shock. In addition, through proteomics data-mining for decoding transcription factor interaction networks followed by validation experiments, we uncovered the functions of two novel transcription factors, Mig1 and Srb2, in enhancing the thermotolerance of the industrial strain. This study has demonstrated that accurate and high-throughput quantitative proteomics not only provides new insights into the molecular basis for complex microbial phenotypes but also pinpoints upstream regulators that can be targeted for improving the desired traits of industrial microorganisms.

Connexin 43 C-terminus directly inhibits the hyperphosphorylation of Akt/ERK through protein-protein interactions in glioblastoma.

Although the deregulation of epidermal growth factor receptor (EGFR) is one of the most common molecular mechanisms of glioblastoma (GBM) pathogenesis, the efficacy of anti-EGFR therapy is limited. Additionally, response to anti-EGFR therapy is not solely dependent on EGFR expression and is more promising in patients with reduced activity of EGFR downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the EGFR signaling pathway to improve the efficacy of anti-EGFR therapies for GBM. In this study, we confirmed the low efficacy of EGFR inhibitors in GBM patients by meta-analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ERK activation, which was caused by the direct interactions between Akt/ERK and Cx43. By comparing the interactions between Akt/ERK and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and ERK, respectively. In addition, Kaplan-Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of GBM patients who express EGFR. Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM. Targeting the interaction between the carboxy terminus of Cx43 and Akt/ERK could be an effective therapeutic strategy against GBM.