Nonlinear dynamics of an interband cascade laser with optical injection.

This work reports the nonlinear dynamics of a mid-infrared interband cascade laser (ICL) subject to optical injection. It is shown that the stable locking regime is asymmetric and broadens with increasing injection strength. Outside the locking regime, the ICL mostly produces period-one oscillations. However, three categories of periodic pulse oscillations are observed in the vicinity of the Hopf bifurcation and the saddle-node bifurcation. In particular, it is found that the ICL generates broadband chaos at a near-threshold pump current, and the chaos bandwidth is over 300 MHz.

Broadband chaos of an interband cascade laser with a 6-GHz bandwidth.

Near-infrared semiconductor lasers subject to optical feedback usually produce chaos with a broad bandwidth of a few GHz. However, the reported mid-infrared interband cascade lasers (ICLs) only show chaos with a limited bandwidth below 1 GHz. Here we show that an ICL with optical feedback is able to generate broadband chaos as well. The mid-infrared chaos exhibits a remarkable bandwidth of about 6 GHz, which is comparable to that of the near-infrared counterpart. In addition, the spectral coverage in the electrical domain reaches as high as 17.7 GHz. It is found that the chaos bandwidth generally broadens with increasing feedback ratio and/or increasing pump current of the laser, while it is insensitive to the feedback length.

Targeting CRAF kinase in anti-cancer therapy: progress and opportunities.

The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.

Effect of esketamine on opioid consumption and postoperative pain in thyroidectomy: A randomized controlled trial.

AIMS: Thyroidectomy is frequently associated with substantial postoperative pain. Esketamine, an N-methyl-d-aspartate receptor antagonist, has been demonstrated to be effective in multiple analgesia scenarios. We hypothesized that intraoperative administration of esketamine may reduce perioperative opioid consumption and postoperative pain in patients undergoing thyroidectomy. METHODS: Sixty patients undergoing thyroidectomy were randomly assigned to two groups. Patients in the esketamine group received a pre-incisional intravenous bolus of esketamine (0.5 mg kg-1 ) followed by a continuous infusion of 0.24 mg kg-1  h-1 until the beginning of wound closure. Patients in the placebo group received 0.9% NaCl (bolus and infusion). The primary outcome was perioperative sufentanil consumption. The postoperative pain, sleep quality and adverse events during the first postoperative 24 h were also evaluated. RESULTS: Patients in the esketamine group consumed significantly less sufentanil than those in the saline group (24.6 ± 3.1 µg vs. 33.7 ± 5.1 µg, mean difference, 9.1; 95% confidence interval [CI], 6.9-11.3, P < .001). Postoperative pain scores were significantly lower in the esketamine group than those in the saline group during the first 24 h postoperatively (P < .05). Patients receiving esketamine experienced higher sleep quality than those in the saline group during surgical night (P = .043). There were no significant differences in adverse events between the two groups. CONCLUSIONS: Intraoperative administration of esketamine reduces perioperative sufentanil consumption and postoperative pain without increasing psychotomimetic side effects in patients undergoing thyroidectomy. The development of combined anaesthesia regimens, including esketamine, may foster strategies for pain management during thyroidectomy.

Genome and systems biology of Melilotus albus provides insights into coumarins biosynthesis.

Melilotus species are used as green manure and rotation crops worldwide and contain abundant pharmacologically active coumarins. However, there is a paucity of information on its genome and coumarin production and function. Here, we reported a chromosome-scale assembly of Melilotus albus genome with 1.04 Gb in eight chromosomes, containing 71.42% repetitive elements. Long terminal repeat retrotransposon bursts coincided with declining of population sizes during the Quaternary glaciation. Resequencing of 94 accessions enabled insights into genetic diversity, population structure, and introgression. Melilotus officinalis had relatively larger genetic diversity than that of M. albus. The introgression existed between M. officinalis group and M. albus group, and gene flows was from M. albus to M. officinalis. Selection sweep analysis identified candidate genes associated with flower colour and coumarin biosynthesis. Combining genomics, BSA, transcriptomics, metabolomics, and biochemistry, we identified a ß-glucosidase (BGLU) gene cluster contributing to coumarin biosynthesis. MaBGLU1 function was verified by overexpression in M. albus, heterologous expression in Escherichia coli, and substrate feeding, revealing its role in scopoletin (coumarin derivative) production and showing that nonsynonymous variation drives BGLU enzyme activity divergence in Melilotus. Our work will accelerate the understanding of biologically active coumarins and their biosynthetic pathways, and contribute to genomics-enabled Melilotus breeding.

Structure-Aware Multimodal Deep Learning for Drug-Protein Interaction Prediction.

Identifying drug-protein interactions (DPIs) is crucial in drug discovery, and a number of machine learning methods have been developed to predict DPIs. Existing methods usually use unrealistic data sets with hidden bias, which will limit the accuracy of virtual screening methods. Meanwhile, most DPI prediction methods pay more attention to molecular representation but lack effective research on protein representation and high-level associations between different instances. To this end, we present the novel structure-aware multimodal deep DPI prediction model, STAMP-DPI, which was trained on a curated industry-scale benchmark data set. We built a high-quality benchmark data set named GalaxyDB for DPI prediction. This industry-scale data set along with an unbiased training procedure resulted in a more robust benchmark study. For informative protein representation, we constructed a structure-aware graph neural network method from the protein sequence by combining predicted contact maps and graph neural networks. Through further integration of structure-based representation and high-level pretrained embeddings for molecules and proteins, our model effectively captures the feature representation of the interactions between them. As a result, STAMP-DPI outperformed state-of-the-art DPI prediction methods by decreasing 7.00% mean square error (MSE) in the Davis data set and improving 8.89% area under the curve (AUC) in the GalaxyDB data set. Moreover, our model is an interpretable model with the transformer-based interaction mechanism, which can accurately reveal the binding sites between molecules and proteins.

SWnet: a deep learning model for drug response prediction from cancer genomic signatures and compound chemical structures.

BACKGROUND: One of the major challenges in precision medicine is accurate prediction of individual patient's response to drugs. A great number of computational methods have been developed to predict compounds activity using genomic profiles or chemical structures, but more exploration is yet to be done to combine genetic mutation, gene expression, and cheminformatics in one machine learning model. RESULTS: We presented here a novel deep-learning model that integrates gene expression, genetic mutation, and chemical structure of compounds in a multi-task convolutional architecture. We applied our model to the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets. We selected relevant cancer-related genes based on oncology genetics database and L1000 landmark genes, and used their expression and mutations as genomic features in model training. We obtain the cheminformatics features for compounds from PubChem or ChEMBL. Our finding is that combining gene expression, genetic mutation, and cheminformatics features greatly enhances the predictive performance. CONCLUSION: We implemented an extended Graph Neural Network for molecular graphs and Convolutional Neural Network for gene features. With the employment of multi-tasking and self-attention functions to monitor the similarity between compounds, our model outperforms recently published methods using the same training and testing datasets.

Integrated analysis of co-expression, conserved genes and gene families reveal core regulatory network of heat stress response in Cleistogenes songorica, a xerophyte perennial desert plant.

BACKGROUND: As global warming continues, heat stress (HS) is becoming an increasingly significant factor limiting plant growth and reproduction, especially for cool-season grass species. The objective of this study was to determine the transcriptional regulatory network of Cleistogenes songorica under HS via transcriptome profiling, identify of gene families and comparative analysis across major Poaceae species. RESULTS: Physiological analysis revealed significantly decreased leaf relative water content (RWC) but increased proline (Pro) content in C. songorica under 24 h of HS. Transcriptome profiling indicated that 16,028 and 14,645 genes were differentially expressed in the shoots and roots of C. songorica under HS, respectively. Two subgenomes of C. songorica provide equal contribution under HS on the basis of the distribution and expression of differentially expressed genes (DEGs). Furthermore, 216 DEGs were identified as key evolutionarily conserved genes involved in the response to HS in C. songorica via comparative analysis with genes of four Poaceae species; these genes were involved in the 'response to heat' and 'heat acclimation'. Notably, most of the conserved DEGs belonged to the heat-shock protein (HSP) superfamily. Similar results were also obtained from co-expression analysis. Interestingly, hub-genes of co-expression analysis were found to overlap with conserved genes, especially heat-shock protein (HSP). In C. songorica, 84 HSP and 32 heat-shock transcription factor (HSF) genes were identified in the allotetraploid C. songorica genome, and might have undergone purifying selection during evolutionary history based on syntenic and phylogenetic analysis. By analysing the expression patterns of the CsHSPs and CsHSFs, we found that the transcript abundance of 72.7% of the CsHSP genes and of 62.5% of the CsHSF genes changed under heat stress in both the shoots and roots. Finally, a core regulatory network of HS was constructed on the basis of the CsHSP, CsHSF and other responsive genes in C. songorica. CONCLUSIONS: Regulatory network and key genes were comprehensively analysed and identified in C. songorica under HS. This study improves our knowledge of thermotolerance mechanisms in native grasses, and also provides candidate genes for potential applications in the genetic improvement of grasses.

Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo.

Esophageal cancer, a leading cause of cancer death worldwide, is associated with abnormal activation of the AKT signaling pathway. Xanthohumol, a prenylated flavonoid tested in clinical trials, is reported to exert anti-diabetes, anti-inflammation and anticancer activities. However, the mechanisms underlying its chemopreventive or chemotherapeutic effects remain elusive. In the present study, we found that xanthohumol directly targeted AKT1/2 in esophageal squamous cell carcinoma (ESCC). Xanthohumol significantly inhibited the AKT kinase activity in an ATP competitive manner, which was confirmed in binding and computational docking models. KYSE70, 450 and 510 ESCC cell lines highly express AKT and knockdown of AKT1/2 suppressed proliferation of these cells. Treatment with xanthohumol inhibited ESCC cell growth and induced apoptosis and cell cycle arrest at the G1 phase. Xanthohumol also decreased expression of cyclin D1 and increased the levels of cleaved caspase-3, -7 and -PARP as well as Bax, Bims and cytochrome c in ESCC cells by downregulating AKT signaling targets, including glycogen synthase kinase 3 beta (GSK3ß), mammalian target of rapamycin, and ribosomal protein S6 (S6K). Furthermore, xanthohumol decreased tumor volume and weight in patient-derived xenografts (PDXs) that highly expressed AKT, but had no effect on PDXs that exhibited low expression of AKT in vivo. Kinase array results showed that xanthohumol treatment decreased phosphorylated p27 expression in both ESCC cell lines and PDX models. Taken together, our data suggest that the inhibition of ESCC tumor growth with xanthohumol is caused by targeting AKT. These results provide good evidence for translation toward clinical trials with xanthohumol.

Purpurogallin is a novel mitogen-activated protein kinase kinase 1/2 inhibitor that suppresses esophageal squamous cell carcinoma growth in vitro and in vivo.

Purpurogallin is a natural compound that is extracted from nutgalls and oak bark and it possesses antioxidant, anticancer, and anti-inflammatory properties. However, the anticancer capacity of purpurogallin and its molecular target have not been investigated in esophageal squamous cell carcinoma (ESCC). Herein, we report that purpurogallin suppresses ESCC cell growth by directly targeting the mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling pathway. We found that purpurogallin inhibits anchorage-dependent and -independent ESCC growth. The results of in vitro kinase assays and cell-based assays indicated that purpurogallin also strongly attenuates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and also directly binds to and inhibits MEK1 and MEK2 activity. Furthermore, purpurogallin contributed to S and G2 phase cell cycle arrest by reducing cyclin A2 and cyclin B1 expression and also induced apoptosis by activating poly (ADP ribose) polymerase (PARP). Notably, purpurogallin suppressed patient-derived ESCC tumor growth in an in vivo mouse model. These findings indicated that purpurogallin is a novel MEK1/2 inhibitor that could be useful for treating ESCC.

Improved Ozonation Efficiency for Polymerization Mother Liquid from Polyvinyl Chloride Production Using Tandem Reactors.

Polymerization mother liquid (PML) is one of the main sources of wastewater in the chlor-alkali industry. The effective degradation of the PML produced in PVC polymerization using three or five ozone reactors in tandem was designed with a focus on improving the ozonation efficiency. The ozonation efficiency of the tandem reactors for the degradation of PML, along with the effect of ozone concentration, the number of reactors utilized in series, and the reaction time on the chemical oxygen demand (COD) removal were investigated in detail. The results showed that the COD removal increased as the ozone concentration was increased from 10.6 to 60 mg·L-1, achieving 66.4% COD removal at ozone concentration of 80.6 mg·L-1. However, when the ozone concentration was increased from 60 mg·L-1 to 80 mg·L-1, the COD removal only increased very little. The COD decreased with increasing ozone concentration. During the initial degradation period, the degradation rate was the highest at both low and high ozone concentrations. The degradation rate decreased with reaction time. The rate at a low ozone concentration decreased more significantly than at high ozone concentration. Although high ozone concentration is desirable for COD removal and degradation rate, the utilization efficiency of ozone decreased with increasing ozone concentration. The ozone utilization efficiency of the five-reactor device was three times higher than that of three tandem reactors, demonstrating that ozonation utilization efficiency can be improved by increasing the number of tandem reactors. Ozonation in tandem reactors is a promising approach for PML treatment.

Functional organic material for roxarsone and its derivatives recognition via molecular imprinting.

Roxarsone, one of feed add drugs containing arsenic, has been most widely used in poultry and swine industry. Roxarsone discharged into the environment has caused serious pollution problem. Herein, a reusable functional material for selective recognition and adsorption of roxarsone and its derivatives were designed and synthesized. The interaction mechanism is based on acid-base interaction and surface molecular imprinting. Dual functionalized core-shell structure with silica gel as the core was prepared to use as carrier for surface molecularly imprinted polymers. Surface molecularly imprinted polymers for roxarsone was successfully designed and synthesized using 3-aminopropyltriethoxysilane and methyl acryloyloxypropyltriethoxy silane as functional monomers, Ethylene glycol dimethacrylate as crosslinker, Azobisisobutyronitrile as initiator, acetonitrile as solvent. Binding study showed that the recognition selectivity for roxarsone and its derivatives can be significantly improved (3.5-4 folds) with molecular imprinting. Moreover, the prepared functional material for selective recognition and adsorption of Roxarsone was reusable for multiple times without significant decreasing their adsorption capacities.

High response and selectivity of a Cu-ZnO nanowire nanogenerator as a self-powered/active H2S sensor.

Room-temperature self-powered H2S sensing with high response and selectivity has been realized from a Cu-ZnO nanowire nanogenerator. Upon exposure to 1000 ppm H2S at room temperature, the piezoelectric output voltage of the device (5 at% Cu-ZnO) under compressive force decreases from 0.552 (in dry air) to 0.049 V, and the response is up to 1045, over 8 times larger than that of undoped ZnO nanowires. The selectivity against H2S is also very high at room temperature. The enhanced room-temperature H2S sensing performance can be attributed to the coupling of the piezoelectric screening effect of ZnO nanowires and the synergistic effect of the Cu dopant. This study should stimulate research into designing a new gas sensor for detecting toxic gases at room temperature.

Enhanced piezo-humidity sensing of a Cd-ZnO nanowire nanogenerator as a self-powered/active gas sensor by coupling the piezoelectric screening effect and dopant displacement mechanism.

Highly sensitive humidity sensing has been realized from a Cd-doped ZnO nanowire (NW) nanogenerator (NG) as a self-powered/active gas sensor. The piezoelectric output of the device acts not only as a power source, but also as a response signal to the relative humidity (RH) in the environment. The response of Cd-ZnO (1 : 10) NWs reached up to 85.7 upon exposure to 70% relative humidity, much higher than that of undoped ZnO NWs. Cd dopant can increase the number of oxygen vacancies in the NWs, resulting in more adsorption sites on the surface of the NWs. Upon exposure to a humid environment, a large amount of water molecules can displace the adsorbed oxygen ions on the surface of Cd-ZnO NWs. This procedure can influence the carrier density in Cd-ZnO NWs and vary the screening effect on the piezoelectric output. Our study can stimulate a research trend on exploring composite materials for piezo-gas sensing.

Synthesis of CdS nanorod arrays and their applications in flexible piezo-driven active H2S sensors.

A flexible piezo-driven active H2S sensor has been fabricated from CdS nanorod arrays. By coupling the piezoelectric and gas sensing properties of CdS nanorods, the piezoelectric output generated by CdS nanorod arrays acts not only as a power source, but also as a response signal to H2S. Under externally applied compressive force, the piezoelectric output of CdS nanorod arrays is very sensitive to H2S. Upon exposure to 600 ppm H2S, the piezoelectric output of the device decreased from 0.32 V (in air) to 0.12 V. Such a flexible device can be driven by the tiny mechanical energy in our living environment, such as human finger pinching. Our research can stimulate a research trend on designing new material systems and device structures for high-performance piezo-driven active gas sensors.

The conversion of PN-junction influencing the piezoelectric output of a CuO/ZnO nanoarray nanogenerator and its application as a room-temperature self-powered active H2S sensor.

Room-temperature, high H2S sensing has been realized from a CuO/ZnO nanoarray self-powered, active gas sensor. The piezoelectric output of CuO/ZnO nanoarrays can act not only as the power source of the device, but also as the H2S sensing signal at room temperature. Upon exposure to 800 ppm H2S at room temperature, the piezoelectric output of the device greatly decreased from 0.738 V (in air) to 0.101 V. The sensitivity increased to 629.8, much higher than bare ZnO nanoarrays. As the device was exposed to H2S, a CuO/ZnO PN-junction was converted into a CuS/ZnO Ohmic contact, which greatly increased the electron density in the nanowire and enhanced the screen effect on the piezoelectric output. Our results can stimulate a research trend on designing new composite piezoelectric material for high-performance self-powered active gas sensors.

Efficacy and safety of caspofungin for the treatment of invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

OBJECTIVES: We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). METHODS: Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. RESULTS: An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. CONCLUSIONS: Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Multi-omics characterization of esophageal squamous cell carcinoma identifies molecular subtypes and therapeutic targets.

Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer and is characterized by an unfavorable prognosis. To elucidate the distinct molecular alterations in ESCC and investigate therapeutic targets, we performed a comprehensive analysis of transcriptomics, proteomics, and phosphoproteomics data derived from 60 paired treatment-naive ESCC and adjacent nontumor tissue samples. Additionally, we conducted a correlation analysis to describe the regulatory relationship between transcriptomic and proteomic processes, revealing alterations in key metabolic pathways. Unsupervised clustering analysis of the proteomics data stratified patients with ESCC into 3 subtypes with different molecular characteristics and clinical outcomes. Notably, subtype III exhibited the worst prognosis and enrichment in proteins associated with malignant processes, including glycolysis and DNA repair pathways. Furthermore, translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1) was validated as a potential prognostic molecule for ESCC. Moreover, integrated kinase-substrate network analysis using the phosphoproteome nominated candidate kinases as potential targets. In vitro and in vivo experiments further confirmed casein kinase II subunit α (CSNK2A1) as a potential kinase target for ESCC. These underlying data represent a valuable resource for researchers that may provide better insights into the biology and treatment of ESCC.

Multi-View and Multi-Order Structured Graph Learning.

Recently, graph-based multi-view clustering (GMC) has attracted extensive attention from researchers, in which multi-view clustering based on structured graph learning (SGL) can be considered as one of the most interesting branches, achieving promising performance. However, most of the existing SGL methods suffer from sparse graphs lacking useful information, which normally appears in practice. To alleviate this problem, we propose a novel multi-view and multi-order SGL (M 2 SGL) model which introduces multiple different orders (multi-order) graphs into the SGL procedure reasonably. To be more specific, M 2 SGL designs a two-layer weighted-learning mechanism, in which the first layer truncatedly selects part of views in different orders to retain the most useful information, and the second layer assigns smooth weights into retained multi-order graphs to fuse them attentively. Moreover, an iterative optimization algorithm is derived to solve the optimization problem involved in M 2 SGL, and the corresponding theoretical analyses are provided. In experiments, extensive empirical results demonstrate that the proposed M 2 SGL model achieves the state-of-the-art performance in several benchmarks.

Rescue analgesia with serratus anterior plane block improved pain relief after thoracic surgery.

BACKGROUND: Video-assisted thoracic surgery (VATS) is frequently associated with substantial postoperative pain, which may lead to hypopnea. Rescue analgesia using opioids has adverse effects. We aimed to evaluate the effects of rescue analgesia with serratus anterior plane block (SAPB) on moderate-to-severe pain and oxygenation in patients undergoing VATS. METHODS: Eighty patients undergoing VATS and reporting a numeric rating scale (NRS, ranging from 0-10) score of cough pain ≥4 on the first postoperative day were randomized to receive either sufentanil or SAPB for rescue analgesia. The primary outcome was the degree of relief in cough pain 30 min after rescue analgesia. Arterial oxygen pressure (PaO2), opioid consumption after rescue analgesia and the incidence of chronic pain were also assessed. RESULTS: The NRS scores were significantly reduced after rescue analgesia in both groups (Ppaired <0.001). Notably, the degree of relief in cough pain was significantly higher in the SAPB group than that in the sufentanil group (medians [interquartiles]: -3 [-4, -2] vs. -2 [-3, -1], P<0.001). Moreover, patients receiving SAPB exhibited significantly higher PaO2 than those before receiving rescue analgesia (Ppaired=0.007). However, there were no significant differences in the PaO2 before and after receiving rescue analgesia in the sufentanil group. No significant differences in opioid consumption or the incidence of chronic pain were observed between groups. CONCLUSIONS: Rescue analgesia with SAPB on the first postoperative day had a greater effect on pain relief and oxygenation after VATS. However, its long-term effect on chronic pain requires further research.