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Song Cao,1,2* Qingmei Li,3* Jingfeng Hou,1 Zhourui Li,1 Xinya Cao,1 Xiaohong Liu,4 Bangyong Qin11Department of Pain Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, People’s Republic of China; 2Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Zunyi 563000, People’s Republic of China; 3Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, People’s Republic of China; 4Department of Physiology, Zunyi Medical University, Zunyi 563000, People’s Republic of China*These authors contributed equally to this workBackground: TRPM8 channel plays central roles in the sensitization of nociceptive transduction and is thought as one of the potential targets for the treatment of neuropathic pain. However, the specific molecular mechanisms are still less clear.Methods: Sciatic chronic constriction injury (CCI) rats were intrathecally administered with AMTB (TRPM8-selective antagonist) or PDTC (nuclear factor-kappa B (NF-κB) inhibitor). Cold-, thermal- and mechanical-pain thresholds were examined in CCI and sham-operated rats before and after intrathecal administration of AMTB or PDTC. Protein expression levels of TRPM8 and NF-κB p65, p-PKC/PKC value and p-PKA/PKA value in the CCI ipsilateral L4-6 dorsal root ganglions (DRGs) were analyzed. In addition, the co-expression of TRPM8 and NF-κB was evaluated in DRG.Results: Intrathecal injection of AMTB decreased the cold hypersensitivity and aggravated the thermal-hyperalgesia in the next 2 weeks after CCI surgery. The protein expression of TRPM8 and NF-κB p65 in the ipsilateral DRGs significantly increased after CCI surgery, which can be reversed by intrathecal administration of AMTB. The PKC, PKA, p-PKC/PKC and p-PKA/PKA values showed significantly increase after CCI surgery, while intrathecal AMTB administration offset the expression increase of PKC, p-PKC and p-PKC/PKC but PKA or p-PKA/PKA in the DRG. NF-κB inhibitor not only efficiently increased the cold-, thermal-pain threshold of CCI rats, but also enhanced AMTB’s anti-cold pain effect although exerted no anti-thermal hyperalgesia effect compared with TRPM8 blockade group. Immunofluorescence results showed co-expression of TRPM8 and NF-κB in DRG neurons.Conclusion: TRPM8 channels in DRGs participate in the pathogenesis of cold and thermal hyperalgesia (not mechanical allodynia) in rats with neuropathic pain, which could be regulated by PKC (not PKA) and NF-κB signaling. TRPM8 channel, PKC and NF-κB are potential targets for cold hyperalgesia treatment in neuropathic pain patients.Keywords: TRPM8, neuropathic pain, dorsal root ganglia, PKC, NF-κB

Viruses drive carcinogenesis in human cancers through diverse mechanisms that have not been fully elucidated but include promoting immune escape. Here we investigated associations between virus-positivity and immune pathway alteration for 2009 tumors across six virus-related cancer types. Analysis revealed that for 3 of 72 human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSC) the HPV genome integrated in immune checkpoint genes PD-L1 or PD-L2, driving elevated expression in the corresponding gene. In addition to the previously described upregulation of the PD-1 immunosuppressive pathway in Epstein-Barr virus (EBV)-positive stomach tumors, we also observed upregulation of the PD-1 pathway in cytomegalovirus (CMV)-positive tumors. Furthermore, we found signatures of T-cell and B-cell response in HPV-positive HNSC and EBV-positive stomach tumors and HPV-positive HNSC patients were associated with better survival when T-cell signals were detected. Our work reveals that viral infection may recruit immune effector cells, and upregulate PD-1 and CTLA-4 immunosuppressive pathways., Cao et al. show that human papillomavirus-positive, head and neck squamous cell carcinoma patients are associated with better survival when T-cells are activated. This study suggests that viral infection may recruit immune effector cells and that it may activate PD-1 and CTLA-4 immunosuppressive pathways.

To explore the novel application of graphene nanomaterials, we investigate the structural, electronic and magnetic properties of transition metals (TM = V, Cr, Mn, Fe, Co and Ni) monatomic chains intercalated AA stacked bilayer graphene nanoribbons ([GTMG]w) using first-principles calculations. The combining processes of all the [GTMG]w compounds are exothermic except the [GCuG]w (w = 5, 6, 7, 8, 9) compounds, accompanying with larger formation energies and charges transfer. The formed TM–C ionic bonds are contributed to enhancing the stability of [GTMG]w compounds. The most stable intercalated structures, are the [GVG]w compounds for the different TM chain, and are the [GTMG]4 compounds for the different widths of bilayer graphene nanoribbons (w = 4, 5, 6, 7, 8, 9). The [GMnG]w compounds have the maximum magnetic moment, but the [GVG]w, [GNiG]w and [GCuG]w compounds have magnetic quenching phenomenon with zero magnetic moment. There are different magnetic properties for the even (w = 4, 6, 8) and odd (w = 5, 7, 9) widths of bilayer graphene nanoribbons in [GTMG] compounds. Therefore, the TM chains intercalated bilayer graphene nanoribbons exhibit tunable magnetic properties for potential spintronics applications.

A novel and efficient method for the synthesis of gem-difluoroallylboronates via copper-catalyzed defluorinative borylation of α-trifluoromethyl alkenes with B2pin2 using Xantphos as ligand and NaOtBu as base was developed.

An efficient synthetic method for preparing trans-difluorocyclopropyl boronates and trans-difluorocyclopropyl silanes was easily achieved through a copper-catalyzed hydroborylation and hydrosilylation of difluorocyclopropenes with bis(pinacolato)diboron and silylboronate, respectively.

PTMcosmos is a comprehensive database with an interactive web portal designed to catalog and visualize post-translational modifications (PTMs) in humans. It contains 469,183 experimentally-validated PTM sites and their supporting evidence from UniProt Knowledge Base, PhosphoSitePlus, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). PTMcosmos summarizes the entire spectrum of CPTAC proteomics data on human cancer patients, including protein and PTM peptide abundance data from 10 different cancer types. Additionally, PTMcosmos contains cancer somatic mutations from The Cancer Genome Atlas (TCGA), thus allowing for the collective integration and analysis of different data types. In PTMcosmos, we have built an ensemble of interactive visualization tools that allow researchers to investigate altered PTM functions due to genetic alterations in close proximity. The database is live at https://ptmcosmos.wustl.edu. We used PTMcosmos to investigate PTM regulation across cancer types. First, we examined the differential abundance of the PTM sites of cancer driver genes, focusing primarily on phosphorylation of the tumor suppressor retinoblastoma protein (encoded by RB1) and acetylation of the histone acetyltransferase E1A Binding Protein P300 (EP300) across cancer types. We analyzed the association between these PTM events and downstream targets, as well as with tumor subtypes, significantly mutated gene (SMG) mutation status, and clinical features. Second, we investigated the association of the protein abundance of cancer driver genes with ubiquitylsites in lung squamous cell carcinoma (LSCC) to nominate potentially novel modes of regulation of these proteins’ activities. We further analyzed the tumor subtype specificity and tumor-normal abundance changes of these ubiquitylsites and their corresponding substrate proteins, identifying several EGFR ubiquitylsites which may regulate EGFR abundance in LSCC. Finally, we identified the linear and spatial clustering of mutations and PTM sites, identifying multiple mutation-PTM clusters in cancer related genes, including TP53, PIK3CA, CTNNB1, EGFR, and IDH1. We envision that PTMcosmos will serve both the CPTAC consortium and the wider research community to better understand the role of PTMs in cancer. Citation Format: Liang-Bo Wang, Akshay Govindan, Song Cao, Li Ding. PTMcosmos: A web portal of post-translational modifications and proteogenomic resources in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5027.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect “B cell-featured” plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options., Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.

A combination of Convolutional Neural Network (CNN), Long-Short Term Memory (LSTM), and Convolutional LSTM (ConvLSTM) is constructed in this work for the fault diagnosis and post-accident prediction for Loss of Coolant Accidents (LOCAs) in Nuclear Power Plants (NPPs). The advantages of ConvLSTM, such as effective feature determination and extraction, are applied to the classification of LOCA cases. The prediction accuracy is enhanced via the collaborative work of CNN and LSTM. Such a hybrid model is proved to be functional, accurate, and adaptive, offering quick accident judgment and a reliable decision basis for the emergency response purpose. It then allows NPPs to have an Artificial Intelligence (AI)-based solution for fault diagnosis and post-accident prediction.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) pandemic is a global threat caused by the severe acute respiratory syndrome coronavirus-2. AIM: To develop and validate a risk stratification tool for the early prediction of intensive care unit (ICU) admission among COVID-19 patients at hospital admission. METHODS: The training cohort included COVID-19 patients admitted to the Wuhan Third Hospital. We selected 13 of 65 baseline laboratory results to assess ICU admission risk, which were used to develop a risk prediction model with the random forest (RF) algorithm. A nomogram for the logistic regression model was built based on six selected variables. The predicted models were carefully calibrated, and the predictive performance was evaluated and compared with two previously published models. RESULTS: There were 681 and 296 patients in the training and validation cohorts, respectively. The patients in the training cohort were older than those in the validation cohort (median age: 63.0 vs 49.0 years, P < 0.001), and the percentages of male gender were similar (49.6% vs 49.3%, P = 0.958). The top predictors selected in the RF model were neutrophil-to-lymphocyte ratio, age, lactate dehydrogenase, C-reactive protein, creatinine, D-dimer, albumin, procalcitonin, glucose, platelet, total bilirubin, lactate and creatine kinase. The accuracy, sensitivity and specificity for the RF model were 91%, 88% and 93%, respectively, higher than those for the logistic regression model. The area under the receiver operating characteristic curve of our model was much better than those of two other published methods (0.90 vs 0.82 and 0.75). Model A underestimated risk of ICU admission in patients with a predicted risk less than 30%, whereas the RF risk score demonstrated excellent ability to categorize patients into different risk strata. Our predictive model provided a larger standardized net benefit across the major high-risk range compared with model A. CONCLUSION: Our model can identify ICU admission risk in COVID-19 patients at admission, who can then receive prompt care, thus improving medical resource allocation.

Mirid bugs are a group of important insect pests that cause large annual losses in agricultural production. Many studies have focused on the isolation and identification of sex pheromones in mirid bugs, and the components and biological activity of the sex pheromones have also been studied as a way to control these pests. However, few studies have focused on the mechanisms of pheromone perception. In this study, we identified the odorant receptor repertoire in three mirid bug species, Apolygus lucorum, Adelphocoris lineolatus, and Adelphocoris suturalis using antennal transcriptome sequencing and bioinformatics analysis. The candidate pheromone receptor (PR) genes were then identified by comparative transcriptomic and expression pattern analysis. Importantly, in vitro functional studies have shown that the candidate PRs have robust responses to the main mirid bug sex pheromone components (E)-2-hexenyl butyrate (E2HB) and hexyl butyrate (HB). Our study uncovered the mechanism of pheromone peripheral coding in these three species and elucidated the mechanism by which mirid bugs can specifically recognize a mate. Moreover, the results of our study will provide a theoretical basis for screening effective sex attractants or mating disturbance agents at the molecular and neural levels for enhanced control of these destructive pests.

Summary This study aimed to explore the effects and possible mechanisms of intravenous lidocaine in postherpetic neuralgia (PHN) rats. Mechanical withdrawal thresholds and thermal withdrawal latencies were measured. Open field test, elevated plus maze test, and tail suspension test were used to assess anxiety- and depressive-like behaviors. Microglia and astrocytes in spinal dorsal horn (SDH), prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus were analyzed. The expression of TNF-α, IL-1β, and IL-4 in SDH and serum were evaluated. Intravenous lidocaine alleviated mechanical allodynia and thermal hypoalgesia, downregulated the expression of TNF-α and IL-1β, and inhibited the activation of microglia and astrocytes in SDH. In addition, it reduced the activation of astrocyte but not microglia in PFC, ACC, and hippocampus. Intravenous lidocaine may relieve PHN by inhibiting the activation of microglia and astrocyte in SDH or by reducing the neuroinflammation and astrocyte activation in PFC, ACC, and hippocampus., Graphical Abstract, Highlights • Intravenous lidocaine alleviates PHN in rats • Intravenous lidocaine inhibits microglia and astrocyte activation • Intravenous lidocaine cannot relieve anxiety and depression in PHN rats, Cellular Physiology; Immunology; Neuroscience

Human umbilical vein endothelial cells (HUVECs) serve a critical role in maintaining normal vascular function. Lipopolysaccharide (LPS), which is released from pathogenic bacteria in the blood, induces HUVEC apoptosis and injury to cause vascular dysfunction and infectious vascular diseases. Procyanidin B2 (PB2) possesses numerous functions, including antioxidant, antitumor, anti‑inflammatory and antiapoptosis effects, but the molecular mechanism is not completely understood. The present study investigated the effects of PB2 on LPS‑induced cytotoxicity and apoptosis in HUVECs, as well as the underlying mechanisms. The effects of PB2 on LPS‑mediated alterations to cytotoxicity, mitochondrial membrane potential, apoptosis were assessed by performing Cell Counting Kit‑8, JC‑1 fluorescence, Hoechst 33258 staining assays, respectively. IL‑1β, IL‑6 and TNF‑α mRNA expression and protein levels were measured by performing reverse transcription‑quantitative PCR and ELISAs, respectively. Bcl‑2, Bax, cleaved caspase‑3, cleaved caspase‑7, cleaved caspase‑9, phosphorylated (p)‑IκB‑α, p‑IκB‑β, p‑NF‑κB‑p65 and total NF‑κB p65 protein expression levels were determined via western blotting. NF‑κB p65 nuclear translocation was assessed via immunofluorescence. PB2 pretreatment markedly attenuated LPS‑induced cytotoxicity and apoptosis in HUVECs. PB2 also significantly downregulated the expression levels of IL‑1β, IL‑6, TNF‑α, Bax, cleaved caspase‑3, cleaved caspase‑7, cleaved caspase‑9 and p‑NF‑κB‑p65, but upregulated the expression levels of Bcl‑2, p‑IκB‑α and p‑IκB‑β in LPS‑induced HUVECs. Moreover, PB2 markedly inhibited LPS‑induced NF‑κB p65 nuclear translocation in HUVECs. The results suggested that the potential molecular mechanism underlying PB2 was associated with the Bax/Bcl‑2 and NF‑κB signalling pathways. Therefore, PB2 may serve as a useful therapeutic for infectious vascular diseases.

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Numerous computational methods have been proposed to predict protein-protein interactions, none of which however, considers the original DNA loci of the interacting proteins in the perspective of 3D genome. Here, we retrospect the DNA origins of the interacting proteins from the perspective of 3D genome and found that by incorporating 3D genome information into existing PPI prediction methods, i.e., Auto Covariance (AC) and Conjoint triad (CT) coding based support vector machine (SVM) and ensemble extreme learning machine (EELM), the predictions can be further improved in terms of accuracy and area under ROC curve (AUC). Combining our previous discoveries, we conjecture this is due to that co-localized DNA elements may lead to increased probability of the co-localization of their downstream RNA elements and protein elements.

Diazoxide post‑conditioning (D‑Post) has been shown to be effective in alleviating myocardial ischemia/reperfusion (I/R) injury; however, the specific mechanisms are not fully understood. In the present study, isolated rat hearts were subjected to I/R injury and D‑Post. The mitochondria were extracted, and mitochondrial protein expression was detected in normal, I/R and D‑Post hearts using two‑dimensional electrophoresis and matrix‑assisted laser desorption ionization‑time of flight mass spectrometry. Differentially expressed proteins were then identified using comparative proteomics. In total, five differentially expressed proteins were identified between the I/R and D‑Post hearts. Compared with the I/R hearts, the expression of NADH dehydrogenase (ubiquinone) flavoprotein 1 (NDUFV1), NADH‑ubiquinone oxidoreductase 75 kDa subunit (NDUFS1), 2‑oxoglutarate dehydrogenase (OGDH) and ATP synthase α subunit (isoform CRA_b, gi|149029482) was increased in D‑Post hearts. In addition, the expression of another isoform of ATP synthase α subunit (isoform CRA_c, gi|149029480) was decreased in the D‑Post group compared with the I/R group. The expression profiles of NDUFV1, NDUFS1 and OGDH in the two groups were further validated via western blotting. The five differentially expressed proteins may be protective effectors in D‑Post, as well as potential targets for the treatment of cardiac I/R injury.

Backgrounds: To describe the clinical characteristics of coronavirus disease 2019 hospitalized patients and further analyze the potential risk factors related to the severity of the disease and 28-day mortality of patients.Methods: A total of 122 coronavirus disease 2019 patients hospitalized in Wuhan Third Hospital from 26 January 2020 to 16 March 2020 were included in this retrospective study. Clinical data of patients were retrospectively analyzed, and the risk factors associated with disease severity and 28-day mortality were screened by cox regression analysis.Results: Of all 122 patients, the median age was 64 years old (interquartile range, 57- 71 years old).Compared with non-severe patients, severe patients had higher indices like cardiac troponin T and respiratory rate. In cox regression analysis, cardiac troponin T correlated with 28-day mortality most.Conclusions: Abnormal cardiac troponin T value after admission were in strong correlation with 28-day survival status.

Numerous computational methods have been proposed to predict protein-protein interactions, none of which however, considers the original DNA loci of the interacting proteins in the perspective of 3D genome. Here we retrospect the DNA origins of the interacting proteins in the context of 3D genome and discovered that 1) if a gene pair is more proximate in 3D genome, their corresponding proteins are more likely to interact. 2) signal peptide involvement of PPI affects the corresponding gene-gene proximity in 3D genome space. 3) by incorporating 3D genome information, existing PPI prediction methods can be further improved in terms of accuracy. Combining our previous discoveries, we conjecture the existence of 3D genome driven cellular compartmentalization, meaning the co-localization of DNA elements lead to increased probability of the co-localization of RNA elements and protein elements.

Odorant receptors (ORs) are essential for plant–insect interactions. However, despite the global impacts of Lepidoptera (moths and butterflies) as major herbivores and pollinators, little functional data are available about Lepidoptera ORs involved in plant-volatile detection. Here, we initially characterized the plant-volatile-sensing function(s) of 44 ORs from the cotton bollworm Helicoverpa armigera, and subsequently conducted a large-scale comparative analysis that establishes how most orthologous ORs have functionally diverged among closely related species whereas some rare ORs are functionally conserved. Specifically, our systematic analysis of H. armigera ORs cataloged the wide functional scope of the H. armigera OR repertoire, and also showed that HarmOR42 and its Spodoptera littoralis ortholog are functionally conserved. Pursuing this, we characterized the HarmOR42-orthologous ORs from 11 species across the Glossata suborder and confirmed the HarmOR42 orthologs form a unique OR lineage that has undergone strong purifying selection in Glossata species and whose members are tuned with strong specificity to phenylacetaldehyde, a floral scent component common to most angiosperms. In vivo studies via HarmOR42 knockout support that HarmOR42-related ORs are essential for host-detection by sensing phenylacetaldehyde. Our work also supports that these ORs coevolved with the tube-like proboscis, and has maintained functional stability throughout the long-term coexistence of Lepidoptera with angiosperms. Thus, beyond providing a rich empirical resource for delineating the precise functions of H. armigera ORs, our results enable a comparative analysis of insect ORs that have apparently facilitated and currently sustain the intimate adaptations and ecological interactions among nectar feeding insects and flowering plants.

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Non-coding mutations can create splice sites, however the true extent of how such somatic non-coding mutations affect RNA splicing are largely unexplored. Here we use the MiSplice pipeline to analyze 783 cancer cases with WGS data and 9494 cases with WES data, discovering 562 non-coding mutations that lead to splicing alterations. Notably, most of these mutations create new exons. Introns associated with new exon creation are significantly larger than the genome-wide average intron size. We find that some mutation-induced splicing alterations are located in genes important in tumorigenesis (ATRX, BCOR, CDKN2B, MAP3K1, MAP3K4, MDM2, SMAD4, STK11, TP53 etc.), often leading to truncated proteins and affecting gene expression. The pattern emerging from these exon-creating mutations suggests that splice sites created by non-coding mutations interact with pre-existing potential splice sites that originally lacked a suitable splicing pair to induce new exon formation. Our study suggests the importance of investigating biological and clinical consequences of noncoding splice-inducing mutations that were previously neglected by conventional annotation pipelines. MiSplice will be useful for automatically annotating the splicing impact of coding and non-coding mutations in future large-scale analyses., Non-coding cancer driver mutations that induce splicing variants exist, but are largely unexplored. Here, the authors find these non-coding mutations in known pan-cancer driver genes and show that they create new exons and might interact with pre-existing potential splice sites.

A facile and practical method for the synthesis of 2,3,4-trisubstituted 2-aminothiophenes by the cyclization of gem-dibromoalkenes or gem-dichloroalkenes with β-keto tertiary thioamides has been developed. The cyclization reaction proceeded chemoselectively and regioselectively under metal-catalyst-free conditions, providing various structurally diverse 2,3,4-trisubstituted N,N'-dialkyl 2-aminothiophenes in good to excellent yields.

The technique of two-electrode voltage-clamp (TEVC) recording from the heterologous expression system of olfactory receptors (ORs) in Xenopus laevis oocytes has been widely used to deorphanize insect ORs, that is to identify specific ligands for each of them. However, there is a controversial issue on whether ORs are activated by the odorant/OBP complex or the odorant alone. The mechanism of interaction among odorants, odorant-binding proteins (OBPs) and ORs remains largely unknown, due to the limitations in the use of scientific and innovative methods. In this chapter, the modified Xenopus oocytes expression system combined with TEVC technique is used to approach this issue. We describe the experimental strategies and provide detailed protocols for recording the signals generated by ORs in response to odorant/OBP complex at different concentrations. Results obtained by this approach have revealed that the presence of OBPs in the system affects the selectivity and sensitivity responses of ORs. Such studies help understanding the molecular mechanism of odorant detection in peripheral nervous system.

Flubendiamide has received considerable attention in the agriculture field due to its novel mode of action and excellent insecticidal activity. However, the high cost and toxicity to aquatic invertebrates associated with flubendiamide limit its agronomic utility. On the basis of the structure of the lead compound, flubendiamide, we designed and synthesized a series of novel analogues of flubendiamide bearing a alkoxyhexafluoroisopropyl moiety using 2-methyl-4-(2-alkoxyhexafluoroisopropyl) anilines as the key intermediates. Their insecticidal activities against the oriental armyworm (Mythimna separata Walker) were evaluated. The results indicated that most of the target compounds exhibited high insecticidal activities. Specifically, compound 8h showed the best insecticidal activity against the armyworm and its insecticidal activity reached 70% at 0.156 mg L−1. The LC50 value of compound 8h (0.0512 mg L−1) is nearly the same as the corresponding commercial product flubendiamide (0.0412 mg L−1). Furthermore, the acute toxicity test showed that the 48 h LC50 values of compound 8h and flubendiamide against Daphnia magna Straus were 0.0066 and 0.0021 mg L−1, respectively. The toxicity of compound 8h is obviously lower than flubendiamide.

Ischemic heart disease has attracted much attention due to its high mortality rates, treatment costs and the increasing morbidity in the young population. Strategies for reperfusion have reduced mortality. However, reperfusion can lead to cardiomyocyte death and subsequent irreversible myocardial damage. At present, the timely and targeted treatment of ischemia-reperfusion (I/R) injury is often lacking.To evaluate if dexmedetomidine (DEX) has a protective effect in myocardiual I/R and explore the possible mechanism behind it.Rat hearts were perfused with a Langendorff perfusion system, and randomly assigned to five groups: control group, perfused with Krebs-Henseleit (K-H) solution for 205 minutes without ischemia; and four test groups that underwent 40 minutes of global ischemia and 120 min of reperfusion. The DEX group, the yohimbine (YOH) group and the DEX + YOH group were perfused with DEX (10 nM), YOH (1 μM) or the combination of DEX and YOH prior to reperfusion, respectively. Cardiac hemodynamics, myocardial infarct size, and myocardial histology were evaluated. The expression of glucose-related protein 78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated PERK, eukaryotic initiation factor 2α (eIF2α), phosphorylated eIF2α, activating transcription factor 4 (ATF4), and CCAAT/enhancer-binding protein homologous protein (CHOP) were assessed. P0.05 was considered to indicate a statistically significant difference.DEX preconditioning improved the cardiac function of I/R hearts, reduced myocardial infarction, myocardial apoptosis, and the expression of GRP78, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP.DEX pretreatment reduced myocardial I/R injury by suppressing apoptosis, which was induced by the PERK pathway.A cardiopatia isquêmica atraiu muito atenção devido às altas taxas de mortalidade, custos do tratamento e a crescente morbidade na população jovem. Estratégias de reperfusão reduziram a mortalidade. Porém, a reperfusão pode levar à morte do cardiomiócito e subsequente dano irreversível ao miocárdio. No momento, não há um tratamento eficiente e direcionado para a lesão de isquemia-reperfusão (I/R).Avaliar se a dexmedetomidina (DEX) tem efeito protetivo na I/R do miocárdio e explorar os possíveis mecanismos por trás dela.Corações de ratos foram perfundidos com o sistema de perfusão de Langendorff e aleatoriamente distribuídos em cinco grupos: grupo controle, perfundido com solução de Krebs-Henseleit (K-H) por 205 minutos sem isquemia; e quatro grupos de teste que foram submetidos a 40 minutos de isquemia global e 120 minutos de reperfusão. O Grupo DEX, o grupo ioimbina (IO) e o grupo DEX + IO foram perfundidos com DEX (10 nM), IO (1 μM) ou a combinação de DEX e IO antes da reperfusão, respectivamente. A hemodinâmica cardíaca, o tamanho do infarto do miocárdio e a histologia do miocárdio foram avaliados. A expressão da proteína-78 regulada pela glicose (GRP78), a proteína quinase do retículo endoplasmático (PERK), a PERK fosforilada, o fator de iniciação eucariótico 2α (eIF2α), eIF2α fosforilado, o fator de transcrição 4 (TCF-4) e a proteína homóloga à proteína ligadora do acentuador CCAAT (CHOP) foram avaliados. P0,05 foi considerado para indicar a diferença estatisticamente significativa.O pré-condicionamento com DEX melhorou a função cardíaca nos corações com I/R, reduziu o infarto do miocárdio, a apoptose do miocárdio e a expressão de GRP78, p-PERK, eIF2α, p-eIF2α, TCF-4 e CHOP.O pré-tratamento com DEX reduziu a lesão de I/R no miocárdio ao suprimir a apoptose, o que foi induzido pela via PERK.

Background The role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging. Methods In this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA. Results Our results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice. Conclusion These results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system.

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation of WHSC1 and FGFR3 in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions at MYC and a neighboring gene, PVT1, which are related to MYC translocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with an NTRK1 fusion., Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.

Background Major depressive disorder (MDD) is a severe mental illness with high prevalence and recurrence rates. Cognitive impairments are found in most depressed patients, but systematic assessment of sex differences in cognitive deficits remains to be investigated. Methods A total of 69 first-diagnosed, drug-naive depressed outpatients (males/females = 28/41; average age: 27.51±8.82 years) and 57 healthy controls (HCs) (males/females = 26/31; average age: 29.05±8.69 years) were recruited. Cognitive function, measured by repeatable battery for the assessment of neuropsychological status [RBANS] scores, was compared between depressed patients and healthy controls in males and females. Results Immediate memory, delayed memory and RBANS total score were significantly decreased in depressed patients compared with healthy controls. Moreover, among patients with first-diagnosed, drug-naive depression, females had lower visuospatial and constructional scores than males, whereas among controls, females had higher language scores than males. Interestingly, impaired attention was negatively associated with the Beck Depression Inventory-II (BDI-II) score in female patients, but not in male patients. Conclusion Female patients with first-diagnosed, drug-naive depression had more serious cognitive impairment than male patients in the visuospatial and constructional categories. Cognitive impairment was associated with depression severity only in female patients. These observations build the basis for future investigation of sex differences in cognitive impairment of depressed patients.

Aim & methods: A decision-analytic model was constructed to simulate a real-world cohort of Chinese patients visiting a Chinese regional mental health center for long-term health outcomes and direct medical costs. Results: When compared with age and gender-matched general population, the Chinese patients with schizophrenia were associated with reduced overall survival by 20.6 years (27.6 vs 48.2 years) and reduced quality-adjusted life years (QALY) by 18.4 QALY (18.4 vs 36.8 QALY), respectively, and increased lifetime direct medical costs by about three-times (US$84,324 vs 33,387 as of 31 December 2017) on average. Conclusion: The burden of schizophrenia was mainly driven by the mortality associated with relapsed schizophrenia and direct medical costs for schizophrenia in local mental health rehabilitation institutes.

Depression is one of the major causes of disability in societies worldwide. However, only a few studies have been conducted to analyze the relationship between vitamin A levels and depression. This study aimed to explore the vitamin A levels in the plasma of first-episode drug-naïve depression patients. 48 healthy controls and 75 first-episode drug-naïve outpatients were recruited in our research and a total of 18 patients were followed for 24 weeks. There was no difference in plasma vitamin A levels among healthy controls and patients with depression. After 24 weeks antidepressant treatment, plasma vitamin A levels were decreased. Interestingly, this alteration of vitamin A was only found in female patients. Moreover, correlation analyses showed that plasma vitamin A levels were significantly associated with depressive symptomatic index only in female depression patients. We found that the levels of vitamin A were decreased in female patients with depression during antidepressant therapy. Further study of gender difference in vitamin A levels is needed to reveal the mechanism.

Objective Multimodal magnetic resonance imaging (MRI) was used to detect whether 6 months after pain relieving, the structural and functional abnormalities in the brain of postherpetic neuralgia (PHN) patients are changeable. Methods Fifteen successfully treated PHN patients were enrolled ; the brain activity and structural abnormalities were detected and compared before and 6 months after treatment. The functional parameters were evaluated with resting-state functional MRI technique, i.e., the regional homogeneity (ReHo) and fractional amp litude of low-frequency fluctuation (fALFF). Structural changes were detected with voxel-based morphometry (VBM) and diffusion kurtosis imaging (DKI). Results Six months after pain relieving, PHN brain showed different ReHo and fALFF values in the frontal lobe, caudate, supramarginal gyrus, anterior cingulate cortex (ACC), cuneus, middle temporal gyrus, and cerebellum. In addition, VBM intensity in the cerebellum increased; DKI values decreased in the thalamus and increased in the temporal lobe after successful treatment. Conclusion Six months after pain relieving, functional and structural changes exist in PHN brain. Changes in some differential areas in PHN brain, such as ACC, frontal lobe, thalamus, and temporal lobe indicate that the central plasticity may be reversible after chronic pain relieving.

Benzoylphenylureas as an important type of insect growth regulators, acting on the moulting stage in immature insects, are highly effective and low toxic. The new benzoylphenylurea TXH09 [N-((2,6-dimethyl-4-(heptafluoropropyl-2-yl)phenyl)carbamoyl)-2,6-difluorobenzamide] has high efficacy against chewing insect pests harming vegetables and rice. In this paper, the efficacy of TXH09 against two intractable borers Ostrinia furnacalis and Grapholitha molesta were evaluated in field, and safety assessment by exploring the characteristics of photodegradation, cytotoxicity, micronucleus generation and chromosome aberration was performed. The results showed that TXH09 had good capability in preventing infested corn and reducing the population of O. furnacalis larvae, and maintained high efficacy on shoot protection and peach conservation against G. molesta larvae. There were no significant differences between the control effects of TXH09 and that of hexaflumuron or diflubenzuron at the same active dose. TXH09 photolysis in solvents N,N-dimethylformamide, toluene and methanol yielded two major products, and the photodegradation of TXH09 was more prone to occur in N,N-dimethylformamide. TXH09 and the mixture of its photoproducts showed higher cytotoxicity on insect Sf-9 cells than on human Hek293 cells. Moreover, TXH09 didn't show significant effects in inducing micronucleated cells in both male and female mice and chromosomal aberrations in mouse spermatocytes by its own. In conclusion, TXH09, as an effective insecticide, has good environmental safety performance against O. furnacalis and G. molesta in field.

The locus nucleus (LC) is a multifunctional nucleus which is also the source of norepinephrine in the brain. To date, there is no simple and easy method to locate the small LC in brain sectioning. Here we report a fast, accurate, and easy-to-follow protocol for the localization of mice LC in frozen sectioning. After fixation and dehydration, the intact brains of adult mice were placed on a horizontal surface and vertically cut along the posterior margin of the bilateral cerebral cortex. In the coronal cutting plane, the aqueduct of midbrain can be seen easily with the naked eyes. After embedding the cerebellum part with optimal cutting temperature (OCT) compound, coronal brain slices were cut from the cutting plane, within 1 mm, the aqueduct of midbrain disappeared and the fourth ventricle appeared, then the brain slices contained LC and were collected. From the first collection, at ~200 μm, the noradrenergic neurons’ most enriched brain slices can be collected. The tyrosine hydroxylase immunofluorescence staining confirmed that the localization of LC with this method is accurate and the noradrenergic neuron most abundant slices can be determined with this method.

The double threshold energy detector has attracted wide attention because of its low detection complexity. However, this comes at the expense of some sensing performance loss. Motivated by this, our paper proposes a novel double threshold detection method. Where maximum and minimum sensing threshold is redesigned and analyzed therein. Additionally, it is expanded to cooperative spectrum sensing for the issue of the hidden terminal. Simulation results verify the validity of the scheme.

The technique of two-electrode voltage-clamp (TEVC) recording from the heterologous expression system of olfactory receptors (ORs) in Xenopus laevis oocytes has been widely used to deorphanize insect ORs, that is to identify specific ligands for each of them. However, there is a controversial issue on whether ORs are activated by the odorant/OBP complex or the odorant alone. The mechanism of interaction among odorants, odorant-binding proteins (OBPs) and ORs remains largely unknown, due to the limitations in the use of scientific and innovative methods. In this chapter, the modified Xenopus oocytes expression system combined with TEVC technique is used to approach this issue. We describe the experimental strategies and provide detailed protocols for recording the signals generated by ORs in response to odorant/OBP complex at different concentrations. Results obtained by this approach have revealed that the presence of OBPs in the system affects the selectivity and sensitivity responses of ORs. Such studies help understanding the molecular mechanism of odorant detection in peripheral nervous system.

The Long Short-Term Memory (LSTM) model is investigated in this work, as a proposed prediction method for the abnormal condition in Nuclear Power Plants (NPPs). Its advantage of processing long timeline data is utilized to overcome the limitation of the traditional Recurrent Neural Network (RNN). With the assistance of the Rolling Update (RU) method, the LSTM model is trained using historical NPP operation data to obtain the capability of predicting abnormal trends. Such prediction ability is validated using simulated accident data, which demonstrates its prediction accuracy with a loss value of 3.7 × 10−6. Moreover, it is verified in this work that LSTM can predict the trends of accidents that belong to same category but differ in certain parameters.

Background: Influenza co-circulates with coronavirus disease 2019 (COVID-19) in the space and time Given the current situation of COVID-19 pandemic and influen

Dendrolimus punctatus Walker (Lepidoptera: Lasiocampidae) is a pine caterpillar moth distributed in most areas of southern China and is an economically important pest of pine, due to its defoliation activity. Understanding fundamental sex pheromone perception mechanisms in D. punctatus may provide effective and sustainable options for novel control strategies. However, the identification and function of pheromone receptors, key genes that receipt the pheromone of this pest, are both unclear now. Previous researches suggested several candidate pheromone receptors whose expression levels were male antennae bias in D. punctatus. In this study, we cloned six candidate pheromone receptors (DpunOR 20/45/46/51/54/58) and Orco from D. punctatus. Phylogenetic tree analysis showed that lepidopteran PRs tend to be conserved and clustered together; however, D. punctatus candidate PRs were located in a distinct clade. Motif analysis of PRs showed clear sequences differences between Dendrolimus spp. and other tested moth species. To illustrate the ligand response properties of the candidate PRs of D. punctatus, each of the six genes was expressed with an Orco gene in Xenopus oocytes and using two-electrode voltage-clamp recordings. Finally, we successfully identified two sex pheromone receptors (PR45 and PR46). Our study, which identified a novel lineage of PRs tuned to Type I pheromones in Lepidoptera, provides evidence for the new evolution origin of sex pheromone communication in moths, and lays a foundation for the development of novel control strategies of D. punctatus.

A rapid and efficient approach to 3-arylated indenes by reactions of indenes with unactivated fluoroarenes with the assistance of lithium diisopropylamide and hexamethylphosphoramide at room temperature was developed.

Objectives To identify the changes of local coherence and intrinsic brain activity in resting-state idiopathic trigeminal neuralgia (ITN) patients by using regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) analysis. Methods ReHo and fALFF were analyzed in 23 ITN patients and 23 age-matched and sex-matched pain-free controls to detect the functional abnormality in the brains of ITN patients. Correlations between ReHo and fALFF were analyses. ITN pain intensity were also assessed in the ITN group. Results Compared with pain-free controls, ITN patients exhibited significantly abnormal ReHo and fALFF in several brain regions, including the cerebellum, cingulate cortex, temporal lobe, putamen, occipital lobe, limbic lobe, precuneus, insula, medial, and superior frontal gyrus compared with healthy controls. Correlation analysis showed that ReHo values of several altered brain areas positively correlated with visual analog scale values. But no correlation was found between fALFF and visual analog scale. Discussion Our results showed that ITN patients exhibited significantly abnormal spontaneous brain activity in several brain regions that are involved in pain modulation and perception. The present study reflects the maladaptive process of daily pain attacks and may enhance the understanding of how chronic pain affects local intrinsic brain activity.

A novel and efficient method for the synthesis of arylacetamides by the reactions of gem-difluoroalkenes with N,N-dialkylformamides, and primary and secondary amines with the assistance of KOtBu and water was developed.

An efficient method for the synthesis of 3-tertiary alkylated 1,1-difluorostyrene derivatives via Cu-catalyzed alkylation of α-(trifluoromethyl)styrenes with tertiary alkylmagnesium reagents at room temperature was developed.