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Abstract Background Ecosystems are brimming with myriad compounds, including some at very low concentrations that are indispensable for insect survival and reproduction. Screening strategies for identifying active compounds are typically based on bioassay-guided approaches. Results Here, we selected two candidate odorant receptors from a major pest of cruciferous plants—the diamondback moth Plutella xylostella—as targets to screen for active semiochemicals. One of these ORs, PxylOR16, exhibited a specific, sensitive response to heptanal, with both larvae and adult P. xylostella displaying heptanal avoidance behavior. Gene knockout studies based on CRISPR/Cas9 experimentally confirmed that PxylOR16 mediates this avoidance. Intriguingly, rather than being involved in P. xylostella–host plant interaction, we discovered that P. xylostella recognizes heptanal from the cuticular volatiles of the parasitoid wasp Cotesia vestalis, possibly to avoid parasitization. Conclusions Our study thus showcases how the deorphanization of odorant receptors can drive discoveries about their complex functions in mediating insect survival. We also demonstrate that the use of odorant receptors as a screening platform could be efficient in identifying new behavioral regulators for application in pest management.

Tight sandstone reservoirs have extremely low porosity and permeability. Bedding-parallel fractures (BPFs) contribute prominently to the storage and seepage capability. However, the distribution of BPFs is remarkably heterogeneous, impeding the prediction and modeling of sweet spots. BPFs are controlled fundamentally by laminations, which are widely distributed in lacustrine tight reservoirs and provide most weakness planes. Based on core and thin section data, BPFs of the upper Triassic Chang 7 tight oil reservoir are characterized microscopically. The lamination combination unit, which is defined by distinctive lamination assemblage and relatively stable lamination thickness and space, is utilized as a homogeneous unit to measure the density of lamination and related BPFs. The influence of laminations on BPFs is discussed further. Results show that most bedding-parallel fractures are unfilled, with apertures generally

Objective The incidence of perioperative neurocognitive disorders (PND) is high, especially after cardiac surgeries, and the underlying mechanisms remain elusive. Here, we conducted a prospective observational study to observe serum proteomics differences in PND patients after cardiac valve replacement surgery. Methods Two hundred and twenty-six patients who underwent cardiac valve surgery were included. They were categorized based on scoring into non-PND group (group non-P) and PND group (group P’). The risk factors associated with PND were analyzed. These patients were further divided into group C and group P by propensity score matching (PSM) to investigate the serum proteome related to the PND by serum proteomics. Results The postoperative 6-week incidence of PND was 16.8%. Risk factors for PND include age, chronic illness, sufentanil dosage, and time of cardiopulmonary bypass (CPB). Proteomics identified 31 down-regulated proteins and six up-regulated proteins. Finally, GSTO1, IDH1, CAT, and PFN1 were found to be associated with PND. Conclusion The occurrence of PND can impact some oxidative stress proteins. This study provided data for future studies about PND to general anaesthesia and surgeries.

Abstract Object detection techniques have been widely used in power system equipment maintenance. However, in power systems, the accuracy of object detection is limited by the scarcity of publicly available datasets and the lack of scene pertinence. In order to solve these problems, an object detection method based on cloud data fusion and transfer learning (YOLO‐DFT) for power system equipment maintenance is proposed. Illustratively, YOLO‐DFT focuses on the object detection task involving birds and humans, generating a substantial and resilient human‐bird dataset through cloud‐based data fusion to compensate for the dearth of public datasets in the power system domain. By seamlessly integrating the YOLOv5 algorithm with a transfer learning strategy, a targeted detection mechanism for specific locations is meticulously formulated. The experimental results demonstrate that YOLO‐DFT effectively addresses object detection challenges in power systems, achieving a Mean Average Precision (MAP) measure of 0.925 across all classes, thereby providing a valuable reference for the maintenance of power system equipment.

AbstractContext Plantamajoside (PMS) possesses rich pharmacological characteristics that have been applied to remedy dozens of diseases. However, the understanding of PMS in sepsis remains insufficient.Objective Role of PMS in sepsis-regulated organ dysfunction and potential mechanisms were investigated.Materials and methods Thirty C57BL/6 male mice were adaptive fed for three days and used to establish acute sepsis model by caecal ligation and perforation (CLP). These experimental mice were divided into Sham, CLP, CLP + 25 mg PMS/kg body weight (PMS/kg), CLP + 50 mg PMS/kg and CLP + 100 mg PMS/kg (n = 6). The pathological and apoptotic changes of lung, liver and heart tissues were observed via HE and TUNEL staining. The injury-related factors of lung, liver and heart were detected by corresponding kits. ELISA and qRT-PCR were applied to assess IL-6/TNF-α/IL-1β levels. Apoptosis-related and TRAF6/NF-κB-related proteins were determined using Western blotting.Results All doses of PMS enhanced the survival rates in the sepsis-induced mouse model. PMS remitted sepsis-mediated lung, liver and heart injury through prohibiting MPO/BALF (70.4%/85.6%), AST/ALT (74.7%/62.7%) and CK-MB/CK (62.3%/68.9%) levels. Moreover, the apoptosis index (lung 61.9%, liver 50.2%, heart 55.7% reduction) and IL-6/TNF-α/IL-1β levels were suppressed by PMS. Furthermore, PMS lowered TRAF6 and p-NF-κB p65 levels, whereas TRAF6 overexpression reversed the protective influences of PMS in organ injury, apoptosis and inflammation triggered by sepsis.Discussion and conclusions PMS suppressed sepsis-induced organ dysfunction by regulating the TRAF6/NF-κB axis, and PMS treatment may be considered as a novel strategy for sepsis-caused damage in future.

Odorant receptor (OR) is crucial for insects to detect and recognize external chemical cues closely related to their survival. The insect OR forms a heteromeric complex composed of a ligand-specific receptor and a ubiquitously odorant receptor coreceptor (Orco). This study used the CRISPR/Cas9 technique to knock out (KO) Orco and reveal its essential role in acting on OR-meditated olfactory behavior in a critical invasive agricultural pest, the fall armyworm (FAW), Spodoptera frugiperda. Electroantennogram (EAG) results suggested that the Orco mutants of both male and female moths severely reduced their electrophysiological responses to the eight tested plant volatiles and two sex pheromones. However, the Orco gene played distinct roles in mating behavior between sexes: the mating behavior was fully disrupted in mutated males but not in mutated females. The oviposition result indicated that the Orco KO females displayed reduced egg laying by 24.1% compared with the mated wild type (WT) females. Overall, these results strongly suggest that Orco is an excellent target for disrupting FAW’s normal behavior and provides a feasible pest control approach.

Abstract Background Fiberoptic bronchoscopy (FOB) and bronchoscopic biopsy are the established methods for diagnosing and treating sputum crust. However, sputum crust in concealed locations can sometimes be missed or undiagnosed, even with bronchoscopy. Case presentation We present the case of a 44-year-old female patient who experienced initial extubation failure and postoperative pulmonary complications (PPCs) due to the missed diagnosis of sputum crust by FOB and low-resolution bedside chest X-ray. The FOB examination showed no apparent abnormalities prior to the first extubation, and the patient underwent tracheal extubation 2 h after aortic valve replacement (AVR). However, she was reintubated 13 h after the first extubation due to a persistent irritating cough and severe hypoxemia, and a bedside chest radiograph revealed pneumonia and atelectasis. Upon performing a repeat FOB examination prior to the second extubation, we serendipitously discovered the presence of sputum crust at the end of the endotracheal tube. Subsequently, we found that the sputum crust was mainly located on the tracheal wall between the subglottis and the end of the endotracheal tube during the “Tracheobronchial Sputum Crust Removal” procedure, and most of the crust was obscured by the retained endotracheal tube. The patient was discharged on the 20th day following therapeutic FOB. Conclusion FOB examination may miss specific areas in endotracheal intubation (ETI) patients, particularly the tracheal wall between the subglottis and distal end of the tracheal catheter, where sputum crust can be concealed. When diagnostic examinations with FOB are inconclusive, high-resolution chest CT can be helpful in identifying hidden sputum crust.

Abstract Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.

Abstract Chemotherapy is one of the main treatments for hematologic malignancies. However, chemotherapy‐induced peripheral neuropathy (CIPN) is one of the most common long‐term toxic reactions in chemotherapy, and the occurrence of CIPN affects patients’ quality of life and can cause interruption of chemotherapy in severe cases, thus reducing the efficacy of chemotherapy. We currently summarize the existing CIPN animal models, including the characteristics of several common animal models such as bortezomib‐induced peripheral neuropathy, vincristine‐induced peripheral neuropathy, and oxaliplatin‐induced peripheral neuropathy. It was found that CIPN may lead to behavioral, histopathological, and neurophysiological changes inducing peripheral neuropathy. However, the mechanism of CIPN has not been fully elucidated, especially the prevention and treatment protocols need to be improved. Therefore, this review article summarizes the progress of research on CIPN animal models and the possible mechanisms and treatment of CIPN.

Abstract Stellate ganglion (SG) intervention is currently widely being studied in many kinds of chronic pain. As one of the convenient ways to treat the sympathetic nervous system, the indications for stellate ganglion intervention (SGI) include complex regional pain syndrome, postherpetic neuralgia, cancer pain of different origins, orofacial pain, and so forth. SGI refers to the reversible or irreversible blocking of the cervical sympathetic trunk, cervical sympathetic ganglion, and their innervation range through noninvasive or minimally invasive treatment. Current treatment options include stellate ganglion block (SGB), SG pulsed radiofrequency, continuous radiofrequency treatment, and noninvasive SGB. In particular, SGB continues to be one of the most studied methods in chronic pain management. However, a single SGB usually provides only short‐term effects; repeated SGB may result in complications such as hoarseness, light‐headedness, and vessel or nerve injury. Meanwhile, the mechanism of SGI is still unclear. This review discusses the research progress of SGI methods, effectiveness, complications, and possible mechanisms in the management of chronic pain.

Abstract Background The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury. Methods The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated. Results Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice. Conclusion These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Abstract Norepinephrine (NE) is an important neurotransmitter in the central nervous system. NE is released from locus coeruleus neurons and is involved in a variety of physiological and pathological processes. Neuroinflammation is a common manifestation of many kinds of neurological diseases. The activation of microglia directly affects the status of neuroinflammation. Several kinds of adrenergic receptors, which anchor on microglia and can be regulated by NE, affect the activation of microglia and neuroinflammation. NE influences chronic pain, anxiety, and depression by regulating the activation of microglia.

Resumo Fundamento 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). Objetivos Avaliar se a dexmedetomidina (DEX) tem efeito protetivo na I/R do miocárdio e explorar os possíveis mecanismos por trás dela. Métodos 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. P< 0,05 foi considerado para indicar a diferença estatisticamente significativa. Resultados 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. Conclusões O pré-tratamento com DEX reduziu a lesão de I/R no miocárdio ao suprimir a apoptose, o que foi induzido pela via PERK.

Abstract Background Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. Method This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. Results Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. Conclusions In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.

Summary: Neonatal repetitive noxious stimuli (RNS) has been shown to cause long-term harmful effects on nociceptive processing, learning, and memory which persist until adulthood. Plasticity-related gene 1 (PRG-1) regulates synaptic plasticity and functional reorganization in the brain during neuronal development. In this study, neonatal RNS rats were established by repetitive needle pricks to neonatal rats on all four feet to model repetitive pain exposure in infants. Neonatal RNS caused thermal hyperalgesia, mechanical allodynia, learning, and memory impairments which manifested in young rats and persisted until adulthood. Hippocampal PRG-1/N-ethylmaleimide sensitive fusion protein (NSF) interaction was determined to be responsible for the RNS-induced impairment via enhanced extracellular glutamate release and AMPAR GluR2 trafficking deficiency in a cell-autonomous manner. These pathways likely act synergistically to cause changes in dendritic spine density. Our findings suggest that PRG-1 prevents the RNS-induced hyperalgesia, learning, and memory impairment by regulating synaptic plasticity via NSF/Glu/GluR2 signaling.

Background: Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used as a general anaesthetic. However, the mechanisms of analgesic/anaesthetic effects induced by ketamine are only partially understood. Previously, studies have demonstrated that various general anaesthetics affect the primary somatosensory cortex (S1), a potential target of general anaesthetics in the central nervous system. However, it is unknown if astrocyte activities affect ketamine’s effects on information transmission in S1 pyramidal neurons. Methods: The whole-cell patch-clamp technique was employed to study the role of astrocytes in ketamine-induced anaesthetic actions. The whole-cell patch-clamp method was used to record the spontaneous postsynaptic currents (SPSCs) of rat S1 pyramidal neurons. We used the glia-selective inhibitor of the aconitase enzyme fluorocitrate (FC), to test if astrocyte activities alter the effects of ketamine on S1 pyramidal neurons. Results: Ketamine lowered the SPSCs of rat S1 pyramidal neurons in a concentration-dependent manner at clinically relevant doses. The concentration-effect curve revealed that ketamine had an EC50 value of 462.1 M for suppressing SPSCs. In rat S1 pyramidal neurons, the glia-selective metabolic inhibitor fluorocitrate (FC), which inhibits the aconitase enzyme, lowered the amplitude and frequency of SPSCs. The inhibitory impact of ketamine on the amplitude and frequency of SPSCs was significantly amplified in the presence of FC. Conclusions: Astrocytes impact the effects of ketamine on pre- and postsynaptic components and play a role in synaptic transmission.

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Background: To analyze the correlation between clinical course and radiographic development on computed tomography (CT) in patients with confirmed coronavirus disease 2019 (COVID-19) and to provide more evidence for treatment. Methods: This retrospective, observational, cohort study enrolled 49 patients with Reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19, which included 30 patients admitted to the intensive care unit (ICU) of Wuhan Third Hospital and 19 patients either admitted to or receiving telemedicine consultation from Shanghai General Hospital, Shanghai Xuhui Dahua Hospital, and hospitals in other provinces. CT scans were performed in all enrolled patients and the radiographic features including simple ground-glass opacities (GGOs), GGO with interlobular septal thickening, consolidations with GGO, and consolidations only were monitored by repeating the CT. The progression of these radiographic features was analyzed in combination with their clinical staging and the time interval between onset of symptoms to CT. Results: Based on illness severity, the 49 patients were classified into four stages: mild (n = 6), moderate (n = 12), severe (n = 16), and critically ill (n = 15). The CT findings were classified into three phases: early (n = 5), progression (n = 39), and recovery (n = 5). Among the 49 patients, 9 had bilateral diffuse GGO or diffuse consolidations (white lungs) and were counted as 18 lesions. Three patients had no abnormal findings on initial CT, but their repeat CT showed new lesions. In all, we identified 892 lesions including simple GGO, GGO with interlobular septal thickening, consolidations with GGO, and consolidations only. Conclusions: Most patients had pulmonary lesions on the posterior, inferior, and peripheral lung fields on CT. The development of GGO with interlobular septal thickening, GGO with consolidations, and consolidations only happened mainly between day 8 and 14. The emergence of consolidations may suggest the progression to the severe phase of the illness, whereas simple consolidations or “white lung” may suggest a critically ill phase.

Background Disorders of consciousness (DOC) are neurocognitive disorders related to sharp fluctuations of attention and consciousness, while DOC is characterized by significant interindividual differences, rapid development, and a higher lethal rate. Case information A 53‐year‐old female patient underwent general anesthesia with tracheal intubation in otoendoscopic tympanoplasty. The patient suddenly appeared moderate DOC after tracheal tube removal with K+ 3.6 (3.5–5.3 mmol/L). Based on the ancillary testing and routine laboratory workup, the possible causes of DOC, such as general anesthesia drugs and cardio cerebral events, were temporarily excluded. DOC was reversed by intravenous administration of KCl 1 g, with K+ 3.78 mmol/L. On one day after surgery, the patient occurred suddenly DOC again after intravenous guttae of 5% glucose 1000 ml, K+ 3.87 mmol/L, possibly because of her recurrent hypokalemic paralysis (HP) of past medical history. The patient's consciousness gradually improved after effective KCl supplementation therapy. Conclusion DOC caused by periodic paralysis (PP) has not been reported, we speculate that hypoactive DOC is closely correlated with normokalemic periodic paralysis (NormoPP) in this case.

BackgroundOmega-3 polyunsaturated fatty acids (n-3 PUFAs) augmentation of antidepressants has shown great potential in the prevention and treatment of major depressive disorders (MDD).ObjectiveTo investigate the effect of n-3 PUFAs plus venlafaxine in patients with first-diagnosed, drug-naïve depression.MethodA total of 72 outpatients with first-diagnosed depression were recruited. The daily dose of 2.4 g/day n-3 PUFAs or placebo plus venlafaxine was used for over 12 weeks. The outcomes were assessed by the Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA), Beck depression inventory (BDI), and Self-rating anxiety scale (SAS).ResultsBoth groups exhibited improvement on clinical characteristics at week 4 and week 12 compared with baseline. The rate of responders for anxiety in n-3 PUFAs group (44.44%) was significantly higher than that in placebo group (21.21%) at week 4 (χ2 = 4.182, p = 0.041), while week 12 did not show a difference (χ2 = 0.900, p = 0.343). The rate of responders for depression at both week 4 (χ2 = 0.261, p = 0.609) and week 12 (χ2 = 1.443, p = 0.230) showed no significant difference between two groups. Further analysis found that Childhood Trauma Questionnaire (CTQ) had positive correlation with HAMA (r = 0.301, p = 0.012), SAS (r = 0.246, p = 0.015), HAMD (r = 0.252, p = 0.038) and BDI (r = 0.233, p = 0.022) with Pearson correlation analysis. Social Support Rating Scale (SSRS) had negative correlation with SAS (r = −0.244, p = 0.015) and BDI (r = −0.365, p = 0.000).ConclusionThis trial found that n-3 PUFAs supplementation in favor of venlafaxine alleviated the anxiety symptoms rather than depressive symptoms at the early stage of treatment (4 weeks) for first-diagnosed, drug-naïve depressed patients. However, the advantage disappeared in long-term treatment. Furthermore, childhood abuse and social support are closely related to the clinical and biological characteristics of depression. Both childhood trauma and lack of social support might be predictors of poor prognosis in depression.Clinical Trial Registration[clinicaltrials.gov], identifier [NCT03295708].

Summary: Two-electrode voltage clamp (TEVC) combined with the Xenopus laevis oocytes heterologous expression system is a powerful electrophysiological tool widely used to study the properties of many transmembrane proteins. Here, we describe a protocol using this combined approach to identify the ligands of odorant receptors that form ligand-gated ion channels. We detail the procedures for site-directed mutagenesis, oocyte microinjection, and TEVC recording. This protocol can also be used to identify the key residues and illustrate the structure-function relationships of these proteins.For complete details on the use and execution of this protocol, please refer to Cao et al. (2021).

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 simple and straightforward addition or defluorination of α-(trifluoromethyl)styrenes with 2-nitroimino-imidazolidine (2a), 2-(nitromethylene)imidazolidine (2b), 2-cyanoimino-thiazolidine (2c), and (E)-1-methyl-2-nitroguanidine (2d), in a controlled manner, was developed. The hydroamination of α-(trifluoromethyl)styrenes with 2a, 2b, 2c, and 2d was completed in the presence of DBN at room temperature within 0.5–6 h, affording structurally diverse β-trifluoromethyl-β-arylethyl analogues of neonicotinoids in moderate to good yields. The γ,γ-difluoro-β-arylallyl analogues of neonicotinoids were also successfully synthesized via defluorination of α-(trifluoromethyl)styrenes, with 2a and 2c using NaH as base at an elevated temperature together with a prolonged reaction time of 12 h. The method features simple reaction setup, mild reaction conditions, broad substrate scope, high functional group compatibility, and easy scalability.

Abstract 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.

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.

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.

BackgroundAbnormalities of functional connectivity (FC) in certain brain regions are closely related to the pathophysiology of major depressive disorder (MDD). Findings are inconsistent with different presuppositions in regions of interest. Our research focused on voxel-wise brain-wide FC changes in patients with MDD in an unbiased manner.MethodWe examined resting-state functional MRI in 23 patients with MDD and 26 healthy controls. Imaging data were analyzed by using global-brain FC (GFC) and used to explore the correlation of abnormal GFC values with clinical variables.ResultsIncreased GFC values in the left medial superior frontal gyrus (SFGmed) and decreased GFC values in the right supplementary motor area (SMA) were observed in the patients with MDD compared with the controls. The decreased GFC values in the right SMA had a positive correlation with vitamin D and Hamilton Anxiety Scale (HAM-A) scores.ConclusionAbnormal GFC in the hate circuit, particularly increased GFC in the left SFGmed and decreased GFC in the right SMA, appears to be a new sight for comprehending the pathological alterations in MDD.

Summary: The sex pheromone processing system of moths has been a major focus of research on olfaction and speciation, as it is highly specific and closely related to reproductive isolation. The two noctuid moths Heliothis virescens and Heliothis subflexa have been used as a model for deciphering the mechanisms underlying differentiation in pheromone communication, but no information exist regarding the functions of the pheromone receptors (PRs) of H. subflexa. Here, we functionally characterized all candidate PRs of H. subflexa, and found that only the response profile of OR6 differed between the two species. Through domain swapping and site-directed mutation followed by functional characterization, we identified a critical amino acid in OR6 caused a one-way alteration in specificity. This result suggests HsubOR6 evolved from an ancestral OR6 gene with a HvirOR6-like function and implies that the evolutionary direction of the receptor specificity was from the H. virescens-like pattern to H. subflexa-like pattern.

The olfactory system of insects is essential in many crucial behaviors, such as host seeking, mate recognition, and locating oviposition sites. Lepidopteran moths possess two main olfactory organs, including antennae and labial palps. Compared to antennae, the labial palps are relatively specific and worthy of further investigation due to the labial-palp pit organ (LPO), which contains a large number of sensilla located on the tip segment. The fall armyworm, Spodoptera frugiperda, is a worldwide lepidopteran pest, which can damage more than 350 plants and cause significant economic losses. In this study, we surveyed the structure of the labial palps and LPO of S. frugiperda using a super-high magnification lens zoom 3D microscope. Then, the distribution and fine structure of sensilla located in the LPO of S. frugiperda were investigated using scanning electron microscopy. Subsequently, the electrophysiological responses of labial palps to CO2 and 29 plant volatiles were recorded by using electrolabialpalpography. Our results showed the fine structure of labial palps, the LPO, and the sensilla located in the LPO of S. frugiperda. Moreover, we demonstrated that the labial palps are olfactory organs that respond to both CO2 and other volatile compounds. Our work established a foundation for further study of the roles of labial palps in insect olfactory related behaviors. Further investigations on the function of labial palps and their biological roles together with CO2 and volatile compound responses in S. frugiperda are necessary, as they may provide better insect behavioral regulators for controlling this pest.

Long non-coding RNAs (lncRNAs) have a considerable regulatory influence on multiple biological processes. Nevertheless, the role of TMEM220-AS1 in hepatocellular carcinoma (HCC) remains unclear. We used The Cancer Genome Atlas (TCGA) database to analyze the differentially expressed lncRNAs. qRT-PCR was used to verify the results for a large population. The in vitro effects of TMEM220-AS1 on HCC cells were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, and Transwell assays in HCC cells. We used qRT-PCR and western blotting to identify the epithelial-mesenchymal transition (EMT). Moreover, we performed bioinformatics analysis, western blotting, dual luciferase reporter gene assay, RNA pull-down, and RNA binding protein immunoprecipitation (RIP) to investigate the underlying molecular mechanisms of TMEM220-AS1 function. Finally, the function of TMEM220-AS1 was verified in vivo. The results showed that TMEM220-AS1 was expressed at considerably low levels in HCC. It was demonstrated that malignant phenotypes and EMT of HCC cells were promoted by the knock down of TMEM220-AS1 both in vivo and in vitro. TMEM220-AS1, which was detected primarily in the cytoplasm, functioned as an miRNA sponge to bind miR-484 and promote the level of membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1), thereby curbing the malignant phenotypes of HCC cells. In conclusion, low levels of TMEM220-AS1 promote proliferation and metastasis through the miR-484/MAGI1 axis in HCC.

Abstract Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer’s disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.

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.

This study aimed to explore the application value of nalbuphine in pulsed radiofrequency operation of trigeminal ganglion in patients with postherpetic neuralgia (PHN). Thirty patients with PHN were randomly divided into the nalbuphine (Nalbu) group and ketorolac tromethamine (KT) group and received CT-guided pulsed radiofrequency surgery on trigeminal ganglion. The numeric rating scale (NRS) scores of patients were recorded at preoperative, intraoperative, and postoperative time points, before going to bed, and the next morning after the operation. In addition, the number of breakthrough pain before operation and within 24 hours after operation, the incidence of nausea and vomiting within 24 hours after surgery, and the patient’s sleep quality before and on the day after surgery were evaluated. The outcome data demonstrated that patients treated with nalbuphine had lower NRS scores after the pulse radiofrequency operation during and after the pulse radiofrequency operation compared to those with KT. In addition, nalbuphine effectively decreased the number of breakthrough pain, reduced the occurrence of nausea and vomiting after surgery, and improved the sleep quality. In conclusion, intramuscular injection of nalbuphine 30 min before trigeminal ganglion pulse radiofrequency surgery can be conducive to pain relief and improve the postoperative comfort of patients, providing an effective alternative for the alleviation of PHN in clinic.

Detection of community structure has become a fundamental step in the analysis of biological networks with application to protein function annotation, disease gene prediction, and drug discovery. This recent impact creates a need to make these techniques and their accompanying visualization schemes available to a broad range of biologists. Here we present a service-oriented, end-to-end software framework, CDAPS (Community Detection APplication and Service), that integrates the identification, annotation, visualization, and interrogation of multiscale network communities, accessible within the popular Cytoscape network analysis platform. With novel design principles, CDAPS addresses unmet new challenges, such as identifying hierarchical community structures, comparison of outputs generated from diverse network resources, and easy deployment of new algorithms, to facilitate community-sourced science. We demonstrate that the CDAPS framework can be applied to high-throughput protein-protein interaction networks to gain novel insights, such as the identification of putative new members of known protein complexes.

Objective To assess the expression of inflammatory cytokines in the affected and normal skin of postherpetic neuralgia (PHN) patients. Methods Affected skin and normal skin samples were collected from PHN patients. Inflammatory cell infiltration in the dermis were evaluated by hematoxylin-eosin (HE) staining. A human inflammatory protein array containing 40 cytokines was used to assess expression differences between PHN and control skin. Enzyme linked immunosorbent assay (ELISA) kits were used to confirm cytokine expression in 10 PHN patients. Results HE staining showed that the epidermis of PHN skin was thicker than that of contralateral normal skin. Compared with normal skin, there was more infiltration of inflammatory cells into the dermis of PHN skin. The cytokine array detected the presence of 21/40 cytokines; however, only interleukin (IL)-1α showed differential expression between PHN skin and normal skin. ELISA results for IL-1α, IL-16, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 were consistent with those of cytokine arrays. Conclusions Expression of inflammatory cytokines in PHN skin was not significantly altered compared with normal skin. Chronic refractory pain in PHN is not necessarily associated with increased inflammation in the affected skin.

The Lepidoptera is the second largest insect order, which has the most extensive knowledge of sex pheromones and mechanisms of pheromone communication since the identification of the first insect pheromone in Bombyx mori. In the past 15 years, pheromone receptors have been identified and functionally characterized in many moth species. HarmOR14 is a typical pheromone receptor of Helicoverpa armigera which showed no response to the tested pheromones in Xenopus oocyte expression system, but its orthologous gene in Heliothis virescens, HvirOR14 could be activated by pheromones in the same expression system. To assess the possible functions of OR14 in vivo, in this study, we knocked out this gene using CRISPR/Cas9 system and compared the mating behaviors and EAG response to pheromones between the wild type and mutant strains. Our results showed that OR14 mutants did not affect the mating rate or the EAG response to pheromones but could prolong the mating duration and change the mating time in undefined manners, which extends our understanding to this kind of pheromone receptors.

Sex pheromone receptors (PRs) are key players in chemical communication between mating partners in insects. In the highly diversified insect order Lepidoptera, male PRs tuned to female-emitted type I pheromones (which make up the vast majority of pheromones identified) form a dedicated subfamily of odorant receptors (ORs). Here, using a combination of heterologous expression and in vivo genome editing methods, we bring functional evidence that at least one moth PR does not belong to this subfamily but to a distantly related OR lineage. This PR, identified in the cotton leafworm Spodoptera littoralis, is highly expressed in male antennae and is specifically tuned to the major sex pheromone component emitted by females. Together with a comprehensive phylogenetic analysis of moth ORs, our functional data suggest two independent apparitions of PRs tuned to type I pheromones in Lepidoptera, opening up a new path for studying the evolution of moth pheromone communication.

Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.

Background: Ketamine is a commonly used intravenous anesthetic which produces dissociation anesthesia, analgesia, and amnesia. The mechanism of ketamine-induced synaptic inhibition in high-level cortical areas is still unknown. We aimed to elucidate the effects of different concentrations of ketamine on the glutamatergic synaptic transmission of the neurons in the primary somatosensory cortex by using the whole-cell patch-clamp method. Methods: Sprague-Dawley rats (11–19 postnatal days, n=36) were used to obtain brain slices (300 μM). Spontaneous excitatory postsynaptic currents (data from 40 neurons) were recorded at a command potential of -70 mV in the presence of bicuculline (a competitive antagonist of GABAA receptors, 30 μM) and strychnine (glycine receptor antagonist, 30 μM). Miniature excitatory postsynaptic currents (data from 40 neurons) were also recorded when 1 μM of tetrodotoxin was added into the artificial cerebrospinal fluid. We used GraphPad Prism5for statistical analysis. Significant differences in the mean amplitude and frequency were tested using the Student paired 2-tailed t test. Values of P

Summary: How general anesthesia causes loss of consciousness has been a mystery for decades. It is generally thought that arousal-related brain nuclei, including the locus coeruleus (LC), are involved. Here, by monitoring locomotion behaviors and neural activities, we developed a larval zebrafish model for studying general anesthesia induced by propofol and etomidate, two commonly used intravenous anesthetics. Local lesion of LC neurons via two-photon laser-based ablation or genetic depletion of norepinephrine (NE; a neuromodulator released by LC neurons) via CRISPR/Cas9-based mutation of dopamine-β-hydroxylase (dbh) accelerates induction into and retards emergence from general anesthesia. Mechanistically, in vivo whole-cell recording revealed that both anesthetics suppress LC neurons’ activity through a cooperative mechanism, inhibiting presynaptic excitatory inputs and inducing GABAA receptor-mediated hyperpolarization of these neurons. Thus, our study indicates that the LC-NE system plays a modulatory role in both induction of and emergence from intravenous general anesthesia. : The locus coeruleus (LC)-norepinephrine (NE) system is involved in general anesthesia. Here, Du et al. show that the LC-NE system plays a modulatory role in the induction and emergence of intravenous general anesthesia induced by propofol and etomidate, both of which suppress LC neuronal activities through a cooperative mechanism. Keywords: propofol, etomidate, intravenous general anesthesia, norepinephrine, locus coeruleus, zebrafish

Lepidopteran insects use sex pheromones for sexual communication. Pheromone receptors expressed on peripheral olfactory receptor neurons (ORNs) are critical part to detect the sex pheromones. In genus Ostrinia, several pheromone receptors were functional analyzed in O. nubilalis and O. scapulalis but the knowledge in O. furnacalis was rare. In this study, seven pheromone receptors were deorphanized by heterologous expression system of Xenopus oocytes. Functional types of sensilla trichoidea were classified by single sensillum recordings to interpret the response pattern of olfactory sensory neurons to Ostrinia pheromone components. OfurOR4 and OfurOR6 responded to the major sex pheromone Z/E12-14:OAc. OfurOR4 is the main receptor for both Z/E12-14:OAc and OfurOR6 mainly responded to E12-14:OAc. Functional differentiation of gene duplication were found between OfurOR5a and OfurOR5b. OfurOR5b showed a broad response to most of the pheromone components in O. furnacalis, whereas OfurOR5a was found without ligands. OfurOR7 showed a specific response to Z9-14:OAc and OfurOR8 mainly responded to Z11-14:OAc and E11-14:OAc. OfurOR3 did not respond to any pheromone components. Our results improved the current knowledge of pheromone reception in Ostrinia species which may contribute to speciation.

Summary: Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. : Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability. Keywords: fusion, cancer, RNA, translocation, gene fusions

Summary: For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. : Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease. Keywords: splicing, RNA, mutations of clinical relevance