Identifications of novel host cell factors that interact with the receptor-binding domain of the SARS-CoV-2 spike protein.

SARS-CoV-2 entry into host cells is facilitated by the interaction between the receptor-binding domain of its spike protein (CoV2-RBD) and host cell receptor, ACE2, promoting viral membrane fusion. The virus also uses endocytic pathways for entry, but the mediating host factors remain largely unknown. It is also unknown whether mutations in the RBD of SARS-CoV-2 variants promote interactions with additional host factors to promote viral entry. Here, we used the GST pull-down approach to identify novel surface-located host factors that bind to CoV2-RBD. One of these factors, SH3BP4, regulates internalization of CoV2-RBD in an ACE2-independent but integrin- and clathrin-dependent manner and mediates SARS-CoV-2 pseudovirus entry, suggesting that SH3BP4 promotes viral entry via the endocytic route. Many of the identified factors, including SH3BP4, ADAM9, and TMEM2, show stronger affinity to CoV2-RBD than to RBD of the less infective SARS-CoV, suggesting SARS-CoV-2-specific utilization. We also found factors preferentially binding to the RBD of the SARS-CoV-2 Delta variant, potentially enhancing its entry. These data identify the repertoire of host cell surface factors that function in the events leading to the entry of SARS-CoV-2.

Reference gene catalog and metagenome-assembled genomes from the gut microbiome reveal the microbial composition, antibiotic resistome, and adaptability of a lignocellulose diet in the giant panda.

The giant panda, a strict herbivore that feeds on bamboo, still retains a typical carnivorous digestive system. Reference catalogs of microbial genes and genomes are lacking, largely limiting the antibiotic resistome and functional exploration of the giant panda gut microbiome. Here, we integrated 177 fecal metagenomes of captive and wild giant pandas to construct a giant panda integrated gene catalog (GPIGC) comprised of approximately 4.5 million non-redundant genes and reconstruct 393 metagenome-assembled genomes (MAGs). Taxonomic and functional characterization of genes revealed that the captivity of the giant panda significantly changed the core microbial composition and the distribution of microbial genes. Higher abundance and prevalence of antibiotic resistance genes (ARGs) were detected in the guts of captive giant pandas, and ARG distribution was influenced by geography, for both captive and wild individuals. Escherichia, as the prevalent genus in the guts of captive giant pandas, was the main carrier of ARGs, meaning there is a high risk of ARG transmission by Escherichia. We also found that multiple mcr gene variants, conferring plasmid-mediated mobile colistin resistance, were widespread in the guts of captive and wild giant pandas. There were low proportions of carbohydrate-active enzyme (CAZyme) genes in GPIGC and MAGs compared with several omnivorous and herbivorous mammals. Many members of Clostridium MAGs were significantly enriched in the guts of adult, old and wild giant pandas. The genomes of isolates and MAGs of Clostridiaceae harbored key genes or enzymes in complete pathways for degrading lignocellulose and producing short-chain fatty acids (SCFAs), indicating the potential of these bacteria to utilize the low-nutrient bamboo diet. Overall, our data presented an exhaustive reference gene catalog and MAGs in giant panda gut and provided a comprehensive understanding of the antibiotic resistome and microbial adaptability for a high-lignocellulose diet.

Association of remnant cholesterol with CVD incidence: a general population cohort study in Southwest China.

Background: Emerging evidence has indicated that remnant cholesterol (RC) could predict cardiovascular disease (CVD) incidence. Nevertheless, the relationship between RC and CVD risk, especially within the general Chinese population, remains scarce. Objective: The present research aimed to assess whether RC concentrations and CVD outcomes in general Chinese adults are related. Methods: The Cox proportional hazard model was established to explore the relationship between RC and the outcomes of CVD and CVD subgroups. A restricted cubic spline (RCS) was utilized to investigate the dose-response connection between RC and the risk of CVD outcomes, and the ROC curve was used to calculate the corresponding cutoff values. Moreover, stratified analysis was conducted to investigate the potential effect modification in the association between RC and CVD outcomes. Results: Significant positive associations were found between elevated categorical RC and increased risk of CVD (HR Q4, 1.80; 95% CI 1.15-2.79; P-value = 0.008), atherosclerotic cardiovascular disease (HR Q4, 2.00; 95% CI 1.22-3.27; P-value = 0.007), stroke (HR Q4, 1.66; 95% CI 1.02-2.69; P-value = 0.040), and ischemic stroke (HR Q4, 1.87, 95% CI 1.08-3.25; P-value = 0.034), respectively. Our study suggested that the incidence of CVD outcomes increased when RC levels were above 0.75 mmol/L. Importantly, the CVD risks related to RC were more likely to be those found in subjects aged above 60 years, women, subjects with BMI <24 kg/m2, and subjects with hypertension and unhealthy diet patterns. Conclusions: Aberrant high level of RC is associated with elevated CVD risk, independent of low-density lipoprotein cholesterol (LDL-C). Our data reveal urgent primary prevention for subjects with high RC levels to a low incidence of CVD, especially for the elderly, women, and those with hypertension and unhealthy diet patterns.

Aging-related histone modification changes in brain function.

Aging can be defined as a decline of physiological function that is more difficult to reverse, characterized by the loss of the physiological integrity of tissues, organs, and cells of an organism over time. Normal aging is associated with structural and functional changes in the brain, involving neuronal apoptosis, synaptic structure, neurotransmission, and metabolism alterations, leading to impairment in sleep, cognitive functions, memory, learning, and motor and sensory systems. Histone modification is a significant aging-related epigenetic change that influences synaptic and mitochondrial function and immune and stress responses in the brain. This review discusses the changes in histone modifications that occur during brain aging, specifically methylation and acetylation, and the associated changes in gene transcription and protein expression. We observed that genes related to synaptic and mitochondrial function are downregulated in the aging brain, while genes related to immune response and inflammatory functions are upregulated.

Genome-centric metagenomics provides new insights into metabolic pathways of polyhydroxyalkanoates biosynthesis and functional microorganisms subsisting on municipal organic wastes.

The microbial community of a sequencing batch reactor operated under feast and famine conditions for production of polyhydroxyalkanoates (PHAs) was characterized through high-throughput sequencing and metagenomic analysis. The fermented food waste and chemically-enhanced primary sludge was fed in this bioreactor. After acclimation, the PHA yield achieved as high as 0.60-0.69 g CODPHA/g CODS. The complete changes of microbial community structure were found during shifts of feedstock. A synthesis of SCL/MCL-PHAs pathway was established for PHA-producing bioreactor in this mixed-culture system. The structure-performance relationship of PHA-producing microbial community and feedstock composition was investigated. The results showed that microbial community tends to be decentralized and prefer team work for PHA synthesis to consume the multiple substrates and digest inevitable non-VFA contents in fermented liquor. This study also discovered unreported potential PHA producers (e.g., genera Tabrizicola, Nannocystis, Ga0077539, Ga0077559, JOSHI-001, SNC69-320 and UBA2334) subsisting on municipal organic wastes and expands the current knowledge about mixed-culture system that the PHA synthesis pathway is widely existed in activated sludge.

STING-IFN-I pathway relieves incision induced acute postoperative pain via inhibiting the neuroinflammation in dorsal root ganglion of rats.

BACKGROUND: The purpose of this study was to study the effect of STING-IFN-I pathway on incision induced postoperative pain in rats and its possible mechanisms. METHODS: The pain thresholds were evaluated by measuring the mechanical withdrawal threshold and the thermal withdrawal latency. The satellite glial cell and macrophage of DRG were analyzed. The expression of STING, IFN-a, P-P65, iNOS, TNF-α, IL-1ß and IL-6 in DRG was evaluated. RESULTS: The activation of STING-IFN-I pathway can reduce the mechanical hyperalgesia, thermal hyperalgesia, down-regulate the expression of P-P65, iNOS, TNF-α, IL-1ß and IL-6, and inhibit the activation of satellite glial cell and macrophage in DRG. CONCLUSIONS: The activation of STING-IFN-I pathway can alleviate incision induced acute postoperative pain by inhibiting the activation of satellite glial cell and macrophage, which reducing the corresponding neuroinflammation in DRG.

Dopamine D1-receptor-expressing pathway from the nucleus accumbens to ventral pallidum-mediated sevoflurane anesthesia in mice.

BACKGROUND: General anesthesia has long been used in clinical practice, but its precise pharmacological effects on neural circuits are not fully understood. Recent investigations suggest that the sleep-wake system may play a role in the reversible loss of consciousness induced by general anesthetics. Studies in mice have shown that microinjection of dopamine receptor 1 (D1R) agonists into the nucleus accumbens (NAc) promotes recovery from isoflurane anesthesia, while microinjection of D1R antagonists has the opposite effect. Furthermore, during the induction and maintenance of sevoflurane anesthesia, there is a significant decrease in extracellular dopamine levels in the NAc, which subsequently increases during the recovery period. These findings suggest the involvement of the NAc in the regulation of general anesthesia. However, the specific role of D1R-expressing neurons in the NAc during general anesthesia and the downstream effect pathways are still not well understood. METHODS: In order to analyze the impact of sevoflurane anesthesia on NAcD1R neurons and the NAcD1R -VP pathway, this study employed calcium fiber photometry to investigate alterations in the fluorescence intensity of calcium signals in dopamine D1-receptor-expressing neurons located in the nucleus accumbens (NAcD1R neurons) and the NAcD1R -VP pathway during sevoflurane anesthesia. Subsequently, optogenetic techniques were utilized to activate or inhibit NAcD1R neurons and their synaptic terminals in the ventral pallidum (VP), aiming to elucidate the role of NAcD1R neurons and the NAcD1R -VP pathway in sevoflurane anesthesia. These experiments were supplemented with electroencephalogram (EEG) recordings and behavioral tests. Lastly, a genetically-encoded fluorescent sensor was employed to observe changes in extracellular GABA neurotransmitters in the VP during sevoflurane anesthesia. RESULTS: Our findings revealed that sevoflurane administration led to the inhibition of NAcD1R neuron population activity, as well as their connections within the ventral pallidum (VP). We also observed a reversible reduction in extracellular GABA levels in the VP during both the induction and emergence phases of sevoflurane anesthesia. Additionally, the optogenetic activation of NAcD1R neurons and their synaptic terminals in the VP resulted in a promotion of wakefulness during sevoflurane anesthesia, accompanied by a decrease in EEG slow wave activity and burst suppression rate. Conversely, the optogenetic inhibition of the NAcD1R -VP pathway exerted opposite effects. CONCLUSION: The NAcD1R -VP pathway serves as a crucial downstream pathway of NAcD1R neurons, playing a significant role in regulating arousal during sevoflurane anesthesia. Importantly, this pathway appears to be associated with the release of GABA neurotransmitters from VP cells.

Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network.

BACKGROUND: Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear. METHODS: LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 µm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC-MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype. RESULTS: Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis. CONCLUSIONS: LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.

Antibiotic and heavy metal resistance genes in sewage sludge survive during aerobic composting.

Municipal sewage sludge has been generated in increasing amounts with the acceleration of urbanization and economic development. The nutrient rich sewage sludge can be recycled by composting that has a great potential to produce stabilized organic fertilizer and substrate for plant cultivation. However, little is known about the metals, pathogens and antibiotic resistance transfer risks involved in applying the composted sludge in agriculture. We studied changes in and relationships between heavy metal contents, microbial communities, and antibiotic resistance genes (ARGs), heavy metal resistance genes (HMRGs) and mobile genetic elements (MGEs) in aerobic composting of sewage sludge. The contents of most of the analyzed heavy metals were not lower after composting. The bacterial α-diversity was lower, and the community composition was different after composting. Firmicutes were enriched, and Proteobacteria and potential pathogens in the genera Arcobacter and Acinetobacter were depleted in the composted sludge. The differences in bacteria were possibly due to the high temperature phase during the composting which was likely to affect temperature-sensitive bacteria. The number of detected ARGs, HMRGs and MGEs was lower, and the relative abundances of several resistance genes were lower after composting. However, the abundance of seven ARGs and six HMRGs remained on the same level after composting. Co-occurrence analysis of bacterial taxa and the genes suggested that the ARGs may spread via horizontal gene transfer during composting. In summary, even though aerobic composting is effective for managing sewage sludge and to decrease the relative abundance of potential pathogens, ARGs and HMRGs, it might include a potential risk for the dissemination of ARGs in the environment.

Glutamatergic neurons in the paraventricular hypothalamic nucleus regulate isoflurane anesthesia in mice.

The glutamatergic-mediated excitatory system in the brain is vital for the regulation of sleep-wake and general anesthesia. Specifically, the paraventricular hypothalamic nucleus (PVH), which contains mainly glutamatergic neurons, has been shown to play a critical role in sleep-wake. Here, we sought to explore whether the PVH glutamatergic neurons have an important effect on the process of general anesthesia. We used c-fos staining and in vivo calcium signal recording to observe the activity changes of the PVH glutamatergic neurons during isoflurane anesthesia and found that both c-fos expression in the PVH and the calcium activity of PVH glutamatergic neurons decreased in isoflurane anesthesia and significantly increased during the recovery process. Chemogenetic activation of PVH glutamatergic neurons prolonged induction time and shortened emergence time from anesthesia by decreasing the depth of anesthesia. Using chemogenetic inhibition of PVH glutamatergic neurons under isoflurane anesthesia, we found that inhibition of PVH glutamatergic neurons facilitated the induction process and delayed the emergence accompanied by deepening the depth of anesthesia. Together, these results identify a crucial role for PVH glutamatergic neurons in modulating isoflurane anesthesia.

Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS.

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGTS) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF's prolonged elimination half-life and TGT's narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the Cmax and AUC0-t of TER were significantly decreased with separate co-administration, as the Cmax and AUC0-t were 30.17 ± 1.55 µg/mL and 24.47 ± 2.50 µg/mL, 374.55 ± 15.54 µg h/mL and 336.94 ± 21.19 µg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb−drug interactions between LEF and TGT have been proven.

FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS: Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS: First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS: Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.

[Clinical features of intestinal polyps and risk factors for secondary intussusception in children: an analysis of 2 669 cases]. / 2 669ä¾‹å„¿ç«¥è‚ æ¯è‚‰çš„ä¸´åºŠç‰¹å¾åŠç»§å‘è‚ å¥—å çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To study the clinical features of intestinal polyps and the risk factors for secondary intussusception in children. METHODS: A retrospective analysis was performed for the medical data of 2 669 children with intestinal polyps. According to the presence or absence of secondary intussusception, they were divided into two groups: intussusception (n=346) and non-intussusception (n=2 323). Related medical data were compared between the two groups. The multivariate logistic regression analysis was used to identify the risk factors for secondary intussusception. RESULTS: Among the children with intestinal polyps, 62.42% were preschool children, and the male/female ratio was 2.08∶1; 92.66% had hematochezia as disease onset, and 94.34% had left colonic polyps and rectal polyps. There were 346 cases of secondary intussusception, with an incidence rate of 12.96% (346/2 669). Large polyps (OR=1.644, P<0.001), multiple polyps (≥2) (OR=6.034, P<0.001), and lobulated polyps (OR=93.801, P<0.001) were the risk factors for secondary intussusception. CONCLUSIONS: Intestinal polyps in children often occur in preschool age, mostly in boys, and most of the children have hematochezia as disease onset, with the predilection sites of the left colon and the rectum. Larger polyps, multiple polyps, and lobulated polyps may increase the risk of secondary intussusception, and endoscopic intervention is needed as early as possible to improve prognosis.

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn.

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-1ß 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.

Phage-Antibiotic Therapy as a Promising Strategy to Combat Multidrug-Resistant Infections and to Enhance Antimicrobial Efficiency.

Infections caused by multidrug-resistant (MDR) bacteria have highlighted the importance of the development of new antimicrobial agents. While bacteriophages (phages) are widely studied as alternative agents to antibiotics, combined treatments using phages and antibiotics have exhibited Phage-Antibiotic Synergy (PAS), in which antibiotics promote phage replication and extraordinary antimicrobial efficacy with reduced development of bacterial resistance. This review paper on the current progress of phage-antibiotic therapy includes aspects of the mechanisms of PAS and the therapeutic performance of PAS in combating multidrug-resistant bacterial infections. The choice of phages and antibiotics, the administration time and sequence, and the concentrations of the two agents impact the bacterial inhibitory effects to different extents.

The effects of different doses of inhaled bacteriophage therapy for Pseudomonas aeruginosa pulmonary infections in mice.

OBJECTIVES: Inhaled phage therapy has been revisited as a potential treatment option for respiratory infections caused by multidrug-resistant Pseudomonas aeruginosa; however, there is a distinct gap in understanding the dose-response effect. The aim of this study was to investigate the dose-response effect of Pseudomonas-targeting phage PEV31 delivered by the pulmonary route in a mouse lung infection model. METHODS: Neutropenic BALB/c mice were infected with multidrug-resistant P. aeruginosa (2 × 104 colony-forming units) through the intratracheal route and then treated with PEV31 at three different doses of 7.5 × 104 (Group A), 5 × 106 (Group B), and 5 × 108 (Group C) plaque-forming units, or phosphate-buffered saline at 2 hours postinoculation. Mice (n = 5-7) were euthanized at 2 hours and 24 hours postinfection, and lungs, kidneys, spleen, liver, bronchoalveolar lavage fluid, and blood were collected for bacteria and phage enumeration. RESULTS: At 24 hours postinfection, all phage-treated groups exhibited a significant reduction in pulmonary bacterial load by 1.3-1.9 log10, independent of the delivered phage dose. The extent of phage replication was negatively correlated with the dose administered, with log10 titre increases of 6.2, 2.7, and 9 for Groups A, B, and C, respectively. Phage-resistant bacterial subpopulations in the lung homogenate samples harvested at 24 hours postinfection increased with the treatment dose (i.e. 30%, 74%, and 91% in respective Groups A-C). However, the mutants showed increased susceptibility to ciprofloxacin, impaired twitching motility, and reduced blue-green pigment production. The expression of the inflammatory cytokines (IL-1ß and IL-6, and TNF-α) was suppressed with increasing PEV31 treatment dose. DISCUSSION: This study provides the dose-response effect of inhaled phage therapy that may guide dose selection for treating P. aeruginosa respiratory infections in humans.

GABAA receptors in the basal forebrain mediates emergence from propofol anaesthesia in rats.

PURPOSE: The aim of the current study was to explore the role of the basal forebrain (BF) in propofol anaesthesia. METHODS: In the present study, we observed the neural activities of the BF during propofol anaesthesia using calcium fibre photometry recording. Subsequently, ibotenic acid was injected into the BF to verify the role of the BF in propofol anaesthesia. Finally, to test whether GABAA receptors in the BF were involved in modulating propofol anaesthesia, muscimol (GABAA receptor agonist) and gabazine (GABAA receptor antagonist) were microinjected into the BF. Cortical electroencephalogram (EEG), time to loss of righting reflex (LORR), and recovery of righting reflex (RORR) under propofol anaesthesia were recorded and analysed. RESULTS: The activity of BF neurons was inhibited during induction of propofol anaesthesia and activated during emergence from propofol anaesthesia. In addition, non-specifical lesion of BF neurons significantly prolonged the time to RORR and increased delta power in the frontal cortex under propofol anaesthesia. Next, microinjection of muscimol into the BF delayed emergence from propofol anaesthesia, increased delta power of the frontal cortex, and decreased gamma power under propofol anaesthesia. Conversely, infusion of gabazine accelerated emergence times and decreased EEG delta power. CONCLUSIONS: The basal forebrain is involved in modulating frontal cortex delta activity and emergence from propofol anaesthesia. Additionally, the GABAA receptors in the basal forebrain are involved in regulating emergence propofol anaesthesia.

Screening of autoantibodies as biomarkers in the serum of renal cancer patients based on human proteome microarray.

The autoantibody in patients' serum can act as a biomarker for diagnosing cancer, and the differences in autoantibodies are significantly correlated with the changes in their target proteins. In this study, 16 renal cancer (RC) patients were assigned to the disease group, and 16 healthy people were assigned to the healthy control (HC) group. The human proteome microarray consisting of>19,500 proteins was used to examine the differences in IgG and IgM autoantibodies in sera between RC and HC. The comparative analysis of the microarray results shows that 101 types of IgG and 25 types of IgM autoantibodies are significantly higher in RC than in HC. Highly responsive autoantibodies can be candidate biomarkers (e.g., anti-KCNAB2 IgG and anti-RCN1 IgM). Extensive enzyme-linked immunosorbent assay (ELISA) was performed to screen sera in 72 RC patients and 66 healthy volunteers to verify the effectiveness of the new autoantibodies. The AUCs of anti-KCNAB2 IgG and anti-GAPDH IgG were 0.833 and 0.753, respectively. KCNAB2 achieves high protein expression, and its high mRNA level is confirmed to be an unfavorable prognostic marker in clear cell renal cell carcinoma (ccRCC) tissues. This study suggests that the high-throughput human proteome microarray can effectively screen autoantibodies in serum as candidate biomarkers, and their corresponding target proteins can lay a basis for the in-depth investigation into renal cancer.

The role of intracerebral dopamine D1 and D2 receptors in sleep-wake cycles and general anesthesia.

Dopamine (DA), a monoamine neurotransmitter, is synthesized and released mainly by neurons in the ventral tegmental area and the substantia nigra (SN) pars compacta of the midbrain. DA and its receptors are essential for the regulation of arousal, movement, cognition, reward, and other neurobiological behaviors. Arousal, locomotion, cognition, reward, and other neurobiological functions are all regulated by dopamine and its receptors. Dopamine receptors can be divided into D1-like receptors (including D1 and D5) or D2-like receptors (containing D2, D3, and D4), with D1 and D2 receptors (D1Rs, and D2Rs) being the most important. Currently, studies indicated that D1Rs and D2Rs are tightly involved with the process of sleep-wake and general anesthesia, but the specific mechanism remains unclear. In this review, we compiled the most recent findings, mainly focusing on the structure, distribution, and signal pathway of D1Rs and D2Rs in the central nervous system, as well as the involvement of D1Rs and D2Rs in sleep-wake and general anesthesia. Thus, the investigations of the D1Rs and D2Rs will benefit not only better knowledge for how sleep-wake control works but also the mechanism of general anesthesia.

Research progress of the paraventricular thalamus in the regulation of sleep-wake and emotional behaviors.

The paraventricular thalamus (PVT) is a major component of the midline structure of the thalamus. It is one of the nonspecific nuclei of the thalamus, which plays a great role in the regulation of cortical arousal. PVT, an important node in the central nervous system, sends widespread outputs to many brain regions and also accepts plentiful inputs from many brain regions to modulate diverse functions, including sleep-wake state, attention, memory, and pain. Recently, with the increasing prevalence of sleep disorders and mood disorders, people pay great attention to PVT, which was implicated in arousal and emotional behaviors. Therefore, the main purpose of this review is to illustrate the characteristic of PVT to provide a reference for future research.