Postoperative cognitive dysfunction (POCD) is a significant postoperative complication, particularly in the elderly, linked to inflammation-mediated neural dysfunction. Insulin resistance and disruptions in transforming growth factor beta (TGF-β) signalling are associated with cognitive decline in aging, yet their roles in POCD are not fully understood. Here, we demonstrated that both insulin and TGF-β pathways were disrupted in POCD mouse models, with recombinant insulin and TGF-β treatments improving cognitive outcomes. These treatments reversed neuroinflammation in vitro, while CREB knockdown abrogated the protective effects, both in vivo and in vitro. Mechanistically, CREB was found to mediate the protective effects of insulin and TGF-β in POCD by directly regulating the expression of the cognitive-related protein NR2B. Altogether, our study identifies a key molecular target involved in the critical signalling pathways associated with POCD, offering promising therapeutic strategies for prevention and treatment.

Postoperative cognitive dysfunction (POCD) is a significant postoperative complication, particularly in the elderly, linked to inflammation-mediated neural dysfunction. Insulin resistance and disruptions in transforming growth factor beta (TGF-(3) signalling are associated with cognitive decline in aging, yet their roles in POCD are not fully understood. Here, we demonstrated that both insulin and TGF-(3 pathways were disrupted in POCD mouse models, with recombinant insulin and TGF-(3 treatments improving cognitive outcomes. These treatments reversed neuroinflammation in vitro, while CREB knockdown abrogated the protective effects, both in vivo and in vitro. Mechanistically, CREB was found to mediate the protective effects of insulin and TGF-(3 in POCD by directly regulating the expression of the cognitive-related protein NR2B. Altogether, our study identifies a key molecular target involved in the critical signalling pathways associated with POCD, offering promising therapeutic strategies for prevention and treatment.

Postoperative cognitive dysfunction is a seve re complication of the central nervous system that occurs after anesthesia and surgery,and has received attention for its high incidence and effect on the quality of life of patients.To date,there are no viable treatment options for postoperative cognitive dysfunction.The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research.To identify the signaling mechanisms contributing to postoperative cognitive dysfunction,we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset,which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus3 days after tibial fracture.The dataset was enriched in genes associated with the biological process "regulation of immune cells," of which Chill was identified as a hub gene.Therefore,we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fractu re surgery.Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 1 24 hours post-surgery,and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests.In addition,protein expression levels of proinflammatory factors(interleukin-1β and inducible nitric oxide synthase),M2-type macrophage markers(CD206 and arginase-1),and cognition-related proteins(brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B) were measured in hippocampus by western blotting.Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment,downregulated interleukin-1βand nducible nitric oxide synthase expression,and upregulated CD206,arginase-1,pNR2B,and brain-derived neurotropic factor expression compared with vehicle treatment.Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1.Collectively,our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus.Therefore,recombinant chitinase-3-like protein1 may have therapeutic potential fo r postoperative cognitive dysfunction.

The soil organic carbon isotope indicator (delta C-13(org)) is widely used in paleoecology and paleoclimate reconstruction due to its ability to record the history of paleovegetation change. Although it has been used as a proxy for precipitation reconstruction, increasing evidence suggests that temperature has played a crucial role in influencing the relative abundance of C-3/C-4 plants in the mid-latitudes during the interglacial period. This opens up the possibility of reconstructing Holocene temperature using delta C-13(org). In this study, the variation of delta C-13(org) values in a Holocene loess profile (GLH profile), located in the eastern Hunshandake Sandy Land, China, was investigated. And we analyzed the correlation between delta C-13(org) values and modern temperatures for a total of 792 surface soil samples from mid-latitudes of the Northern Hemisphere, which had thermal conditions comparable to the GLH profile. Strong positive correlations were found between delta C-13(org) values of surface soil samples and both summer temperatures (r = 0.672, p < 0.001) and growing season temperatures (r = 0.669, p < 0.001). Additionally, delta C-13(org) values showed significant positive correlations with accumulated temperatures above 10 degrees C (r = 0.641, p < 0.001) and above 0 degrees C (r = 0.527, p < 0.001). However, the correlation with mean annual temperature was weak (r = 0.280, p < 0.001). The delta C-13(org) variation in the GLH profile recorded a mixed C-3/C-4 vegetation composition, with C-4 plants comprising between 23.40% and 1.70% of the total abundance during the Holocene. The combined evidence from modern processes and profile variations confirms that warm-season temperature was the main factor driving variations in the delta C-13(org) values in the GLH profile. Therefore, we used delta C-13(org)-temperature conversion equations to quantify Holocene seasonal and accumulated temperatures based on the GLH profile. The reconstructed summer temperatures peaked at 9.3 ka, followed by a fluctuating downward trend during the mid- and late-Holocene, which is consistent with variations in summer solar insolation. Mean summer temperatures were relatively high at 23.3 degrees C and 22.5 degrees C in the early and mid-Holocene, respectively, while the lowest mean summer temperature of 20.5 degrees C occurred in the late Holocene. Accumulated temperatures above 10 degrees C and above 0 degrees C in the early Holocene were 3722 degrees Cd and 4641 degrees Cd, respectively, similar to modern observations in the Beijing area, indicating a southward shift of the temperature zone by nearly three degrees of latitude since the early Holocene. These reconstruction results are supported by modern observations, TraCE21 simulations, and other studies. This study is significant for extending the application of the delta C-13(org) indicator for quantitative paleoclimate reconstructions. It verifies its effectiveness in quantifying Holocene temperatures in the marginal zone of the East Asian summer monsoon.

Objectives:Post-traumatic stress disorder (PTSD) is characterized by recurrent episodes of severe anxiety after exposure to traumatic events. It is believed that these episodes are triggered at least in part by environmental stimuli associated with the precipitating trauma through classical conditioning, termed conditioned fear. However, traditional methods of conditioned fear memory extinction are frequently ineffective for PTSD treatment due to the contribution of non-associative sensitization caused by trauma. Anesthetics have shown promise for treating various psychiatric diseases such as depression.Methods:In this study, we examined if the inhaled anesthetic sevoflurane can suppress stress-enhanced fear learning (SEFL) in PTSD model mice. Model mice exposed to 2.4% sevoflurane for 6 h exhibited reduced freezing time and behavioral anxiety compared to sham-treated model mice. To explore the underlying mechanisms, we evaluated the regional expression levels of glucocorticoid receptors (GRs), cannabinoid CB1 receptors (CB1Rs), D1 dopamine receptors (D1Rs), and D2 dopamine receptors (D2Rs).Results:We verified that both GR and CB1R were significantly upregulated in the hippocampus, amygdaloid nucleus, and prefrontal cortex (PFC) of model mice, while D1R and D2R were downregulated. All of these expression changes were partially normalized in the PFC by 6 h but not with 2 h sevoflurane exposure.Conclusions:These results showed that sevoflurane exposure following traumatic events may be an effective treatment for PTSD.

Abstract Background Due to high rates of incidence and disability, postoperative cognitive dysfunction (POCD) currently receives a lot of clinical attention. Disturbance of fatty acid oxidation is a potential pathophysiological manifestation underlying POCD. Peroxisome proliferator-activated receptor α (PPARα) is a significant transcription factor of fatty acid oxidation that facilitates the transfer of fatty acids into the mitochondria for oxidation. The potential role of PPARα intervention in POCD warrants consideration. Objective The present study is aimed to investigate whether PPARα agonist fenofibrate (FF) could protect long-term isoflurane anesthesia-induced POCD model and to explore the potential underlying function of fatty acid oxidation in the process. Methods We established the POCD model via 6 h long-term isoflurane anesthesia in vivo with C57BL/6J mice and in vitro with N2a cells. Cells and mice were pretreated with PPARα agonist FF before anesthesia, after which fatty acid oxidation and cognitive function were assessed. The level of fatty acid oxidation-related proteins was determined using western blotting. The contextual fear conditioning test was utilized to evaluate mice’s learning and memory. Results Our results showed that 6 h long-term isoflurane anesthesia induced contextual memory damage in mice, accompanied by decreases of fatty acid oxidation-related proteins (peroxisome proliferator-activated receptor γ coactivator 1α, carnitine palmitoyltransferase 1A, and PPARα) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPARα agonist FF led to the upregulation of fatty acid oxidation-related proteins. In vivo results showed that preconditioned FF reached similar effects. More crucially, FF has been shown to reduce cognitive damage in mice after long-term isoflurane anesthesia. Additionally, our data showed that after blocking fatty acid oxidation by Etomoxir, FF failed to protect cognitive function from long-term isoflurane anesthesia. Conclusions Pretreatment of PPARα agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation. Graphical abstract

Parabolic dunes can transform from and into other types of dunes in response to environmental changes. The sand hills, including some parabolic dunes, on the shore of Poyang Lake mainly accumulated during the Last Glaciation and are rare inland aeolian landforms in the humid monsoon climate zone in East China. However, the characteristics, distribution and formation of the parabolic dunes in this region are still not clear. Three sand hills with similar scales and wind regimes at Shaling, Jishan and Songmenshan were selected as the research targets. Integrating topographical, hydrological, vegetation and wind data, we found that the development of the parabolic dunes was effectively controlled by both the vegetation cover of the sand hills and the space available downwind of the sand hills. No parabolic dunes were found at Songmenshan and Shaling; the former has too little vegetation cover, favouring the formation of blowouts, and the latter lacks available space since Shaling is surrounded by villages and farmlands. Three types of parabolic dunes that developed sequentially in the downwind direction, namely, type A, type B and type C dunes, are observed at Jishan, and their formation is related to a narrowly unimodal and high-energy wind regime. Different from existing models, type A dunes are found to originate from the wedge-shaped depositional lobes of trough blowouts; type B dunes transform from type A dunes after migration; and type C dunes develop from very low sand drifts. Composite parabolic dunes are formed when the sand supply is plentiful, while simple parabolic dunes appear when the sand supply is limited. The formation of the parabolic dunes occurred approximately 250 years ago, which is close to the documented time when the sand hills were reactivated due to the vegetation being anthropogenically damaged. Therefore, anthropogenic destruction of vegetation is a trigger for producing parabolic dunes in this humid area. This study may shed light on the evolution of aeolian landforms in humid monsoon climate zones. (c) 2021 Published by Elsevier B.V.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication involving the central nervous system, but the underlying mechanism is not well understood. Neuroinflammation secondary to surgery and anesthesia is strongly correlated with POCD. A key aspect of neuroinflammation is microglia activation. Triggering receptor expressed on myeloid cells (TREM)2, which is highly expressed in microglia, is an innate immune receptor that modulates microglia function. In this study we investigated the role of TREM2 in cognitive impairment and microglia-mediated neuroinflammation using a mouse model of POCD and in vitro systems. We found that hippocampus-dependent learning and memory were impaired in POCD mice, which was accompanied by activation of microglia and downregulation of TREM2. Pretreatment with the TREM2 agonist heat shock protein (HSP)60 inhibited surgery-induced microglia activation and alleviated postoperative cognitive impairment. In BV2 microglial cells, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 significantly reversed the attenuation of TREM2 activation on lipopolysaccharide (LPS)-induced neuroinflammation and abrogated the protective effect of activated TREM2 against LPS-induced neuronal injury in a microglia/neuron coculture system. Accordingly, the beneficial effects of TREM2 activation on cognitive function were reversed by preoperative administration of LY294002 in the POCD mouse model. These results demonstrate that TREM2 is involved in the regulation of the inflammatory response mediated by microglia and cognitive impairment following surgery. Activation of TREM2 can attenuate neuroinflammation by modulating PI3K/protein kinase B (Akt) signaling, thereby alleviating postoperative learning and memory deficits.

Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is closely related to oxidative stress. The core response of the ISR is phosphorylation of eIF2α. Various cellular stress stimuli trigger activation of eIF2α kinases, thus causing phosphorylation of eIF2α. ISR is associated with many neurodegenerative diseases; however, the relationship between POCD and ISR has not been defined. In the present study, the tibias in 4-month-old male C57BL/6 mice were fractured under isoflurane anesthesia to establish the POCD animal model. Cognitive function was assessed by fear conditioning tests and the Y-maze from 3 to 14 days post-surgery. Western blot was used to determine the levels of PeIF2α, eIF2α, ATF4, GADD34, CHOP, BDNF, proBDNF, and p-NR2B expression. The levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to determine oxidative stress in hippocampal tissues. After tibial fracture surgery in mice, the hippocampus had increased levels of PeIF2α, ATF4, GADD34, and CHOP protein, ROS-positive cells, and average fluorescence intensity, SOD activity was decreased, and the MDA level was increased. The ISR inhibitor, ISRIB, reduced the levels of PeIF2α, ATF4, GADD34, and CHOP protein, and alleviated oxidative stress in the hippocampus of POCD mice. Moreover, ISRIB ameliorated cognitive dysfunction in POCD mice. Our findings suggested that targeting ISR may represent an effective approach to combat POCD.

Aging decreases cognitive functions, especially learning and memory. Neuroinflammation is mediated by microglia and occurs in age-related neurodegenerative diseases. The expression profiles in a dataset of cognitively normal controls (GSE11882) were obtained from the Gene Expression Omnibus (GEO) database. Microarray data were used to explore the expression of age-related genes in the human hippocampus. A total of 120 differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein–protein interaction (PPI) network was constructed. A total of 18 key genes were identified by the plugin cytoHubba in Cytoscape software. Two genes with a positive impact on cognition during aging were teased out: triggering receptor expressed on myeloid cells 2 (TREM2) and a scavenger receptor (CD163). Finally, the results of reverse transcription–quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) verified that the mRNA expression of these two genes was significantly upregulated in aged mice. Moreover, the levels of the inflammatory factors IL-1β and IL-6 were significantly increased. TREM2 and CD163 may be upregulated to alleviate the inflammatory environment resulting from microglial activation in the aging brain, thereby delaying cognitive decline.

Inhalation is a promising and challenging method in pharmaceutical and biological science research. A stable environment is critical in dynamic inhalation administration. However, the establishment of a stable inhalation system is very challenging. Indacaterol glycopyrronium bromide inhalation powder (IM/GP mixed powder) is composed of indacaterol maleate and glycopyrronium bromide powder to treat chronic obstructive pulmonary disease (COPD). The aim of this study is to build suitable inhalation conditions and then to evaluate the pulmonary safety of this drug in Sprague-Dawley(SD) rats. In the research, through the coordination of the atomization flow, air pump flow, and scraper speed, aerosols were stabilized at 200 ± 20% mg/m3, and then rats were nose-only administered with the IM/GP mixed powder, Ultibro, and lactose-magnesium stearate mixed powder at 2.6 mg/kg/day for 14 days and 14 days of recovery period, respectively. After exposure, hematology, inflammatory cytokines in rats bronchoalveolar lavage fluid (BALF) and serum, histopathological examination were performed. Results showed that the stability of powder aerosols can be realized under the atomization generation flow: 10 L/min, sampling flow: 2 L/min, system pumping capacity: 10 L/min and powder scraper speed: 8–10 L/min, and there were no significant adverse effects on body weight, clinic signs, hematology, and pathology in rats. Overall, the results suggested that the IM/GP mixed powder inhalation at the dose of 2.6 mg/kg/d can be reached when the aerosol concentration is within the range of 200 ± 20% mg/m3, and there were no pulmonary toxicity effects in rats.

General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the anesthesia-induced cognitive dysfunction. 5-HT7R, a serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT7R in the long-term isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT7R before anesthesia has modulating effects on this memory impairment. In this study, 5-HT7R selective agonist LP-211 and 5-HT7R selective antagonist SB-269970 were pretreated intraperitoneally to mice before anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT7R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT7R mRNA expression, which could be attenuated by SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT7R is involved in the memory impairment induced by long-term isoflurane anesthesia, and the prior blockade of 5-HT7R with SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term isoflurane exposure.

Confined by the eastern and western boundary faults, Lu Mountain has long been considered a block mountain uplifted due to Mesozoic and Cenozoic crustal deformation in East China. However, the formation and evolution of this block mountain are still debated. In this study, the eastern boundary fault is investigated to confirm the tectonic style of the block mountain. In addition, the burial ages of sediments on the fans of the eastern piedmont are measured by 26 Al/ 10 Be dating to evaluate the denudation rate. Field evidence indicates the presence of a reverse fault (Xingzi reverse fault) acting as the eastern boundary fault, which demonstrates that the block mountain is not a horst as once thought but an extrusion structure. Corrected 26 Al/ 10 Be burial ages show that the sediments on the high-level fans were deposited at approximately 1.1–1.2 Ma, which indicates denudation rates ranging from 0.033 to 0.082 m/kyr. The vertical displacement along the Xingzi reverse fault is estimated to be at least 1,100 m. The hanging wall could have been eroded to its present position within 13–33 Myr at the above denudation rates. Combining our results with regional geological and geomorphological evidence, we suggest that Lu Mountain was mainly uplifted in the Miocene due to crustal compression deformation, which may have been a response to the movement of the Pacific plate.

Alzheimer's Disease (AD) is a neurodegenerative disease featured by cognitive impairment. This bioinformatic analysis was used to identify hub genes related to cognitive dysfunction in AD. The gene expression profile GSE48350 in the hippocampus of AD patients aged >70 years was obtained from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were identified, and subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses; a protein-protein interaction (PPI) network was constructed. The DEGs were enriched in synapse-related changes. A protein cluster was teased out of PPI. Furthermore, the cognition ranked the first among all the terms of biological process (BP). Next, 4 of 10 hub genes enriched in cognition were identified. The function of these genes was validated using APP/PS1 mice. Cognitive performance was validated by Morris Water Maze (MWM), and gene expression by RT-qPCR, Cholecystokinin (CCK), Tachykinin precursor 1 (TAC1), Calbindin 1 (CALB1) were downregulated in the hippocampus. These genes can provide new directions in the research of the molecular mechanism of AD.

Objectives Massive research has examined the cause of major depressive disorder (MDD) and accumulating evidence has revealed that the gene for the norepinephrine transporter (NET) is involved in MDDs etiology as well as the antidepressant response. The G1287A (rs5569, GRCh38, Chromosome 16, 55697923) is located in the exon 9 region of the SLC6A2 gene. It was found to be connected with MDD and antidepressant response in people of different genetic ancestries. However, the results are still inconsistent. Methods A meta-analysis was conducted to evaluate the overall association of rs5569 polymorphisms with MDD and the antidepressant response. Results Sixteen articles that studied the connection between the G1287A polymorphism and MDD or antidepressant response were identified, and their outcomes revealed there was a significant connection between the polymorphisms and MDD and antidepressant response. Our study indicated that the GG genotype may be a protection factor against the development of MDD [odds ratio (OR = 0.78, 95% confidence interval (CI) = 0.64–0.96, P = 0.02 for Asian population; OR = 0.79, 95% CI = 0.63–0.98, P = 0.03 for Han Chinese population] while the GG genotype had a worse antidepressant response (OR = 0.49, 95% CI = 0.25–0.94, P = 0.03). Conclusions: NET G1287A polymorphisms are involved in the etiology of MDD and antidepressant response.