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Abstract As our planet is entering into the “global boiling” era, understanding regional climate change becomes imperative. Effective downscaling methods that provide localized insights are crucial for this target. Traditional approaches, including computationally-demanding regional dynamical models or statistical downscaling frameworks, are often susceptible to the influence of downscaling uncertainty. Here, we address these limitations by introducing a diffusion probabilistic downscaling model (DPDM) into the meteorological field. This model can efficiently transform data from 1° to 0.1° resolution. Compared with deterministic downscaling schemes, it not only has more accurate local details, but also can generate a large number of ensemble members based on probability distribution sampling to evaluate the uncertainty of downscaling. Additionally, we apply the model to generate a 180-year dataset of monthly surface variables in East Asia, offering a more detailed perspective for understanding local scale climate change over the past centuries.

Abstract The observed Southern Ocean sea surface temperature (SST) has experienced prominent inter-decadal variability nearly in phase with the Inter-decadal Pacific Oscillation (IPO), but less associated with the Atlantic Multidecadal Variability (AMV), challenging the prevailing view of Pacific-Atlantic synergistic effects. Yet, the mechanisms of distinct trans-hemispheric connections to the Southern Ocean remain indecisive. Here, by individually constraining the observed cold-polarity and warm-polarity IPO and AMV SSTs in a climate model, we show that the IPO is influential in initiating a basin-wide Southern Ocean response, with the AMV secondary. A tropical Pacific-wide cooling triggers a basin-scale Southern Ocean cold episode through a strong Rossby wave response to the north-to-south cross-equatorial weakened Hadley circulation. By contrast, due to the competing role of tropical Pacific cooling, an Atlantic warming partly cools the Southern Ocean via a weak Rossby wave response to the south-to-north cross-equatorial enhanced Hadley circulation. Conversely, tropical Pacific warming leads to a warm Southern Ocean episode. Our findings highlight that properly accounting for the tropical Pacific SST variability may provide a potential for skillful prediction of Southern Ocean climate change and more reliable estimates of climate sensitivity, currently overestimated by the misrepresented Southern Ocean warming.

Abstract Understanding both positive and negative impacts of climate change is essential for comprehensively assessing and well adapting to the impacts of changing climate. Conventionally, climate warming is revealed to negatively impact human activities. Here, we reveal that human beings’ performance in anaerobic sports may benefit from climate warming. Using global weather observation and athletes’ performance datasets, we show that world-top athletes’ performances in nearly all athletics anaerobic events (i.e., sprints, jumps and throws) substantially improve as ambient temperature rises. For example, 100 m performance monotonically improves by 0.26 s as ambient temperature rises from 11.8° to 36.4 °C. Using Coupled Model Intercomparison Project Phase 6 datasets, we further show that global warming can substantially improve world-top athletes’ performance in eleven of the thirteen Olympics athletics anaerobic events by 0.27%–0.88% and 0.14–0.48% under high-emission and medium-emission scenarios, respectively, during 1979–2100. Among them, the improvements for 100 m are 0.59% (0.063 s) and 0.32% (0.034 s), respectively. Mechanism analysis shows that the warmed ambient atmosphere can improve competitors’ performance through expanding the air and thus reducing the air resistance to the competitors and throwing implements for hummer throw and all the sprints, hurdling and jumps. Quantitative analysis estimates that this thermodynamic process is essential for the impacts of warmed ambient atmosphere on the performances in these events as physiological processes are.

Abstract The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.

Abstract The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis.

Network Function Virtualization (NFV) technology can tie together a set of Virtual Network Functions (VNFs) as a Service Function Chain (SFC). Although NFV is a promising technology for the placement of user service requests, SFCs often suffer from high delay and low throughput. This paper develops an efficient approach based on Deep Reinforcement Learning (DRL) with the aim of deploying VNFs with low delay during heterogeneous bandwidth demands in Data Center Networks (DCNs). We design an architecture that exploits the dependencies of VNFs to parallelize them and also preserve more resources for processing future requests by extracting the distribution of initialized VNFs. Our algorithm is expected to maximize the long-term reward and improve the computational acceleration in provisioning user service requests. Our evaluations show that the proposed algorithm reduces the service delay by 12% through parallelized VNFs.

Abstract Background Sepsis‐associated muscle weakness is common in patients of intensive care units (ICUs), and it is closely associated with poor outcomes. The mechanism of sepsis‐induced muscle weakness is unclear. Recent studies have found that gut microbiota and metabolites are involved in the regulation of skeletal muscle mass and metabolism. This study aimed to investigate the effects of gut microbiota and metabolites on sepsis‐associated muscle weakness. Methods In a lipopolysaccharide (LPS)‐induced inflammation mouse model, mice with different sensitivities to LPS‐induced inflammation were considered as donor mice for the faecal microbiota transplantation (FMT) assay, and recipient mice were divided into sensitive (Sen) and resistant (Res) groups. Skeletal muscle mass and function, as well as colonic barrier integrity were tested and gut microbiota and metabolite composition were analysed in both groups of mice. The effect of intestinal differential metabolite vitamin K1 on LPS‐triggered muscle damage was investigated, and the underlying mechanism was explored. Results Recipients exhibited varying LPS‐triggered muscle damage and intestinal barrier disruption. Tibialis anterior (TA) muscle of Sen exhibited upregulated expression levels of MuRF‐1 (0.825 ± 0.063 vs. 0.304 ± 0.293, P = 0.0141) and MAFbx (1.055 ± 0.079 vs. 0.456 ± 0.3, P = 0.0092). Colonic tight junction proteins ZO‐1 (0.550 ± 0.087 vs. 0.842 ± 0.094, P = 0.0492) and occludin (0.284 ± 0.057 vs. 0.664 ± 0.191, P = 0.0487) were significantly downregulated in the Sen group. Metabolomic analysis showed significantly higher vitamin K1 in the faeces (P = 0.0195) and serum of the Res group (P = 0.0079) than those of the Sen group. After vitamin K1 intervention, muscle atrophy‐related protein expression downregulated (P

AIM: To explore the brain mechanism of acupuncture for children with anisometropic amblyopia using the voxel-mirror homotopic connectivity (VMHC) analysis method of resting functional magnetic resonance imaging (rs-fMRI) technology based on clinical effectiveness. METHODS: Eighty children with anisometropic monocular amblyopia were randomly divided into two groups: control (40 cases, 1 case of shedding) and acupuncture (40 cases, 1 case of shedding) groups. The control group was treated with glasses, red flash, grating, and visual stimulations, with each procedure conducted for 5min per time. Based on routine treatment, the acupuncture group underwent acupuncture of “regulating qi and unblocking meridians to bright eyes”, Jingming (BL1), Cuanzhu (BL2), Guangming (GB37), Fengchi (GB20) acupoints were taken on both sides, with the needle kept for 30min each time. Both groups were treated once every other day, three times per week, for a total of 4wk. After the treatment, the overall curative effect of the two groups and the latency and amplitude changes of P100 wave of pattern visual-evoked potential were counted. At the same time, nine children with left eye amblyopia were randomly selected from the two groups and were scanned with rs-fMRI before and after treatment. The differences in the brain regions between the two groups were compared and analyzed with VMHC. RESULTS: Chi-square test showed a notable difference in the total efficiency rate between the acupuncture (94.87%) and control groups (79.49%). Regarding the P100 wave latency and amplitude, the acupuncture group had significantly shorter latency and higher amplitude of P100 wave than the control group. Moreover, the VMHC values of the bilateral temporal lobe, superior temporal gyrus, and middle temporal gyrus were notably increased in the acupuncture group after treatment. CONCLUSION: Acupuncture combined with conventional treatment can significantly improve the corrected visual acuity and optic nerve conduction in children with anisometropic amblyopia. Compared with the conventional treatment, the regulation of acupuncture on the functional activities of the relevant brain areas in the anterior cerebellum may be an effective acupuncture mechanism for anisometropic amblyopia.

Abstract Accurate detection and attribution of past climate change are crucial for projecting future climate change and formulating proper policies. In this study, we show that the warming of the tropical Indian Ocean contributes to the observed wetting trend in the Tibetan plateau. The warming tropical Indian Ocean can lead to more precipitation around the Arabian Sea. The associated diabatic heating triggers the cyclonic atmospheric response in the lower troposphere over the Arabian Sea and eastern Africa. It also causes the enhancement and westward extension of the western North Pacific subtropical high. The in‐between airflow transports more moisture northward to the plateau, leading to the increased precipitation over the plateau. These large‐scale circulation patterns can be detected from the long‐term trends based on the observations and the large‐ensemble historical simulations. They can also be simulated by an atmospheric general circulation model forced by the observed warming merely in the tropical Indian Ocean.

Diaphragm dysfunction (DD) can be classified as mild, resulting in diaphragmatic weakness, or severe, resulting in diaphragmatic paralysis. Various factors such as prolonged mechanical ventilation, surgical trauma, and inflammation can cause diaphragmatic injury, leading to negative outcomes for patients, including extended bed rest and increased risk of pulmonary complications. Therefore, it is crucial to protect and monitor diaphragmatic function. Impaired diaphragmatic function directly impacts ventilation, as the diaphragm is the primary muscle involved in inhalation. Even unilateral DD can cause ventilation abnormalities, which in turn lead to impaired gas exchange, this makes weaning from mechanical ventilation challenging and contributes to a higher incidence of ventilator-induced diaphragm dysfunction and prolonged ICU stays. However, there is insufficient research on DD in non-ICU patients, and DD can occur in all phases of the perioperative period. Furthermore, the current literature lacks standardized ultrasound indicators and diagnostic criteria for assessing diaphragmatic dysfunction. As a result, the full potential of diaphragmatic ultrasound parameters in quickly and accurately assessing diaphragmatic function and guiding diagnostic and therapeutic decisions has not been realized.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

Background Earlier studies have investigated the association between overweight/obesity and an elevated risk of breast cancer in women. However, some studies have found that it may not be scientifically accurate to solely analyze the association between overweight/obesity and breast cancer in women for overweight/obesity can be classified into different metabolic phenotypes. The current findings on the association of different metabolic phenotypes with breast cancer remain inconsistent. Objective To prospectively analyze the associations of different metabolic obesity phenotypes with the risk of breast cancer in women. Methods In this prospective cohort study, female employees (n=23 406) of Kailuan Group who participated in physical examinations for the first time in Kailuan General Hospital and its 11 affiliated hospitals from 2006 to 2008 were selected as the study subjects and received questionnaire investigation, physical examination and laboratory tests. The study subjects were divided into the four groups based on the types of metabolic syndrome and BMI, including metabolically healthy normal weight (MHNW) group (n=12 739), metabolically unhealthy normal weight (MUNW) group (n=1 060), metabolically healthy overweight/obese (MHO) group (n=6 394), and metabolically unhealthy overweight/obese (MUO) group (n=3 213). The subjects were followed up, with the first physical examination attended as the starting point, and new onset breast cancer, death, or the end of follow-up time (2020-12-31) as the endpoints. Multivariate Cox proportional hazard regression model was used to estimate the association of the four groups with the risk of breast cancer. Results During an average follow-up of (13.26±1.85) years, with 353 new cases of breast cancer and an incidence density of 11.38 cases per 10 000 person-years in the total population. The incidence cases in the MHNW, MUNW, MHO, and MUO groups were 154, 21, 113, and 65, respectively, with the incidence density of 9.08, 15.37, 13.27, and 15.49 per 10 000 person-years, and the cumulative incidence of 1.22%, 2.01%, 1.67%, and 1.93%, respectively. Multivariate Cox proportional hazard regression model analysis, after adjusting for confounders, showed that compared with the MHNW group, the risk of breast cancer was increased by 42% (HR=1.42, 95%CI=1.11-1.82) and 59% (HR=1.59, 95%CI=1.17-2.17) in the MHO group and MUO group, respectively. Stratified analysis by menopausal status showed that compared to the MHNW group, the MUO group was associated with a 69% increase in risk of premenopausal breast cancer (HR=1.69, 95%CI=1.01-2.83). The risk of postmenopausal breast cancer was increased by 85% (HR=1.85, 95%CI=1.09-3.14), 50% (HR=1.50, 95%CI=1.06-2.13), and 55% (HR=1.55, 95%CI=1.05-2.28) for the MUNW, MHO, and MUO groups, respectively, compared to the MHNW group. Conclusion Overweight/obesity is a risk factor for female breast cancer, and overweight/obesity with metabolic abnormalities further increases the risk of breast cancer. Additionally, normal weight postmenopausal women who are metabolically unhealthy may be at an increased risk of postmenopausal breast cancer.

Purpose: To evaluate the myopia risk in school-aged children one year after lifting a pandemic-related lockdown and develop a tool to identify high-risk groups. Methods: In total, 38,079 children without myopia from 38 schools were included. The outcomes were myopia incidence and progression in 1 year after the COVID-19 lockdown was lifted, both obtained by the spherical equivalent refraction (SER). We separated the population into an exploratory (75%) and a validation sample (25%) to construct the risk score model. Results: In total, 9811 (29.57%) students became myopic, and the overall myopia progression was 0.22 ± 0.62 D. Even less myopia progression was noted in the pre-myopia group at baseline (All: P = 0.045, Boy: P = 0.005). The risk score model included seven predictors: gender, grade, SER at baseline, residence, parental myopia, eye discomfort symptoms, and online courses. The model had a score range of 0–46 and an optimal cutoff of 34. The area under the receiver operating curve of the model was 0.726 (0.719–0.732) for the exploratory sample and 0.731 (0.720–0.742) for the validation sample. Conclusions: The risk score can serve as a practical tool for classifying the risk of myopia in school-aged children.

AbstractContext Kazinol B (KB), an isoprenylated flavan derived from Broussonetia kazinoki Sieb. (Moraceae) root, has long been used in folk medicine.Objective This study examines the protective effects of KB and its underlying mechanisms in hypoxia and reoxygenation (H/R)-induced cardiac injury in H9c2 rat cardiac myoblasts.Materials and methods H9c2 cells were incubated with various concentrations of KB (0, 0.3, 1, 3, 10 and 30 μM) for 2 h and then subjected to H/R insults. The protective effects of KB and its underlying mechanisms were explored.Results KB significantly elevated cell viability (1 μM, 1.21-fold; 3 μM, 1.36-fold, and 10 μM, 1.47-fold) and suppressed LDH release (1 μM, 0.77-fold; 3 μM, 0.68-fold, and 10 μM, 0.59-fold) in H/R-induced H9c2 cells. Further, 10 μM KB blocked apoptotic cascades, as shown by the Annexin-V/PI (0.41-fold), DNA fragmentation (0.51-fold), caspase-3 (0.52-fold), PARP activation (0.27-fold) and Bax/Bcl-2 expression (0.28-fold) assays. KB (10 μM) downregulated reactive oxygen species production (0.51-fold) and lipid peroxidation (0.48-fold); it upregulated the activities of GSH-Px (2.08-fold) and SOD (1.72-fold). KB (10 μM) induced Nrf2 nuclear accumulation (1.94-fold) and increased ARE promoter activity (2.15-fold), HO-1 expression (3.07-fold), AKT (3.07-fold) and AMPK (3.07-fold) phosphorylation. Nrf2 knockdown via using Nrf2 siRNA abrogated KB-mediated protective effects against H/R insults. Moreover, pharmacological inhibitors of AKT and AMPK also abrogated KB-induced Nrf2 activation and its protective function.Discussion and conclusions KB prevented H/R-induced cardiomyocyte injury via modulating the AKT and AMPK-mediated Nrf2 induction. KB might be a promising drug candidate for managing ischemic cardiac disorders.

Abstract The influence of Atlantic Niño on the following El Niño–Southern Oscillation becomes significant since mid‐1970s. However, exact mechanisms for this inter‐decadal change are still unclear. Here, we perform a set of model pacemaker experiments to probe the relative contributions of the changes in the Atlantic Niño itself and the mean‐state under global warming. The results suggest that the warmer background of the tropical Atlantic plays an essential role in enhancing local mean precipitation, inducing stronger divergence and low‐level easterlies in the Pacific. Under a favorable condition in the Pacific, even a weak Atlantic Niño‐related warming could promote the development of La Niña through cross‐basin Walker circulation and the Indian Ocean‐relayed Kelvin wave response. In contrast, the Atlantic Niño pattern change itself induces feeble convection anomalies in the western Atlantic, which cannot induce significant atmospheric response in the Pacific. These results imply an important modulation of global warming on the inter‐basin connection.

Phragmites australis is a prevalent species in the Chongming Dongtan wetland and is capable of thriving in various tidal flat environments, including high salinity habitats. P. australis population displays inconsistent ecological performances, highlighting the need to uncover their survival strategies and mechanisms in tidal flats with diverse soil salinities. Upon comparing functional traits of P. australis at multiple tidal flats (low, middle, and high) and their responses to soil physicochemical properties, this study aimed to clarify the salt-tolerant strategy of P. australis and the corresponding mechanisms. These results showed that leaf characteristics, such as specific leaf area and leaf dry matter content, demonstrated more robust stability to soil salinity than shoot height and dry weight. Furthermore, as salt stress intensified, the activities of superoxide dismutase (SOD), catalase (CAT) and peroxisome (POD) in P. australis leaves at low tidal flat exhibited an increased upward trend compared to those at other tidal flats. The molecular mechanism of salt tolerance in Phragmites australis across various habitats was investigated using transcriptome sequencing. Weighted correlation network analysis (WGCNA) combined with differentially expressed genes (DEGs) screened out 3 modules closely related to high salt tolerance and identified 105 core genes crucial for high salt tolerance. Further research was carried out on the few degraded populations at low tidal flat, and 25 core genes were identified by combining WGCNA and DEGs. A decrease in the activity of ferroptosis marker gonyautoxin-4 and an increase in the content of Fe3+ in the degenerated group were observed, indicating that ferroptosis might participate in degradation. Furthermore, correlation analysis indicated a possible regulatory network between salt tolerance and ferroptosis. In short, this study provided new insights into the salt tolerance mechanism of P. australis population along tidal flats.

As the leading killer of life and health, stroke leads to limb paralysis, speech disorder, dysphagia, cognitive impairment, mental depression and other symptoms, which entail a significant financial burden to society and families. At present, physiology, clinical medicine, engineering, and materials science, advanced biomaterials standing on the foothold of these interdisciplinary disciplines provide new opportunities and possibilities for the cure of stroke. Among them, hydrogels have been endowed with more possibilities. It is well-known that hydrogels can be employed as potential biosensors, medication delivery vectors, and cell transporters or matrices in tissue engineering in tissue engineering, and outperform many traditional therapeutic drugs, surgery, and materials. Therefore, hydrogels become a popular scaffolding treatment option for stroke. Diverse synthetic hydrogels were designed according to different pathophysiological mechanisms from the recently reported literature will be thoroughly explored. The biological uses of several types of hydrogels will be highlighted, including pro-angiogenesis, pro-neurogenesis, anti-oxidation, anti-inflammation and anti-apoptosis. Finally, considerations and challenges of using hydrogels in the treatment of stroke are summarized.

Global cerebral ischemia/reperfusion (GCI/R) injury poses a risk for cognitive decline, with neuroinflammation considered pivotal in this process. This study aimed to unravel the molecular mechanisms underlying GCI/R injury and propose a potential therapeutic strategy for associated cognitive deficits. Utilizing bioinformatics analysis of a public microarray profile (GSE30655 and GSE80681) in cerebral ischemic mice, it was observed that neuroinflammation emerged as a significant gene ontology item, with an increase in the expression of thioredoxin-interacting protein (TXNIP) and NLRP3 genes. Experimental models involving bilateral occlusion of the common carotid arteries in mice revealed that GCI/R induced cognitive impairment, along with a time-dependent increase in TXNIP and NLRP3 levels. Notably, TXNIP knockdown alleviated cognitive dysfunction in mice. Furthermore, the introduction of adeno-associated virus injection with TXNIP knockdown reduced the number of activated microglia, apoptosis neurons, and levels of oxidative stress and inflammatory cytokines in the hippocampus. Collectively, these findings underscore the significance of TXNIP/NLRP3 in the hippocampus in exacerbating cognitive decline due to GCI/R injury, suggesting that TXNIP knockdown holds promise as a therapeutic strategy.

In order to build a composite application scenario for the synergistic development of clean energy generation and agricultural production, this research designs a solar chimney equipped with a rectangular collection system according to the structural characteristics of agricultural greenhouses. With collector efficiency as the primary objective and theoretical power as the secondary objective, the infusion angle is designed for the connecting section between the collection system and the chimney from the perspective of reducing the local resistance loss, and the transition factor ζ is introduced to define it accurately. Response surface methodology was then used to analyze the effect of the level of key system characteristics on collector efficiency and static pressure, and a regression model was developed to determine the best combination within the target optimization range. Results show that the infusion angle prevents too much solar energy from being lost in the vortex by reducing the local resistance loss, which increases the collector efficiency of the system. And when the transition factor is 0, the divergence angle is 2.86°, and the inlet height is 0.05 m, the collector efficiency and static pressure reach 48.75 % and −6.1 pa, respectively, which are 213 % and 563 % higher than the original model.

Abstract Esketamine provides an immediate and noticeable antidepressant effect, although the underlying molecular processes are yet unclear. Irisin induced by aerobic exercise has been implicated in the alleviation of depressive symptoms, whether irisin expression responds to the administration of esketamine remains unknown. In this study, we found that irisin was reduced in the hippocampus and peripheral blood of chronic unpredictable mild stress (CUMS) mice, whereas the irisin level was rescued by esketamine treatment. The reduction of PGC-1α expression (transcriptional regulator of irisin gene expression) in the CUMS mice was rescued by esketamine treatment, PGC-1α knockdown significantly reduced the irisin level induced by esketamine. Additionally, FNDC5/irisin-knockout mice developed more severe depressant-like behaviors than wild-type mice under CUMS stimulation, with an attenuated the antidepressant effect of esketamine. Further research indicated that irisin-mediated modulation of esketamine on depressive-like behaviors in CUMS mice involved the ERK1/2 pathway. Overall, the PGC-1α/irisin/ERK1/2 signaling activation may be a new mechanism underlying the antidepressant activity of esketamine, denoting that irisin may be a promising therapeutic target for the treatment of depression.

Abstract Investigating the Indian Ocean Dipole (IOD) during the Last Interglacial (LIG) can advance knowledge of IOD behaviors in orbitally‐induced warmer‐than‐present scenarios. Based on multiple model outputs from the Paleoclimate Modeling Intercomparison Project Phase 4, the analysis suggests reduced frequencies of the IOD compared to the preindustrial period. Spatially, the whole growing and mature stages of the IOD feature suppressed variability over the west and westward expansions of eastern anomalies, while the eastern perturbation enhances only at the initial phase. The overall amplitude assessed by the dipole mode index shows only minor reductions. These changes are attributed to orbitally‐induced enhancement in mean‐state westward currents along the equator, which transport more anomalous cold water westward. In addition, the subdued El Niño–Southern Oscillation (ENSO) during the LIG is unlikely to cause a weakening of the IOD, in association with a less important role of ENSO in the formation of the IOD.