Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.

BACKGROUND: Toxoplasmosis affects a quarter of the world's population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96aregulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.

A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

Size, distribution, and vulnerability of the global soil inorganic carbon.

Global estimates of the size, distribution, and vulnerability of soil inorganic carbon (SIC) remain largely unquantified. By compiling 223,593 field-based measurements and developing machine-learning models, we report that global soils store 2305 ± 636 (±1 SD) billion tonnes of carbon as SIC over the top 2-meter depth. Under future scenarios, soil acidification associated with nitrogen additions to terrestrial ecosystems will reduce global SIC (0.3 meters) up to 23 billion tonnes of carbon over the next 30 years, with India and China being the most affected. Our synthesis of present-day land-water carbon inventories and inland-water carbonate chemistry reveals that at least 1.13 ± 0.33 billion tonnes of inorganic carbon is lost to inland-waters through soils annually, resulting in large but overlooked impacts on atmospheric and hydrospheric carbon dynamics.

A comprehensive clinical evaluation of HER2-TKIs in patients with previously treated HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC.

Histone H3Y99sulf regulates hepatocellular carcinoma responding to hypoxia.

Histone H3 tyrosine-99 sulfation (H3Y99sulf) is a recently identified histone mark that can cross-talk with H4R3me2a to regulate gene transcription, but its role in cancer biology is less studied. Here, we report that H3Y99sulf is a cancer-associated histone mark that can mediate hepatocellular carcinoma (HCC) cells responding to hypoxia. Hypoxia-stimulated SNAIL pathway elevates the expression of PAPSS2, which serves as a source of adenosine 3'-phosphate 5'-phos-phosulfate for histone sulfation and results in upregulation of H3Y99sulf. The transcription factor TDRD3 is the downstream effector of H3Y99sulf-H4R3me2a axis in HCC. It reads and co-localizes with the H3Y99sulf-H4R3me2a dual mark in the promoter regions of HIF1A and PDK1 to regulate gene transcription. Depletion of SULT1B1 can effectively reduce the occurrence of H3Y99sulf-H4R3me2a-TDRD3 axis in gene promoter regions and lead to downregulation of targeted gene transcription. Hypoxia-inducible factor 1-alpha and PDK1 are master regulators for hypoxic responses and cancer metabolism. Disruption of the H3Y99sulf-H4R3me2a-TDRD3 axis can inhibit the expression and functions of hypoxia-inducible factor 1-alpha and PDK1, resulting in suppressed proliferation, tumor growth, and survival of HCC cells suffering hypoxia stress. The present study extends the regulatory and functional mechanisms of H3Y99sulf and improves our understanding of its role in cancer biology.

Investigating the impact of HMI on drivers' merging performance in intelligent connected vehicle environment.

Intelligent Connected Vehicle (ICV) is considered one of the most promising active safety technologies to address current transportation challenges. Human-Machine Interface (HMI) plays a vital role in enhancing user driving experience with ICV technology. However, in an ICV environment, drivers may exhibit excessive reliance on HMI, resulting in diminished proactive observation and analysis of the road environment, and subsequently leading to a potential decrease in drivers' situational awareness. This reduced situational awareness may consequently lead to a decline in their overall engagement in driving tasks. Therefore, to comprehensively investigate the impact of HMI on driver performance in various ICV environments, this study incorporates three distinct HMI systems: Control group, Warning group, and Guidance group. The Control group provides basic information, the Warning group adds front vehicle icon and real-time headway information, while the Guidance group further includes speed and voice guidance features. Additionally, the study considers three types of mainline vehicle gaps, namely, 30 m, 20 m, and 15 m. Through our self-developed ICV testing platform, we conducted driving simulation experiments on 43 participants in a freeway interchange merging area. The findings reveal that, drivers in the Guidance group exhibited explicit acceleration while driving on the ramp. Drivers in the Guidance and Warning groups demonstrated smoother speed change trends and lower mean longitudinal acceleration upon entering the acceleration lane compared to the Control group, indicating a preference for more cautious driving strategies. During the pre-merging section, drivers in the Warning group demonstrated a more cautious and smooth longitudinal acceleration. The Guidance group's HMI system assisted drivers in better speed control during the post-merging section. Differences in mainline vehicle gaps did not significantly impact the merging positions of participants across the three HMI groups. Drivers in the Guidance group merged closest to the left side of the taper section, while the Control group merged farthest. The research findings offer valuable insights for developing dynamic human-machine interfaces tailored to specific driving scenarios in the environment of ICVs. Future research should investigate the effects of various HMIs on driver safety, workload, energy efficiency, and overall driving experience. Conducting real-world tests will further validate the findings obtained from driving simulators.

Clinical predictors of prognosis in stroke patients after endovascular therapy.

Endovascular therapy (EVT) is effective in the treatment of large vascular occlusive stroke. However, many factors are associated with the outcomes of acute ischemic stroke (AIS) after EVT. This study aimed to identify the main factors related to the prognosis of AIS patients after EVT. We analyzed the clinical data of AIS patients in the neurology department of our medical center from June 2017 to August 2021 following treatment with EVT. The data included the patients' blood pressure upon admission, blood glucose concentration, National Institutes of Health Stroke Scale (NIHSS) score, 90-day modified Rankin scale (mRs) score follow-up data, and time from LKN to the successful groin puncture (GP). A good outcome was defined as a 90-day mRs score of 0-2, and a poor outcome was defined as a 90-day mRs score of 3-6. A total of 144 patients were included in the study. Admission, smoking, and LKN-to-GP time, NIHSS score of 6-12 was found to be relevant to the prognosis. The results of multivariate analysis showed that prognosis was significantly influenced by baseline NIHSS (odds ratio = 3.02; 95% confidence interval, 2.878-4.252; P = 0.001), LKN-to-GP time (odds ratio = 2.17; 95% confidence interval, 1.341-2.625; P = 0.003), and time stratification (6-12 h) (odds ratio = 4.22; 95% confidence interval, 2.519-5.561; P = 0.001). Our study indicated that smoking, baseline NIHSS score, and LKN-to-GP time were the risk factors for a poor outcome in stroke patients following an EVT. Quitting smoking and shortening LKN time to GP should improve the outcome of AIS after EVT.

Molecular characteristics of carbapenem-resistant Raoultella ornithinolytica.

Aim of this study was to explore molecular characteristics and resistance mechanisms of carbapenem-resistant Raoultella ornithinolytica (CR-ROR) isolated from patients in a hospital in China. Three CR-ROR strains were collected and bacterial identification was done by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) Vitek-MS and by digital DDH analysis. VITEK 2 compact system and Kirby-Bauer (K-B) disk diffusion were used for antimicrobial susceptibility testing. Whole genome sequencing was carried out using the Illumina platform NovaSeq sequencer. Abricate software was used for the prediction of antibiotic resistance genes of three CR-ROR strains. The phylogenetic tree was constructed through genome SNPs to investigate the genetic relationship of three CR-ROR strains. Three CR-ROR (WF1357, WF2441, and WF3367) strains were collected in this study. Two strains were isolated from neurosurgery (WF1357 and WF2441), and one was isolated from pulmonology department (WF3367). All strains harboured multiple antibiotic resistance genes. Two strains (WF1357, WF2441) carried the blaNDM-1 gene, one of the strains (WF3367) carried the blaKPC-2 gene. Three CR-RORs were resistant to different antimicrobial agents including carbapenems. The three CR-ROR strains collected in this study and 51 CR-ROR strain genomes downloaded from NCBI, were divided into six evolutionary groups (A-F). In this study, three CR-ROR strains were found to have a higher level of resistance to antibacterial agents and carried multiple antibiotic resistance genes. The CR-ROR strains carrying multiple antibacterial resistant genes require the stringent monitoring to avoid the spread of multidrug-resistant bacterial strains.

Greenhouse gas emission in the whole process of forest fire including rescue: a case of forest fire in Beibei District of Chongqing.

In the context of global high temperature, the harm of greenhouse gases (GHG) emissions caused by frequent forest fires to the environment cannot be ignored. Existing research only calculates the GHG generated by the burning of forest vegetation, ignoring the GHG generated by the fire-driven social rescue activities. Taking the forest fire in Beibei District, Chongqing City, China, as an example, this paper studies and establishes the GHG emission accounting method for the whole process of forest fire from ignition to fire extinguishing through three processes: vegetation burning, rescue transportation, and on-site fire extinguishing. It covers three GHG calculation types: biomass burning, traffic activity level comprehensive energy consumption, and machine energy consumption. Among them, the CO2 produced by the burning of coniferous forest, the support transportation of rescue teams in Yunnan province, and the motorcycle transportation at the fire extinguishing site accounted for a relatively high proportion in the corresponding processes, reaching 12,761.445 t, 118.750 t, and 1056.980 t, respectively. Finally, through data analysis, suggestions on GHG emission reduction related to forest tree regulation and optimization of rescue and fire extinguishing management are put forward, which provides a direction for future research on carbon reduction in the whole process of forest fire events.

Relationship between cognitive dysfunction and the promoter methylation of PER1 and CRY1 in patients with cerebral small vessel disease.

Background and purpose: The prevalence of cerebral small vessel disease (CSVD) is increasing due to the accelerating global aging process, resulting in a substantial burden on all countries, as cognitive dysfunction associated with CSVD is also on the rise. Clock genes have a significant impact on cognitive decline and dementia. Furthermore, the pattern of DNA methylation in clock genes is strongly associated with cognitive impairment. Thus, the aim of this study was to explore the connection between DNA promoter methylation of PER1 and CRY1 and cognitive dysfunction in patients with CSVD. Methods: We recruited patients with CSVD admitted to the Geriatrics Department of the Lianyungang Second People's Hospital between March 2021 and June 2022. Based on their Mini-Mental State Examination score, patients were categorized into two groups: 65 cases with cognitive dysfunction and 36 cases with normal cognitive function. Clinical data, 24-h ambulatory blood pressure monitoring parameters, and CSVD total load scores were collected. Moreover, we employed methylation-specific PCR to analyze the peripheral blood promoter methylation levels of clock genes PER1 and CRY1 in all CSVD patients who were enrolled. Finally, we used binary logistic regression models to assess the association between the promoter methylation of clock genes (PER1 and CRY1) and cognitive dysfunction in patients with CSVD. Results: (1) A total of 101 individuals with CSVD were included in this study. There were no statistical differences between the two groups in baseline clinical data except MMSE and AD8 scores. (2) After B/H correction, the promoter methylation rate of PER1 was higher in the cognitive dysfunction group than that in the normal group, and the difference was statistically significant (adjusted p < 0.001). (3) There was no significant correlation between the promoter methylation rates of PER1 and CRY1 in peripheral blood and circadian rhythm of blood pressure (p > 0.05). (4) Binary logistic regression models showed that the influence of promoter methylation of PER1 and CRY1 on cognitive dysfunction were statistically significant in Model 1 (p < 0.001; p = 0.025), and it still existed after adjusting for confounding factors in Model 2. Patients with the promoter methylation of PER1 gene (OR = 16.565, 95%CI, 4.057-67.628; p < 0.001) and the promoter methylation of CRY1 gene (OR = 6.017, 95%CI, 1.290-28.069; p = 0.022) were at greater risk of cognitive dysfunction compared with those with unmethylated promoters of corresponding genes in Model 2. Conclusion: The promoter methylation rate of PER1 gene was higher in the cognitive dysfunction group among CSVD patients. And the hypermethylation of the promoters of clock genes PER1 and CRY1 may be involved in affecting cognitive dysfunction in patients with CSVD.

Soil calcium prompts organic carbon accumulation after decadal saline-water irrigation in the Taklamakan desert.

Soil organic carbon (SOC), as a crucial measure of soil quality, is typically low in arid regions due to salinization, which is a global issue. How soil organic carbon changes with salinization is not a simple concept, as high salinity simultaneously affects plant inputs and microbial decomposition, which exert opposite effects on SOC accumulation. Meanwhile, salinization could affect SOC by altering soil Ca2+ (a salt component), which stabilizes organic matter via cation bridging, but this process is often overlooked. Here, we aimed to explore i) how soil organic carbon changes with salinization induced by saline-water irrigation and ii) which process drives soil organic carbon content with salinization, plant inputs, microbial decomposition, or soil Ca2+ level. To this end, we assessed SOC content, plant inputs represented by aboveground biomass, microbial decomposition revealed by extracellular enzyme activity, and soil Ca2+ along a salinity gradient (0.60-31.09 g kg-1) in the Taklamakan Desert. We found that, in contrast to our prediction, SOC in the topsoil (0-20 cm) increased with soil salinity, but it did not change with the aboveground biomass of the dominant species (Haloxylon ammodendron) or the activity of three carbon-cycling relevant enzymes (ß-glucosidase, cellulosidase, and N-acetyl-beta-glucosaminidase) along the salinity gradient. Instead, SOC changed positively with soil exchangeable Ca2+, which increased linearly with salinity. These results suggest that soil organic carbon accumulation could be driven by increases in soil exchangeable Ca2+ under salinization in salt-adapted ecosystems. Our study provides empirical evidence for the beneficial impact of soil Ca2+ on organic carbon accumulation in the field under salinization, which is apparent and should not be disregarded. In addition, the management of soil carbon sequestration in salt-affected areas should be taken into account by adjusting the soil exchangeable Ca2+ level.

Molecular Basis of KAT2A Selecting Acyl-CoA Cofactors for Histone Modifications.

Emerging discoveries about undocumented acyltransferase activities of known histone acetyltransferases (HATs) advance our understandings in the regulation of histone modifications. However, the molecular basis of HATs selecting acyl coenzyme A (acyl-CoA) substrates for histone modification is less known. We here report that lysine acetyltransferase 2A (KAT2A) as an illustrative instance of HATs can selectively utilize acetyl-CoA, propionyl-CoA, butyryl-CoA, and succinyl-CoA to directly deposit 18 histone acylation hallmarks in nucleosome. By analyzing the co-crystal structures of the catalytic domain of KAT2A in complex with acetyl-CoA, propionyl-CoA, butyryl-CoA, malonyl-CoA, succinyl-CoA, and glutaryl-CoA, we conclude that the alternative substrate-binding pocket of KAT2A and the length and electrostatic features of the acyl chain cooperatively determine the selection of the acyl-CoA substrates by KAT2A. This study reveals the molecular basis underlying the pluripotency of HATs that selectively install acylation hallmarks in nucleosomes, which might serve as instrumental mechanism to precisely regulate histone acylation profiles in cells.

Constitutively activated AMPKα1 protects against skeletal aging in mice by promoting bone-derived IGF-1 secretion.

Senile osteoporosis is characterized by age-related bone loss and bone microarchitecture deterioration. However, little is known to date about the mechanism that maintains bone homeostasis during aging. In this study, we identify adenosine monophosphate-activated protein kinase alpha 1 (AMPKα1) as a critical factor regulating the senescence and lineage commitment of mesenchymal stem cells (MSCs). A phospho-mutant mouse model shows that constitutive AMPKα1 activation prevents age-related bone loss and promoted MSC osteogenic commitment with increased bone-derived insulin-like growth factor 1 (IGF-1) secretion. Mechanistically, upregulation of IGF-1 signalling by AMPKα1 depends on cAMP-response element binding protein (CREB)-mediated transcriptional regulation. Furthermore, the essential role of the AMPKα1/IGF-1/CREB axis in promoting aged MSC osteogenic potential is confirmed using three-dimensional (3D) culture systems. Taken together, these results can provide mechanistic insight into the protective effect of AMPKα1 against skeletal aging by promoting bone-derived IGF-1 secretion.

Change rates of soil inorganic carbon vary with depth and duration after land conversion across drylands in North China.

Soil inorganic carbon (SIC) accounts for 30-70% of the total soil C in global drylands. Despite the slow turnover rate, recent studies indicate that SIC could be altered by land-use change as soil organic C (SOC). Neglecting SIC change could contribute greatly to the uncertainty of soil C dynamics in drylands. However, due to the spatial-temporal variation in SIC, the direction and magnitude of SIC change (rate) induced by land-use change at a large spatial scale is understudied and poorly understood. Here, we used the space-for-time approach to test how the SIC change varied with the duration and type of land-use change and soil depth across China's drylands. We assessed the temporal and spatial variations in the SIC change rate and explored the influencing factors based on a regional dataset comprising 424 pairs of data across North China. We found that the SIC change rate of 0-200 cm after land-use change was 12.80 (5.47‒20.03) g C m-2 yr-1 (mean with 95% confidence interval), which was comparable to the SOC change rate (14.72, (5.27-24.15 g C m-2 yr-1)). Increased SIC occurred only in deep soils (>30 cm) and in the conversion from deserts to croplands or woodlands. In addition, the SIC change rate decreased with the duration of land-use change, implying that quantifying the temporal pattern of SIC change is necessary to accurately estimate SIC dynamics. The SIC change was strongly related to changes in soil water content. The SIC change rate was weakly and negatively correlated with the SOC change rate, and this relationship varied with soil depth. Together, this study highlights that to improve the prediction of soil C dynamics following land-use change in drylands, we should quantify the temporal and vertical patterns of both soil inorganic and organic C changes in the region.

Identification of a tsRNA Contributor to Impaired Diabetic Wound Healing via High Glucose-Induced Endothelial Dysfunction.

Purpose: Delayed skin healing in diabetic wounds is a major clinical problem. The tRNA-derived small RNAs (tsRNAs) were reported to be associated with diabetes. However, the role of tsRNAs in diabetic wound healing is unclear. Our study was designed to explore the tsRNA expression profile and mine key potential tsRNAs and their mechanism in diabetic wounds. Methods: Skin tissues of patients with diabetic foot ulcers and healthy controls were subjected to small RNA sequencing. The role of candidate tsRNA was explored by loss- and gain-of-function experiments in HUVECs. Results: A total of 55 differentially expressed tsRNAs were identified, including 12 upregulated and 43 downregulated in the diabetes group compared with the control group. These tsRNAs were mainly concentrated in intercellular interactions and neural function regulation in GO terms and enriched in MAPK, insulin, FoxO, calcium, Ras, ErbB, Wnt, T cell receptor, and cGMP-PKG signaling pathways. tRF-Gly-CCC-039 expression was upregulated in vivo and in vitro in the diabetic model. High glucose disturbed endothelial function in HUVECs, and tRF-Gly-CCC-039 mimics further harmed HUVECs function, characterized by the suppression of proliferation, migration, tube formation, and the expression of Coll1a1, Coll4a2, and MMP9. Conversely, the tRF-Gly-CCC-039 inhibitor could attenuate high-glucose-induced endothelial injury to HUVECs. Conclusion: We investigated the tsRNAs expression profile in diabetic foot ulcers and defined the impairment role of tRF-Gly-CCC-039 in endothelial function in HUVECs. This study may provide novel insights into accelerating diabetic skin wound healing.

Clinical characteristics of cerebral venous sinus thrombosis patients with new-onset of headache.

OBJECTIVE: This study aimed to assess the clinical characteristics of cerebral venous sinus thrombosis (CVT) patients with new-onset headache and to identify the risk factors for headache in this population. METHODS: We retrospectively reviewed the demographic and clinical data of 69 CVT patients recruited between September 2017 and September 2019. Patients were classified into two groups, the headache group and the non-headache group, according to the presence or absence of new-onset headache symptoms at admission. The following characteristics and parameters were measured and analyzed, including gender, age, amount of thromboembolic cerebral venous sinus(ATCVS), and other relevant indicators. RESULTS: The incidence of headache was 75% in this cohort. The proportion of female patients in the headache group was higher than that in the non-headache group. Patients in the headache group were younger than those without headache. CVT patients of headache group showed higher lymphocyte ratio (LR), blood urea nitrogen (BUN), and intracranial pressure (ICP) compared to the non-headache group, whereas mean corpuscular volume (MCV) and levels of protein (cerebrospinal fluid, CSF) and lactic dehydrogenase (LDH) in CSF were lower in headache patients. The data also revealed younger age and the increased level of chloride ion CI-(CSF) were the risk factors for the occurrence of headache in CVT patients. CONCLUSION: Age, LR, MCV, BUN levels, ICP, protein (CSF), and LDH (CSF) in patients with headache were significantly different from those in the non-headache group at admission. Younger age and a level of CI- (CSF) were risk factors for headache in CVT patients. These findings may provide guidance for clinical diagnosis and treatment of CVT.

GluA1 Degradation by Autophagy Contributes to Circadian Rhythm Effects on Cerebral Ischemia Injury.

The mechanisms of many diseases, including central nervous system disorders, are regulated by circadian rhythms. The development of brain disorders such as depression, autism, and stroke is strongly associated with circadian cycles. Previous studies have shown that cerebral infarct volume is smaller at night (active phase) than during the day (inactive phase) in ischemic stroke rodent models. However, the underlying mechanisms remain unclear. Increasing evidence suggests that glutamate systems and autophagy play important roles in the pathogenesis of stroke. Here, we report that GluA1 expression was decreased and autophagic activity was increased in active-phase male mouse models of stroke compared with the inactive-phase models. In the active-phase model, induction of autophagy decreased the infarct volume, whereas inhibition of autophagy increased the infarct volume. Meanwhile, GluA1 expression was decreased following activation of autophagy and increased following inhibition of autophagy. We used Tat-GluA1 to uncouple p62, an autophagic adapter, from GluA1 and found that this blocked the degradation of GluA1, an effect similar to that of inhibition of autophagy in the active-phase model. We also demonstrated that knock-out of the circadian rhythm gene Per1 abolished the circadian rhythmicity of the volume of infarction and also abolished GluA1 expression and autophagic activity in wild-type (WT) mice. Our results suggest an underlying mechanism by which the circadian rhythm participates in the autophagy-dependent regulation of GluA1 expression, which influences the volume of infarction in stroke.SIGNIFICANCE STATEMENT Circadian rhythms affect the pathophysiological mechanisms of disease. Previous studies suggested that circadian rhythms affect the infarct volume in stroke, but the underlying mechanisms remain largely unknown. Here, we demonstrate that the smaller infarct volume after middle cerebral artery occlusion/reperfusion (MCAO/R) during the active phase is related to lower GluA1 expression and activation of autophagy. The decrease in GluA1 expression during the active phase is mediated by the p62-GluA1 interaction, followed by direct autophagic degradation. In short, GluA1 is the substrate of autophagic degradation, which mainly occurs after MCAO/R during the active phase but not the inactive phase.