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In order to solve the problem of logging calibration without a free pipe in the process of acoustic variable density logging and the subjective problem of the free pipe calibration method, this paper studies an attenuation rate calibration method based on acoustic variable density logging. Using the developed acoustic wave probe response relationship device and the acoustic wave probe calibration device, the response consistency of the receiving probe of the acoustic wave instrument and the frequency of the transmitting probe can be calibrated in the laboratory, and the response consistency and frequency calibration coefficient can be obtained. Through this coefficient, the acoustic wave attenuation rate can be derived. After converting the acoustic wave attenuation rate into a relative sound amplitude, the scale coefficients of the well can be obtained. The relative acoustic amplitude of each measuring point in the well can be obtained by using the scale coefficient to evaluate the cementing quality. The acoustic variable density field test of 18 wells in the oilfield shows that the relative acoustic amplitude calculation results obtained by the attenuation rate correlation calibration method are basically consistent with the theoretical values, and the maximum deviation is 6.9%. The deviation is caused by the presence of ahead fluid in the outer annulus of the casing, the presence of trace bubbles in the casing, and the incomplete centering of the instrument. Compared with the traditional free pipe calibration method, the attenuation rate correlation calibration method innovatively replaces the free pipe calibration in the well with the indoor calibration of the acoustic instrument and solves the problem of acoustic variable density calibration when there is no free pipe in cementing quality logging. This method has better accuracy and a greater application range, which lays a foundation for the quantitative interpretation of acoustic variable density., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Although it is a leading cause of cancer-related mortality among women globally, breast cancer (BC) has drawn increased attention owing to its poor prognosis and the challenges associated with limited treatment options. SLC35A2 was shown to be dysregulated in a number of tumor types according to multiple investigations. However, its function in BC was rarely reported. This study aims to investigate the expression of SLC35A2 in BC and its impact on the functionality and prognosis of BC cells. We collected 11 pairs of BC tissues and normal specimens, obtaining clinical information from 1,118 BC patients through RNA sequencing analysis. Different BC cell lines were used in experiments, and the roles of SLC35A2 in cell proliferation, invasion, and migration was assessed through gene silencing and functional assays. Additionally, a prognostic model, including SLC35A2 expression levels, age, T-stage, M-stage, N-stage, and clinical stage, was constructed, and its predictive performance in overall survival was validated using time-dependent receiver operating characteristic curves. High SLC35A2 expression was correlated positively with patient age and T-stage. Kaplan-Meier survival curves and Cox regression analysis confirmed the independent and significant prognostic value of SLC35A2 in overall survival. Functional experiments demonstrated that SLC35A2 silencing inhibited the proliferation, migration, and invasion of BC cells, affecting their metastatic potential through modulation of the Wnt/β-catenin/EMT signaling pathway. In conclusion, our study reveals the crucial role of SLC35A2 in BC, providing a novel biomarker for clinical management and valuable insights into the underlying mechanisms of BC pathogenesis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study has been approved by the ethics committee institution of Shenzhen Hospital of Union Medical College of Huazhong University of Science and Technology (2022-No.056). Research involving human research participants has been done in accordance with the Declaration of Helsinki., (© 2024. The Author(s).)

Phortica okadai, known as the vector of Thelazia callipaeda in Asia, is of concern to public health in the past few decades. We generated a high-quality chromosome-level genome assembly of P. okadai with a size of 263.82 Mb and a contig N50 of 15 Mb, scaffold N50 of 47.45 Mb, combining PacBio HiFi, Illumina short-reads, and Hi-C sequencing data. Approximately 98.5% of 100 contigs could be properly ordered and oriented into 6 pseudo-chromosomes and a total of 15,052 protein-coding genes were obtained from the P. okadai genome, of which 91.76% were functionally annotated. BUSCO analysis revealed that 96.20% of 1315 predicted genes were clearly covered the conserved invertebrate genes within the database. Additionally, 302 rRNAs, 377 tRNAs, 52 miRNAs, 40 snRNAs and 21 snoRNAs were detected. In conclusion, this high-quality chromosome level reference genome will be a valuable resource for furthering the fields of ecology, genetics, evolution and functional genomics of P. okadai., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In this study, the Carnegie-Ames-Stanford approach model was used to estimate the net primary productivity (NPP) of Wuyishan National Park from 1990 to 2020. Variation in NPP in parks was examined, and the influencing factors were identified. NPP showed an increasing trend annually with climate change. The value (625.67 gC m -2  a -1 ) obtained in this study was higher than the regional value along similar latitudes and coastlines. Affected by the spatial distribution characteristics of vegetation, NPP in the study area exhibited significant spatial heterogeneity, with a distribution of higher values in the northwestern region and lower values in the southeastern region. However, the growth rates showed the opposite trend. The higher growth rate of NPP in the ecological restoration zone was attributed to the ecological conservation efforts undertaken in Wuyishan National Park. Among the various environmental factors, the vapor pressure deficit contributed substantially to NPP temporal distribution, accounting for 25.71%. Terrain factors, which are influenced by the spatial distribution characteristics of vegetation and environmental factors, are important variables that affect the spatial distribution of NPP within the study area. The highest vegetation NPP in Wuyishan National Park was observed in regions with an elevation of approximately 1000 m, slopes ranging from 20° to 40°, and an aspect of approximately 150°. Compared with slope and aspect, elevation provides a stronger explanatory power (R 2  = 0.93) for the spatial distribution patterns of vegetation NPP in Wuyi Mountain National Park. This study suggests that Wuyishan National Park has considerable carbon sequestration potential. In the context of climate warming, the favorable aspects of climate warming should be considered, and ecological restoration measures tailored to local conditions should be implemented.Article title mismatch between manuscript and publisher provided information, so we have follow the manuscript. Kindly check and confirm.Variations and influencing factors of vegetation net primary productivity over 31 years in Wuyishan National Park, China., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The operation mode of UAV equipped with LiDAR can significantly reduce the efficiency and cost of highway terrain acquisition. At present, due to the complicated terrain and weak signal of mountain road, it is difficult to collect terrain data. In view of the above problems, this paper puts forward the technology of BDS assisted terrain acquisition and processing on complex mountain roads. This paper describes in detail the new signal unfuzzy acquisition and tracking algorithm and multi-antenna positioning and attitude determination technology and equipment of BDS-3 mountain highway, through millimeter wave Lidar altimetry technology, imitation ground flight, air-ground multi-source data combined with air three-direction method and other technologies. To realize efficient 3D collection and 3D reconstruction of massive original images of terrain of complex mountain traffic lines in the range of 100 km. Finally, a case study of 100 km mountain road is taken to verify the effectiveness of the method., (© 2024. The Author(s).)

Digital images have become an important way of transmitting information, and the risk of attacks during transmission is increasing. Image watermarking is an important technical means of protecting image information security and plays an important role in the field of information security. In the field of image watermarking technology, achieving a balance between imperceptibility, robustness, and embedding capacity is a key issue. To address this issue, this paper proposes a high-capacity color image adaptive watermarking scheme based on discrete wavelet transform (DWT), Heisenberg decomposition (HD), and singular value decomposition (SVD). In order to enhance the security of the watermark, Logistic chaotic mapping was used to encrypt the watermark image. By adaptively calculating the embedding factor through the entropy of the cover image, and then combining it with Alpha blending technology, the watermark image is embedded into the Y component of the YCbCr color space to enhance the imperceptibility of the algorithm. In addition, the robustness of the algorithm was further improved through singular value correction methods. The experimental results show that the average PSNR and SSIM of the watermarking scheme are 45.3437dB and 0.9987, respectively. When facing various attacks, the average NCC of the extracted watermark reaches above 0.95, indicating good robustness. The embedding capacity of this scheme is 0.6667bpp, which is higher than other watermarking schemes, and the average running time is 1.1136 seconds, which is better than most schemes., (© 2024. The Author(s).)

Sensory stimulations at 40 Hz gamma (but not any other frequency), have shown promise in reversing Alzheimer's disease (AD)-related pathologies. What distinguishes 40 Hz? We hypothesized that stimuli at 40 Hz might summate more efficiently (temporal summation) or propagate more efficiently between cortical layers (vertically), or along cortical laminas (horizontally), compared to inputs at 20 or 83 Hz. To investigate these hypotheses, we used brain slices from AD mouse model animals (5xFAD). Extracellular (synaptic) stimuli were delivered in cortical layer 4 (L4). Leveraging a fluorescent voltage indicator (VSFP) expressed in cortical pyramidal neurons, we simultaneously monitored evoked cortical depolarizations at multiple sites, at 1 kHz sampling frequency. Experimental groups (AD-Female, CTRL-Female, AD-Male, and CTRL-Male) were tested at three stimulation frequencies (20, 40, and 83 Hz). Despite our initial hypothesis, two parameters-temporal summation of voltage waveforms and the strength of propagation through the cortical neuropil-did not reveal any distinct advantage of 40 Hz stimulation. Significant physiological differences between AD and Control mice were found at all stimulation frequencies tested, while the 40 Hz stimulation frequency was not remarkable., (© 2024. The Author(s).)

Establishing predictive models for the pathological response and lymph node metastasis in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) based on MRI radiomic features derived from the tumor and mesorectal compartment (MC). This study included 209 patients with LARC who underwent rectal MRI both before and after nCRT. The patients were divided into a training set (n = 146) and a test set (n = 63). Regions of interest (ROIs) for the tumor and MC were delineated on both pre- and post-nCRT MRI images. Radiomic features were extracted, and delta radiomic features were computed. The predictive endpoints were pathological complete response (pCR), pathological good response (pGR), and lymph node metastasis (LNM). Feature selection for various models involved sequentially removing features with a correlation coefficient > 0.9, and features with P-values ≥ 0.05 in univariate analysis, followed by LASSO regression on the remaining features. Logistic regression models were developed, and their performance was evaluated using the area under the receiver operating characteristic curve (AUC). Among the 209 LARC patients, the number of patients achieving pCR, pGR, and LNM were 44, 118, and 40, respectively. The optimal model for predicting each endpoint is the combined model that incorporates pre- and delta-radiomics features for both the tumor and MC. These models exhibited superior performance with AUC values of 0.874 (for pCR), 0.801 (for pGR), and 0.826 (for LNM), outperforming the MRI tumor regression grade (mrTRG) which yielded AUC values of 0.800, 0.715, and 0.603, respectively. The results demonstrate the potential utility of the tumor and MC radiomics features, in predicting treatment efficacy among LARC patients undergoing nCRT., (© 2024. The Author(s).)

Inorganic phosphate (Pi) is a fundamental macronutrient for all living organisms, the homeostasis of which is critical for numerous biological activities 1-3 . As the only known human Pi exporter to date, XPR1 has an indispensable role in cellular Pi homeostasis 4,5 . Dysfunction of XPR1 is associated with neurodegenerative disease 6-8 . However, the mechanisms underpinning XPR1-mediated Pi efflux and regulation by the intracellular inositol polyphosphate (InsPP) sensor SPX domain remain poorly understood. Here we present cryo-electron microscopy structures of human XPR1 in Pi-bound closed, open and InsP 6 -bound forms, revealing the structural basis for XPR1 gating and regulation by InsPPs. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and a conserved W573 acts as a molecular switch for gating. In addition, the SPX domain binds to InsP 6 and facilitates Pi efflux by liberating the C-terminal loop that limits Pi entry. This study provides a conceptual framework for the mechanistic understanding of Pi homeostasis by XPR1 homologues in fungi, plants and animals., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APP NLGF , we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD prevention and therapeutic strategies., (© 2024. The Author(s).)

Preeclampsia (PE) is a heterogeneous disease that seriously affects the health of mothers and fetuses. Lack of detection assays, its diagnosis and intervention are often delayed when the clinical symptoms are atypical. Using personalized pathway-based analysis and machine learning algorithms, we built a PE diagnosis model consisting of nine core pathways using multiple cohorts from the Gene Expression Omnibus database. The model showed an area under the receiver operating characteristic (AUROC) curve of 0.959 with the data from the placental tissue samples in the development cohort. In the two validation cohorts, the AUROCs were 0.898 and 0.876, respectively. The model also performed well with the maternal plasma data in another validation cohort (AUROC: 0.815). Moreover, we identified tyrosine-protein kinase Lck (LCK) as the hub gene in this model and found that LCK and pLCK proteins were downregulated in placentas from PE patients. The pathway-level model for PE can provide a novel direction to develop molecular diagnostic assay and investigate potential mechanisms of PE in future studies., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Objective: This study was to systematically assess the occipital lobe gray and white matter volume of isolated ventriculomegaly (IVM) fetuses with MRI and to follow up the neurodevelopment of participants., Method: MRI was used to evaluate 37 IVM fetuses and 37 control fetuses. The volume of gray and white matter in each fetal occipital gyrus was manually segmented and compared, and neurodevelopment was followed up and assessed in infancy and early childhood., Result: Compared with the control group, the volume of gray matter in occipital lobe increased in the IVM group, and the incidence of neurodevelopmental delay increased., Conclusion: We tested the hypothesis that prenatal diagnosis IVM represents a biological marker for development in fetal occipital lobe. Compared with the control group, the IVM group showed differences in occipital gray matter development and had a higher risk of neurodevelopmental delay., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Recent studies have explored the association between primary aldosteronism and cardiovascular disease incidence. The association between specific primary aldosteronism treatments and differential improvement in cardiovascular event rates is yet to be established. This study was designed to compare the relative effects of spironolactone therapy and surgical intervention on cardiovascular outcomes among primary aldosteronism patients. This retrospective observational study included 853 primary aldosteronism patients from the First Affiliated Hospital of China Medical University between 2014 and 2022. Patients who had completed abdominal computed tomography (CT) examinations with similar metabolic characteristics and 6-month follow-up analyses were included in this study. These patients were separated into a surgical treatment group (n = 33) and a spironolactone treatment group (n = 51). Demographic data, biochemical analysis results, liver/spleen (L/S) X-ray attenuation ratio, hospitalization frequency, and cardiovascular events were compared between the two groups. The spironolactone group demonstrated significantly improved metabolic characteristics compared to the surgical group, shown by lower BMI, blood pressure, total cholesterol (TC), insulin resistance index (IRI), and reduced non-alcoholic fatty liver disease prevalence. Metabolic parameters did not differ significantly within the surgical treatment group when comparing pre- and postoperative values. The incidence of cardiovascular events was lower in the spironolactone group compared to the surgery group (23/33 vs. 20/51, P < 0.001) despite higher hospitalization rates(37/31 vs. 61/53, P < 0.001). In patients with primary aldosteronism, spironolactone treatment is more effective than surgical intervention in remediating abnormal lipid and glucose metabolism while improving cardiovascular outcomes. Chinese clinical trial registry registration number: ChiCTR2300074574., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Human immunodeficiency virus (HIV) infection increases the risk of acute myocardial infarction (AMI). However, little is known about its association with in-hospital outcomes and temporal trends in patients with AMI undergoing percutaneous coronary intervention (PCI). We queried patients with AMI who underwent PCI from the National Inpatient Sample Database (2003-2015) and stratified them into three groups: symptomatic, asymptomatic, and HIV-negative. After 1:2 case-control matching (CCM), logistic regression analysis was conducted to determine how HIV infection affected in-hospital outcomes. We also evaluated their recent trends from 2003 to 2015. The total weighted national estimate of 2,191,129 AMI cases included 2,178,995 HIV/AIDS-negative, 4994 asymptomatic, and 7140 symptomatic HIV cases. Symptomatic but not asymptomatic patients with HIV suffered more than triple the in-hospital mortality (adjusted odds ratio (aOR) 3.6, 95% confidence interval (CI) 2.5-5.2), over one-fold incidence of acute kidney injury (aOR 2.6 95% CI 1.9-3.4) and cardiogenic shock risk (aOR 1.9, 95% CI 1.3-2.7), a longer length of hospital stay (beta 1.2, 95% CI 1.0-1.5), and had more procedures (beta 1.3, 95% CI 1.2-1.5). These disparities relating to symptomatic HIV infection persisted from 2003 to 2015. In patients with AMI who underwent PCI, symptomatic HIV infection was associated with higher in-hospital mortality and more severe outcomes., (© 2024. The Author(s).)

Aquifer confinement represents a pivotal property that significantly influences the vulnerability and contamination risk of groundwater resources. Several methods have been proposed for determining aquifer confinement by analyzing the response of well water level to Earth tides and atmospheric tides. In this study, we evaluated the performance of the existing single methods and put forward an optimized comprehensive approach. We compared the determination results of the three single methods with those of a comprehensive method using water-level data from 39 earthquake precursor monitoring wells in North China. The results demonstrate that the comprehensive method effectively determined aquifer confinement, significantly reducing the uncertainty associated with the three single methods. The application of the comprehensive method in North China reveals that aquifer confinement may undergo temporal variations during long-term continuous observation, especially in areas where the confining properties of aquifers may vary due to human activities and earthquakes. In such areas, the comprehensive method facilitates accurate assessment of groundwater vulnerability, as well as the potential dispersion of underground pollutants., (© 2024. The Author(s).)

Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission 1-3 . Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression 4-6 . Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease 7,8 , respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. The structures in three distinct states also reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutic agents., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks 1 . Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOR OXT ) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvl OXTR ) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvl OXTR cells minimally respond to aggressor cues. During defeat, aVMHvl OXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvl OXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

High-story residential structures and off-site prefabrication have been dominant choices in the construction industry. There is a substantial quantity of greenhouse gas (GHG) emissions produced by the construction industry. In fact, the construction industry is responsible for 30 percent of all GHG emissions. In this study, we analyse the differences between the conventional technique of building and the off-site prefabricating construction method. First, we evaluate the emissions emitted from key processes during the off-site prefabricating construction. In addition, we analyse the qualitative and quantitative differences between two prefabrication structural systems, namely concrete and steel, which are the two most common structural systems utilised in residential construction projects in China. We examine and analyse four different case studies in order to exemplify the proposed methodology and offer managerial insights., (© 2023. The Author(s).)

In the past 2 years, three earthquakes of magnitude 6.0 and above occurred consecutively in Qinghai province, China, i.e., the 22 May 2021 M s 7.4 Maduo, 8 January 2022 M s 6.9 Menyuan, and 26 March 2022 M s 6.0 Delingha earthquakes. The hydrological observation instruments set up by the China Earthquake Administration allow us to study the dynamic processes in the well-aquifer systems during the establishment of criticality. Particularly, the observations played an important role in the prediction of the 8 January 2022 M s 6.9 Menyuan earthquake that was approved by the People's Government of Qinghai province. This work presents the hydrological data recorded by 7 stations to show the short-term anomalies before these earthquakes. To explore the performance of the hydrological observations in detecting earthquakes that occurred on different active tectonic blocks, we calculate the relative amplitudes of the pre-seismic changes. Results indicate that markedly pre-seismic change is found if the observation station and the detection earthquake are on the same block, and moderate change is found if they are on the adjacent blocks, while the precursor is hard to be identified if they are on the separated blocks. The variations in the hydrological responses may be caused by the strength weakening (or dilatancy) of source media. And the increased volumes in the crust can be evidenced by the changes in the geodetic time series in the same neighborhoods and during the same period, augmenting stress loading between the blocks., (© 2023. The Author(s).)

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state 1,2 . Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring 3,4 . The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits 5,6 , we use the medial preoptic area (MPOA), a key site for maternal behaviours 7-11 , as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTpr ESR1 ) are necessary, sufficient and naturally activated during infanticide in female mice. MPOA ESR1 and BNSTpr ESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOA ESR1 and BNSTpr ESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aggression is costly and requires tight regulation. Here we identify the projection from estrogen receptor alpha-expressing cells in the caudal part of the medial preoptic area (cMPOA Esr1 ) to the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential pathway for modulating aggression in male mice. cMPOA Esr1 cells increase activity mainly during male-male interaction, which differs from the female-biased response pattern of rostral MPOA Esr1 (rMPOA Esr1 ) cells. Notably, cMPOA Esr1 cell responses to male opponents correlated with the opponents' fighting capability, which mice could estimate based on physical traits or learn through physical combats. Inactivating the cMPOA Esr1 -VMHvl pathway increased aggression, whereas activating the pathway suppressed natural intermale aggression. Thus, cMPOA Esr1 is a key population for encoding opponents' fighting capability-information that could be used to prevent animals from engaging in disadvantageous conflicts with superior opponents by suppressing the activity of VMHvl cells essential for attack behaviors., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Eucommia ulmoides staminate flowers (EUF), a newly approved functional food in China, have great potential for hormonal regulation. Herein, we aim to demonstrate the chemical composition and pharmacological activity of EUF in testosterone production and hormonal regulation. EUF extract and its components, kaempferol and geniposidic acid, exhibited a strong stimulating effect by increasing testosterone secretion, reducing ROS production, or promoting viability in Leydig cells. Meanwhile, the increased testosterone production was related to the upregulation of mRNA and protein expression of the steroidogenic pathway, such as steroidogenic acute-regulatory protein (StAR), 3β -hydroxysteroid dehydrogenase type 1 (HSD3B1), 17α-hydroxylase/17,20-lyase (CYP17A1), and nuclear receptor subfamily 5 group A member 1 (NR5A1). However, PKA inhibitor H89 or adenylyl cyclase inhibitor SQ22536 could block their effect. The results of transgenic yeast models showed the androgenic agonistic effects of kaempferol and naringenin and the estrogenic agonistic effects of rutin. These results indicated that the testosterone promotional effect of EUF was related to the activation of the steroidogenic pathway and potential hormonal regulation. Kaempferol and geniposidic acid might be the key active ingredients., (© 2022. The Author(s).)

RNA-guided systems, such as CRISPR-Cas, combine programmable substrate recognition with enzymatic function, a combination that has been used advantageously to develop powerful molecular technologies 1,2 . Structural studies of these systems have illuminated how the RNA and protein jointly recognize and cleave their substrates, guiding rational engineering for further technology development 3 . Recent work identified a new class of RNA-guided systems, termed OMEGA, which include IscB, the likely ancestor of Cas9, and the nickase IsrB, a homologue of IscB lacking the HNH nuclease domain 4 . IsrB consists of only around 350 amino acids, but its small size is counterbalanced by a relatively large RNA guide (roughly 300-nt ωRNA). Here, we report the cryogenic-electron microscopy structure of Desulfovirgula thermocuniculi IsrB (DtIsrB) in complex with its cognate ωRNA and a target DNA. We find the overall structure of the IsrB protein shares a common scaffold with Cas9. In contrast to Cas9, however, which uses a recognition (REC) lobe to facilitate target selection, IsrB relies on its ωRNA, part of which forms an intricate ternary structure positioned analogously to REC. Structural analyses of IsrB and its ωRNA as well as comparisons to other RNA-guided systems highlight the functional interplay between protein and RNA, advancing our understanding of the biology and evolution of these diverse systems., (© 2022. The Author(s).)

Medication-related osteonecrosis of the jaw (MRONJ) is primarily associated with administering antiresorptive or antiangiogenic drugs. Despite significant research on MRONJ, its pathogenesis and effective treatments are still not fully understood. Animal models can be used to simulate the pathophysiological features of MRONJ, serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ. Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ, but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ. Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic. This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency. Currently, there is a lack of a unified assessment system for MRONJ models, which hinders a standard definition of MRONJ-like lesions in rodents. Therefore, this review comprehensively summarizes assessment systems based on published peer-review articles, including new approaches in gross observation, histological assessments, radiographic assessments, and serological assessments. This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ., (© 2022. The Author(s).)

Information Extraction (IE) in Natural Language Processing (NLP) aims to extract structured information from unstructured text to assist a computer in understanding natural language. Machine learning-based IE methods bring more intelligence and possibilities but require an extensive and accurate labeled corpus. In the materials science domain, giving reliable labels is a laborious task that requires the efforts of many professionals. To reduce manual intervention and automatically generate materials corpus during IE, in this work, we propose a semi-supervised IE framework for materials via automatically generated corpus. Taking the superalloy data extraction in our previous work as an example, the proposed framework using Snorkel automatically labels the corpus containing property values. Then Ordered Neurons-Long Short-Term Memory (ON-LSTM) network is adopted to train an information extraction model on the generated corpus. The experimental results show that the F1-score of γ' solvus temperature, density and solidus temperature of superalloys are 83.90%, 94.02%, 89.27%, respectively. Furthermore, we conduct similar experiments on other materials, the experimental results show that the proposed framework is universal in the field of materials., (© 2022. The Author(s).)

Frequent outbreaks of coronaviruses underscore the need for antivirals and vaccines that can counter a broad range of coronavirus types. We isolated a human antibody named 76E1 from a COVID-19 convalescent patient, and report that it has broad-range neutralizing activity against multiple α- and β-coronaviruses, including the SARS-CoV-2 variants. 76E1 also binds its epitope in peptides from γ- and δ-coronaviruses. 76E1 cross-protects against SARS-CoV-2 and HCoV-OC43 infection in both prophylactic and therapeutic murine animal models. Structural and functional studies revealed that 76E1 targets a unique epitope within the spike protein that comprises the highly conserved S2' site and the fusion peptide. The epitope that 76E1 binds is partially buried in the structure of the SARS-CoV-2 spike trimer in the prefusion state, but is exposed when the spike protein binds to ACE2. This observation suggests that 76E1 binds to the epitope at an intermediate state of the spike trimer during the transition from the prefusion to the postfusion state, thereby blocking membrane fusion and viral entry. We hope that the identification of this crucial epitope, which can be recognized by 76E1, will guide epitope-based design of next-generation pan-coronavirus vaccines and antivirals., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) has aroused concerns over their increased infectivity and transmissibility, as well as decreased sensitivity to SARS-CoV-2-neutralizing antibodies (NAbs) and the current coronavirus disease 2019 (COVID-19) vaccines. Such exigencies call for the development of pan-sarbecovirus vaccines or inhibitors to combat the circulating SARS-CoV-2 NAb-escape variants and other sarbecoviruses. In this study, we isolated a broadly NAb against sarbecoviruses named GW01 from a donor who recovered from COVID-19. Cryo-EM structure and competition assay revealed that GW01 targets a highly conserved epitope in a wide spectrum of different sarbecoviruses. However, we found that GW01, the well-known sarbecovirus NAb S309, and the potent SARS-CoV-2 NAbs CC12.1 and REGN10989 only neutralize about 90% of the 56 tested currently circulating variants of SARS-CoV-2 including Omicron. Therefore, to improve efficacy, we engineered an IgG-like bispecific antibody GW01-REGN10989 (G9) consisting of single-chain antibody fragments (scFv) of GW01 and REGN10989. We found that G9 could neutralize 100% of NAb-escape mutants (23 out of 23), including Omicron variant, with a geometric mean (GM) 50% inhibitory concentration of 8.8 ng/mL. G9 showed prophylactic and therapeutic effects against SARS-CoV-2 infection of both the lung and brain in hACE2-transgenic mice. Site-directed mutagenesis analyses revealed that GW01 and REGN10989 bind to the receptor-binding domain in different epitopes and from different directions. Since G9 targets the epitopes for both GW01 and REGN10989, it was effective against variants with resistance to GW01 or REGN10989 alone and other NAb-escape variants. Therefore, this novel bispecific antibody, G9, is a strong candidate for the treatment and prevention of infection by SARS-CoV-2, NAb-escape variants, and other sarbecoviruses that may cause future emerging or re-emerging coronavirus diseases., (© 2022. The Author(s).)

Under stress, the endomembrane system undergoes reorganization to support autophagosome biogenesis, which is a central step in autophagy. How the endomembrane system remodels has been poorly understood. Here we identify a new type of membrane contact formed between the ER-Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) in the ER-Golgi system, which is essential for promoting autophagosome biogenesis induced by different stress stimuli. The ERGIC-ERES contact is established by the interaction between TMED9 and SEC12 which generates a short distance opposition (as close as 2-5 nm) between the two compartments. The tight membrane contact allows the ERES-located SEC12 to transactivate COPII assembly on the ERGIC. In addition, a portion of SEC12 also relocates to the ERGIC. Through both mechanisms, the ERGIC-ERES contact promotes formation of the ERGIC-derived COPII vesicle, a membrane precursor of the autophagosome. The ERGIC-ERES contact is physically and functionally different from the TFG-mediated ERGIC-ERES adjunction involved in secretory protein transport, and therefore defines a unique endomembrane structure generated upon stress conditions for autophagic membrane formation., (© 2021. The Author(s), under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)

α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an important cellular metabolite-sensing enzyme that can directly sense changes not only in ATP but also in metabolites associated with carbohydrates and fatty acids. However, less is known about whether and how AMPK senses variations in cellular amino acids. Here, we show that cysteine deficiency significantly triggers calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-mediated activation of AMPK. In addition, we found that CaMKK2 directly associates with cysteinyl-tRNA synthetase (CARS), which then binds to AMPKγ2 under cysteine deficiency to activate AMPK. Interestingly, we discovered that cysteine inhibits the binding of CARS to AMPKγ2, and thus, under cysteine deficiency conditions wherein the inhibitory effect of cysteine is abrogated, CARS mediates the binding of AMPK to CaMKK2, resulting in the phosphorylation and activation of AMPK by CaMKK2. Importantly, we demonstrate that blocking AMPK activation leads to cell death under cysteine-deficient conditions. In summary, our study is the first to show that CARS senses the absence of cysteine and activates AMPK through the cysteine-CARS-CaMKK2-AMPKγ2 axis, a novel adaptation strategy for cell survival under nutrient deprivation conditions., (© 2021 The Authors.)

Tumors are one of the main causes of death in humans. The development of safe and effective methods for early diagnosis and treatment of tumors is a difficult problem that needs to be solved urgently. It is well established that the occurrence of tumors involves complex biological mechanisms, and the tumor microenvironment (TME) plays an important role in regulating the biological behavior of tumors. Cancer-associated fibroblasts (CAFs) are a group of activated fibroblasts with significant heterogeneity and plasticity in the tumor microenvironment. They secrete a variety of active factors to regulate tumor occurrence, development, metastasis, and therapeutic resistance. Although most studies suggest that CAFs have significant tumor-promoting functions, some evidence indicates that they may have certain tumor-suppressive functions in the early stage of tumors. Current research on CAFs continues to face many challenges, and the heterogeneity of their origin, phenotype, and function is a major difficulty and hot spot. To provide new perspectives for the research on CAFs and tumor diagnosis and treatment, this review summarizes the definition, origin, biomarkers, generation mechanism, functions, heterogeneity, plasticity, subpopulations, pre-metastasis niches (PMN), immune microenvironment, and targeted therapy of CAFs, describes the research progress and challenges, and proposes possible future research directions based on existing reports., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2., (© 2021. The Author(s).)

T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways., (© 2021. The Author(s).)

Dysregulation of lipid metabolism could lead to the development of metabolic disorders. We report here that the F-box protein JFK promotes excessive lipid accumulation in adipose tissue and contributes to the development of metabolic syndrome. JFK transgenic mice develop spontaneous obesity, accompanied by dyslipidemia, hyperglycemia, and insulin resistance, phenotypes that are further exacerbated under high-fat diets. In contrast, Jfk knockout mice are lean and resistant to diet-induced metabolic malfunctions. Liver-specific reconstitution of JFK expression in Jfk knockout mice leads to hepatic lipid accumulation resembling human hepatic steatosis and nonalcoholic fatty liver disease. We show that JFK interacts with and destabilizes ING5 through assembly of the SCF complex. Integrative transcriptomic and genomic analysis reveals that the SCF JFK -ING5 axis interferes with AMPK activity and fatty acid β-oxidation, leading to the suppression of hepatic lipid catabolism. Significantly, JFK is upregulated and AMPKα1 is down-regulated in liver tissues from NAFLD patients. These results reveal that SCF JFK is a bona fide E3 ligase for ING5 and link the SCF JFK -ING5 axis to the development of obesity and metabolic syndrome., (© 2021 The Authors.)

Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified. Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics. Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.

Single-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type-specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons. We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons after perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.

LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC 50 values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-L-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design.