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Abstract Background HCC is characterized by a high interstitial fluid pressure (HIFP) environment, which appears to support cancer cell survival. However, the mechanisms behind this phenomenon are not fully understood. Methods This study investigates the role of kinesin family member 11 (KIF11) in HCC under HIFP conditions, using both in vivo and in vitro models. In vitro experiments replicated the HIFP environment to observe changes in HCC cell behavior and protein expression, while in vivo studies involved mice portal hypertension to create an orthotopic liver cancer model, allowing for the evaluation of tumor progression. Additionally, clinical samples from HCC patients were analyzed for consistency with the experimental findings. Results Results demonstrated that the HIFP environment significantly increased the proliferation, invasion, and metastasis in HCC cells. Omics analysis and subsequent molecular validation revealed that KIF11 protein levels were markedly upregulated under HIFP, despite no significant change in mRNA levels. Further investigation showed that this upregulation was linked to a reduction in KIF11's ubiquitin-mediated degradation, suggesting that the HIFP environment stabilizes KIF11 expression by inhibiting its degradation pathway. Co-immunoprecipitation and proteomic analysis identified ubiquitin-specific peptidase 1 (USP1) as a crucial factor in this process, deubiquitinating KIF11 at the K77 site, thus stabilizing its protein levels. Clinical analysis confirmed that both USP1 and KIF11 were significantly overexpressed in HCC patients with portal hypertension, with a strong correlation between the two. Inhibition of USP1 using ML323 significantly reduced KIF11 protein levels and suppressed tumor progression in the mouse model. Conclusion These findings suggest that the HIFP environment fosters HCC progression through USP1-mediated stabilization of KIF11, highlighting USP1 as a potential therapeutic target, especially in patients with portal hypertension.

Abstract Chronic ischemia in moyamoya disease (MMD) impaired white matter microstructure and neural functional network. However, the coupling between cerebral blood flow (CBF) and functional connectivity and the association between structural and functional network are largely unknown. 38 MMD patients and 20 sex/age-matched healthy controls (HC) were included for T1-weighted imaging, arterial spin labeling imaging, resting-state functional MRI and diffusion tensor imaging. All patients had preoperative and postoperative digital subtraction angiography. Upon constructing the structural connectivity (SC) and functional connectivity (FC) networks, the SC-FC coupling was calculated. After obtaining the graph theoretical parameters, neurovascular coupling represented the spatial correlation between node degree centrality (DC) of functional networks and CBF. The CBF-DC coupling and SC-FC coupling were compared between MMD and HC groups. We further analyzed the correlation between coupling indexes and cognitive scores, as well as postoperative collateral formation. Compared with HC, CBF-DC coupling was decreased in MMD (p = 0.021), especially in the parietal lobe (p = 0.047). SC-FC coupling in MMD decreased in frontal, occipital, and subcortical regions. Cognitive scores were correlated with the CBF-DC coupling in frontal lobes (r = 0.394, p = 0.029) and SC-FC coupling (r = 0.397, p = 0.027). The CBF-DC coupling of patients with good postoperative collateral formation was higher (p = 0.041). Overall, neurovascular decoupling and structure-functional decoupling at the cortical level may be the underlying neuropathological mechanisms of MMD.

Abstract Pancreatic cancer (PC) is a highly malignant solid tumor whose resistance to gemcitabine (GEM) chemotherapy is a major cause of poor patient prognosis. Although PC is known to thrive on malnutrition, the mechanism underlying its chemotherapy resistance remains unclear. The current study analyzed clinical tissue sample databases using bioinformatics tools and observed significantly upregulated expression of the deubiquitinase STAMBP in PC tissues. Functional experiments revealed that STAMBP knockdown remarkably increases GEM sensitivity in PC cells. Multiple omics analyses suggested that STAMBP enhances aerobic glycolysis and suppresses mitochondrial respiration to increase GEM resistance in PC both in vitro and in vivo. STAMBP knockdown decreased PDK1 levels, an essential regulator of the aerobic glycolytic process, in several cancers. Mechanistically, STAMBP promoted the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1 via direct binding to E2F1 and suppressing its degradation and ubiquitination. High-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified the FDA drug entrectinib as a potent GEM sensitizer and STAMBP inhibitor, augmenting the antitumor effect of GEM in a patient-derived xenograft (PDX) model. Overall, we established a novel mechanism, via the STAMBP–E2F1–PDK1 axis, by which PC cells become chemoresistant in a nutrient-poor tumor microenvironment.

Background Changes in levels of hemoglobin would result in alterations of cerebral blood flow (CBF). However, the impact of hemoglobin on CBF in moyamoya disease (MMD) remains largely unknown. This study sought to determine whether CBF would be influenced by hemoglobin before surgical revascularization and to analyze the relationships between hemoglobin and CBF with clinical outcome after surgery in patients with MMD. Methods and Results We prospectively enrolled adult patients with MMD undergoing surgical revascularization between June 2020 and December 2022. Preoperative CBF was measured in the territories of anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA, respectively) using 3‐dimensional pseudo‐continuous arterial spin labeling magnetic resonance imaging. Clinical outcome at 1 year after surgery was evaluated using the modified Rankin Scale. A total of 60 patients with MMD were included, with 25% (n=15) experiencing unfavorable outcomes. Patients with MMD exhibited lower CBF (ACA: P=0.007; MCA: P

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

This study examined whether preference for online social interaction (POSI) was related to poorer affective well-being via compulsive dating app use and whether algorithmic beliefs attenuated the negative association between compulsive use and affective well-being. An online survey among Chinese dating app users (N = 361) was conducted. The sample included participants aged 18–60, with the majority (89.47%) falling within the 18–35 age range (M = 29.19, SD = 6.02). Women comprised a slightly larger proportion (56.2%) of the sample than men (43.8%). Results of the survey revealed that POSI was positively associated with compulsive use, which was positively related to post-dating app joviality. Furthermore, the relationship between algorithmic beliefs and post-dating app sadness was only significant among individuals with a low level of algorithm beliefs. The findings extended prior research on social network sites to dating apps and demonstrated the potential positive relationship between technology use and transient emotional states. Furthermore, our results suggest that algorithmic beliefs, which essentially reflect human-technology relations, may affect interpersonal communication outcomes on dating apps.

Abstract Background Disruption of brain functional connectivity has been detected after stroke, but whether it also occurs in moyamoya disease (MMD) is unknown. Impaired functional connectivity is always correlated with abnormal white matter fibers. Herein, we used multimodal imaging techniques to explore the changes in brain functional and structural connectivity in MMD patients. Methods We collected structural images, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging for each subject. Cognitive functions of MMD patients were evaluated using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Trail Making Test parts A and B (TMT-A/-B). We calculated the functional connectivity for every paired region using 90 regions of interest from the Anatomical Automatic Labeling Atlas and then determined the differences between MMD patients and HCs. We extracted the functional connectivity of paired brain regions with significant differences between the two groups. Correlation analyses were then performed between the functional connectivity and variable cognitive functions. To explore whether the impaired functional connectivity and cognitive performances were attributed to the destruction of white matter fibers, we further analyzed fiber integrity using tractography between paired regions that were correlated with cognition. Results There was lower functional connectivity in MMD patients as compared to HCs between the bilateral inferior frontal gyrus, between the bilateral supramarginal gyrus, between the left supplementary motor area (SMA) and the left orbital part of the inferior frontal gyrus (IFGorb), and between the left SMA and the left middle temporal gyrus (P

Abstract Objective The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. Methods In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. Results A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8–30.5 months) and the median PFS was 15.7 months (95% CI: 14.7–16.6 months). The ORR was 58.8% (95% CI: 47.2–69.6) and DCR reached 81.2% (95% CI: 71.0–89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060–0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184–0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. Conclusion TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination.

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow–b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21–75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test–retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21–38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization.

IntroductionThe Golgi apparatus (GA) is the center of protein and lipid synthesis and modification in normal cells and is involved in regulating various cellular process as a signaling hub, the dysfunction of which can lead to the development of various pathological conditions, including tumors. Mutations in Golgi apparatus-related genes (GARGs) are prevalent in most tumors, and their mutations can make them pro-tumor metastatic. The aim of this study was to analyze the predictive role of GARGs in the prognosis and immunotherapeutic outcome of hepatocellular carcinoma.MethodsWe used TCGA, GEO and ICGC databases to classify hepatocellular carcinoma samples into two molecular subtypes based on the expression of GARGs. Signature construction was then performed using GARGs, and signature genes were selected for expression validation and tumor phenotype experiments to determine the role of GARGs in the prognosis of hepatocellular carcinoma.ResultsUsing the TCGA, GEO and ICGC databases, two major subtypes of molecular heterogeneity among hepatocellular carcinoma tumors were identified based on the expression of GARGs, C1 as a high-risk subtype (low survival) and C2 as a low-risk subtype (high survival). The high-risk subtype had lower StromalScore, ImmuneScore, ESTIMATEScore and higher TumorPurity, indicating poorer treatment outcome for ICI. Meanwhile, we constructed a new risk assessment profile for hepatocellular carcinoma based on GARGs, and we found that the high-risk group had a worse prognosis, a higher risk of immune escape, and a higher TP53 mutation rate. Meanwhile, TME analysis showed higher tumor purity TumorPurity and lower ESTIMATEScore, ImmuneScore and StromalScore in the high-risk group. We also found that the high-risk group responded more strongly to a variety of anticancer drugs, which is useful for guiding clinical drug use. Meanwhile, the expression of BSG was experimentally found to be associated with poor prognosis of HCC. After interfering with the expression of BSG in HCC cells SMMC-7721, the proliferation and migration ability of HCC cells were significantly restricted.DiscussionThe signature we constructed using GARGs can well predict the prognosis and immunotherapy effect of hepatocellular carcinoma, providing new ideas and strategies for the treatment of hepatocellular carcinoma.

ObjectiveThe progression of the asymptomatic hemisphere of moyamoya disease (MMD) is largely unknown. In this study, we investigated the differences in subcortical gray matter structure and angiographic features between asymptomatic and symptomatic hemispheres in patients with MMD.MethodsWe retrospectively reviewed patients with MMD in consecutive cases in our center. We compared subcortical gray matter volume and three types of collaterals (lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis) between symptomatic and asymptomatic hemispheres. Symptomatic hemispheres were classified as ischemic hemisphere (i-hemisphere) and hemorrhagic hemisphere (h-hemisphere). Asymptomatic hemispheres were classified as contralateral asymptomatic hemisphere of i-hemisphere (ai-hemisphere), contralateral asymptomatic hemisphere of h-hemisphere (ah-hemisphere), bilateral asymptomatic hemispheres in asymptomatic group (aa-hemisphere).ResultsA total of 117 MMD patients were reviewed, and 49 of them met the inclusion criteria, with 98 hemispheres being analyzed. The thalamic volume was found to differ significantly between the i- and ai-hemispheres (P = 0.010), between the i- and ah-hemispheres (P = 0.004), as well as between the h- and ai-hemispheres (P = 0.002), between the h- and ah-hemispheres (P < 0.001). There was a higher incidence of thalamic anastomosis in the ai-hemispheres than i-hemispheres (31.3% vs. 6.3%, P = 0.070), and in the ah-hemispheres than h-hemispheres (29.6% vs. 11.1%, P = 0.088). Additionally, the hemispheres with thalamic anastomosis had a significantly greater volume than those without thalamic anastomosis (P = 0.024). Univariate and multivariate logistic regression analysis showed that thalamic volume was closely associated with thalamic anastomosis.ConclusionThe thalamic volume and the incidence of thalamic anastomosis increase in asymptomatic hemispheres and decrease in symptomatic hemispheres. Combining these two characteristics may be helpful in assessing the risk of stroke in the asymptomatic hemispheres of MMD as well as understanding the pathological evolution of the disease.

Abstract Background Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. Methods Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. Results AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. Conclusion Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.

Abstract Background Circular RNA hsa_circ_0008305 (circPTK2), miR-181c-5p and High mobility group box-1 (HMGB1) had a targeted regulatory relationship through bioinformatics analysis. This study explained the effects of these genes in microglia and sepsis mice. Methods Lipopolysaccharide (LPS) or Cecal Ligation and Puncture (CLP) was used to induce inflammation cell model or sepsis mouse model, as needed. Gene levels were measured by enzyme linked immunosorbent assay (ELISA), quantitative real-time PCR or Western blot, as required. Apoptosis was detected by TUNEL assay, and RNase R was used to test the stability of circPTK2. Targeting relationships between genes were analyzed using bioinformatics analysis and dual luciferase assay. Morris water maze test and mitochondrial membrane potential (MMP) detection were conducted to analyze the effects of genes on cognitive dysfunction of mice. Results Lipopolysaccharide induction triggered the release of pro-inflammatory cytokines, the upregulation of HMGB1 and circPTK2, and the downregulation of miR-181c-5p in microglia. Overexpression of HMGB1 enhanced the effect of LPS, while silencing HMGB1 partially counteracted the effect of LPS. Moreover, miR-181c-5p was a target of circPTK2 and bound to HMGB1. MiR-181c-5p mimic partially reversed the functions of LPS and HMGB1 overexpression, reduced the levels of TNF-α, IL-1β, and HMGB1, and inhibited apoptosis. CircPTK2 knockdown had the same effect as miR-181c-5p up-regulation. In vivo, sicircPTK2 improved cognitive function, restored MMP level, inhibited apoptosis, reduced the levels of inflammatory factors and apoptotic factors, and increased the survival rate of CLP-induced mice. Conclusion Our research reveals that circPTK2 regulates microglia activation and hippocampal neuronal apoptosis induced by sepsis via miR-181c-5p-HMGB1 signaling.

ObjectiveCerebral ischemia and intracranial hemorrhage are the two main phenotypes of moyamoya disease (MMD). However, the pathophysiological processes of these two MMD phenotypes are still largely unknown. Here, we aimed to use multimodal neuroimaging techniques to explore the brain structural and functional differences between the two MMD subtypes.MethodsWe included 12 patients with ischemic MMD, 10 patients with hemorrhagic MMD, and 10 healthy controls (HCs). Each patient underwent MRI scans and cognitive assessment. The cortical thickness of two MMD subtypes and HC group were compared. Arterial spin labeling (ASL) and diffusion tensor imaging (DTI) were used to inspect the cerebral blood flow (CBF) of cortical regions and the integrity of related white matter fibers, respectively. Correlation analyses were then performed among the MRI metrics and cognitive function scores.ResultsWe found that only the cortical thickness in the right middle temporal gyrus (MTG) of hemorrhagic MMD was significantly greater than both ischemic MMD and HC (p < 0.05). In addition, the right MTG showed higher ASL-CBF, and its associated fiber tract (arcuate fasciculus, AF) exhibited higher fractional anisotropy (FA) values in hemorrhagic MMD. Furthermore, the cortical thickness of the right MTG was positively correlated with its ASL-CBF values (r = 0.37, p = 0.046) and the FA values of right AF (r = 0.67, p < 0.001). At last, the FA values of right AF were found to be significantly correlated with cognitive performances within patients with MMD.ConclusionsHemorrhagic MMD shows increased cortical thickness on the right MTG in comparison with ischemic MMD and HCs. The increased cortical thickness is associated with the higher CBF values and the increased integrity of the right AF. These findings are important to understand the clinical symptoms and pathophysiology of MMD and further applied to clinical practice.

Abstract Sweet spots control the production of the tight oil reservoir, so sweet spots evaluation is a critical work for tight oil exploration and development. This paper proposes a source–reservoir chart method for tight oil sweet spots evaluation and an application in Permian of Jimsar Sag, Junggar Basin. Firstly, the evaluation chart is plotted based on the relationships between the TOC and Ro parameters of source rocks, the porosity and the oil saturation of reservoirs through the experimental data of hydrocarbon generation simulation and mercury injection. Secondly, according to the evaluation criteria of TOC, Ro of source rock and porosity, oil saturation of reservoir in the study area, the chart is divided into three sweet spots zones and a non-sweet spots zone. Finally, each grid of the study area is assigned parameters and plotted in the chart of different zones, and the sweet spots are mapped. Production data show the reliability of the evaluation results. This method provides a convenient and efficient procedure for evaluating sweet spots of tight oil based on integrating the quality of source rocks and reservoirs.

Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

Cavernous malformations are benign vascular malformations. Giant cavernous malformations are very rare. All reported cases have been symptomatic because of the large size and compression of the surrounding brain tissue. We report two asymptomatic cases of giant cavernous malformation that were both misdiagnosed as neoplasms because of their atypical presentations. The first case was a 54-year-old man whose computed tomography and magnetic resonance imaging scans revealed an inhomogeneous lesion of 6 cm diameter and mild enhancement in the left frontal lobe. A left lateral supraorbital and transcortical approach was applied and the lesion was completely removed. The second case was a 36-year-old man with an irregular large mass in the parasellar region. Craniopharyngioma was suspected and gross total resection was performed. Post-surgical pathological analyses confirmed the diagnoses as cavernous malformations. Both patients recovered uneventfully. The rare asymptomatic giant cavernous malformations reported here in adults had benign behavior for this specific disease entity. The different clinical characteristics of ordinary cavernous malformation and adult and pediatric giant cavernous malformation imply complex and distinct genetic backgrounds. Concerns should be raised when considering giant cavernous malformation as a differential diagnosis for atypical large lesions. Surgical resection is recommended as the primary treatment option.

Abstract Background The sperm-associated antigen 5 (SPAG5) plays a key role in controlling various cellular phenomena, including cell cycle progression and proliferation. However, the role of SPAG5 in hepatocellular carcinoma (HCC) remains unknown. Methods This study investigated the function and clinical significance of SPAG5 protein expression in hepatocellular carcinoma. We analyzed SPAG5 expression in surgical specimens from 136 HCC patients. The correlation between the clinical characteristics and prognosis was also determined. Furthermore, the SPAG5 was overexpressed in HCC cell and silenced with shRNA in HCC cells. Moreover, cell proliferation and apoptosis were measured using Edu assay and flow cytometry and a molecular mechanism of SPAG5 promotes HCC progression was explored. Results Herein, our study showed that upregulation of SPAG5 was detected frequently in primary HCC tissues, and was associated with significantly worse survival among the HCC patients. Multivariate analyses revealed that high SPAG5 expression was an independent predictive marker for the poor prognosis of HCC. SPAG5 silence effectively abolished the proliferation abilities of SPAG5 in vivo and in vitro, while induced apoptosis in HCC cells. Furthermore, our results indicate that SPAG5 promoted cell progression by decreasing SCARA5 expression, which has been reported to control the progression of HCC, and our data demonstrated that SCARA5 is crucial for SPAG5-mediated HCC cell progression in vitro and in vivo. Moreover, we found that the expression of SPAG5 and SCARA5 are inversely correlated in HCC tissues. In addition, we demonstrated that SPAG5 promoted progression in HCC via downregulating SCARA5 depended on the β-catenin/TCF4 signaling pathway. Interestingly, the underlying mechanism is which SPAG5 regulates SCARA5 expression by modulating β-catenin degradation. Conclusions Taken together, our data provide a novel evidence for the biological and clinical significance of SPAG5 as a potential biomarker, and we demonstrate that SPAG5-β-catenin-SCARA5 might be a novel pathway involved in HCC progression.

An online modelling method for secondary path of two distinct variable step-size strategies based on the filtered-x least square (FXLMS) algorithm is proposed. In this method, the variable step-size strategy with two distinct steps is used, and two variable step-size strategies are used before and after the secondary path modelling process converges, so that the convergence rate is guaranteed. At the same time, it can effectively avoid the fluctuation after the system converges and improve the stability and modelling accuracy of the system. Due to the white noise, the signal of secondary path modelling will affect the control part. A white noise control strategy is proposed to adjust the white noise according to the change of the step-size of the secondary path. On the premise of ensuring identification speed and precision, the influence of white noise on the control part is eliminated as far as possible. Compared to the existing methods, the simulation result shows that the proposed method can significantly improve the modelling accuracy of the secondary path while ensuring the convergence speed and has a better performance in vibration control effects.

Aiming at the issue that the application effect of current 3-D hydrocarbon migration and accumulation modeling technique cannot meet the actual requirement because of over-simplified geologic model, a 3-D dynamic geologic model using PEBI grid in bedding and columnar shape was established, which can be used to solve the heterogeneity in reservoirs of various sedimentary facies, and to reduce the effect of mixed lithologies on modeling accuracy. A 3-D numerical modeling technique based on finite volume method was established, including the construction of variable grid flow equation, decomposition and calculation of full-tensor permeability, and calculation of conductivity etc. Some related processing techniques, such as smoothing of key parameter curves, stability processing of upstream and downstream of grid flow, etc. were used to improve the convergence of Newton's iteration. Automatic adjustment of time step and multi-core parallel computation were taken to enhance the running efficiency of the software. In a case study of Nanpu sag in the Bohai Bay Basin, the hydrocarbon migration and accumulation process, oil saturation and hydrocarbon resources abundance in various periods were simulated, the modeled oil saturation, accumulation quantity and hydrocarbon distribution locations coincide with current exploration status. The results also showed that the proved ratio of hydrocarbon resources in target layers is 84.4%, the majority of the resources are distributed in Block B and Block C, and it is predicted that undiscovered resources are mainly near Well NP2-16 in Block C and in the structure north of Well NP5-4 in Block A. Key words: 3-D hydrocarbon migration and accumulation modeling technique, finite volume method, PEBI grid in bedding and columnar shape, variable grid flow equation, Nanpu sag

The tight sandstone gas accumulation is mainly driven by overpressure arising from the gas generation in source rocks. This paper proposes a quantitative computation model for the pressurization from gas generation in source rocks, establishes a dynamic equilibrium equation and a modeling process for tight sandstone gas accumulation, and simulates the gas generation quantity and source rock overpressure history in the Hechuan-Tongnan area of the Sichuan Basin. The modeling reveals that: (1) The gas generation intensity determines the degree of pressurization from gas generation, whereas the reservoir property determines the distribution of gas reservoirs; the conventional gas reservoir is complementary with the tight sandstone gas reservoir in terms of horizontal and vertical distribution, the former is mainly distributed at the top of reservoir with porosity over 7% on local structural highs while the latter is mainly distributed at the bottom of reservoir on local structural lows near source rocks of large gas generation quantity. (2) During the uplifting process from the maximum burial depth (65 Ma) to the current burial depth, because of the pressure drop of formation water and the increase of gas-water pressure difference, the tight sandstone gas migrates farther and increases in accumulation quantity; however, the conventional gas does not migrate basically and has no increase in accumulation quantity; (3) The quantity of the tight sandstone gas in the T3x2 is 5.9 times that of the conventional gas, and the undiscovered resource is mainly tight sandstone gas distributed in northeast of Hechuan, and north and southeast of Tongnan. 摘要: ：烃源岩生气产生的超压是致密砂岩气藏成藏的主要驱动力，提出烃源层生气增压定量计算模型，建立致密砂岩气藏动力平衡方程，制定致密砂岩气成藏模拟流程，并模拟了四川盆地合川—潼南地区须一段生气量及其引起的烃源岩超压史。模拟结果证实：①烃源层生气强度决定生气增压的大小，储集层物性决定气藏的分布，常规气藏与致密砂岩气藏在平面和纵向上的分布均具有互补的特点，前者主要分布于孔隙度大于7%的局部构造高点；后者主要分布于孔隙度较低的构造相对低部位且靠近生气量大的烃源层；②从最大埋深（距今65 Ma）到现今的抬升过程中，由于地层水压力降低，气水压差增大，致密砂岩气运移更远，聚集量增大，但常规气基本不发生运移，聚集量也未增大；③须二段致密砂岩气量是常规气量的5.9倍，未发现资源主要为致密砂岩气，分布在合川的东北部、潼南北部和潼南的东南部等地区。图12表2参37 Key words: tight sandstone gas, accumulation modeling, formation pressure, continuous gas accumulation, resource assessment

Geothermal energy is a clean, green renewable resource, which can be utilized for power generation, heating, cooling, and could effectively replace oil, gas, and coal. In recent years, oil companies have put more efforts into exploiting and utilizing geothermal energy with advanced technologies for heat-tracing oil gathering and transportation, central heating, etc., which has not only reduced resource waste, but also improved large-scale and industrial resource utilization levels, and has achieved remarkable economic and social benefits. Based on the analysis of oilfield geothermal energy development status, resource potential, and exploitation and utilization modes, the advantages and disadvantages of harnessing oilfield geothermal resource have been discussed. Oilfield geothermal energy exploitation and utilization have advantages in resources, technical personnel, technology, and a large number of abandoned wells that could be reconstructed and utilized. Due to the high heat demand in oilfields, geothermal energy exploitation and utilization can effectively replace oil, gas, coal, and other fossil fuels, and has bright prospects. The key factors limiting oilfield geothermal energy exploitation and utilization are also pointed out in this paper, including immature technologies, lack of overall planning, lack of standards in resource assessment, and economic assessment, lack of incentive policies, etc.

Abstract Human‐machine cooperative control has become an important area of intelligent driving, where driver intention recognition and dynamic control authority allocation are key factors for improving the performance of cooperative decision‐making and control. In this paper, an online learning method is proposed for human‐machine cooperative control, which introduces a priority control parameter in the reward function to achieve optimal allocation of control authority under different driver intentions and driving safety conditions. Firstly, a two‐layer LSTM‐based sequence prediction algorithm is proposed to recognise the driver's lane change (LC) intention for human‐machine cooperative steering control. Secondly, an online reinforcement learning method is developed for optimising the steering authority to reduce driver workload and improve driving safety. The driver‐in‐the‐loop simulation results show that our method can accurately predict the driver's LC intention in cooperative driving and effectively compensate for the driver's non‐optimal driving actions. The experimental results on a real intelligent vehicle further demonstrate the online optimisation capability of the proposed RL‐based control authority allocation algorithm and its effectiveness in improving driving safety.

BackgroundExisting epidemiological data indicated a correlation between thyroid cancer (THCA) and the risk of secondary primary malignancies (SPMs). However, the correlation does not always imply causality.MethodsThe Mendelian randomization (MR) analyses were performed to investigate the causal relationships between THCA and SPMs based on international multicenter data. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The Cancer Genome Atlas (TCGA) was used to explore potential mechanisms shared by THCA and bladder cancer (BLCA).ResultsSummary datasets of genome-wide association studies (GWAS) on 30 types of cancers were obtained from the United Kingdom Biobank (UKB) and FinnGen database. Meta-analysis of the UKB and FinnGen results revealed that THCA was significantly positively correlated with BLCA (OR = 1.140; 95% CI, 1.072-1.212; P < 0.001). Four genes, including WNT3, FAM171A2, MLLT11, and ULBP1, were identified as key genes shared by both TCHA and BLCA. Correlation analysis indicated that THCA may increase the risk of secondary BLCA through augmentation of N2 neutrophil infiltration.ConclusionsThis study showed that THCA was causally related to BLCA. It is recommended to conduct more rigorous screenings for BLCA during the follow-up of THCA patients.