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Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors, leading to progressive photoreceptor loss. Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival. This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation (tcES) in mice affected by inherited retinal degeneration. Additionally, the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans. In this study, we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular, sine, and ramp waveforms. To investigate the functional effects of electrical stimulation on photoreceptors, we used human retinal explant cultures and rhodopsin knockout (Rho–/–) mice, demonstrating progressive photoreceptor degeneration with age. Human retinal explants isolated from the donors’ eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro. Photoreceptor density was evaluated by rhodopsin immunolabeling. In vivo Rho–/– mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms. Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response (OMR), respectively. Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas. Oscilloscope recordings indicated effective delivery of rectangular, sine, and ramp waveforms to the retina by transcorneal electrical stimulation, of which the ramp waveform required the lowest voltage. Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes. The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro (~0.5–1.5°C). Electrical stimulation increased photoreceptor survival in human retinal explant cultures, particularly at the ramp waveform. Transcorneal electrical stimulation (rectangular + ramp) waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results. Histology and immunolabeling demonstrated increased photoreceptor survival, improved outer nuclear layer thickness, and increased bipolar cell sprouting in Rho–/– mice. These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina, improves photoreceptor survival in both human and mouse retinas, and increases visual function in Rho–/– mice. Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.

The generation of high-precision ground digital elevation models (DEMs) based on synthetic aperture radar interferometry (InSAR) technology has attracted wide attention. Compared with the linear InSAR technique, the 360$^\circ$ aperture gives circular InSAR (In-CSAR) the capability to generate a full-angle DEM of the observed region. The backprojection (BP) algorithm is considered as a preferred candidate for In-CSAR imaging since it does not impose any restrictions on flight trajectories. After phase unwrapping, a global unknown phase ambiguity exists in the unwrapped phase. Up to now, high-efficient frequency-domain methods, such as the split-bandwidth technique, have commonly been used to estimate the phase ambiguity. However, the split-bandwidth technique cannot be effectively integrated with the BP-focusing image due to the highly nonlinear and nonparallel trajectories of the airborne In-CSAR platforms. We present, for the first time, the combination of BP and split-bandwidth techniques for absolute phase estimation of In-CSAR interferogram in this article. The proposed method can avoid the phase offset induced by split-bandwidth processing under the conditions of highly nonlinear and nonparallel platform trajectories. In addition, the spectral characteristics of the BP-focusing subimage are derived in detail to correct its 2-D space-variant spectral support. In order to reduce the impact of coherence, the weighted least square is adopted to estimate unknown phase ambiguity. The processing results of simulation and real data verify that the proposed approach can effectively estimate the phase ambiguity even under the conditions of highly nonlinear and nonparallel platform trajectories.

Airborne Wide angle staring Synthetic Aperture Radar (WasSAR) is a novel SAR imaging technique that enables multiangle and long-time staring imaging of an observation region. The combination of WasSAR and Ground Moving Target Indication (GMTI) facilitates the long-time tracking of moving targets in key areas, thereby obtaining dynamic sensing information. Herein, we initially constructed a moving target echo model for airborne multi-channel WasSAR, followed by an analysis of the characteristics of a moving target during WasSAR imaging. Further, group phase shift calibration and modified A2DC methods are proposed to mitigate the influence of platform attitude errors and channel imbalances. In accordance with this, an extended airborne multi-channel WasSAR ground moving target detection and tracking method is proposed, which achieves accurate detection and tracking of targets moving on complex roads. Finally, a trajectory reconstruction method for moving targets in airborne multi-channel WasSAR-GMTI is presented, demonstrating accurate trajectory reconstruction for targets on complex roads. Moreover, a flight experiment using our independently developed airborne multi-channel WasSAR-GMTI system, along with the associated real data processing results, is presented. These results confirm the validity and practicability of airborne WasSAR-GMTI for moving target dynamic surveillance and serve as a foundation for future research.

Circular synthetic aperture radar (CSAR) has attracted a lot of interest, recently, for its excellent performance in civilian and military applications. However, in CSAR imaging, the result is to be defocused when the height of an object deviates from a reference height. Existing approaches for this problem rely on digital elevation models (DEMs) for error compensation. It is difficult and costly to collect DEM using specific equipment, while the inversion of DEM based on echo is computationally intensive, and the accuracy of results is unsatisfactory. Inspired by multi-focus image fusion in optical images, a spatial-domain fusion method is proposed based on the sum of modified Laplacian (SML) and guided filter. After obtaining CSAR images in a stack of different reference heights, an all-in-focus image can be computed by the proposed method. First, the SMLs of all source images are calculated. Second, take the rule of selecting the maximum value of SML pixel by pixel to acquire initial decision maps. Secondly, a guided filter is utilized to correct the initial decision maps. Finally, fuse the source images and decision maps to obtain the result. A comparative experiment has been processed to verify the exceptional performance of the proposed method. The final processing result of real-measured CSAR data demonstrated that the proposed method is effective and practical.

Holographic synthetic aperture radar (HoloSAR) introduces a cutting-edge three-dimensional (3-D) imaging mode to the field of synthetic aperture radar (SAR), enriching the scattering information of targets by observing them across multiple spatial dimensions. However, independent phase errors among baselines, such as those caused by platform jitter and measurement inaccuracies, pose significant challenges to imaging quality. The phase gradient autofocus (PGA) method effectively estimates phase errors, but struggles to accurately estimate the linear component, causing vertical shift in HoloSAR subaperture imaging result. Therefore, this paper proposes a PGA-based phase error compensation method for HoloSAR to address the vertical shift issue caused by linear phase errors. This method can achieve phase error correction in both the echo domain and image domain with enhanced efficiency. Experimental results of simulated targets and real data from the GOTCHA system demonstrate the effectiveness and practicality of the proposed method.

Abstract Understanding the interaction between molybdenum (Mo) and organic matter during microbial sulfate reduction is critical for the use of Mo to reconstruct marine redox conditions throughout Earth's history. However, little is known about Mo isotope fractionation and how it relates to organic matter remineralization during microbial sulfate reduction. Here, we report Mo abundances and isotopic (δ98Mo) compositions for bulk‐rock, non‐lithogenic and sequentially extracted fractions, including carbonate (carb), pyrite, and organic matter (OM), of seep carbonate rocks. Our data indicate that the difference between δ98Mocarb and δ98MoOM (Δ98Mocarb‐OM) displays significant variability in the studied samples, ranging between 0.72 and 1.01‰. Remarkably, the obtained Δ98Mocarb‐OM values indicate correlative trends with stable carbon isotope ratios and bulk abundances of (a) total organic carbon, (b) Mo, and (c) pyrite in seep carbonates, which we interpret as reflecting sustained adsorption of isotopically light Mo onto organic matter during enhanced sulfate reduction. On this basis, we put forward the concept that Δ98Mocarb‐OM of authigenic carbonate rocks can be used as a measure of the intensity of sulfate reduction and for reconstructing past interactions between Mo and organic matter in marine sediments.

IntroductionPresbyopia, the leading cause of vision impairment globally, is common during working years. However, no trials have assessed presbyopia's impact on income.MethodsIn April 2017, we conducted a census among 59 Bangladesh villages to identify persons aged 35 to 65 years with presbyopia (presenting distance vision > = 6/12 bilaterally and correctable inability to see 6/13 at 40 cm with both eyes), who never had owned glasses. Participants were randomized (1:1) to receive immediate free reading glasses (intervention) or glasses delivered 8 months later (control). Visual demand of different jobs was stratified into three levels. Outcomes were between-group differences in the 8 month change in: self-reported monthly income (primary) and Near Vision Related Quality of Life (NVRQOL, secondary).ResultsAmong 10,884 census participants, 3,655 (33.6%) met vision criteria and 863 (23.6%) comprised a sample enriched for near vision-intensive jobs, but 39 (4.52%) could not be reached. All participants allocated to intervention (n = 423, 51.3%) and control (n = 401, 48.7%) received the appropriate intervention, and follow-up was available for 93.4% and 96.8% respectively. Groups were similar at baseline in all characteristics: mean age was 47 years, 50% were male, 35% literate, and about half engaged in "most near vision-intensive" occupations. Glasses wear at 8-month follow-up was 88.3% and 7.81% in intervention and control respectively. At baseline, both the intervention and control groups had a self-reported median monthly income of US$35.3. At endline, the median income for the intervention group was US$47.1 compared with US$35.3 for control, a difference of 33.4%. Predictors of greater income increase in multivariate models included intervention group allocation (OR 1.45, 95% CI 1.12, 1.88, P = 0.005), male sex (OR 2.41, 95% CI 1.84, 3.16, P ConclusionProvision of reading glasses increases income in near vision-intensive occupations, and may facilitate return to work for those currently unemployed.

Carbonate gas reservoirs with edge and bottom water contain abundant reserves, making them key production targets in the Tarim Basin, Sichuan Basin, Ordos Basin, and other petroleum provinces. Water invasion may occur in the middle and late development stages of such reservoirs, leading to reduction of gas displacement efficiency and gas recovery. In this paper, a pore-scale water-gas immiscible flow model is established by coupling the fluid flow equation and the gas-water contact (GWC) tracking equation. The process of gas displacement with water is simulated in the heterogeneous porous media generated by the quartet structure generation set (QSGS). Finally, the mechanisms of remaining gas distribution and formation are analyzed, and the variation mechanism of microscopic gas displacement efficiency is discussed. The results are obtained in three aspects. First, the remaining gas is distributed at the blind end, in the pore-throat and as clusters, with their proportions and scales jointly controlled by microscopic pore structures, wettability and capillary number. The remaining gas can be further produced by changing the production pressure differential to disturb the original pressure system and gas expansion, so as to improve the microscopic gas displacement efficiency. Second, the microscopic gas displacement efficiency is closely related to the gas flow process. Formation or expansion of each water flow path may cause rapid increase of water cut and slows down the increase of gas displacement efficiency. Third, the microscopic pore structure and wettability are the inherent features of the gas reservoir, so the capillary number can be optimized to change the mode of GWC advancement, and then to effectively improve the microscopic gas displacement efficiency. It is concluded that for real gas wells, the evolution of mechanical mechanisms of GWC advancement should be revealed depending upon the microscopic pore structure and wettability of the reservoir, and then the optimal capillary number can be determined. Furthermore, clarifying the pore-scale water-gas flow characteristics and physical mechanism of microscopic gas displacement provides guidance for the planning of enhanced gas recovery.

Abstract Authigenic molybdenum (Moauth) in marine sediments holds great potential to archive the Mo isotopic composition of seawater and biogeochemical processes. However, the factors that control authigenic Mo isotope (δ98Moauth) distribution patterns remain poorly constrained. Here, we report Mo abundances and δ98Mo compositions for bulk‐rock (bulk) and sequentially extracted fractions—including total authigenic (auth; i.e., non‐lithogenic fraction), carbonate (carb), iron and manganese oxyhydroxides, pyrite (py), and organic fractions (OM)—of authigenic carbonates recovered from various hydrocarbon seep sites in the Gulf of Mexico and the South China Sea. Extracted pyrite fractions exhibit Mo contents varying from 0.1 to 23.4 μg/g and generally dominate the Mo budget of seep carbonate rocks. Our data indicate large ranges of δ98Mobulk and δ98Moauth values relative to NIST 3134 (0.25‰), varying from 1.02 to 1.98‰ (n = 4) and from 0.15 to 3.07‰ (n = 34), respectively. The difference in δ98Mo values between carbonate and pyrite fractions of seep carbonate rocks formed under sulfidic conditions increases with higher Moauth contents, suggesting a control of dissolved hydrogen sulfide concentrations on Mo isotope fractionation during carbonate precipitation. Compared with δ98Moauth and δ98Mopy, δ98Mocarb of seep carbonate rocks formed under sulfidic conditions shows a relatively narrow range with an average of 1.98 ± 0.31‰ (1 SD; n = 10), providing constraints on the δ98Mo composition of seawater in the course of Earth history. Overall, our findings show that the δ98Mo composition of sequentially extracted phases of carbonate‐rich sedimentary rocks can provide insights into seawater‐sediment interactions and biogeochemical pathways of Mo during early diagenesis.

Abstract The accumulation of authigenic carbonate in marine sediments has been regarded as a significant contributor to the carbon cycle over Earth's history. However, accurate quantification of the extent of authigenic carbonate formation in both modern and ancient oceans has been challenging due to limited approaches. Here, we analyzed calcium, magnesium, dissolved inorganic carbon, and alkalinity pore‐water profiles of 153 sites influenced by methane diffusion from the northern South China Sea. By combining these data with published data of diffusive sulfate flux, we found a significant positive correlation between carbonate precipitation rate and sulfate flux in the subseafloor. This correlation can be used to quantify the regional extent of authigenic carbonate formation, representing an advantage over a spatial interpolation approach. We therefore propose that the observed correlation can serve as a new approach for quantifying authigenic carbonate formation in shallow sediments along continental margins for both modern and ancient oceans.

This article proposes an along-track swarm synthetic aperture radar (ATS-SAR) system to accomplish the high frame rate and enhance imaging resolution simultaneously. Unlike the current along-track multistatic SAR (Multi-SAR), each platform of the proposed ATS-SAR only collects part of the aperture data. Then, the bistatic pair acquisitions of ATS-SAR are transformed into virtual monostatic subapertures, and a large aperture is combined in a short time. Considering the practical motion state difference of each individual platform, various ATS-SAR echo models are thoroughly investigated and established. Furthermore, a subaperture collaboration imaging algorithm for ATS-SAR (SACIm-ATS) based on sparse constraints is also proposed. An effective phase compensation function is designed to improve echo sparsity by homogenizing the ATS-SAR echo. Then, the compressed sensing method can be utilized to accurately estimate more azimuth data, obtaining a higher azimuth resolution. Simulations and a real measured experiment are carried out to verify the effectiveness of the proposed ATS-SAR and the SACIm-ATS algorithm. Compared with the state-of-the-art imaging algorithms, the proposed SACIm-ATS algorithm can significantly enhance the ATS-SAR imaging performance.

With the continuous development of synthetic aperture radar (SAR) technology, SAR image data are becoming increasingly abundant. For the same scene, dual-frequency (high-frequency and low-frequency) SAR images can present different details and feature information. SAR image fusion of the two frequencies can combine the advantages of both, thus describing targets more comprehensively. Because high-resolution SAR images contain a large amount of detailed information, such as edges and textures, the traditional fusion methods cannot fuse this information better, resulting in a loss of information. To solve the problem, this article proposes a fusion method suitable for airborne dual-frequency, high-resolution SAR images. First, the source SAR images are decomposed to obtain their low-pass bands and high-pass bands by using the nonsubsampled Shearlet transform (NSST). Then, we apply the improved nonnegative matrix factorization to merge the low-pass bands and use the new sum of modified Laplacian to merge the high-pass bands. After that, the fused low-pass bands and high-pass bands are reconstructed by the inverse NSST, to obtain the final fused image. Finally, by processing the airborne SAR data, the effectiveness of the proposed method is verified.

Abstract Background As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. Methods Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models. Results CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. Conclusion The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

Airborne circular synthetic aperture radar (CSAR) can realize high-resolution imaging of the scene over 360 degrees azimuth angle variation. Aiming at the problem of focusing of buildings for the airborne CSAR, this paper first analyzes the phase errors of CSAR buildings focusing in detail, and the analytic relationship between the scatterer height and azimuth focusing quality is deduced. Then, a focusing method of CSAR buildings based on the back projection algorithm is proposed. This method adopts the processing strategy of multi-layers imaging, and it is able to improve azimuth focusing quality of the buildings which have large height dimension. The proposed method is especially suitable for the high-resolution imaging and monitoring of the urban site with high-rise buildings in the airborne CSAR scenario. The correctness of the theoretical analysis and the validity of the proposed method are verified by using both simulation results and Ku-band airborne CSAR real data processing results.

Objective: Previous laboratory reports implicate heat shock protein (HSP)–specific T-cell responses in glaucoma pathogenesis; here, we aimed to provide direct clinical evidence by correlating systemic HSP-specific T-cell levels with glaucoma severity in patients with primary open-angle glaucoma (POAG). Design: Cross-sectional case-control study. Subjects: Thirty-two adult patients with POAG and 38 controls underwent blood draw and optic nerve imaging. Methods: Peripheral blood monocytes (PBMC) were stimulated in culture with HSP27, α-crystallin, a member of the small HSP family, or HSP60. Both interferon-γ (IFN-γ)+ CD4+ T helper type 1 cells (Th1) and transforming growth factor-β1 (TGF-β1)+ CD4+ regulatory T cells (Treg) were quantified by flow cytometry and presented as a percentage of total PBMC counts. Relevant cytokines were measured using enzyme-linked immunosorbent assays. Retinal nerve fiber layer thickness (RNFLT) was measured with OCT. Pearson’s correlation (r) was used to assess correlations. Main Outcome Measures: Correlations of HSP-specific T-cell counts, and serum levels of corresponding cytokine levels with RNFLT. Results: Patients with POAG (visual field mean deviation, –4.7 ± 4.0 dB) and controls were similar in age, gender, and body mass index. Moreover, 46.9% of POAG and 60.0% of control subjects had prior cataract surgery (P = 0.48). Although no significant difference in total nonstimulated CD4+ Th1 or Treg cells was detected, patients with POAG exhibited significantly higher frequencies of Th1 cells specific for HSP27, α-crystallin, or HSP60 than controls (7.3 ± 7.9% vs. 2.6 ± 2.0%, P = 0.004; 5.8 ± 2.7% vs. 1.8 ± 1.3%, P < 0.001; 13.2 ± 13.3 vs. 4.3 ± 5.2, P = 0.01; respectively), but similar Treg specific for the same HSPs compared with controls (P ≥ 0.10 for all). Concordantly, the serum levels of IFN-γ were higher in POAG than in controls (36.2 ± 12.1 pg/ml vs. 10.0 ± 4.3 pg/ml; P < 0.001), but TGF-β1 levels did not differ. Average RNFLT of both eyes negatively correlated with HSP27– and α-crystallin-specific Th1 cell counts, and IFN-γ levels in all subjects after adjusting for age (partial correlation coefficient r = –0.31, P = 0.03; r = –0.52, P = 0.002; r = –0.72, P < 0.001, respectively). Conclusions: Higher levels of HSP-specific Th1 cells are associated with thinner RNFLT in patients with POAG and control subjects. The significant inverse relationship between systemic HSP-specific Th1 cell count and RNFLT supports the role of these T cells in glaucomatous neurodegeneration. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Summary: Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.

Abstract Purpose Transcorneal electrical stimulation (TcES) is increasingly applied as a therapy for preserving and improving vision in retinal neurodegenerative and ischemic disorders. However, a common complaint about TcES is its induction of eye pain and dryness in the clinic, while the mechanisms remain unknown. Method TcES or transpalpebral ES (TpES) was conducted in C57BL6j mice for 14 days. The contralateral eyes were used as non-stimulated controls. Levels of intracellular [Ca2+] ([Ca2+]i) were assessed by Fura-2AM. The conductance resistances of the eye under various ES conditions were measured in vivo by an oscilloscope. Results Although TcES did not affect tear production, it significantly induced damage to the ocular surface, as revealed by corneal fluorescein staining that was accompanied by significantly decreased mucin (MUC) 4 expression compared to the control. Similar effects of ES were detected in cultured primary corneal epithelium cells, showing decreased MUC4 and ZO-1 levels after the ES in vitro. In addition, TcES decreased secretion of MUC5AC from the conjunctiva in vivo, which was also corroborated in goblet cell cultures, where ES significantly attenuated carbachol-induced [Ca2+]i increase. In contrast to TcES, transpalpebral ES (TpES) did not induce corneal fluorescein staining while significantly increasing tear production. Importantly, the conductive resistance from orbital skin to the TpES was significantly smaller than that from the cornea to the retina in TcES. Conclusion TcES, but not TpES, induces corneal epithelial damage in mice by disrupting mucin homeostasis. TpES thus may represent a safer and more effective ES approach for treating retinal neurodegeneration clinically.

Hydraulic fracturing technique increases shale gas well productivity significantly. Horizontal well fracture optimization has been studied by many researchers worldwide in the past decade. However, most of these researches relied on computationally expensive numerical simulation models for objectives evaluation during the optimization process. This affects the optimization efficiency significantly. To address this issue, surrogate model methods which adapt a simple approximate model are employed to lessen the computational burden. In this study therefore, a novel intelligent variable-fidelity radial basis function (VFRBF) surrogate-assisted model for multi-objective fracture stage placement optimization, namely VFRBF-FSO, is proposed to reduce the computational burden of the numerical simulation-based production optimization. In the VFBRF-FSO method, low-fidelity (LF) and high-fidelity (HF) samples were adopted simultaneously to establish the variable-fidelity (VF) surrogate model. To the best of our knowledge, this is the first time that variable-fidelity model is used for shale gas horizontal well fracture stage placement optimization. The uniqueness of this proposed method is that a scaling factor and an augment matrix are used to integrate the LF and HF samples to increase the accuracy of the surrogate model. Moreover, two cases with different wells and well types were studied to illustrate the effectiveness and accuracy of the VFRBF-FSO method. The optimization results showed that the VFRBF-FSO method performed comparably with the HF model-based method in terms of convergence and diversity. However, the VFRBF-FSO reduced the simulation runs on the two cases with different wells and fracture types to about five times that of the HF model.

In the practical application of Tomographic Synthetic Aperture Radar (TomoSAR), the number of acquisitions is usually restricted due to their expensive cost. A coprime TomoSAR technique was proposed to reduce the required number of acquisitions by sparsely distributing acquisitions and elongating baseline aperture. To guarantee a reliable tomogram, this study aims to determine the minimum number of acquisitions for the coprime TomoSAR when adopting a subspace method for performing the tomographic reconstruction. However, the performance of the subspace method depends on multiple parameters. In light of this, the selection of acquisition times has to comprehensively weigh the effects of all these parameters on the reconstruction performance. To this end, a prerequisite for reliable reconstruction is established by quantifying the relationship between the sample eigenvalues and all related parameters. Compared with conventional estimation approaches for the minimum number of acquisitions, the proposed approach has twofold advantages of containing all related parameters and of having a closed-form expression. Finally, the simulation experiments verify that the number of acquisitions estimated by our approach is close to the minimum and can guarantee reconstruction reliability.

Primary hepatic carcinoma is a common malignant tumor. The classic molecular targeted drug sorafenib is costly and is only effective for some patients. Therefore, it is of great clinical significance to search for new molecular targeted drugs. Eupalinolide B (EB) from Eupatorium lindleyanum DC. is used to treat chronic tracheitis in clinical practice. However, the role of EB in hepatic carcinoma is unknown. In this study, we first measure the effect of EB on tumor growth in a xenograft model and PDX model. The cell proliferation and migration are also detected in human hepatocarcinoma cell lines (SMMC-7721 and HCCLM3). Then, we investigate cell cycle, cell apoptosis, cell necrosis, cell autophagy, and ferroptosis by flow cytometry, western blot analysis and electron microscopy. The results demonstrate that EB exerts anti-proliferative activity in hepatic carcinoma by blocking cell cycle arrest at S phase and inducing ferroptosis mediated by endoplasmic reticulum (ER) stress, as well as HO-1 activation. When HO-1 is inhibited, EB-induced cell death and ER protein expression are rescued. The migration-related mechanism consists of activation of the ROS-ER-JNK signaling pathway and is not connected to ferroptosis. In summary, we first discover that EB inhibits cell proliferation and migration in hepatic carcinoma, and thus EB is a promising anti-tumor compound that can be used for hepatic carcinoma.

Abstract Submarine methane seepage can potentially be promoted by the dissociation of the marine hydrates surrounding the continental margins due to oceanic warming since the Last Glacial Maximum. This seepage could be archived by authigenic carbonates at seeping sites, but the time lag caused by heat transmission through the sediment column leads to an inconsistency between the ages of the carbonate and the period of bottom water warming. Here we present the records of the authigenic carbonate crust from drilling site D1 in the Mid‐Okinawa Trough. Uranium–thorium dating results show that the carbonate crust mainly grew downwards during 14–6 ka. Gas hydrates hosted in the relatively thin stability zone dissociated in a rapid response to bottom water warming and intensified the methane seepage. Our study better supports the hypothesis that a considerable amount of methane can be released from marine hydrates due to global climatic changes.

Abstract Benefitting from the maximum atom utilization efficiency, special size quantum effects and tailored active sites, single‐atom catalysts (SACs) have been promising candidates for bifunctional catalysts toward water splitting. Besides, due to the unique structure and properties, some amorphous materials have been found to possess better performance than their crystalline counterparts in electrocatalytic water splitting. Herein, by combining the advantages of ruthenium (Ru) single atoms and amorphous substrates, amorphous molybdenum‐based oxide stabilized single‐atomic‐site Ru (Ru SAs‐MoO3−x/NF) catalysts are conceived as a self‐supported electrode. By virtue of the large surface area, enhanced intrinsic activity and fast reaction kinetics, the as‐prepared Ru SAs‐MoO3−x/NF electrode effectively drives both oxygen evolution reaction (209 mV @ 10 mA cm−2) and hydrogen evolution reaction (36 mV @ 10 mA cm−2) in alkaline media. Impressively, the assembled electrolyzer merely requires an ultralow cell voltage of 1.487 V to deliver the current density of 10 mA cm−2. Furthermore, such an electrode also exhibits a great application potential in alkaline seawater electrolysis, achieving a current density of 100 mA cm−2 at a low cell voltage of 1.759 V. In addition, Ru SAs‐MoO3−x/NF only has very small current density decay in the long‐term constant current water splitting test.

Methane (CH4) is a powerful greenhouse gas and its largest reservoir on Earth is held in marine sediments. CH4 in marine sediments is mainly stored in gas-hydrate reservoirs and deep sedimentary strata along continental margins, where large amounts of deep-sourced CH4 ascend to different degrees toward the seafloor. However, the amount of deep-sourced CH4 and its role in subseafloor carbon and sulfur cycling remains poorly constrained. We analyzed sulfate (SO42−) profiles of 157 sites along with previous published 85 sites to determine the regional distribution and amount of SO42− reduction for an area of 1.23 × 105 km2 of the northern South China Sea. Then we compared these obtained results with estimates based on sedimentation rates from the same area. Significantly higher regional SO42− flux estimates based on SO42− profiles (4.26 × 10−3 Tmol a−1), compared to lower estimates based on sedimentation rates (1.23 × 10−3 Tmol a−1), reflect abundant ascending deep-sourced CH4. The difference of the regional SO42− flux estimates (3.03 × 10−3 Tmol a−1) represents the amount of SO42− reduced by CH4 through the anaerobic oxidation of CH4 (AOM). Deep-sourced CH4 contributes 71% to total SO42− consumption in the study area, largely exceeding SO42− consumption by organoclastic sulfate reduction. Our findings substantiate that deep-sourced CH4 governs subseafloor carbon and sulfur cycling to a previously underrated extent, fueling extensive chemosynthesis-based ecosystems along continental slope and rise.

Abstract Background Gait disability affects the daily lives of patients with stroke in both home and community settings. An abnormal foot–ankle position can cause instability on the supporting surface and negatively affect gait. Our research team explored the ability of a portable peroneal nerve-targeting electrical stimulator to improve gait ability by adjusting the foot–ankle position during walking in patients with chronic stroke undergoing home-based rehabilitation. Methods This was a double-blinded, parallel-group randomized controlled trial. Thirty-one patients with chronic stroke and ankle–foot motor impairment were randomized to receive 3 weeks of gait training, which involved using the transcutaneous peroneal nerve stimulator while walking (tPNS group; n = 16, mean age: 52.25 years), or conventional home and/or community gait training therapy (CT group; n = 15, mean age: 54.8 years). Functional assessments were performed before and after the 3-week intervention. The outcome measures included spatiotemporal gait parameters, three-dimensional kinematic and kinetic data on the ankle–foot joint, and a clinical motor and balance function assessment based on the Fugl–Meyer Assessment of Lower Extremity (FMA-LE) and Berg Balance scales (BBS). Additionally, 16 age-matched healthy adults served as a baseline control of three-dimensional gait data for both trial groups. Results The FMA-LE and BBS scores improved in both the tPNS groups (p = 0.004 and 0.001, respectively) and CT groups (p = 0.034 and 0.028, respectively) from before to after training. Participants in the tPNS group exhibited significant differences in spatiotemporal gait parameters, including double feet support, stride length, and walking speed of affected side, and the unaffected foot off within a gait cycle after training (p = 0.043, 0.017, 0.001 and 0.010, respectively). Additionally, the tPNS group exhibited significant differences in kinematic parameters, such as the ankle angle at the transverse plane (p = 0.021) and foot progression angle at the frontal plane (p = 0.009) upon initial contact, and the peak ankle joint angle at the transverse plane (p = 0.023) and foot progression angle (FPA) at the frontal and transverse planes (p = 0.032 and 0.046, respectively) during gait cycles after 3 weeks of training. Conclusions Use of a portable tPNS device during walking tasks appeared to improve spatiotemporal gait parameters and ankle and foot angles more effectively than conventional home rehabilitation in patients with chronic stroke. Although guidelines for home-based rehabilitation training services and an increasing variety of market devices are available, no evidence for improvement of motor function and balance was superior to conventional rehabilitation. Trial registration Chictr, ChiCTR2000040137. Registered 22 November 2020, https://www.chictr.org.cn/showproj.aspx?proj=64424

AbstractAccurately predicting the development height of the water-conducting fracture zone (HW) is imperative for safe mining in coal mines, in addition to the protection of water resources and the environment. At present, there are relatively few fine-scale zoning studies that specifically focus on predicting the HW under high-intensity mining conditions in western China. In view of this, this paper takes the Yushen mining area as an example, studies the relationship between the water-conducting fissure zone and coal seam mining height, coal seam mining depth, hard rock scale factor, and working face slope length, finally proposing a method to determine the development height of the HW based on multiple nonlinear regression models optimized using the entropy weight method (EWM-MNR). To compare the reliability of this model, random forest regression (RFR) and support vector machine regression (SVR) models were constructed for prediction. The findings of this study showed that the results of the EWM-MNR model were in better agreement with the measured values. Finally, the model was used to accurately predict the development height of the hydraulic conductivity fracture zone in the 112201 working face of the Xiaobaodang coal mine. The research results provide a theoretical reference for water damage control and mine ecological protection in the Yushen mine and other similar high-intensity mining areas.

To solve the problem of the moving target synthetic aperture radar (SAR) imaging from an incomplete echo, we proposed a novel SAR imaging method for the moving target with the azimuth missing data (MTIm-AMD) in this article. Instead of directly reconstructing the moving target image using the sparse SAR imaging method, we estimate and reconstruct the noncooperative moving target's complete echo from the azimuth incomplete echo based on its sparsity. At first, the noncooperative moving target's motion parameters are estimated from the incomplete echo. Then, to ensure that the complete echo can be well reconstructed using the compressed sensing method, these parameters are exploited to design a phase compensation function. Finally, using the reconstructed data, the fine-focused moving target can be obtained via the traditional SAR imaging algorithm. The simulation and experiment data results verify the effectiveness of the proposed MTIm-AMD method and demonstrate that the moving target can be fine imaging when the echo signal-to-noise ratio (SNR) is higher than $-$20 dB and the azimuth missing ratio (AMR) is less than 70%. This implies that the proposed MTIm-AMD method achieves satisfactory robustness to echo SNR and can handle most AMR cases.

Microwave radar has advantages in detection accuracy and robustness, and it is an area of active research in unmanned ground vehicles. However, the existing conventional automotive corner radar, which employs real-aperture antenna arrays, has limitations in terms of observable angle and azimuthal resolution. This paper proposes a novel 3D ArcSAR method to address this issue, which combines rotational synthetic aperture radar (SAR) and direction estimation algorithms. The method aims to reconstruct 3D images of 360° scenes and offers distinctive advantages in both azimuthal and altitudinal sensing. Nevertheless, due to the unique structural characteristics of vehicle SAR, it is limited to receiving only a single snapshot signal for 3D sensing. We propose a resolution algorithm based on ArcSAR and the iterative adaptive approach (IAA) to resolve the limitation. Furthermore, the errors in altitude angle estimation of the proposed algorithm and conventional algorithms are analyzed under various conditions, including different target spacing and signal-to-noise ratio (SNR). Finally, we design and implement a prototype of the 3D ArcSAR sensing system, which utilizes a millimeter-wave MIMO radar system and a rotating scanning mechanical system. The experimental results obtained from this prototype effectively validate the effectiveness of the proposed method.

Due to significant electromagnetic interference, radar interruptions, and other factors, Azimuth Missing Data (AMD) may occur in Synthetic Aperture Radar (SAR) echo, resulting in severe defocusing and even false targets. An important approach to solving this problem is to utilize Compressed Sensing (CS) methods on AMD echo to reconstruct complete echo, which can be abbreviated as the AMD Imaging Algorithm (AMDIA). However, the State-of-the-Art AMDIA (SOA-AMDIA) do not consider the influence of motion phase errors, resulting in an unacceptable estimation error of the complete echo reconstruction. Therefore, in order to enhance the practical applicability of AMDIA, this article proposes an improved AMDIA using Sparse Representation Autofocusing (SRA-AMDIA). The proposed SRA-AMDIA aims to accurately focus the imaging result, even in the Phase Error AMD (PE-AMD) echo case. Firstly, a Phase-Compensation Function (PCF) based on the phase history of the scene centroid is designed. When the PCF is multiplied with the PE-AMD echo in the range-frequency domain, a coarse-focused sparse representation signal can be obtained in the range-Doppler domain. However, due to the influence of unknown PE, the sparsity of this sparse representation signal is unsatisfying, breaking the sparse constraints requirement of the CS method. Therefore, we introduced a minimum entropy autofocusing algorithm to autofocus this sparse representation signal. Next, the estimated PE is compensated for this sparse representation signal, and a more sparse representation signal is obtained. Hence, the non-PE complete echo can be reconstructed. Finally, the estimated complete echo can be used with classic imaging algorithms to obtain high-resolution imaging results under the PE-AMD condition. Simulation and real measured data have verified the effectiveness of the proposed SRA-AMDIA.

Non-invasive electric stimulation (ES) employing a low-intensity electric current presents a potential therapeutic modality that can be applied for treating retinal and brain neurodegenerative disorders. As neurons are known to respond directly to ES, the effects of ES on glia cells are poorly studied. A key question is if ES directly mediates microglial function or modulates their activity merely via neuron-glial signaling. Here, we demonstrated the direct effects of ES on microglia in the BV-2 cells—an immortalized murine microglial cell line. The low current ES in a biphasic ramp waveform, but not that of rectangular or sine waveforms, significantly suppressed the motility and migration of BV-2 microglia in culture without causing cytotoxicity. This was associated with diminished cytoskeleton reorganization and microvilli formation in BV-2 cultures, as demonstrated by immunostaining of cytoskeletal proteins, F-actin and β-tubulin, and scanning electron microscopy. Moreover, ES of a ramp waveform reduced microglial phagocytosis of fluorescent zymosan particles and suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokine expression in BV-2 cells as shown by Proteome Profiler Mouse Cytokine Array. The results of quantitative PCR and immunostaining for cyclooxygenase-2, Interleukin 6, and Tumor Necrosis Factor-α corroborated the direct suppression of LPS-induced microglial responses by a ramp ES. Transcriptome profiling further demonstrated that ramp ES effectively suppressed nearly half of the LPS-induced genes, primarily relating to cellular motility, energy metabolism, and calcium signaling. Our results reveal a direct modulatory effect of ES on previously thought electrically “non-responsive” microglia and suggest a new avenue of employing ES for anti-inflammatory therapy.

Modern cold seeps are of fluctuant flux, which could result in variabilities of geochemical archives through intensively influencing the redox condition in pore fluids. However, the geochemical archives are not fully understood when the redox condition changes. Here, tubular carbonates from the Shenhu Sea Area were used to reconstruct the formation environment and redox conditions. The moderately negative δ13C values of the carbonates (−40.1‰ to −30.8‰, VPDB) indicate a mixed carbon source of thermogenic and biogenic methane. The low δ18O values (−2.7‰ to 1.0‰, VPDB) suggest a type of 18O-depleted pore fluid possibly influenced by gas hydrate formation. Co-variation of MoEF, WEF, CoEF, and CrEF suggests that high Fe contents in the rims of samples R1 and R2 are induced by Fe (oxyhydr)oxidation enrichment, while the positive correlation between MoEF and Mn/Al ratio indicates that high Mn contents in the rims of samples R3 and R4 are induced by Mn (oxyhydr)oxidation enrichment. The occurrence of Fe or Mn enrichment in the rims and the absence of Fe/Mn enrichment in the cores suggest Fe/Mn (oxyhydr)oxides forming in pore fluid rather than in bottom seawater. The carbonate phases of the rims enriched in Fe (oxyhydr)oxides are dominated by high magnesium calcite, while those of the rims enriched in Mn (oxyhydr)oxides are dominated by aragonite. The occurrence of Fe or Mn (oxyhydr)oxides corresponds to the previously proposed formation depth for the carbonate phase. The occurrence of dissolution textures in these rims indicates episodic oxic conditions, which would facilitate Fe2+/Mn2+ oxidation. We suppose that the Fe2+ and Mn2+ could be supplied through fluid seepage or diffusion from underlying sediments when the flux decreased. Similar archives may be applied to qualitatively reflect the changes of redox conditions in seep systems. Similar scenarios may help us understand the geochemical records in seeps of fluctuant flux.

The natural dynamics of fluid flow at methane seeps and increasingly human activities influence the biogeochemistry of the microenvironment and further determine the activity of the chemosynthetic communities within these ecosystems. However, ways to reconstruct short-term fluid flow dynamics and to decipher the influence of scientific exploration at seeps are limited. In this study, we present high-resolution trace elements/Ca ratios (Li/Ca, Mg/Ca, Ti/Ca, Mn/Ca, Co/Ca, Cu/Ca, Zn/Ca, Sr/Ca, Zr/Ca, Mo/Ca, Ba/Ca, Th/Ca and U/Ca ratios) from the shells of two species of chemosymbiotic bivalves (the thiotrophic vesicomyid clam Archivesica marissinica and the methanotrophic mussel Gigantidas haimaensis) from the Haima cold seeps of the South China Sea. We found that the complex distribution patterns of some trace elements (Mg/Ca, Sr/Ca, Mo/Ca and U/Ca ratios) in G. haimaensis are largely controlled by mineral composition or age. The observation of Co/Ca and Ba/Ca ratios in both species indicate strong physiological and environmental control on the incorporation of trace elements during the biomineralization process. Besides, the distribution patterns of other trace elements provide information that can be used to discuss open issues such as the loss of trace elements after death of the bivalves, and the possible influence of human activities such as sediment disturbance. Overall, this study emphasizes the potential for using high-resolution element geochemistry of seep bivalve shells to reveal the physiological and environmental factors that control the growth of bivalves, and to elucidate the potential history of fluid discharge at cold seeps.

After nearly 20 years of exploration, various areas of the seafloor with hydrocarbon seepage have been discovered in the South China Sea (SCS). Through linking subsurface and seafloor biospheres, seeps have become natural laboratories to enhance our knowledge on the processes of hydrocarbon migration and associated hydrocarbon-based ecosystems in the marine environment. This review summarizes the distribution of macrofauna in the active seep areas of the SCS and describes the physiological characteristics of three groups of representative macrofauna (bathymodioline mussels, pliocardiine clams, siboglinid tubeworms). In addition, a comparison is made between the seep macrofauna of the SCS and the Northwest Pacific Ocean. Modes of energy transfer and microbial processes are elucidated by integrating trace element, stable isotope, and lipid biomarker data of macrofaunal soft tissues. Our aims are to provide an overview of the macro-ecology of the SCS seeps and to underscore aspects which desire more research efforts in the future.

BackgroundStroke is among the leading causes of long-term disability worldwide. Motor impairments after stroke not only impact the individuals quality of life but also lay substantial burdens on the society. Motor planning is a key component of cognitive function that impacts motor control. Hand movements such as grasping or reaching to grasp require the application of correct force and the coordination of multiple limb segments. Successful completion of hand motor task requires a certain degree of cognitive function to anticipate the requirement of the task. Cognitive function may thus be a confounding factor to rehabilitation outcomes. ObjectiveThis study aims to explore the impact of cognitive function on functional outcomes in people with subacute stroke after VR intervention. MethodsPatients with stroke were first stratified into cognitively normal (CN) and cognitively impaired (CI), followed by allocation to the VR or control group (CG). Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Barthel Index (BI), and Instrumental Activities of Daily Living (IADL) were recorded at baseline, 3 weeks after the intervention, and 3 and 6 months after the intervention. The between-group and within-group differences were assessed by repeated-measures analysis of variance (ANOVA). ResultsThe between-group comparison indicated that FMA-UE, BI, and IADL (time effect P

Cold seeps globally host dense unique oasis-type ecosystems, mainly fuelled by chemosynthetic microorganisms via reduced gases such as methane and hydrogen sulfide. However, the origin and pathway of nitrogen chemosynthesis in this widely distributed symbiont ecosystem remain poorly understood. Here, we explore biomarker methods (bulk stable isotope, amino acid (AA), fatty acid (FA) and compound-specific isotope analyses in gill tissues of mussels) to demonstrate the relative contributions of inorganic and organic nitrogen to symbiotic mussels at cold seeps in the South China Sea and their impact on the synthesis and metabolism of amino acids. Gigantidas platifrons (G. platifrons) symbioses with type II methanotrophs via the Serine pathway, and Bathymodiolus aduloides (B. aduloides) thrives with sulfur-oxidizing bacteria via the Calvin pathway, as revealed by bulk δ13C and δ13C of FAs. Based on the δ15N values in gill tissues of mussels, organic nitrogen from sediment is estimated as the dominant nitrogen source for B. aduloides (97-98%), in contrast, NH4+ was the main nitrogen source for G. platifrons. Different dominant nitrogen sources result in the δ15N of AAs in the gills of two mussel species having opposite trends, which might be related to synthesis and metabolism of AAs in symbiotic bacteria and host, respectively. Our findings reveal that the mechanism of nitrogen acquisition in cold seep systems is plastic and related to DIN sources/uptake and changing environmental conditions. These findings uncover novel biosynthesis of nitrogen in the deep sea, typically at cold seeps, and may have important implications for nitrogen biogeochemistry and deep-sea conservation.

Due to the substantial electromagnetic interference, radar interruptions, and other factors, the SAR system may fail to receive valid data in some azimuth areas. This phenomenon is known as Azimuth Missing Data (AMD). If classical SAR imaging algorithms are performed directly using AMD echo, the imaging results may be defocused or even display false targets, which seriously affects the accuracy of the image. Thus, we proposed a Sub-echo Segmentation and Reconstruction Azimuth Missing Data SAR Imaging Algorithm (SSR-AMDIA) to solve the problem of incomplete echo SAR imaging in this article. Instead of using the motion compensation step of the Polar Format algorithm (PFA) to recover the full echo from the AMD echo, the proposed SSR-AMDIA eliminates the effect of the planar approximation in PFA and expands the maximum depth of focus (DOF). The raw AMD echo was first subjected to range compression and Range Cell Migration Correction (RCMC), after which the AMD-RCMC echo was divided along the range direction. Then, we constructed a series of phase compensation functions based on the sub-segment AMD-RCMC echoes to guarantee the perfect recovery of the full RCMC echoes corresponding to the sub-scenes. Finally, we combined them to obtain the complete RCMC echo, and an excellent focused imaging result was then obtained via azimuth compression. Simulation and experimental data verified the effectiveness of the proposed algorithm. Furthermore, we derived the mathematical expressions for the two-dimensional maximum DOFs of the proposed algorithm. In contrast to the State-Of-the-Art (SOA) AMDIA, the SSR-AMDIA can obtain a superior imaging performance in a larger imaging scope under the conditions of most AMD cases.

With the large-scale mining of coal resources in western China, coal resources are gradually shifting from shallow to deep mining. In coal seam mining, the overlying rock water-conducting fractured zone (WCFZ) is the main factor causing mine water damage and water resource damage. Accurately grasping the development height of the water-conducting fissure zone is the key to the prevention of water hazards and the protection of water resources in medium–deep coal seams. In this study, the 3D development form of the WCFZ in the middle and deep coal seam mining is studied by the integrated method of drilling and 3D seismic survey, taking the first mining face of Xiaobodang No.1 mine in Yushen such that the height of the WCFZ measured by drilling is 81.50–177.07 m. The height of WCFZ development in the 3D seismic survey was 79.83–178.03 m, and the morphology of the WCFZ was saddle-shaped. This study provides methodological guidance for predicting the 3D morphology and developmental characteristics of the WCFZ. The results obtained are of great significance for the safe, green, and efficient mining of coal seams in medium and deep buried ecologically fragile environments.

Glaucoma is a leading cause of blindness worldwide. It is suggested that primary open angle glaucoma (POAG), the most common form of glaucoma, may be associated with significant metabolic alternations, but the systemic literature review and meta-analysis in the area have been missing. Altered metabolomic profiles in the aqueous humor and plasma may serve as possible biomarkers for early detection or treatment targets. In this article, we performed a systematic meta-analysis of the current literature surrounding the metabolomics of patients with POAG and metabolites associated with the disease. Results suggest several metabolites found to be specifically altered in patients with POAG, suggesting broad generalizability and pathways for future research.

Graph convolutional networks (GCNs) have achieved remarkable performance on skeleton-based action recognition. Existing GCN-based methods usually apply the fixed graph topology and one fixed temporal convolution kernel to extract the spatial features of joints and temporal features, which is from a single-scale perspective. Actually, human actions are coordinated by various body parts in the spatial domain, and exhibit different characteristics in the temporal domain. Therefore, it is appropriate to model the multi-scale information that can enhance both the explainability and stability, which is ignored in current literatures. To address this issue, we propose a multi-scale spatial-temporal graph neural network (MSTGNN) to discover multi-scale discriminative features from spatial and temporal aspects simultaneously. Our contributions are three-folds: 1) For the spatial domain, inspired by the kinematics of the human action, we develop a three-scale graph data structures in a fine-to-coarse way. A novel hybrid spatial pooling module is then proposed to dynamically exploit the global and comprehensive information step-by-step. 2) For the temporal domain, we design a multi-scale temporal convolution module adaptively fusing the temporal features extracted by different scale convolution kernels. 3) As utilizing one-stream architecture instead of multi-stream architecture, the proposed model can be trained in an end-to-end manner. MSTGNN achieves state-of-the-art performance with less computation complexity. Experimental results conducted on two large datasets (NTU-RGB+D and NTU-RGB+D-120) demonstrate the superiority of MSTGNN.

Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. Results: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. Conclusions: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress.

Cancer is one of the leading causes of death and the most important impediments to the efforts to increase life expectancy worldwide. Currently, chemotherapy is the main treatment for cancer, but it is often accompanied by side effects that affect normal tissues and organs. The search for new alternatives to chemotherapy has been a hot research topic in the field of antineoplastic medicine. Drugs targeting diseased tissues or cells can significantly improve the efficacy of drugs. Therefore, organelle-targeted antitumor drugs are being explored, such as mitochondria-targeted antitumor drugs. Mitochondria is the central site of cellular energy production and plays an important role in cell survival and death. Moreover, a large number of studies have shown a close association between mitochondrial metabolism and tumorigenesis and progression, making mitochondria a promising new target for cancer therapy. Combining mitochondrial targeting agents with drug molecules is an effective way of mitochondrial targeting. In addition, hyperpolarized tumor cell membranes and mitochondrial membrane potentially allow selective accumulation of mitochondria-targeted drugs. This enhances the direct killing of tumor cells by drug molecules while minimizing the potential toxicity to normal cells. In this review, we discuss the common pro-mitochondrial agents, the advantages of triphenylphosphine (TPP) in mitochondrial-targeted cancer therapy and systematically summarize various TPP-based mitochondria-targeting anticancer drugs.

Invertebrates living at methane seeps such as mussels and clams gain nutrition through symbiosis with chemosynthetic, chiefly methanotrophic and thiotrophic bacteria. Lipid biomarkers, including their compound-specific carbon stable isotope compositions, extracted from the host tissues are predestined for deciphering the various sources of diets and the associations among varying environments, endosymbionts, and hosts. Here, we investigated lipid inventories of soft tissues of two bathymodiolin mussel species hosting aerobic methanotrophic bacteria (Gigantidas platifrons from Site F and Gigantidas haimaensis from Haima seeps), one bathymodiolin mussel with thiotrophic bacteria (Bathymodiolus aduloides from Haima seeps), and one vesicomyid clam (Archivesica marissinica from Haima seeps) from the South China Sea. The gills of mussels hosting methanotrophic symbionts were found to contain high amounts of lipids of aerobic methanotrophic bacteria, such as the 4,4-dimethyl lanosterol, and other 4-methyl sterols, and the type I methanotroph-specific monounsaturated fatty acids (MUFAs) C16:1ω9 and C16:1ω8. Production of methyl-sterols is favored over fatty acids at low oxygen concentrations, as demonstrated in culture experiments with Methylococcus capsulatus. Since lesser fatty acids and abundant sterols are found in G. haimaensis compared to G. platifrons, G. haimaensis apparently lived at very low oxygen levels. Extremely high levels of MUFAs C16:1ω7 and C18:1ω7 were found in gill tissue of both B. aduloides and the vesicomyid clam A. marissinica. Given the absence of ω8 fatty acids, both B. aduloides and the vesicomyid clam contain thiotrophic bacteria only. The occurrence of 13C-enriched 24-methylenecholesterol in B. aduloides indicates that the animal complemented its diet by filter-feeding (ca. 3% of the total sterol inventory) on photosynthetically derived carbon, whereas the majority of sterols are pointing to a diet relying on endosymbionts. Different types of 4-methyl sterols were observed between the thiotroph-containing mussel and methanotroph-containing mussels, suggesting different biosynthetic steps are present from lanosterol to cholesterol between animal hosts and aerobic methanotrophs. Among the four bivalve species, specific lipid biomarker patterns diagnostic for either the symbionts or the hosts yielded similar δ13C values in each species, indicating that the host obtained its nutrition either directly from the symbionts or derived at least most of its carbon in this way. The information derived from lipid biomarkers of bivalves and their corresponding symbionts in modern environments is vital to interpret data from the rock record, where most other methods to study microbial community composition are not applicable.

The magnesium (Mg) isotopic composition of marine authigenic carbonates is considered as promising archive of ancient seawater geochemistry and paleoenvironments. Previous experimental and theoretical work has shown that Mg isotope fractionation during carbonate mineral formation is a function of mineralogy and precipitation rate. However, information on Mg isotope fractionation is limited for well-defined precipitation rates in natural settings. Here, we investigate pore waters from sediments of an area of active methane seepage in the South China Sea. Low δ13C values (< −48.3‰ VPDB) of dissolved inorganic carbon (DIC) near the sulfate-methane transition zone (SMTZ) indicate that sulfate-driven anaerobic oxidation of methane (SD-AOM) is the predominant biogeochemical process. Pore water composition of dissolved Mg, calcium (Ca), and strontium (Sr) agrees with aragonite as the dominant carbonate mineral at the site ROV1, and high Mg-calcite at sites ROV2 and ROV4. Calculated carbonate precipitation rates are 0.92 μmol cm−2 yr−1 for site ROV2 and 1.24 μmol cm−2 yr−1 for site ROV4; these estimates are similar to previous calculations for seeps from other areas. The pore water δ26Mg values (−0.88‰ to −0.71‰) obtained for the three study sites are similar to those of seawater, in accord with a minor effect of Rayleigh fractionation due to abundant supply of Mg from seawater and insignificant consumption of Mg during carbonate precipitation. The modeled Mg isotope fractionation (ϵ = −2.0‰ to −1.0‰ for core ROV2; ϵ = −1.3‰ to −0.3‰ for core ROV4) can be explained by kinetic isotope fractionation during carbonate precipitation. The calculated carbonate precipitation rates and the degree of fractionation of Mg isotopes support the notion that fractionation is small at high precipitation rates. However, the carbonate precipitation rates calculated for the studied seep environments are much smaller than those in laboratory experiments, documenting a discrepancy of isotopic fractionation between carbonate authigenesis in laboratory experiments and natural environments. These results, including the modeled precipitation rates, provide new constraints for Mg isotope fractionation in natural settings.

Retinal ischemia is a common cause of many retinal diseases, leading to irreversible vision impairment and blindness. Excessive neuroinflammation, including microglial activation and T-cell responses, has been identified as a critical factor associated with neurodegeneration in retinal ischemia. Baicalein is a natural flavonoid reported to have broad anti-inflammatory and neuroprotective bioactivities. Herein, the effects of baicalein on microglia activation in vitro and in vivo were investigated. We found that baicalein exhibited robust anti-inflammatory effect on cultured human and mouse microglia, as demonstrated by decreased induction of pro-inflammatory cytokines and the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor kappa B (NFκB). Proteomic analysis further unraveled baicalein’s effect on modulating IL-17 signaling pathways and its upstream regulator IL-1β. Intravitreal administration of baicalein in the mouse model of retinal ischemia/reperfusion (I/R) injury attenuated microglial activation and retinal T-cell infiltration, particularly the T helper 17 cells. Additionally, baicalein was shown to exert neuroprotective effects by significantly reducing the retinal ganglion cell (RGC) loss after I/R injury, leading to an improved retinal function and spatial vision. These results suggest that baicalein, a natural flavonoid, acts as a negative regulator of activated microglia and immune responses both in vitro and in vivo, effectively alleviating neurodegeneration in retinal I/R injury. This finding indicates that baicalein could be a potential therapeutic agent against currently incurable degenerative retinal diseases.

Groundwater leakage in the loess gully terrain is one of the main hazards of coal seam mining at shallow burial depth. The burial depth of the 5−2 coal seam is less than 50 m from the ground in the gully of the study site. The fissures that expand upward after mining can easily penetrate the ground to form a water-conducting channels. During rainy periods, there is a potential risk of groundwater leakage. In order to reveal the characteristics of plane development and the dynamic evolution of gully ground fissures, the typical U-shaped gully in the northern Shaanxi coal mine was studied using the field measurement methods of “On-site measurement” and UAV aerial photography. Based on the experimental platform of ground fissure leakage developed and designed by the team, an indoor test model corresponding to the actual situation was established. In addition, the mathematical models of actual flood inrush, fissure width, and flood flow in the channel were established. The actual mine water flow and the mine drainage capacity were compared and analyzed, thus proposing criteria for classifying gully mining ground fissure collapsed water hazards. These criteria can provide theoretical references for predicting fissure leakage hazard zones in the ground gully of shallow buried coal seams. According to the development height of the water-conducting fissure zone (WCFZ), the treatment methods of ground fissures in gullies under different security conditions were designed, which was applied in the field with good results. The results showed that the treatment methods in this paper could effectively prevent the leakage of groundwater in the gullies along the ground fissures.

Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.

Surface damage caused by coal mining is one of the problems perplexing ecological environment restorations in coal mining areas. Accurately evaluating and predicting the degree of surface damage induced by coal mining with reasonable and correct indexes are of great significance to the restoration and treatment of the ecological environment. In this paper, these methods including the unmanned aerial vehicle aerial photography and manual measurement were used to investigate the development characteristics of surface damage caused by 2# coal seam mining in Yangchangwan Coal Mine. The results showed that with the change of mining conditions, the characteristics of surface cracks change obviously, which can be adopted to indicate the degree of surface damage. Thus, based on the results of the investigation, the classification standard of surface damage degree was established based on the evaluation indexes including density of crack, drop height of surface crack, crack width, maximum surface subsidence, and geological disaster caused by cracks and the damage characteristics of buildings. The evaluation method and process of surface damage degree also were given. Based on the ratio of the buried depth to the thickness of the coal seam (H/M), ratio of the thickness of overlying bedrock to the thickness of the coal seam, the thickness of loose layers (Ms), geomorphology, distance to faults, and distance to folds, the prediction model of surface damage degree was built on the GIS platform. The weight coefficient of each prediction index was obtained by the analytic hierarchy process (AHP) method. The surface damage degree map of 2# coal seam in Yangchangwan Coal Mine was divided into four classes: very minor, minor, moderate, and serious, which provides a relatively applicable method for the prediction of surface damage degree in Yangchangwan Coal Mine and its adjacent mining areas.