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Abstract Background Introducing new goat breeds or transferring adult goats from farms to slaughterhouses requires transportation, which can engender adverse effects, such as oxidative stress, pathological cell apoptosis and autophagy. Current evidence suggests that malondialdehyde (MDA) is a metabolite of lipid peroxidation during oxidative stress, while superoxide dismutase (SOD) and catalase (CAT) can alleviate injury caused by free radicals and reactive oxygen species (ROS). Meanwhile, Bcl-2, Bax, LC3B, PINK1 and Parkin are important proteins that participate in pathological cell apoptosis and autophagy. This study aimed to investigate the effects of transportation stress on oxidative stress indexes and expressions of Bcl-2, Bax, LC3B, PINK1 and Parkin in the small intestine of goats. Twelve healthy adult male goats from western Jiangxi province were randomly divided into control, 2 h transportation stress, and 6 h transportation stress groups (n = 4 per group). Results Our results showed that MDA in the small intestine significantly increased after transportation, while SOD and CAT activities decreased, with a significantly increased apoptosis rate of the small intestine cells. The jejunum and duodenum exhibited the highest apoptosis rate in the 2 h and 6 h transportation groups, respectively. The expression of apoptosis-related genes Bcl-2 and Bax and their corresponding proteins exhibited varying degrees of down-regulation or up-regulation, while Bcl-2 and Bax genes in the small intestine were upregulated in the 6 h transportation group. In addition, autophagosomes and autophagolysosomes were found in various parts of the small intestine by transmission electron microscopy, and autophagy-related genes LC3B, PINK1 and Parkin were significantly down-regulated in the 2 h group and up-regulated in the 6 h group. Conclusions Our results indicate that the contents of MDA, SOD and CAT in the small intestine, the expression of pathologic apoptosis-related genes Bcl-2 and Bax, and autophagy-related genes LC3B, PINK1 and Parkin correlated with stress duration caused by transportation. Moreover, this study provides a foothold for further studies on the mechanism of transportation stress in goats and improving animal welfare.

Abstract Background Conversion or editing of adenosine (A) into inosine (I) catalyzed by specialized cellular enzymes represents one of the most common post-transcriptional RNA modifications with emerging connection to disease. A-to-I conversions can happen at specific sites and lead to increase in proteome diversity and changes in RNA stability, splicing, and regulation. Such sites can be detected as adenine-to-guanine sequence changes by next-generation RNA sequencing which resulted in millions reported sites from multiple genome-wide surveys. Nonetheless, the lack of extensive independent validation in such endeavors, which is critical considering the relatively high error rate of next-generation sequencing, leads to lingering questions about the validity of the current compendiums of the editing sites and conclusions based on them. Results Strikingly, we found that the current analytical methods suffer from very high false positive rates and that a significant fraction of sites in the public databases cannot be validated. In this work, we present potential solutions to these problems and provide a comprehensive and extensively validated list of A-to-I editing sites in a human cancer cell line. Our findings demonstrate that most of true A-to-I editing sites in a human cancer cell line are located in the non-coding transcripts, the so-called RNA 'dark matter'. On the other hand, many ADAR editing events occurring in exons of human protein-coding mRNAs, including those that can recode the transcriptome, represent false positives and need to be interpreted with caution. Nonetheless, yet undiscovered authentic ADAR sites that increase the diversity of human proteome exist and warrant further identification. Conclusions Accurate identification of human ADAR sites remains a challenging problem, particularly for the sites in exons of protein-coding mRNAs. As a result, genome-wide surveys of ADAR editome must still be accompanied by extensive Sanger validation efforts. However, given the vast number of unknown human ADAR sites, there is a need for further developments of the analytical techniques, potentially those that are based on deep learning solutions, in order to provide a quick and reliable identification of the editome in any sample.

Abstract Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

The theridiid spider genus Stemmops O. Pickard-Cambridge, 1894 includes 27 extant species and is distributed in America (23 spp.) and Asia (4 spp.). Three species, S. forcipus Zhu, 1998 (♂♀), S. nigrabdomenus Zhu, 1998 (♂) and S. nipponicus Yaginuma, 1969 (♂♀), are currently known from China.Two new species of Stemmops are described from China: S. atratus sp. n. (♀, Jiangsu, Zhejiang) and S. lini sp. n. (♂♀, Fujian, Zhejiang). In addition, the previously unknown female of S. nigrabdomenus Zhu, 1998 is described. Photos and morphological descriptions are provided.

Abstract Background Chronic heart failure (CHF) is actually a disease caused by an imbalanced energy metabolism between myocardial energy demand and supply, ultimately resulting in abnormal myocardial cell structure and function. Energy metabolism imbalance plays an important role in the pathological process of chronic heart failure (CHF). Improving myocardial energy metabolism is a new strategy for the treatment of CHF. Shengxian decoction (SXT), a well-known traditional Chinese medicine (TCM) formula, has good therapeutic effects on the cardiovascular system. However, the effects of SXT on the energy metabolism of CHF is unclear. In this study, we probed the regulating effects of SXT on energy metabolism in CHF rats using various research methods. Methods High-performance liquid chromatography (HPLC) analysis was used to perform quality control of SXT preparations. Then, SD rats were randomly assigned into 6 groups: sham, model, positive control (trimetazidine) and high-, middle-, and low-dose SXT groups. Specific reagent kits were used to detect the expression levels of ALT and AST in rats’ serum. Echocardiography was used to evaluate cardiac function. H&E, Masson and TUNEL staining were performed to examine myocardial structure and myocardial apoptosis. Colorimetry was used to determine myocardial ATP levels in experimental rats. Transmission electron microscopy was used to observe the ultrastructure of myocardial mitochondria. ELISA was used to estimate CK, cTnI, and NT-proBNP levels, and LA、FFA、MDA、SOD levels. Finally, Western blotting was used to examine the protein expression of CPT-1, GLUT4, AMPK, p-AMPK, PGC-1α, NRF1, mtTFA and ATP5D in the myocardium. Results HPLC showed that our SXT preparation method was feasible. The results of ALT and AST tests indicate that SXT has no side effect on the liver function of rats. Treatment with SXT improved cardiac function and ventricular remodelling and inhibited cardiomyocyte apoptosis and oxidative stress levels induced by CHF. Moreover, CHF caused decrease ATP synthesis, which was accompanied by a reduction in ATP 5D protein levels, damage to mitochondrial structure, abnormal glucose and lipid metabolism, and changes in the expression of PGC-1α related signal pathway proteins, all of which were significantly alleviated by treatment with SXT. Conclusion SXT reverses CHF-induced cardiac dysfunction and maintains the integrity of myocardial structure by regulating energy metabolism. The beneficial effect of SXT on energy metabolism may be related to regulating the expression of the PGC-1α signalling pathway.

Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2′-deoxyguanosine-5′-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.

ABSTRACTCoxsackievirus A16 (CA16), a main causative agent of hand, foot, and mouth disease (HFMD), has become a serious public health concern in the Asia-Pacific region. Here, we generated an anti-CA16 monoclonal antibody, DMA2017, derived from an epidemic strain CA16. Surprisingly, although DMA2017 could not neutralize the original and circulating CA16 strains in vitro, the passive transfer of DMA2017 (10 μg/g) could protect suckling mice from a lethal challenge with CA16 in vivo. Then, we confirmed the protective effect of DMA2017 relies on the Fc-dependent effector functions, such as antibody-dependent cellular cytotoxicity (ADCC). The linear epitope of DMA2017 was mapped by phage display technique to a conserved patch spanning residues 143–148 (NSHPPY) of the VP2 EF-loop of CA16. DMA2017 could inhibit the binding of the antibodies present in the sera of naturally infected children to CA16, indicating that the epitope of DMA2017 is immunodominant for CA16. Our results confirm, for the first time, that a potential preventive and therapeutic effect could be mediated by a non-neutralizing antibody elicited against CA16. These findings bring a hitherto understudied protective role of non-neutralizing antibodies during viral infections into the spotlight and provide a new perspective on the design and evaluation of CA16 vaccines.

ABSTRACTOver one billion people have received 2–3 dosages of an inactivated COVID-19 vaccine for basic immunization. Whether a booster dose should be delivered to protect against the Omicron variant and its sub-lineages, remains controversial. Here, we tested different vaccine platforms targeting the ancestral or Omicron strain as a secondary booster of the ancestral inactivated vaccine in mice. We found that the Omicron-adapted inactivated viral vaccine promoted a neutralizing antibody response against Omicron in mice. Furthermore, heterologous immunization with COVID-19 vaccines based on different platforms remarkably elevated the levels of cross- neutralizing antibody against Omicron and its sub-lineages. Omicron-adapted vaccines based on heterologous platforms should be prioritized in future vaccination strategies to control COVID-19.

Abstract Background TP53 mutations have a prognostic significance in relapsed and refractory diffuse large B‐cell lymphoma (rrDLBCL) patients, and their treatment still faces a great challenge. This study aimed to evaluate the prognosis of patients with TP53 mutations (TP53mut) in the context of CAR‐T therapy (Chimeric antigen receptor T‐cell therapy) as well as explore the heterogeneity in their cohort and identify the possible risk factors. Methods A retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients with TP53 mutations and their prognostic factors, receiving CAR‐T therapy. And the expression level of TP53 and DDX3X, which was an important co‐mutation of TP53 revealed in the cohort, were explored in public databases and cell lines. Results The median overall survival time of 40 patients with TP53 mutations was 24.5 months, while their median progression‐free survival time after CAR‐T was 6.8 months. There were no significant differences in the ORR (objective remission rate, X2 = 3.0498, p > 0.05) and PFS (after CAR‐T therapy) between the patients with wild‐type and mutated TP53 genes after CAR‐T therapy, while the OS of patients with TP53 mutations was significantly worse (p

Abstract The interplay between quantum interference, electron-electron interaction (EEI), and disorder is one of the central themes of condensed matter physics. Such interplay can cause high-order magnetoconductance (MC) corrections in semiconductors with weak spin-orbit coupling (SOC). However, it remains unexplored how the magnetotransport properties are modified by the high-order quantum corrections in the electron systems of symplectic symmetry class, which include topological insulators (TIs), Weyl semimetals, graphene with negligible intervalley scattering, and semiconductors with strong SOC. Here, we extend the theory of quantum conductance corrections to two-dimensional (2D) electron systems with the symplectic symmetry, and study experimentally such physics with dual-gated TI devices in which the transport is dominated by highly tunable surface states. We find that the MC can be enhanced significantly by the second-order interference and the EEI effects, in contrast to the suppression of MC for the systems with orthogonal symmetry. Our work reveals that detailed MC analysis can provide deep insights into the complex electronic processes in TIs, such as the screening and dephasing effects of localized charge puddles, as well as the related particle-hole asymmetry.

[Objective] The spatial and temporal dynamic law and future change trend of groundwater level in Shanshan County of Xinjiang Uygur Autonomous Region during 2011—2020 were studied in order to provide scientific support for the determination of groundwater overexploitation control and a groundwater level control index in this area. [Methods] The dynamic types of groundwater were divided by combining cluster analysis and correlation analysis. The spatio-temporal variation of groundwater level and its main driving factors were analyzed by time series analysis, geostatistics, and multivariate logistic regression model. The R/S analysis method was used to predict the future variation trend of groundwater level. [Results] ① Groundwater dynamic types were divided into exploitation type, runoff type, runoff-exploitation type, and evaporation type. The dominant type was exploitation type, accounting for 75% of cases. ② From 2015 to 2018, the groundwater level in the north basin changed from a downward trend to an upward trend. A downward trend was observed after 2018. The groundwater level in the south basin had been declining, and the rate of decline slowed significantly after 2015. ③ The main driving factors of groundwater level change in the north basin were groundwater exploitation and surface runoff, accounting for 68.46% and 28.37% of cases, respectively. The main driving factor in the south basin was groundwater exploitation, accounting for 89.74% of cases. ④ If the external environment is stable, it is expected that the groundwater level in Qiketai Town and the northern irrigation area of the south basin will continue to decline, the groundwater level in Pizhan Township will continue to rise, and the groundwater levels in other areas will show no obvious change. [Conclusion] Groundwater exploitation is the most important factor affecting the change of groundwater level. To control the decline of groundwater level, it will be necessary to further reduce groundwater overexploitation in areas with significant groundwater level declines.

For the past 20 years, Global Navigation Satellite System reflectometry (GNSS-R) technology has successfully shown its potential for remote sensing of the Earth’s surface, including ocean and land surfaces. It is a multistatic radar that uses the GNSS signals reflected from the Earth’s surface to extract land and ocean characteristics. Because of its numerous advantages such as low cost, multiple signal sources, and all-day/weather and high-spatiotemporal-resolution observations, this new technology has attracted the attention of many researchers. One of its most promising applications is GNSS-R ocean altimetry, which can complement existing techniques such as tide gauging and radar satellite altimetry. Since this technology for ocean altimetry was first proposed in 1993, increasing progress has been made including diverse methods for processing reflected signals (such as GNSS interferometric reflectometry, conventional GNSS-R, and interferometric GNSS-R), different instruments (such as an RHCP antenna with one geodetic receiver, a linearly polarized antenna, and a system of simultaneously used RHCP and LHCP antennas with a dedicated receiver), and different platform applications (such as ground-based, air-borne, or space-borne). The development of multi-mode and multi-frequency GNSS, especially for constructing the Chinese BeiDou Global Navigation Satellite System (BDS-3), has enabled more free signals to be used to further promote GNSS-R applications. The GNSS has evolved from its initial use of GPS L1 and L2 signals to include other GNSS bands and multi-GNSS signals. Using more advanced, multi-frequency, and multi-mode signals will bring new opportunities to develop GNSS-R technology. In this paper, studies of GNSS-R altimetry are reviewed from four perspectives: (1) classifications according to different data processing methods, (2) different platforms, (3) development of different receivers, and (4) our work. We overview the current status of GNSS-R altimetry and describe its fundamental principles, experiments, recent applications to ocean altimetry, and future directions.

Neutralizing antibodies (NtAbs) against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are indicators of vaccine efficacy that enable immunity surveillance. However, the rapid mutation of SARS-CoV-2 variants prevents the timely establishment of standards required for effective XBB vaccine evaluation. Therefore, we prepared four candidate standards (No. 11, No. 44, No. 22, and No. 33) using plasma, purified immunoglobulin, and a broad-spectrum neutralizing monoclonal antibody. Collaborative calibration was conducted across nine Chinese laboratories using neutralization methods against 11 strains containing the XBB and BA.2.86 sublineages. This study demonstrated the reduced neutralization potency of the first International Standard antibodies to SARS-CoV-2 variants of concern against XBB variants. No. 44 displayed broad-spectrum neutralizing activity against XBB sublineages, effectively reduced interlaboratory variability for nearly all XBB variants, and effectively minimized the geometric mean titer (GMT) difference between the live and pseudotyped virus. No. 22 showed a broader spectrum and higher neutralizing activity against all strains but failed to reduce interlaboratory variability. Thus, No. 44 was approved as a National Standard for NtAbs against XBB variants, providing a unified NtAb measurement standard for XBB variants for the first time. Moreover, No. 22 was approved as a national reference reagent for NtAbs against SARS-CoV-2, offering a broad-spectrum activity reference for current and potentially emerging variants.

Expansins (EXPs) loosen plant cell walls and are involved in diverse developmental processes through modifying cell-walls; however, little is known about the role of PpEXPs in peach fruit. In this study, 26 PpEXP genes were identified in the peach genome and grouped into four subfamilies, with 20 PpEXPAs, three PpEXPBs, one PpEXPLA and two PpEXPLBs. The 26 PpEXPs were mapped on eight chromosomes. The primary mode of gene duplication of the PpEXPs was dispersed gene duplication (DSD, 50%). Notably, cis-elements involved in light responsiveness and MeJA-responsiveness were detected in the promoter regions of all PpEXPs, while ethylene responsive elements were observed in 12 PpEXPs. Transcript profiling of PpEXPs in the peach fruit varieties of MF (melting), NMF (non-melting) and SH (stony hard) at different stages showed that PpEXPs displayed distinct expression patterns. Among the 26 PpEXPs, 15 PpEXPs were expressed in the fruit. Combining the expressing patterns of PpEXPs in fruits with different flesh textures, PpEXPA7, PpEXPA13 and PpEXPA15 were selected as candidate genes, as they were highly consistent with the patterns of previous reported key genes (PpPGM, PpPGF and PpYUC11) in regard to peach fruit texture. The genes with different expression patterns between MF and NMF were divided into 16 modules, of which one module, with pink and midnightblue, negatively correlated with the phenotype of fruit firmness and was identified as PpEXPA1 and PpEXPA7, while the other module was identified as PpERF in the pink module, which might potentially effect fruit texture development by regulating PpEXPs. These results provide a foundation for the functional characterization of PpEXPs in peach.

PurposeThe study aimed to explore the efficacy and safety of the Neuroform EZ stent in treating acute anterior circulation large artery occlusion.MethodsThe clinical data of 42 consecutive patients with acute anterior circulation large atherosclerotic occlusion who were treated with the Neuroform EZ stent from January 2018 to August 2019 in our stroke care center, including baseline characteristics, images, therapeutic condition, and follow-up data were retrospectively analyzed.ResultsThere were 42 mechanical thrombectomy (MT) failure cases of intracranial atherosclerotic stenosis with rescue Neuroform EZ stent implantation, of which 78.6% (33/42) had a good prognosis and 88.1% (37/42) showed no re-stenosis at follow-up. The average time from puncture to recanalization is 79.50 ± 14.19 min. The successful rate of intraoperative stent release is 97.6%, while there is one case of stent displacement, three cases of thrombus escape, and six cases of hemorrhage.ConclusionRescue therapy of the Neuroform EZ stent for acute anterior circulation large atherosclerotic occlusion can archive good short-term imaging and clinical results, while long-term follow-up is still needed to verify.

Summary: Single-cell technologies promise to uncover how transcriptional programs orchestrate complex processes during embryogenesis. Here, we apply a combination of single-cell technology and genetic analysis to investigate the dynamic transcriptional changes associated with Drosophila embryo morphogenesis at gastrulation. Our dataset encompassing the blastoderm-to-gastrula transition provides a comprehensive single-cell map of gene expression across cell lineages validated by genetic analysis. Subclustering and trajectory analyses revealed a surprising stepwise progression in patterning to transition zygotic gene expression and specify germ layers as well as uncovered an early role for ecdysone signaling in epithelial-to-mesenchymal transition in the mesoderm. We also show multipotent progenitors arise prior to gastrulation by analyzing the transcription trajectory of caudal mesoderm cells, including a derivative that ultimately incorporates into visceral muscles of the midgut and hindgut. This study provides a rich resource of gastrulation and elucidates spatially regulated temporal transitions of transcription states during the process.

Metasurfaces have emerged as crucial materials for optical information encryption and storage, lauded for their ease of operation and high programmability. However, the inherent inflexibility following metasurface fabrication leaves room for improvement in terms of information storage capacity. Incorporating multiplexed channels in metasurface boasts independent coding degrees of freedom, which bolsters the utility of metasurfaces for optical information storage and encryption. Most multiplexed metasurfaces conventionally rely on optical variables that can be controlled, such as wavelength, orbital angular momentum (OAM), forward/backward incidence of light, and polarization state, etc. However, there has been limited attention given to the inherent spatial properties of metasurfaces, let alone to combine these spatial properties with optical variables for multiplexing. To address this gap, we proposes a combined approach to develop a nanoprinting and meta-holography metasurface, which harnesses both metasurface-space and angular multiplexing to store seven independent holographic and nanoprinted images. This work not only unlocks new avenues for advanced optical information storage and encryption, but also pushes the boundaries of metasurface technology.

Background: The blood-feeding behavior of kissing bugs (subfamily Triatominae, family Reduviidae, order Hemiptera) means they are potential vectors of multiple humans pathogens. However, investigations of vector-borne pathogens harbored by kissing bugs are rare. Methods: In the current study, 22 adult kissing bugs (Triatoma rubrofasciata) were captured in Huizhou City, Guangdong Province, south China. The presence of vector-borne pathogens in the kissing bugs was tested, and the genetic diversity of these potential pathogens was investigated. Results: All the kissing bugs were negative for Anaplasmataceae bacteria, Rickettsia, and Coxiella. Bartonella DNA was detected in 36.4% (8/22) of the kissing bugs. The sequences of the Bartonella gltA genes divided into two clades in a phylogenetic tree, with close relationships to B. tribocorum and uncultured Bartonella sp. clone MYR-283, respectively. All the groEL sequences were closely related to those of B. kosoyi (identity 98.75%–100%). The ftsZ and rpoB sequences were most closely related to those of B. elizabethae, a recognized human pathogen, with nucleotide similarities of 98.70%–100% and 99.45%–100%, respectively. Conclusions: We report the detection of Bartonella DNA in Triatoma kissing bugs in southern China. Although the sample size is limited, the high positive rate of detection of Bartonella DNA, the close relationship of the gene sequences to those of zoonotic Bartonella species, and the distribution of the kissing bugs near human residences, hint at a risk to public health.

In this article, an experimental study was carried out to investigate the cooling efficiency of a vortex tube equipped with a rectifier utilizing the Taguchi method for analysis. The Coefficient of Performance (COP) was determined as the quality characteristics. In the current study, the inlet pressure, distance between the rectifier and the hot end, the position of the rectifier, the height of the rectifier, the number of blades, the length of blades, the inclination angle of blades with and without ring were selected as the key control factors and levels. Taguchi L18 orthogonal array was applied to design the experiments. The Signal-to-Noise Ratio (SNR), regression, Analysis of Variance (ANOVA) and residual analysis were applied to optimise the combination for COP of the vortex tube. The tests were also conducted to validate the reliability of the predicted optimisation method. Experimental results indicated that: (i) the predicted optimal value falls within a Confidence Interval (CI) of 95%. The analysis also revealed that the length of the blades could be the most influential control factor, accounting for 36.9% of the cooling performance. (ii) the height of the rectifier shows little impact, only contributing 4.7% to the overall cooling performance. (iii) the order of other control factors on COP was inlet pressure (21%), whether the rectifiers with or without ring (12.8%), distance between the rectifier and the hot end (7.9%), the inclination angle of blades (6.2%) and the number of blades (5.3%).

[Objective] The ecological water requirement for restoring an area of damaged vegetation in an arid environment was analyzed in order to provide a scientific basis for determining the water resources required in different stages of ecological restoration and the optimal allocation of water resources. [Methods] Based on a series of Landsat images acquired in 1990, 2000, 2010, 2015, and 2020, the temporal and spatial evolution characteristics of vegetation water consumption and ecological restoration water demand in the plain area of Habahe County, Xinjiang Wei Autonomous Region were quantitatively analyzed by remote sensing technology combined with an improved Penman formula method. [Results] ① From 1990 to 2020, the average water consumption of natural vegetation was 7.55×108 m3, and decreased at a rate of 3.60×107 m3/5 yr. Correspondingly, the area of natural vegetation decreased at a rate of 17.36 km2/yr, and the vegetation coverage changed from high vegetation coverage to medium vegetation coverage, resulting in serious ecological damage. ② There were great differences in the spatial and temporal distributions of vegetation water consumption in the region: the spatially high values were mainly located in the Haba River basin, while the vegetation water consumption in the Bie River basin was generally low. Temporally, vegetation water consumption in 2000 was the highest, and vegetation water consumption in a given year was mainly concentrated in the middle growth period. ③ The ecological restoration water demand in an oasis area was 4.62×108 m3 for maintaining the status quo (2020), 6.65×108 m3 for restoring to the average ecological level from 1990 to 2020, and 9.55×108 m3 for reaching the best ecological level from 1990 to 2020 (2000). [Conclusion] Under the dual actions of human activities and nature, the ecological environment of the irrigation area showed a degradation trend from 1990 to 2020, and the spatial distribution of ecological water consumption was unbalanced. The spatial and temporal allocation of water demand for ecological restoration of an area of damaged vegetation should be optimized and improved according to the spatial and temporal distribution of water consumption.

Abstract Nuclear architecture underlies the transcriptional programs within the cell to establish cell identity. As previously demonstrated, long-range chromatin interactions of the Oct4 distal enhancer (DE) are correlated with active transcription in naïve state embryonic stem cells. Here, we identify and characterize extreme long-range interactions of the Oct4 DE through a novel CRISPR labeling technique we developed and chromosome conformation capture to identify lethal giant larvae 2 (Llgl2) and growth factor receptor-bound protein 7 (Grb7) as putative functional interacting target genes in different chromosomes. We show that the Oct4 DE directly regulates expression of Llgl2 and Grb7 in addition to Oct4. Expression of Llgl2 and Grb7 closely correlates with the pluripotent state, where knock down of either result in loss of pluripotency, and overexpression enhances somatic cell reprogramming. We demonstrated that biologically important interactions of the Oct4 DE can occur at extreme distances that are necessary for the maintenance of the pluripotent state.

Wood-based panels, which contain wood raw materials along with urea-formaldehyde (UF) or phenol-formaldehyde (PF) resins, can increase the indoor air concentration of formaldehyde. Formaldehyde can stimulate the upper respiratory mucosa and cross-linking reaction with cell proteins and DNA, and this can result in degeneration and necrosis of respiratory cells and damaged cell proliferation. Formaldehyde can induce health hazards such as nasal cancer, leukemia, and destruction of the reproductive system. Acetaldehyde dehydrogenase 5 (ADH5) in the body cooperates with Fanconi anaemia complementation group D2 (FANCD2) to quickly metabolize formaldehyde into formate and maintain the balance of endogenous formaldehyde. However, when both ADH5 and FANCD2 proteins have defects or mutations, damaged DNA repair failure and cell proliferation induce a variety of health diseases. The damage has been found in the upper respiratory area, not on distal body tissues such as liver, kidney, and bone marrow. Meanwhile epidemiological survey has not shown a positive correlation between formaldehyde and health hazards. It is recommended that the use of wood formaldehyde-based products should be reduced, and pathogenesis genes and damage repair mechanism should be studied systematically and deeply to develop gene drugs to remove excess formaldehyde and activate the damage gene repair mechanism in the future.

The high spatial-temporal variability of soil moisture necessitates monitoring at a high resolution in order to improve our understanding of Earth system processes. Current large-scale soil moistures inferred from the microwave satellites have limited spatial resolution, typically in the range of tens of kilometers. Recent studies have revealed that synthetic aperture radar (SAR) backscatter exhibits qualitative relationships with soil moisture, suggesting the potential for large-scale high-resolution mapping of soil moisture. Here, we proposed a method for directly estimating soil moisture content based on the advanced integral equation model and Mironov dielectric model. The approach involves establishing a series of semiempirical models, independent of preceding surface roughness determination, using two Envisat advanced synthetic aperture radar (ASAR) alternating polarization (AP) model precision products. We generate a time series of high-resolution soil moisture using Envisat ASAR AP data acquired from 2004 to 2011, with an uncertainty of approximately 0.05 m3/m3. Our soil moisture retrievals demonstrate very good agreement with European Space Agency Climate Change Initiative soil moisture products and the European Centre for Medium-Range Weather Forecasts ERA5 reanalysis hourly products, even in the absence of synchronous ground measurements. Furthermore, our study reveals good temporal coherence between drought and heavy rainfall events, and SAR-derived soil moisture, which suggests a potential to capture heavy rainfall and drought events. We conclude that SAR-derived soil moisture is a more direct and efficient method in quantifying soil moisture at a high spatial resolution, making it more suitable for watershed scale hydrological studies.

The fully completed Quasi-Zenith Satellite System (QZSS) and BeiDou Navigation Satellite System (BDS-3) can provide higher precision code observations owing to their advanced signal modulation. However, the performance of Global Navigation Satellite System-Reflectometry (GNSS-R) code-level altimetry using the new codes is rarely be tested. In this study, interoperable signals with the frequency of 1575.42 MHz, i.e., L1C/A and L1C from QZSS and B1C from BDS, were tested for GNSS-R altimetry simultaneously for the first time. Moreover, a joint weighted GNSS-R altimetry method is proposed to improve retrieval precision based on combinations of the path delays obtained from different signals. To investigate the performance of the signals and their combinations, a ground-based GNSS-R altimetry experiment was conducted and raw intermediate-frequency data were collected over several hours. These data were processed using a software-defined receiver to compute the path delay between the direct and reflected signals. Solutions were derived separately for each code and their combinations. Through comparison with reflector heights obtained from an in situ 26 GHz radar gauge, results showed that the performance of GNSS-R altimetry based on binary offset carrier modulation signals was better than that from binary phase-shift keying. Moreover, results from the joint weighted GNSS-R altimetry method showed further improvement in altimetry precision.

As a kind of promising aerospace material, TiAl alloys need to withstand extreme conditions such as high-rate impact loads and high temperatures. The mechanism on the failure and fracture of TiAl alloys under extreme conditions is related with the microstructure, including phase and grain size. In the present research, two kinds of TiAl alloys tailored with different microstructures, near lamellar (NL) and near gamma (NG), were fabricated by thermo-mechanical treatment. Microstructural characterization was analyzed by XRD and EBSD. The dynamic behavior of the TiAl alloys under different temperatures ranging from 293 K–873 K was investigated by a split Hopkinson pressure bar. The strain rate sensitivity and temperature sensitivity was analyzed. The microstructural evolution was concerned to understand the failure mechanism of the two kinds of the TiAl alloys. The NG-TiAl had the homogeneous deformation with synergy effect between homogeneous equiaxed grain and lamellar structure, and no failure occurred in NG-TiAl. However, the NL-TiAl showed heterogeneous deformation with both “orange peel effect” and cracks, which was attributed to large equiaxed grain and brittle γ-lamellae with similar orientation. Further, the cracks were easily nucleated and propagated from the interface between γ-lamellae structures, especially in the γ-lamellae structures parallel with the loading direction. Finally, the modified Johnson–Cook constitutive model was proposed to describe the deformation behavior, in which both strain rate hardening and temperature softening terms were expressed as a function of strain and strain rate.

Abstract Background The mechanical properties of an ankle–foot orthosis (AFO) play an important role in the gait mechanics of the end user. However, testing methodologies for evaluating these mechanical properties are not standardized. The purpose of this study was to compare five different evaluation frameworks to assess AFO stiffness. Method The same 13 carbon composite AFOs were tested with five different methods. Four previously reported custom test fixtures (the BRUCE, KST, SMApp, and EMPIRE) rotated an AFO into dorsiflexion about a defined axis in the sagittal plane. The fifth method involved quasi-static deflection of AFOs into dorsiflexion by hanging weights (HW) from the footplate. AFO rotational stiffness was calculated as the linear fit of the AFO resistive torque and angular deflection. Differences between methods were assessed using descriptive statistics and a repeated measures Friedman with post-hoc Bonferroni–Holm adjusted Wilcoxon signed-rank tests. Results There were significant differences in measured AFO stiffnesses between test methods. Specifically, the BRUCE and HW methods measured lower stiffness than both the EMPIRE and the KST. Stiffnesses measured by the SMApp were not significantly different than any test method. Stiffnesses were lowest in the HW method, where motion was not constrained to a single plane. The median difference in absolute AFO stiffness across methods was 1.03 Nm/deg with a range of [0.40 to 2.35] Nm/deg. The median relative percent difference, measured as the range of measured stiffness from the five methods over the average measured stiffness was 62% [range 13% to 156%]. When the HW method was excluded, the four previously reported test fixtures produced a median difference in absolute AFO stiffness of 0.52 [range 0.38 to 2.17] Nm/deg with a relative percent difference between the methods of 27% [range 13% to 89%]. Conclusions This study demonstrates the importance of developing mechanical testing standards, similar to those that exist for lower limb prosthetics. Lacking standardization, differences in methodology can result in large differences in measured stiffness, particularly for different constraints on motion. Non-uniform measurement practices may limit the clinical utility of AFO stiffness as a metric in AFO prescription and future research.

Abstract High-frequency mutations in tumor genomes could be exploited as an asset for developing tumor vaccines. In recent years, with the tremendous breakthrough in genomics, intelligence algorithm, and in-depth insight of tumor immunology, it has become possible to rapidly target genomic alterations in tumor cell and rationally select vaccine targets. Among a variety of candidate vaccine platforms, the early application of mRNA was limited by instability low efficiency and excessive immunogenicity until the successful development of mRNA vaccines against SARS-COV-2 broken of technical bottleneck in vaccine preparation, allowing tumor mRNA vaccines to be prepared rapidly in an economical way with good performance of stability and efficiency. In this review, we systematically summarized the classification and characteristics of tumor antigens, the general process and methods for screening neoantigens, the strategies of vaccine preparations and advances in clinical trials, as well as presented the main challenges in the current mRNA tumor vaccine development.

Abstract Dynamic alignment in prosthetic fitting is important because it affects the user’s stability, kinematics, and kinetics such as socket reaction moments. It is performed by tuning the spatial relationship between the transtibial prosthetic socket and the foot following sequential observational gait analysis in the three anatomical planes. However, the order of planes in which the adjustment should be performed is still unclear. To investigate the appropriate sequence of dynamic alignment adjustment, ten participants with transtibial amputation were asked to walk in different alignment conditions (flexion, extension, adduction, abduction; lateral, medial, anterior, and posterior translation of the socket, and plantarflexion, dorsiflexion, inversion, and eversion of the foot) to measure socket reaction moments in the out-of-planes (e.g., the effect of sagittal alignment on the coronal moment). A significant difference was found only among socket posterior translation, socket flexion, and baseline alignment in the coronal moment (P = 0.02). The results of the current and previous studies suggest that moments in the coronal plane are affected by alignment changes in all three planes, whereas moments in the sagittal plane are affected only by sagittal alignment changes. It is suggested that the procedure of alignment adjustments should be finalized in the coronal plane.

Land subsidence has become a challenging problem with urbanization and underground exploitation. The land subsidence in Wuhan, China, was inferred from 47 Sentinel-1A images acquired between June 2015 to October 2020 based on Synthetic Aperture Radar (SAR) Interferometric Point Target Analysis (IPTA) technology. Results show that significant subsidence mainly occurred in Houhu, Qinshan, Baishazhou, and Zhuankou areas, and the most significant subsidence occurred in Baishazhou, reaching an annual subsidence rate of 41.0 mm/a with accumulated subsidence of 219.4 mm., The subsidence was more significant in the carbonate solution zone with the overlying Holocene strata compared to the rest carbonate karst belts. Analysis shows thatland building construction is a major reason for land subsidence in Wuhan. The construction of subway underground stations is another factor causing land subsidence. The effect of water level fluctuations of the Yangtze River on long-term trends is negligible. Our study provides further insight into the temporal-spatial pattern of Wuhan’s displacements and suggests that the land subsidence should be continuously monitored for alleviation of potential destructive hazards, especially during the period of construction of a land building, such as residential, public facilities, and subway.

Abstract Background Volatile components are important secondary metabolites essential to fruit aroma quality, thus, in the past decades many studies have been extensively performed in clarifying fruit aroma formation. However, aroma components and biosynthesis in the fruit of Binzi (Malus pumila × Malus asiatica), an old local species with attractive aroma remain unknown. Results We investigated two Binzi cultivars, ‘Xiangbinzi’ (here named high-fragrant Binzi, ‘HFBZ’) and ‘Hulabin’ (here named low-fragrant Binzi, ‘LFBZ’) by monitoring the variation of volatiles and their precursors by Gas Chromatography–Mass Spectrometer (GC–MS), as well as their related genes by RNA-seq during post-harvest ripening. We firstly confirmed that ‘HFBZ’ and ‘LFBZ’ fruit showed respiratory climacteric by detecting respiratory rate and ethylene emission during post-harvest; found that esters were the major aroma components in ‘HFBZ’ fruit, and hexyl 2-methylbutyrate was responsible for the ‘fruity’ note and most potent aroma component, followed by ethyl acetate, ethyl butanoate, (E)-2-hexenal, and 1-hexanol. Regarding aroma synthesis, fatty acid metabolism seemed to be more important than amino acid metabolism for aroma synthesis in ‘HFBZ’ fruit. Based on RNA-seq and quantitative reverse transcription PCR (RT-qPCR), LOX2a, LOX5a, ADH1, and AAT1 genes are pointed to the LOX pathway, which may play a vital role in the aroma formation of ‘HFBZ’ fruit. Conclusion Our study firstly investigated the aroma components and related genes of Binzi fruit, and provided an insight into the fragrant nature of Malus species.

Abstract Background Delayed-onset post stroke cognitive impairment (PSCI) results from secondary neurodegeneration induced by stroke. Whereas targeted prevention or treatment strategies are still missing due to lack of evidences. This trial aims to evaluate the preventive effects of DL-3-n-butylphthalide (NBP) on delayed-onset PSCI. Methods Effects of NBP on Delayed-onset Post Stroke Cognitive Impairment (End-PSCI) is a prospective, parallel-group, open-label, multicenter, randomized controlled trial with blinded outcome assessment. Hospital patients with acute cerebral infarction (within 2 weeks of onset) will be randomized into either standard medical therapy group or standard medical therapy combined NBP treatment group (NBP 200 mg, three times per day for 24 weeks). The primary outcome is the difference of incidence of delayed-onset PSCI between two groups. The secondary outcomes include difference of white matter degeneration, cognitive scores and prevalence of early-onset PSCI between two groups. Discussion End-PSCI trial will provide evidences for NBP preventing delayed-onset PSCI. The secondary outcomes will also provide valuable insights into the pathogenesis of delayed-onset PSCI and mechanism of NBP’s actions. Trial registration Trialsearch.who.int , ChiCTR2000032555, 2020/5/2, prospectively registered.

Abstract Background Sleep is conducive to the elimination of brain metabolites and the recovery of brain function. However, the relationship between sleep disturbance and Mild Cognitive Impairment is not fully been determined. Methods This was a community population-based cross-sectional study. A total of 1,443 participants from a village in the suburbs of Xi’an, China were enrolled in 2017. Sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI), and sleep disturbance was defined as a PSQI score > 5. Mini-Mental State Examination (MMSE) was used to assess cognitive function and Mild Cognitive Impairment(MCI) was defined as the MMSE score less than cutoff values and meets the diagnostic criteria. Univariate and multivariate analyses were used to analyze the relationships between sleep disturbance and MCI. Results Among 1,443 subjects, 69(4.78%) had MCI, and 830 (57.52%) had sleep disturbance. In bivariate analysis, MCI was associated with sleep disturbance (ρ = 0.094, P

The riparian zone is an important location of nitrogen removal in the terrestrial and aquatic ecosystems. Many studies have focused on the nitrogen removal efficiency and one or two nitrogen removal processes in the riparian zone, and less attention has been paid to the interaction of different nitrogen transformation processes and the impact of in situ environmental conditions. The molecular biotechnology, microcosm culture experiments and 15N stable isotope tracing techniques were used in this research at the riparian zone in Weinan section of the Wei River, to reveal the nitrogen removal mechanism of riparian zone with multi-layer lithologic structure. The results showed that the nitrogen removal rate in the riparian zone was 4.14–35.19 μmol·N·kg−1·h−1. Denitrification, dissimilatory reduction to ammonium (DNRA) and anaerobic ammonium oxidation (anammox) jointly achieved the natural attenuation process of nitrogen in the riparian zone, and denitrification was the dominant process (accounting for 59.6%). High dissolved organic nitrogen and nitrate ratio (DOC:NO3−) would promote denitrification, but when the NO3− content was less than 0.06 mg/kg, DNRA would occur in preference to denitrification. Furthermore, the abundances of functional genes (norB, nirS, nrfA) and anammox bacterial 16S rRNA gene showed similar distribution patterns with the corresponding nitrogen transformation rates. Sedimentary NOX−, Fe(II), dissolved organic carbon (DOC) and the nitrogen transformation functional microbial abundance were the main factors affecting nitrogen removal in the riparian zone. Fe (II) promoted NO3− attenuation through nitrate dependent ferrous oxidation process under microbial mediation, and DOC promotes NO3− attenuation through enhancing DNRA effect. The results of this study can be used for the management of the riparian zone and the prevention and control of global nitrogen pollution.

Water electrolysis is a green technology for hydrogen fuel production, but greatly hampered by the slow kinetics of the anodic oxygen evolution reaction (OER) and the cathodic hydrogen evolution reaction (HER). In this work, we report an efficient strategy to simultaneously promote OER and HER performance on Co3O4 hexagonal nanosheets via Fe-doping-induced cation substitution and anion vacancies. Benefiting from the integrated advantages of well-defined ultrathin nanosheets, abundant vacancies, and unique three-dimensional electrode configuration, the optimized Fe-doped Co3O4 hexagonal nanosheets/nickel foam (Fe0.4Co2.6O4 HNSs/NF) can achieve overpotentials of 328 mV at 100 mA cm−2 for OER and 315 mV at 500 mA cm−2 for HER, respectively, which is comparable to those of the benchmark noble electrocatalysts. More importantly, the Fe0.4Co2.6O4 HNSs/NF-assembled electrolyzer for overall water splitting can deliver a current density of 100 mA cm−2 at a cell voltage as low as 1.66 V and work steadily at 50 mA cm−2 with a negligible fading up to 140 h.

Abstract Generally, long wavelength absorbed near‐infrared II (NIR‐II) dyes have a low fluorescence efficiency in aggregate states for aggregate‐caused quenching effect, simultaneously enhancing efficiency and extending absorption is a challenging issue for NIR‐II dyes. Here, three benzo[1,2‐c:4,5‐c']bis[1,2,5]thiadiazole (BBT) derivatives (TPA‐BBT, FT‐BBT, and BTBT‐BBT) are used to clarify fluorescence quenching mechanisms. When the BBT derivatives are doped into a small molecule matrix, they show quite different fluorescence behaviors. Structure‐distorted TPA‐BBT displays fluorescence quenching originating from short‐range exchange interaction, while FT‐BBT and BTBT‐BBT with a co‐planar‐conjugated backbone exhibit concentration‐dependent quenching processes, namely changing from long‐range dipole‐dipole interaction to exchange interaction, which could be majorly ascribed to large spectral overlap between absorption and emission. By precisely tuning doping concentration, both FT‐BBT and BTBT‐BBT nanoparticles (NPs) present the optimal NIR‐II fluorescence brightness at ∼2.5 wt% doping concentration. The doped NPs have good biocompatibility and could be served as fluorescence contrast agents for vascular imaging with a high resolution under 980‐nm laser excitation. Those paradigms evidence that molecular doping can promote fluorescence efficiency of long wavelength‐absorbed NIR‐II fluorophores via suppressing long‐range energy migration.

Bandwidth-tunable light absorption enhancement in monolayer graphene is practically important for graphene-based photoelectric devices. Especially, it is still a huge challenge to achieve high-efficiency graphene absorption with extremely narrow sub-nanometer bandwidth much smaller than one nanometer. In this work, both broadband and narrowband absorption peaks of monolayer graphene are numerically achieved in visible and near-infrared wavelength ranges. The broadband absorption peak is ascribed to localized dipolar plasmon resonances in individual silver nanodisks, and the narrowband absorption peak arises from collective first-order diffraction coupling effect in periodic array of silver nanodisks. By changing the array period, the full width at half maximum (FWHM) of the broadband absorption peak can vary from 100 nm to 50 nm. Correspondingly, the FWHM of the narrowband absorption peak is tuned from about 6.4 nm to only 0.25 nm, thus realizing an ultra-narrow sub-nanometer bandwidth.

Underwater Sound Speed Profile (SSP) distribution is crucial for the propagation mode of acoustic signals, so fast and accurate estimation of SSP is of great importance in building underwater observation systems. The state-of-the-art SSP inversion methods include frameworks of matched field processing (MFP), compressive sensing (CS), and feed-forward neural networks (FNNs), among which the FNN shows better real-time performance while maintaining the same level of accuracy. However, the training of FNN needs quite a lot historical SSP samples, which is difficult to satisfy in many ocean areas. This situation is called few-shot learning. To tackle this issue, we propose a multi-task learning (MTL) model with partial parameter sharing among different training tasks. By MTL, common features could be extracted, which accelerates the learning process on given tasks, and reduces the demand for reference samples, enhancing the generalization ability in few-shot learning. To verify the feasibility and effectiveness of MTL, a deep-ocean experiment was held in April 2023 in the South China Sea. Results show that MTL outperforms the other mainstream methods in terms of accuracy for SSP inversion, while inheriting the real-time advantage of FNN during the inversion stage.

With the emergence of user privacy leakage and online fraud, traditional detection mechanisms can no longer stop the intensified attacks and new methods are needed to assist in web security detection.As a bridge between users and network data, browsers are widely used in the interaction between users and various applications.The browser fingerprint contains various characteristic information of the user’s browser and device, and its uniqueness can greatly improve the accuracy of user identification.However, browser fingerprints may change over time, and solutions based on static fingerprints cannot meet the requirements of dynamic fingerprints detection.Motivated by this challenge, it’s necessary to improve the recognition and link detection capabilities of dynamic browser fingerprints.Besides, parameters from multi-dimensional perspective need to be obtained and screened to get fine-grained and high-discrimination features for model detecting, preventing the calculation cost caused by too many unnecessary parameters.Bidirectional Gating Recurrent Unit (BiGRU) was introduced into the fingerprint detection, and a stacked BiGRU detection model based on dynamic browser fingerprints was proposed.It solved the problem of low detection accuracy caused by ignoring the interaction of forward and backward information in the process of fingerprints detection, and it also had a certain improvement in indicators such as accuracy and linking time.Furthermore, in view of the different importance of different feature parameters, the same weight given to parameters will result in detection error.Combined with the attention mechanism to focus more stable fingerprint features, an Att-BiGRU fingerprint detection model based on dynamic browser fingerprints was proposed.It optimized the detection ability compared to BiGRU, further improved the detection accuracy of browser fingerprinting, and showed good linking ability on the comprehensive index under the benchmark model.

Abstract Zinc borates have merits of low voltage polarization and suitable redox potential, but usually suffer from low rate capability and poor cycling life, as an emerging anode candidate for Na+ storage. Here, a new intercalator‐guided synthesis strategy is reported to simultaneously improve rate capability and stabilize cycling life of N, B co‐doped carbon/zinc borates (CBZG). The strategy relies on a uniform dispersion of precursors and simultaneously stimulated combustion activation and solid‐state reactions capable of scalable preparation. The Na+ storage mechanism of CBZG is studied: 1) ex situ XRD and XPS demonstrate two‐step reaction sequence of Na+ storage: Zn6O(OH)(BO3)3+Na++e−↔3ZnO+Zn3B2O6+NaBO2+0.5H2 ①, Zn3B2O6+6Na++6e−↔3Zn+3Na2O+B2O3 ②; reaction ① is irreversible in ether‐based electrolyte while reversible in ester‐based electrolyte. 2) Electrochemical kinetics reveal that ether‐based electrolyte possesses faster Na+ storage than ester‐based electrolyte. The composite demonstrates an excellent capacity of 437.4 mAh g−1 in a half‐cell, together with application potential in full cells (discharge capacity of 440.1 mAh g−1 and stable cycle performance of 2000 cycles at 5 A g−1). These studies will undoubtedly provide an avenue for developing novel synthetic methods of carbon‐based borates and give new insights into the mechanism of Na+ storage in ether‐based electrolyte for the desirable sodium storage.