High-performance electrode materials of heteroatom-doped lignin-based carbon materials for supercapacitor applications.

Supercapacitors are the preferred option for supporting renewable energy sources owing to many benefits, including fast charging, long life, high energy and power density, and saving energy. While electrode materials with environmentally friendly preparation, high performance, and low cost are important research directions of supercapacitors. At present, the growing global population and the increasingly pressing issue of environmental pollution have drawn the focus of numerous researchers worldwide to the development and utilization of renewable biomass resources. Lignin, a renewable aromatic polymer, has reserves second only to cellulose in nature. Ten million tonnes of industrial lignin are produced in pulp and paper mills annually, most of which are disposed of as waste or burned for fuel, seriously depleting natural resources and polluting the environment. One practical strategy to accomplish sustainable development is to employ lignin resources to create high-value materials. Based on the high carbon content and rich functional groups of lignin, the lignin-based carbon materials generated after carbonization treatment display specific electrochemical properties as electrode materials. Nevertheless, low electrochemical activity of untreated lignin precludes it from achieving its full potential for application in energy storage. Heteroatom doping is a common modification method that aims to improve the electrochemical performance of the electrode materials by optimizing the structure of the lignin, improving its pore structure and increasing the number of active sites on its surface. This paper aims to establish theoretical foundations for design, preparation, and optimizing the performance of heteroatom-doped lignin-based carbon materials, as well as for developing high-value-added lignin materials. The most reported the mechanism of supercapacitors, the doping process involving various types of heteroatoms, and the analysis of how heteroatoms affect the performance of lignin-based carbon materials are also detailed in this review.

Dissolving Chitin by Novel Deep Eutectic Solvents for Effectively Enzymatic Hydrolysis.

Chitin is the most productive nitrogen-containing polysaccharide in nature with immense potential for transforming into a range of chemicals. However, its dense crystal structure poses a challenge for depolymerization, limiting its applications. To overcome these challenges, a novel series of deep eutectic solvents (DESs) based on benzyltrimethylammonium chloride (TMBAC) as the hydrogen bond acceptor was developed. These TMBAC-based DESs, in combination with lactic acid, oxalic acid, and malic acid as the hydrogen bond donor demonstrated efficient chitin dissolution, achieving a solubility of up to 12% and an 88% recovery rate of regenerated chitin. The regenerated chitin was characterized using XRD, FT-IR, SEM, and 13C CP-MAS NMR, which indicated the preservation of chitin's chemical structure, a significant decrease in crystallinity, and a reduction in the molecular weight. Furthermore, the enzymatic hydrolysis efficiency of chitin was nearly doubled after treatment with TMBAC-based DESs, surpassing the effectiveness of untreated chitin. This approach holds promise for facilitating subsequent transformation and utilization of chitin.

Lower plasma linoleic acids as a risk factor for gout: an integrated analysis of population-based cohort and genetic data.

Background: Gout is a nutrition-related, highly prevalent inflammatory arthritis with undesirable effects on the quality of life. The relationships between circulating fatty acids (FAs) and gout remain poorly understood. Method: We included 268 174 participants with plasma FAs measured using nuclear magnetic resonance at the baseline (2006-2010) from the UK Biobank, of which 15 194 participants had repeated measures of FAs between 2012 and 2013. Cox proportional hazards models were used to assess the association of the baseline and longitudinal changes in relative levels of plasma FAs (% total FAs) with incident gout. Mendelian randomization (MR) analyses were conducted to assess the potential causality of the examined association. Results: Over a median follow-up of 12.8 years, 5160 incident cases of gout occurred. Baseline polyunsaturated fatty acids (PUFAs), n-6 PUFAs, and linoleic acids (LAs) were inversely associated with incident gout (all P-trend values < 0.0001). Baseline monounsaturated fatty acids (MUFAs), n-3 PUFAs, and docosahexaenoic acids (DHAs) were positively associated with incident gout (all P-trend values < 0.0001). Longitudinal increments of n-6 PUFAs and LAs were associated with a lower risk of subsequent gout, whereas an increment of n-3 PUFAs was associated with a higher risk. In two-sample MR analyses, genetically determined higher levels of PUFAs, n-6 PUFAs, and LAs were associated with a decreased risk of gout (all P values < 0.05). Conclusions: Our findings consistently indicate a causal relationship of elevated levels of n-6 PUFAs, especially LAs, with a reduced risk of gout.

Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies.

Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.

Soy Peptide Supplementation Mitigates Undernutrition through Reprogramming Hepatic Metabolism in a Novel Undernourished Non-Human Primate Model.

In spite of recent advances in the field of undernutrition, current dietary therapy relying on the supply of high protein high calorie formulas is still plagued with transient recovery of impaired organs resulting in significant relapse of cases. This is partly attributed to the inadequacy of current research models in recapitulating clinical undernutrition for mechanistic exploration. Using 1636 Macaca fascicularis monkeys, a human-relevant criterion for determining undernutrition weight-for-age z-score (WAZ), with a cutoff point of ≤ -1.83 is established as the benchmark for identifying undernourished nonhuman primates (U-NHPs). In U-NHPs, pathological anomalies in multi-organs are revealed. In particular, severe dysregulation of hepatic lipid metabolism characterized by impaired fatty acid oxidation due to mitochondria dysfunction, but unlikely peroxisome disorder, is identified as the anchor metabolic aberration in U-NHPs. Mitochondria dysfunction is typified by reduced mito-number, accumulated long-chain fatty acids, and disruption of OXPHOS complexes. Soy peptide-treated U-NHPs increase in WAZ scores, in addition to attenuated mitochondria dysfunction and restored OXPHOS complex levels. Herein, innovative criteria for identifying U-NHPs are developed, and unknown molecular mechanisms of undernutrition are revealed hitherto, and it is further proved that soypeptide supplementation reprogramed mitochondrial function to re-establish lipid metabolism balance and mitigated undernutrition.

Association study of FLT4 and HYDIN single nucleotide polymorphisms with atrial septal defect susceptibility in the Han Chinese population of Southwest China.

BACKGROUND: Atrial septal defect (ASD) is a common form of congenital heart disease. Although several genes related to ASD have been found, the genetic factors of ASD remain unclear. This study aimed to evaluate the correlation between 10 candidate single nucleotide polymorphisms (SNPs) and sporadic atrial septal defects. METHODS: Based on the results of 34 individual whole exome sequences, 10 candidate SNPs were selected. In total, 489 ASD samples and 420 normal samples were collected. The 10 SNPs in the case group and the control group were identified through Snapshot genotyping technology. The χ2-test and unconditional regression model were used to evaluate the relationship between ASD and each candidate SNP. Haploview software was used to perform linkage disequilibrium and haplotype analysis. RESULTS: The χ2 results showed that the FLT4 rs383985 (P = 0.003, OR = 1.115-1.773), HYDIN rs7198975 (P = 0.04621, OR = 1.003-1.461), and HYDIN rs1774266 (P = 0.04621, OR = 1.003-1.461) alleles were significantly different between the control group and the case group (P < 0.05). Only the association with the FLT4 polymorphism was statistically significant after adjustment for multiple comparisons. CONCLUSION: These findings suggest that a possible molecular pathogenesis associated with sporadic ASD is worth exploring in future studies.

Aberrant METTL14 gene expression contributes to malignant transformation of benzene-exposed myeloid cells.

Benzene is a known contributor to human leukaemia through its toxic effects on bone marrow cells, and epigenetic modification is believed to be a potential mechanism underlying benzene pathogenesis. However, the specific roles of N6-methyladenosine (m6A), a newly discovered RNA post-transcriptional modification, in benzene-induced hematotoxicity remain unclear. In this study, we identified self-renewing malignant proliferating cells in the bone marrow of benzene-exposed mice through in vivo bone marrow transplantation experiments and Competitive Repopulation Assay. Subsequent analysis using whole transcriptome sequencing and RNA m6A methylation sequencing revealed a significant upregulation of RNA m6A modification levels in the benzene-exposed group. Moreover, RNA methyltransferase METTL14, known as a pivotal player in m6A modification, was found to be aberrantly overexpressed in Lin-Sca-1+c-Kit+ (LSK) cells of benzene-exposed mice. Further analysis based on the GEO database showed a positive correlation between the expression of METTL14, mTOR, and GFI and benzene exposure dose. In vitro cellular experiments, employing experiments such as western blot, q-PCR, m6A RIP, and CLIP, validated the regulatory role of METTL14 on mTOR and GFI1. Mechanistically, continuous damage inflicted by benzene exposure on bone marrow cells led to the overexpression of METTL14 in LSK cells, which, in turn, increased m6A modification on the target genes' (mTOR and GFI1) RNA. This upregulation of target gene expression activated signalling pathways such as mTOR-AKT, ultimately resulting in malignant proliferation of bone marrow cells. In conclusion, this study offers insights into potential early targets for benzene-induced haematologic malignant diseases and provides novel perspectives for more targeted preventive and therapeutic strategies.

Magnetically driven molecular orientational ordering in plastic crystals: The case of d-camphor.

Many solid crystals exhibit a structural phase transition where a subset of its ions or entire molecules become orientationally ordered. As to why such ordering occurs remains mostly unresolved. We consider the extremely weak magnetic elements arising from the reorientations of the molecules experiencing mutual resonance to play the chief role. Two new features are identified in d-camphor: (1) the magnetic susceptibility abruptly changes when crossing the order-disorder phase transition at TII-III = 239.8 K during cooling and at TIII-II = 245.2 K during warming and (2) the complex dielectric constant exhibits two successive discontinuities only 0.2 K apart near the critical temperatures when the sweeping rate is only 0.1 K/min. We discuss how the change in entropy associated with order-disorder transitions in plastic crystals represents temporal changes rather than spatial changes in the system. Our findings may be extended to study why many other crystalline solids exhibit orientational ordering and irreversibility.

Transcriptomics analysis of LINC02202/XBP1 axis in melanoma: Implications for drug targeting and PD-1 monoclonal antibody efficacy.

Malignant melanoma (MM) is a highly aggressive and deadly form of skin cancer, primarily caused by recurrence and metastasis. Therefore, it is crucial to investigate the regulatory mechanisms underlying melanoma recurrence and metastasis. Our study has identified a potential targeted regulatory relationship between LINC02202, miR-526b-3p and XBP1 in malignant melanoma. Through the regulation of the miR-526b-3p/XBP1 signalling pathway, LINC02202 may play a role in tumour progression and immune infiltration and inhibiting the expression of LINC02202 can increase the efficacy of immunotherapy for melanoma. Our findings shed light on the impact of LINC02202/XBP1 on the phenotype and function of malignant melanoma cells. Furthermore, this study provides a theoretical foundation for the development of novel immunotherapy strategies for malignant melanoma.

Schisandrin B from Schisandra chinensis alleviated pain via glycine receptors, Nav1.7 channels and Cav2.2 channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis, the dried and ripe fruit of the magnolia family plant Schisandra chinensis (Turcz.) Baill, was commonly used in traditional analgesic prescription. Studies have shown that the extract of Schisandra chinensis (SC) displayed analgesic activity. However, the analgesic active component and the exact mechanisms have yet to be revealed. AIM OF THE STUDY: The present study was to investigate the anti-nociceptive constituent of Schisandra chinensis, assess its analgesic effect, and explore the potential molecular mechanisms. MATERIALS AND METHODS: The effects of a series of well-recognized compounds from SC on glycine receptors were investigated. The analgesic effect of the identified compound was evaluated in three pain models. Mechanistic studies were performed using patch clamp technique on various targets expressed in recombinant cells. These targets included glycine receptors, Nav1.7 sodium channels, Cav2.2 calcium channels et al. Meanwhile, primary cultured spinal dorsal horn (SDH) neurons and dorsal root ganglion (DRG) neurons were also utilized. RESULTS: Schisandrin B (SchB) was a positive allosteric modulator of glycine receptors in spinal dorsal horn neurons. The EC50 of SchB on glycine receptors in spinal dorsal horn neurons was 2.94 ± 0.28 µM. In three pain models, the analgesic effect of SchB was comparable to that of indomethacin at the same dose. Besides, SchB rescued PGE2-induced suppression of α3 GlyR activity and alleviated persistent pain. Notably, SchB could also potently decrease the frequency of action potentials and inhibit sodium and calcium channels in DRG neurons. Consistent with the data from DRG neurons, SchB was also found to significantly block Nav1.7 sodium channels and Cav2.2 channels in recombinant cells. CONCLUSION: Our results demonstrated that, Schisandrin B, the primary lignan component of Schisandra chinensis, may exert its analgesic effect by acting on multiple ion channels, including glycine receptors, Nav1.7 channels, and Cav2.2 channels.

Robust and sensitive conductive nanocomposite hydrogel with bridge cross-linking-dominated hierarchical structural design.

Conductive hydrogels have a remarkable potential for applications in soft electronics and robotics, owing to their noteworthy attributes, including electrical conductivity, stretchability, biocompatibility, etc. However, the limited strength and toughness of these hydrogels have traditionally impeded their practical implementation. Inspired by the hierarchical architecture of high-performance biological composites found in nature, we successfully fabricate a robust and sensitive conductive nanocomposite hydrogel through self-assembly-induced bridge cross-linking of MgB2 nanosheets and polyvinyl alcohol hydrogels. By combining the hierarchical lamellar microstructure with robust molecular B─O─C covalent bonds, the resulting conductive hydrogel exhibits an exceptional strength and toughness. Moreover, the hydrogel demonstrates exceptional sensitivity (response/relaxation time, 20 milliseconds; detection lower limit, ~1 Pascal) under external deformation. Such characteristics enable the conductive hydrogel to exhibit superior performance in soft sensing applications. This study introduces a high-performance conductive hydrogel and opens up exciting possibilities for the development of soft electronics.

A 3D nanoscale optical disk memory with petabit capacity.

High-capacity storage technologies are needed to meet our ever-growing data demands1,2. However, data centres based on major storage technologies such as semiconductor flash devices and hard disk drives have high energy burdens, high operation costs and short lifespans2,3. Optical data storage (ODS) presents a promising solution for cost-effective long-term archival data storage. Nonetheless, ODS has been limited by its low capacity and the challenge of increasing its areal density4,5. Here, to address these issues, we increase the capacity of ODS to the petabit level by extending the planar recording architecture to three dimensions with hundreds of layers, meanwhile breaking the optical diffraction limit barrier of the recorded spots. We develop an optical recording medium based on a photoresist film doped with aggregation-induced emission dye, which can be optically stimulated by femtosecond laser beams. This film is highly transparent and uniform, and the aggregation-induced emission phenomenon provides the storage mechanism. It can also be inhibited by another deactivating beam, resulting in a recording spot with a super-resolution scale. This technology makes it possible to achieve exabit-level storage by stacking nanoscale disks into arrays, which is essential in big data centres with limited space.

Effect of magnetic resonance imaging in liver metastases.

This letter to the editor is a commentary on a study titled "Liver metastases: The role of magnetic resonance imaging." Exploring a noninvasive imaging evaluation system for the biological behavior of hepatocellular carcinoma (HCC) is the key to achieving precise diagnosis and treatment and improving prognosis. This review summarizes the role of magnetic resonance imaging in the detection and evaluation of liver metastases, describes its main imaging features, and focuses on the added value of the latest imaging tools (such as T1 weighted in phase imaging, T1 weighted out of phase imaging; diffusion-weighted imaging, T2 weighted imaging). In this study, I investigated the necessity and benefits of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid for HCC diagnostic testing and prognostic evaluation.

Characterization and Mechanism Study of a Novel PL7 Family Exolytic Alginate Lyase from Marine Bacteria Vibrio sp. W13.

Alginate lyase can degrade alginate into oligosaccharides through ß-elimination for various biological, biorefinery, and agricultural purposes. Here, we report a novel PL7 family exolytic alginate lyase VwAlg7A from marine bacteria Vibrio sp. W13 and achieve the heterologous expression in E. coli BL21 (DE3). VwAlg7A is 348aa with a calculated molecular weight of 36 kDa, containing an alginate lyase 2 domain. VwAlg7A exhibits specificity towards poly-guluronate. The optimal temperature and pH of VwAlg7A are 30 °C and 7.0, respectively. The activity of VwAlg7A can be significantly inhibited by the Ni2+, Zn2+, and NaCl. The Km and Vmax of VwAlg7A are 36.9 mg/ml and 395.6 µM/min, respectively. The ESI and HPAEC-PAD results indicate that VwAlg7A cleaves the sugar bond in an exolytic mode. Based on the molecular docking and mutagenesis results, we further confirmed that R98, H169, and Y303 are important catalytic residues.

Systemic and cerebrospinal fluid biomarkers for tuberculous meningitis identification and treatment monitoring.

IMPORTANCE: Tuberculous meningitis is a life-threatening infection with high mortality and disability rates. Current diagnostic methods using cerebrospinal fluid (CSF) samples have limited sensitivity and lack predictive biomarkers for evaluating prognosis. This study's findings reveal excessive activation of the immune response during tuberculous meningitis (TBM) infection. Notably, a strong negative correlation was observed between CSF levels of monokine induced by interferon-γ (MIG) and the CSF/blood glucose ratio in TBM patients. MIG also exhibited the highest area under the curve with high sensitivity and specificity. This study suggests that MIG may serve as a novel biomarker for differentiating TBM infection in CSF or serum, potentially leading to improved diagnostic accuracy and better patient outcomes.

POOE: predicting oomycete effectors based on a pre-trained large protein language model.

Oomycetes are fungus-like eukaryotic microorganisms which can cause catastrophic diseases in many plants. Successful infection of oomycetes depends highly on their effector proteins that are secreted into plant cells to subvert plant immunity. Thus, systematic identification of effectors from the oomycete proteomes remains an initial but crucial step in understanding plant-pathogen relationships. However, the number of experimentally identified oomycete effectors is still limited. Currently, only a few bioinformatics predictors exist to detect potential effectors, and their prediction performance needs to be improved. Here, we used the sequence embeddings from a pre-trained large protein language model (ProtTrans) as input and developed a support vector machine-based method called POOE for predicting oomycete effectors. POOE could achieve a highly accurate performance with an area under the precision-recall curve of 0.804 (area under the receiver operating characteristic curve = 0.893, accuracy = 0.874, precision = 0.777, recall = 0.684, and specificity = 0.936) in the fivefold cross-validation, considerably outperforming various combinations of popular machine learning algorithms and other commonly used sequence encoding schemes. A similar prediction performance was also observed in the independent test. Compared with the existing oomycete effector prediction methods, POOE provided very competitive and promising performance, suggesting that ProtTrans effectively captures rich protein semantic information and dramatically improves the prediction task. We anticipate that POOE can accelerate the identification of oomycete effectors and provide new hints to systematically understand the functional roles of effectors in plant-pathogen interactions. The web server of POOE is freely accessible at http://zzdlab.com/pooe/index.php. The corresponding source codes and data sets are also available at https://github.com/zzdlabzm/POOE.IMPORTANCEIn this work, we use the sequence representations from a pre-trained large protein language model (ProtTrans) as input and develop a Support Vector Machine-based method called POOE for predicting oomycete effectors. POOE could achieve a highly accurate performance in the independent test set, considerably outperforming existing oomycete effector prediction methods. We expect that this new bioinformatics tool will accelerate the identification of oomycete effectors and further guide the experimental efforts to interrogate the functional roles of effectors in plant-pathogen interaction.

AraPathogen2.0: An Improved Prediction of Plant-Pathogen Protein-Protein Interactions Empowered by the Natural Language Processing Technique.

Plant-pathogen protein-protein interactions (PPIs) play crucial roles in the arm race between plants and pathogens. Therefore, the identification of these interspecies PPIs is very important for the mechanistic understanding of pathogen infection and plant immunity. Computational prediction methods can complement experimental efforts, but their predictive performance still needs to be improved. Motivated by the rapid development of natural language processing and its successful applications in the field of protein bioinformatics, here we present an improved XGBoost-based plant-pathogen PPI predictor (i.e., AraPathogen2.0), in which sequence encodings from the pretrained protein language model ESM2 and Arabidopsis PPI network-related node representations from the graph embedding technique struc2vec are used as input. Stringent benchmark experiments showed that AraPathogen2.0 could achieve a better performance than its precedent version, especially for processing the test data set with novel proteins unseen in the training data.

The Olink proteomics profile in nasal secretion of patients with allergic rhinitis.

KEY POINTS: Nasal secretions of allergic rhinitis patients were analyzed by Olink proteomics. Fifteen differentially expressed proteins (DEPs) were identified. The DEPs were significantly correlated with the total nasal symptom scores of patients with allergic rhinitis.

3D-Printed Lattice Structures for Sound Absorption: Current Progress, Mechanisms and Models, Structural-Property Relationships, and Future Outlook.

The reduction of noises, achieved through absorption, is of paramount importance to the well-being of both humans and machines. Lattice structures, defined as architectured porous solids arranged in repeating patterns, are emerging as advanced sound-absorbing materials. Their immense design freedom allows for customizable pore morphology and interconnectivity, enabling the design of specific absorption properties. Thus far, the sound absorption performance of various types of lattice structures are studied and they demonstrated favorable properties compared to conventional materials. Herein, this review gives a thorough overview on the current research status, and characterizations for lattice structures in terms of acoustics is proposed. Till date, there are four main sound absorption mechanisms associated with lattice structures. Despite their complexity, lattice structures can be accurately modelled using acoustical impedance models that focus on critical acoustical geometries. Four defining features: morphology, relative density, cell size, and number of cells, have significant influences on the acoustical geometries and hence sound wave dissipation within the lattice. Drawing upon their structural-property relationships, a classification of lattice structures into three distinct types in terms of acoustics is proposed. It is proposed that future attentions can be placed on new design concepts, advanced materials selections, and multifunctionalities.

Schisandrin B, a dual positive allosteric modulator of GABAA and glycine receptors, alleviates seizures in multiple mouse models.

Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill and has multiple neuroprotective effects, sedative and hypnotic activities. In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established. We showed that injection of SchB (10, 30, 60 mg/kg, i.p.) dose-dependently delayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection of SchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 µM, and application of SchB (10 µM) alone did not activate the channels in the absence of GABA or glycine. Furthermore, SchB (10 µM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine). Moreover, SchB (10 µM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition, the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)ß2(N289S)γ2L receptors by site-directed mutagenesis tests abolished SchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.