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In recent years, edge computing networks have been widely adopted to achieve low latency, save bandwidth, and improve flexibility. However, most of the current Edge Nodes (ENs) are in semi-trusted or untrusted environments, where interactions among users are unsafe. Therefore, providing cost-effective protection strategies for ENs under resource limitations remains a great challenge. To cope with this, we propose an edge computing model with “End-Edge-Cloud” collaborative services, and a Privacy Preservation Strategy with Pseudo-Addresses (P2SPA) is constructed to maximize the cost-effectiveness while protecting the location privacy of the ENs. We quantify the privacy protection preference of user information using the Analytic Hierarchy Process (AHP) to select the optimal EN. Considering the dynamic change in the attack frequency, a pseudo-address selection and updating strategy is constructed based on the Stackelberg game theory; thus, the optimal pseudo-address update frequency is achieved. Numerical estimations are performed to verify the effectiveness of the proposed P2SPA strategy. Compared with the existing methods, P2SPA achieves a compromise service strategy with satisfactory performance on both the defense effect and defense cost.

Clubroot disease, caused by Plasmodiophora brassicae, is a serious soil-borne disease in Brassica crops worldwide. It seriously occurs in conducive soils of southern China, while never happens in some areas of northern China with suppressive soils. To understanding the differences, we measured the soil suppressiveness, chemical properties, and microbial communities in suppressive and conducive soils by bioassay and sequencing of 16S and 18S rRNA amplicons. The biological basis of clubroot suppressiveness was supported by the ability to remove it by pasteurization. The pH value and calcium content in the suppressive soils were higher than those in the conducive soils. Suppressive soils were associated with higher fungal diversity and bacterial abundance. The fungal phyla Chytridiomycota, Olpidiomycota, and Mucoromycota and the bacterial phyla Acidobacteriota and Gemmatimonadota were enriched in suppressive soils. More abundant beneficial microbes, including Chaetomium and Lysobacter, were found in the suppressive soils than in the conducive soils. Molecular ecological network analysis revealed that the fungal network of suppressive soils was more complex than that of conducive soils. Our results indicate that plant health is closely related to soil physicochemical and biological properties. This study is of great significance for developing strategies for clubtroot disease prevention and control.

BackgroundSeasons were found to be related to the occurrences of venous thromboembolism (VTE) in hospitalized patients. No previous study has explored whether seasons were associated with VTE risk in pregnant women. This study aimed to investigate the relationships between the season of delivery and VTE risk during hospitalization among pregnant women.MethodsThis is a multi-center retrospective cohort study of pregnant women. Participants were those who delivered at seven designated sites in Hubei Province, China, during the period from January 2017 to December 2022. They were categorized according to their season/month of delivery. Information on new-onset VTE during hospitalization was followed.ResultsApproximately 0.28% (104/37,778) of the pregnant women developed new-onset VTE during hospitalization for delivery. After adjustment, compared with participants in the spring group, participants in the summer, autumn, and winter groups had an increased risk of VTE during hospitalization. The ORs were 2.59 [1.30, 5.15], 2.83 [1.43, 5.60], and 2.35 [1.17, 4.75] for the summer, autumn, and winter groups, respectively. Pregnant women in the combined group (summer + autumn + winter) had an increased risk of VTE during hospitalization than those in the spring group (OR, 2.59 [1.39, 4.85]). By restricting the analyses among pregnant women without in vitro fertilization, gestational diabetes mellitus, and preterm, the results still remained robust. Compared with participants who delivered in March, April, and May, participants who delivered in June, July, September, November, December, and February had a higher risk of VTE during hospitalization.ConclusionThis study demonstrated that pregnant women who delivered in summer, autumn, and winter had an increased VTE risk during hospitalization compared with those who delivered in spring.

Saliva plays important roles in insect feeding, but its roles in insect reproduction were rarely reported. Here we reported that the knockdown of a salivary gland-specific gene NlG14 disrupted the reproduction through inhibiting the ovulation of the brown planthopper (BPH), Nilaparvata lugens (Stål), one of the most devastating rice pests in Asia. NlG14 knockdown caused the displacement of the lateral oviduct secreted components (LOSC), leading to the ovulation disorder and the accumulation of mature eggs in the ovary. The RNAi-treated females laid much less eggs than their control counterparts, though they had the similar oviposition behavior on rice stems as controls. NlG14 protein was not secreted into the hemolymph, indicating an indirect effect of NlG14 knockdown on BPH reproduction. NlG14 knockdown caused the malformation of A-follicle of the principal gland and affected the underlying endocrine mechanism of salivary glands. NlG14 reduction might promote the secretion of insulin-like peptides NlILP1 and NlILP3 from the brain, which up-regulated the expression of Nllaminin gene and then caused the abnormal contraction of lateral oviduct muscle. Another explanation was NlG14 reduction disrupted the ecdysone biosynthesis and action through the insulin-PI3K-Akt signaling in ovary. Altogether, this study indicated that the salivary gland specific protein NlG14 indirectly mediated BPH ovulation process, which established a connexon in function between insect salivary gland and ovary.

Abstract Background TLPs (Tubby-like proteins) are widespread in eukaryotes and highly conserved in plants and animals. TLP is involved in many biological processes, such as growth, development, biotic and abiotic stress responses, while the underlying molecular mechanism remains largely unknown. In this paper we characterized the biological function of cucumber (Cucumis sativus L.) Tubby-like protein 8 (CsTLP8) in Arabidopsis. Results In cucumber, the expression of the tubby-like protein CsTLP8 was induced by NaCl treatment, but reduced by PEG (Polyethylene Glycol) and ABA (Abscisic Acid) treatment. Subcellular localization and transcriptional activation activity analysis revealed that CsTLP8 possessed two characteristics of classical transcription factors: nuclear localization and trans-activation activity. Yeast two-hybrid assay revealed interactions of CsTLP8 with CsSKP1a and CsSKP1c, suggesting that CsTLP8 might function as a subunit of E3 ubiquitin ligase. The growth activity of yeast with ectopically expressed CsTLP8 was lower than the control under NaCl and mannitol treatments. Under osmotic and salt stresses, overexpression of CsTLP8 inhibited seed germination and the growth of Arabidopsis seedlings, increased the content of MDA (Malondialdehyde), and decreased the activities of SOD (Superoxide Dismutase), POD (Peroxidase) and CAT (Catalase) in Arabidopsis seedlings. Overexpression of CsTLP8 also increased the sensitivity to ABA during seed germination and ABA-mediated stomatal closure. Conclusion Under osmotic stress, CsTLP8 might inhibit seed germination and seedling growth by affecting antioxidant enzymes activities. CsTLP8 acts as a negative regulator in osmotic stress and its effects may be related to ABA.

Abstract Objective To control the transmission of coronavirus disease 2019 (COVID-19), the Chinese government encouraged people to stay at home. This study aimed to evaluate the effects of home confinement on the occurrence of fractures among children. Study design We retrospectively reviewed children admitted to Children’s Hospital of Chongqing Medical University, for traumatic injury from January 24 to March 10, 2020, and the same time period in 2017, 2018 and 2019. At the same time, children with fracture were screened out and the date for the past 4 years was compared in terms of etiology, location of fracture, sex and age to evaluate the effects of home confinement on the epidemiology of pediatric fractures during the COVID-19 outbreak. Results There were 6066 fractures in5,346 patients in 2017–2019, and 1034 fractures in 862 patients in 2020; the number of patients in all years reached a peak at the age of 2 to 4 years. The patients were slightly younger in 2020 than in 2017–2019 (t = 9.953, 95% CI: 0.846–1.262), and the proportion of boys in 2017–2019 is higher than in 2020 (X2 = 6.944, P = 0.008). Home confinement and traffic restriction resulted in a reduction in traffic accidents-associated fractures among children (X2 = 16.399, P

With the prevalence of cloud computing, the outsourcing of computation has gained significant attention. Clients with limited computing power often outsource complex computing tasks to the cloud to save on computing resources and costs. In outsourcing the computation of functions, a function owner delegates a cloud server to perform the function’s computation on the input received from the user. There are three primary security concerns associated with this process: protecting function privacy for the function owner, protecting input privacy for the user and guaranteeing that the cloud server performs the computation correctly. Existing works have only addressed privately verifiable outsourcing computation with privacy or publicly verifiable outsourcing computation without input privacy or function privacy. By using the technologies of homomorphic encryption, proxy re-encryption and verifiable computation, we propose the first publicly verifiable outsourcing computation scheme that achieves both input privacy and function privacy for matrix functions, which can be extended to arbitrary multivariate polynomial functions. We additionally provide a faster privately verifiable method. Moreover, the function owner retains control over the function.

Abstract Background miR-431-5p is dysregulated in various cancers and plays an important function in the development of cancer. However, its role in fibroblast-like synoviocytes (FLSs) in patients with rheumatoid arthritis (RA) remains to be understood. Methods Quantitative real-time polymerase chain reaction was used to detect the relative expression of miR-431-5p in synovial tissues and FLSs. Cell proliferation assays helped examine RA FLS proliferation. Flow cytometry was performed to determine apoptosis and cell cycle progression in RA FLSs. We used dual-luciferase assays to determine the correlation between miR-431-5p and its putative target, X-linked inhibitor of apoptosis (XIAP). Quantitative real-time PCR and western blotting were used to measure XIAP levels in synovial tissues and transfected RA FLSs. Results miR-431-5p was downregulated in synovial tissues and FLSs of patients with RA. Upregulation of miR-431-5p prohibited cell proliferation and the G0/G1-to-S phase transition but promoted apoptosis in RA FLSs, while miR-431-5p inhibition showed the opposite results. miR-431-5p directly targeted XIAP in RA FLSs and reversely correlated with XIAP levels in synovial tissues. Notably, XIAP silencing partially restored the effects of miR-431-5p inhibition in RA FLSs. Conclusion miR-431-5p regulates cell proliferation, apoptosis, and cell cycle of RA FLSs by targeting XIAP, suggesting its potential in the treatment of RA.

Abstract Background The purpose of the present study is to investigate the therapeutic effect of fasciotomy through multiple small skin incisions for the treatment of early osteofascial compartment syndrome in children. Methods From January 2009 to May 2017, 56 pediatric patients with early osteofascial compartment syndrome in their limbs were admitted into our department and treated with multiple small skin incisions for decompression at the early stage. The skin incisions, function, and sensation of the limbs were followed up. Results The osteofascial compartment syndrome was diagnosed at 7.4 ± 2.1 h after injury, and then fasciotomy was performed at 1.4 ± 0.4 h later. The average procedure time of fasciotomy was 12.7 ± 4.8 min. No postoperative incision infections or neurovascular injuries were observed in all the patients. The incisions completely healed in 7–10 days with an average healing time of 8 days without secondary suture. The patients were followed up for an average of 5.1 years. No Volkmann’s contractures in the injured limbs were found. The appearance, electromyography, and nerve conduction velocity of the affected limbs were not significantly different from that of the contralateral limbs. All the patients were free of symptoms and were fully recovered of sensation and function, being an “excellent” outcome at the latest follow-up. Conclusion Fasciotomy through multiple small skin incisions, which can be useful to decompress the compartment pressure with fewer complications, is a simple and effective strategy for the treatment of early osteofascial compartment syndrome in children.

Homeobox (HOX) transcript antisense RNA (Hotair) is elevated in many cancers significantly. However, the oncogenic role of Hotair in human laryngeal squamous cell carcinoma (LSCC) is still unknown. Thus, we explored the expression profile of Hotair and its function in LSCC. We observed high expression levels of Hotair in six LSCC cell lines compared to the human nasopharyngeal epithelial cell line. Knockdown of Hotair inhibited proliferation and enhanced apoptosis of Tu212 and Hep-2 cell lines in vitro. Moreover, the overexpression of hsa-miR-30a-5p inhibited the expression of GRP78 and PD-L1, but Hotair overexpression in LSCC cells rescues both proteins. Furthermore, the impacts of hsa-miR-30a-5p upregulation on the apoptosis and proliferation of LSCC cells were rescued by overexpression of Hotair. Finally, we combined si-Hotair and a VEGF inhibitor to treat LSCC cells in vitro or in vivo and surprisingly observed a significant inhibition of LSCC growth. In summary, these results indicate that Hotair displays an oncogenic role in both malignancy and immune escape in LSCC related to hsa-miR-30a-5p/GRP78/PD-L1 signaling. Therefore, Hotair may be a potential target for treating LSCC.

It is inevitable that reclaimed cotton stalks will contain a certain amount of plastic film due to the wide application of plastic mulching during the process of cotton cultivation, and this makes it inappropriate to return it to the field or for it to be processed into silage. In this study, biochars were prepared by the co-pyrolysis of cotton stalk with low-density polyethylene (LDPE) in the proportions of 1:0, 3:1, 2:1, and 1:1 (w/w) at 400 °C, 450 °C, and 500 °C and maintaining them for 1 h. The effects of the co-pyrolysis of cotton stalk with LDPE on the properties of biochars (e.g., pH, yield, elemental analysis, specific surface area, etc.) and the Pb(II) removal capacity were analyzed. Co-pyrolysis cotton stalks with LDPE could delay the decomposition of LDPE but could promote the decomposition of cotton stalk. At 400 °C and 450 °C, the addition of LDPE decreased the H/C ratio, while no significant difference was found between the pristine biochar and the blended biochar pyrolyzed at 500 °C. An FTIR analysis indicated that the surface functional groups of biochar were not affected by the addition of LDPE, except for CH3 and CH2. The results of the SEM showed that LDPE could cover the surface of biochar when pyrolyzed at 400 °C, while many macropores were found in the blended biochar that was pyrolyzed at 450 °C and 500 °C, thus increasing its surface area. The blended biochar that was pyrolyzed at 500 °C was more effective in the removal of Pb(II) than the cotton-stalk-derived biochar, which was dominated by monolayer adsorption with a maximum adsorption capacity of approximately 200 mg·g−1. These results suggested that the co-pyrolysis of cotton stalks and LDPE may be used to produce biochar, which is a cost-effective adsorbent for heavy metal removal from aqueous solutions.

Glioblastoma (GBM) is one of the most frequent primary malignant brain tumors with a poor prognosis. Unfortunately, due to the intrinsic or acquired chemoresistance of GBM cells, it easily becomes refractory disease and tumors are easy to recur. Therefore, it is critical to elucidate the molecular mechanisms underlying the chemoresistance of GBM cells to discover more efficient therapeutic treatments. Kinesin family member C1 (KIFC1) is a normal nonessential kinesin motor that affects the progression of multiple types of cancers. However, whether KIFC1 have a function in GBM is still unexplored. Here we found that KIFC1 was upregulated in human temozolomide (TMZ)-resistant GBM tissues. KIFC1 silencing is sufficient to inhibit GBM cell proliferation and amplify TMZ-induced repression of cell proliferation. Mechanistically, KIFC1 silencing contributed to DNA damage, cell cycle arrest, and apoptosis through regulating Rad51, Akt, and DNA-PKcs phosphorylation. We also noticed that KIFC1 silencing also inhibited tumor formation and increased TMZ sensitivity through regulating Ki67, Rad51, γ-H2AX, and phosphorylation of AKT in vivo . Our findings therefore confirm the involvement of KIFC1 in GBM progression and provide a novel understanding of KIFC1-Akt axis in the sensitivity of GBM to chemotherapy.

Biomaterial mediated bone regeneration is an attractive strategy for bone defect treatment. Organic/inorganic composites have been well established as effective bone graft. Here, the bone regenerative effect of the composites made from tannic acid (TA) modified hydroxyapatite (HA) (THA) or TA & silver nanoparticles (Ag NPs) modified HA (Ag-THA) and polyurethane (PU) was evaluated on critical-sized calvarial defects in rats. The in vivo study indicates that PU/THA and PU/Ag-THA scaffolds exhibited acceptable biocompatibility and induced significantly enhanced bone mineral densities comparing with the blank control (CON) group as well as PU/HA group. The inclusion of TA on HA brought the composites with enhanced osteogenesis and angiogenesis, evidenced by osteocalcin (OCN) and vascular endothelial growth factor (VEGF) immunohistochemical staining. Tartrate resistant acid phosphatase (TRAP) staining showed high osteoclast activity along with osteogenesis, especially in PU/THA and PU/Ag-THA groups. However, further introduction of Ag NPs on HA depressed the angiogenesis of the composites, leading to even lower VEGF expression than that of CON group. This study once more proved that THA can serve as a better bone composite component that pure HA and can promote osteogenesis and angiogenesis. While, the introduction of antimicrobial Ag NPs on HA need to be controlled in some extent not to affect the angiogenesis of the composites.

Accumulating evidence suggests that miR-483−3p is implicated in maintaining biological properties in human cancers. However, its biological roles in rheumatoid arthritis (RA) remain unknown. miR-483−3p levels in synovial tissue samples and fibroblast-like synoviocytes (FLSs) were determined using quantitative real-time PCR. The CCK-8 assay and EdU staining were performed to assess cell proliferation in RA FLSs after transfection with miR-483−3p mimics or inhibitor. Flow cytometry with Annexin V-FITC staining or PI staining was performed to assess apoptosis or cell cycle progression in RA FLSs, respectively. miR-483−3p was upregulated in RA, which markedly promoted cell proliferation, induced the G0/G1-to-S phase transition, and suppressed apoptosis in RA FLSs, whereas miR-483−3p silencing yielded opposite results. Moreover, insulin growth factor 1 (IGF-1) was detected as a direct miR-483−3p target. IGF-1 silencing partially restored cell proliferation, the G0/G1-to-S phase transition, and apoptosis suppression in RA FLSs via miR-483−3p inhibition. Our results showed that miR-483−3p promotes RA FLSs proliferation by targeting IGF-1, suggesting a potential strategy for diagnostic and treatment strategy for RA.

LncRNA NEAT1 functions as an oncogene in multiple human cancers. However, its expression and role in fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) remain unclear. Thus, we investigated the expression of NEAT1 in synovial tissues and FLSs in RA, to determine its role in the development of RA. Quantitative real-time polymerase chain reaction was used to measure the expression of NEAT1. FLS proliferation was evaluated using cell proliferation assays. Flow cytometry was used to analyze cell cycle progression and apoptosis in FLSs. Binding between NEAT1 and miR-410-3p was demonstrated by dual-luciferase assays. We found that NEAT1 was upregulated in synovial tissues and FLSs in RA. Upregulation of NEAT1 promoted cell proliferation, induced S-to G2/M phase transition, and suppressed apoptosis in RA FLSs. NEAT1 directly bound to and negatively modulated miR-410-3p expression, while positively regulating YinYang 1(YY1; a miR-410-3p target). Inhibiting miR-410-3p and upregulating YY1 partially restored the inhibitory role in cell viability induced by the depletion of NEAT1 in RA FLSs. Besides pro-proliferative and anti-apoptotic roles, upregulation of NEAT1 promoted migration, invasion, and inflammatory cytokines secretion in RA FLSs. Taken together, our results suggest that the NEAT1 may serve as a novel diagnostic and therapeutic target for patients with RA.

The complete mitochondrial genome of the leafhopper Parathailocyba orla (Dworakowska, ) was sequenced and annotated in this study. The mitochondrial genome is 15,382 bp long, and nucleotide composition of the whole mitogenome is highly A + T biased (A: 45.8%, T: 33.3%, G: 8.6%, C: 12.3%). 12 PCGs have ATN as the start codon, except for atp8 gene uses TTG. All protein-coding genes used TAA as stop codon, except for nad5, cox2 and cox3, which use incomplete T–– as stop codon. Phylogenetic analysis using 13 PCGs showed that P. orla was clustered with three Typhlocybinae species, which was consistent with the conventional classification.

The complete mitochondrial genome of the leafhopper species Paraahimia luodianensis was sequenced and annotated. It is 16,497 bp in length and consists of 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two rRNA genes, and one AT-rich region. Most of PCGs started with ATN and stopped with TAA, except for ATP8 started with TTG, COX2, COX3, NAD5, and NAD1 used incomplete T–– as a stop codon. We constructed a phylogenetic tree from 12 species (Hemiptera) based on neighbour-joining method and using 13 mitochondrial protein-coding genes. The result showed that both species of Limassolla lingchuanensis and P. luodianensis which belonging to Zyginellini were clustered into one clade. This study further enriched mitogenome database of the tribe Zyginellini.

The complete mitochondrial genome of the leafhopper Limassolla lingchuanensis was determined. It is 15,716 bp in length and consists of 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 rRNA genes, and a putative control region. ATN and TTG were initiation codons, and TAA, TAG, and T were termination codons. The phylogenetic relationships based on the neighbor-joining method were revealed using 13 PCGs with 10 leafhopper species of family Cicadellidae, which agree with the conventional taxonomy.

The complete mitogenome of Mitjaevia protuberanta (GenBank accession number MN627216) is 14,032 bp (AT: 77.43%) in length, including 13 protein-coding, 22 transfer RNAs, and 2 ribosomal RNAs. All protein-coding genes used ATN as initiation codon except ND5 that used TTG as initiation codon, and TAA, TAG, and T were termination codons. We constructed a phylogenetic tree from 14 species (Hemiptera) based on the nucleotide sequence of 13 mitochondrial protein-coding genes. The phylogenetic analysis results showed that mitochondrial genome of M. protuberanta had the same characteristics as other Cicadellidae species.

Background: Soft tissue sarcomas (STS) are heterogeneous tumors derived from mesenchymal cells that differentiate into soft tissues. The prognosis of patients who present with an STS is influenced by the regulation of a complex gene network.Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with STS (Samples = 156).Results: Among the 11 modules identified, the black and blue modules were highly correlated with STS. However, using preservation analysis, the black module demonstrated low preservation, therefore the blue module was chosen as the module of interest. Furthermore, a total of 20 network hub genes were identified in the blue module, 12 of which were also hub nodes in the protein-protein interaction network of the module genes. Following additional verification, 4 of 12 genes (RRM2, BUB1B, CENPF, and KIF20A) demonstrated poorer overall survival and disease-free survival rate in the test datasets. In addition, gene set enrichment analysis (GSEA) demonstrated that samples with a high level of blue module eigengene (ME) were enriched in cell cycle and metabolism associated signaling pathways.Conclusion: In summary, co-expression network analysis identified four hub genes associated with prognosis for STS, which may diminish the prognosis by influencing cell cycle and metabolism associated signaling pathways.

Ankyrin repeat (ANK) C3HC4-type RING finger (RF) genes comprise a large family in plants and play important roles in various physiological processes of plant life. In this study, we identified 187 ANK C3HC4-type RF proteins from 29 species with complete genomes and named the ANK C3HC4-type RF proteins the XB3-like proteins because they are structurally related to the rice (Oryza sativa) XB3. A phylogenetic relationship analysis suggested that the XB3-like genes originated from ferns, and the encoded proteins fell into 3 major groups. Among these groups, we found that the spacing between the metal ligand position 6 and 7, and the conserved residues, which was in addition to the metal ligand amino acids, in the C3HC4-type RF were different. Using a wide range of protein structural analyses, protein models were established, and all XB3-like proteins were found to contain two to seven ANKs and a C3HC4-type RF. The microarray data for the XB3-like genes of Arabidopsis, Oryza sative, Zea mays and Glycine max revealed that the expression of XB3-like genes was in different tissues and during different life stages. The preferential expression of XB3-like genes in specified tissues and the response to phytohormone and abiotic stress treatments of Arabidopsis and Zea mays not only confirmed the microarray analysis data but also demonstrated that the XB3-like proteins play roles in plant growth and development as well as in stress responses. Our data provide a very useful reference for the identification and functional analysis of members of this gene family and also provide a new method for the genome-wide analysis of gene families.

Protein S-acyltransferases (PATs) containing Asp-His-His-Cys within a Cys-rich domain (DHHC-CRD) are polytopic transmembrane proteins that are found in eukaryotic cells and mediate the S-acylation of target proteins. S-acylation is an important secondary and reversible modification that regulates the membrane association, trafficking and function of target proteins. However, little is known about the characteristics of PATs in plants. Here, we identified 804 PATs from 31 species with complete genomes. The analysis of the phylogenetic relationships suggested that all of the PATs fell into 8 groups. In addition, we analysed the phylogeny, genomic organization, chromosome localisation and expression pattern of PATs in Arabidopsis, Oryza sative, Zea mays and Glycine max. The microarray data revealed that PATs genes were expressed in different tissues and during different life stages. The preferential expression of the ZmPATs in specific tissues and the response of Zea mays to treatments with phytohormones and abiotic stress demonstrated that the PATs play roles in plant growth and development as well as in stress responses. Our data provide a useful reference for the identification and functional analysis of the members of this protein family.