Simultaneous realization of high gain and low DMG of four-mode EDFA under bidirectional hybrid-mode pump.

We theoretically and experimentally verify that, the bidirectional hybrid-mode pumping scheme can address the optimization problem of trade-off between high gain and low differential modal gain (DMG) of four-mode erbium-doped fiber amplifier (4M-EDFA), in comparison with traditional both forward and backward hybrid-mode pumping scheme. It is noticed that, when the total pump power is fixed, the bidirectional hybrid-mode pumping scheme can not only achieve higher gain, but also suppress DMG due to different overlap integrals for the forward and backward pumping schemes. The bidirectional hybrid-mode pumped 4M-EDFA is developed with the forward pumping at LP02 mode and the backward pumping at LP21 mode, under a pump power ratio of 30%:70%. Thus, we can achieve an average gain of up to 21.16 dB and a low DMG of 0.43 dB at 1550 nm, and an average gain of up to 20.64 dB with a DMG of less than 1.6 dB over the C-band. In particular, the bidirectional hybrid-mode pumping scheme allows us to tailor the gain characteristics of the few-mode erbium-doped fiber amplifiers (FM-EDFAs), by adjusting the power ratio between forward and backward pumps.

Alleviatory Role of Panax Notoginseng Saponins in Modulating Inflammation and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease: mechanisms and Implications.

COPD is an inflammatory lung disease that limits airflow and remodels the pulmonary vascular system. This study delves into the therapeutic potential and mechanistic underpinnings of Panax notoginseng Saponins (PNS) in alleviating inflammation and pulmonary vascular remodeling in a COPD rat model. Symmap and ETCM databases provided Panax notoginseng-related target genes, and the CTD and DisGeNET databases provided COPD-related genes. Intersection genes were subjected to protein-protein interaction analysis and pathway enrichment to identify downstream pathways. A COPD rat model was established, with groups receiving varying doses of PNS and a Roxithromycin control. The pathological changes in lung tissue and vasculature were examined using histological staining, while molecular alterations were explored through ELISA, RT-PCR, and Western blot. Network pharmacology research suggested PNS may affect the TLR4/NF-κB pathway linked to COPD development. The study revealed that, in contrast to the control group, the COPD model exhibited a significant increase in inflammatory markers and pathway components such as TLR4, NF-κB, HIF-1α, VEGF, ICAM-1, SELE mRNA, and serum TNF-α, IL-8, and IL-1ß. Treatment with PNS notably decreased these markers and mitigated inflammation around the bronchi and vessels. Taken together, the study underscores the potential of PNS in reducing lung inflammation and vascular remodeling in COPD rats, primarily via modulation of the TLR4/NF-κB/HIF-1α/VEGF pathway. This research offers valuable insights for developing new therapeutic strategies for managing and preventing COPD.

Non-orthogonal optical multiplexing empowered by deep learning.

Orthogonality among channels is a canonical basis for optical multiplexing featured with division multiplexing, which substantially reduce the complexity of signal post-processing in demultiplexing. However, it inevitably imposes an upper limit of capacity for multiplexing. Herein, we report on non-orthogonal optical multiplexing over a multimode fiber (MMF) leveraged by a deep neural network, termed speckle light field retrieval network (SLRnet), where it can learn the complicated mapping relation between multiple non-orthogonal input light field encoded with information and their corresponding single intensity output. As a proof-of-principle experimental demonstration, it is shown that the SLRnet can effectively solve the ill-posed problem of non-orthogonal optical multiplexing over an MMF, where multiple non-orthogonal input signals mediated by the same polarization, wavelength and spatial position can be explicitly retrieved utilizing a single-shot speckle output with fidelity as high as ~ 98%. Our results resemble an important step for harnessing non-orthogonal channels for high capacity optical multiplexing.

AsOBP1 is required for bioallethrin repellency in the malaria vector mosquito Anopheles sinensis.

The use of insecticides, primarily pyrethroids, is a pivotal strategy for mosquito control globally. Bioallethrin, the first commercially available volatile pyrethroid, can elicit spatial (i.e., noncontact) repellency to mosquitoes through the coactivation of olfactory receptor neurons and sodium channels. However, the olfactory mechanism of the repellency elicited by bioallethrin in mosquitoes is still unclear. Here, we demonstrated the involvement of AsOBP1 in the bioallethrin repellency in Anopheles sinensis, one of the main vectors of vivax malaria in China and other Southeast Asian countries. The behavioral and electrophysiological analyses in AsOrco-/- mutant found that the spatial repellency elicited by bioallethrin depended on the odorant receptor (OR)-mediated olfactory pathway. Furthermore, the repellency was reduced in the AsOBP1-/- mutant and a pyrethroid-resistant strain, in which the expression of AsOBP1 was significantly decreased. Moreover, recombinant AsOBP1 protein bound to bioallethrin in an in vitro competition assay. These results indicate that activation of the AsOBP1-mediated olfactory pathway is an important component of bioallethrin repellency. Our research lays the foundation for further elucidation into the olfactory mechanism of bioallethrin repellency and the behavioral modifications of pyrethroid-resistant mosquitoes.

Implications of left atrial volume index in patients with three-vessel coronary disease: A 6.6-year follow-up cohort study.

BACKGROUND: Risk assessment and treatment stratification for three-vessel coronary disease (TVD) remain challenging. This study aimed to investigate the prognostic value of left atrial volume index (LAVI) with the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score II, and its association with the long-term prognosis after three strategies (percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], and medical therapy [MT]) in patients with TVD. METHODS: This study was a post hoc analysis of a large, prospective cohort of patients with TVD in China, that aimed to determine the long-term outcomes after PCI, CABG, or optimal MT alone. A total of 8943 patients with TVD were consecutively enrolled between 2004 and 2011 at Fuwai Hospital. A total of 7818 patients with available baseline LAVI data were included in the study. Baseline, procedural, and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which was a composite of all-cause death, myocardial infarction (MI), and stroke. Secondary endpoints included all-cause death, cardiac death, MI, revascularization, and stroke. Long-term outcomes were evaluated among LAVI quartile groups. RESULTS: During a median follow-up of 6.6 years, a higher LAVI was strongly associated with increased risk of MACCE (Q3: hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.06-1.37, P = 0.005; Q4: HR 1.85, 95%CI 1.64-2.09, P <0.001), all-cause death (Q3: HR 1.41, 95% CI 1.17-1.69, P <0.001; Q4: HR 2.54, 95%CI 2.16-3.00, P <0.001), and cardiac death (Q3: HR 1.81, 95% CI 1.39-2.37, P <0.001; Q4: HR 3.47, 95%CI 2.71-4.43, P <0.001). Moreover, LAVI significantly improved discrimination and reclassification of the SYNTAX score II. Notably, there was a significant interaction between LAVI quartiles and treatment strategies for MACCE. CABG was associated with lower risk of MACCE than MT alone, regardless of LAVI quartiles. Among patients in the fourth quartile, PCI was associated with significantly increased risk of cardiac death compared with CABG (HR: 5.25, 95% CI: 1.97-14.03, P = 0.001). CONCLUSIONS: LAVI is a potential index for risk stratification and therapeutic decision-making in patients with three-vessel coronary disease. CABG is associated with improved long-term outcomes compared with MT alone, regardless of LAVI quartiles. When LAVI is severely elevated, PCI is associated with higher risk of cardiac death than CABG.

TRIM24-Mediated Acetylation of STAT6 Suppresses Th2-Induced Allergic Rhinitis.

PURPOSE: Allergic rhinitis (AR) is a T helper type 2 (Th2)-mediated inflammatory disease. The E3 ligase tripartite motif-containing 24 (TRIM24) regulates the recruitment of acetyltransferase CREB-binding protein (CBP) to signal transducer and activator of transcription 6 (STAT6). CBP mediates the acetylation of STAT6 and decreases its activity. To date, the precise role of TRIM24 in AR has not been fully interpreted. Herein, our study aimed to explore the functions of TRIM24 in AR. METHODS: The expression of TRIM24 in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from patients with AR was measured. TRIM24-conditional knockout mice with TRIM24 deficiency in CD4+ T cells were generated. Wide-type (WT) AR mice and TRIM24-conditional knockout AR mice were established. Then, AR symptoms and interleukin (IL)-4 levels were compared. Further, the proliferation, activation and polarization of CD4+ T cells from WT mice and TRIM24 knockout mice after stimulation were determined. The effects of TRIM24 deficiency on STAT6 activities were also evaluated. RESULTS: Downregulated TRIM24 expression was detected in PBMCs and CD4+ T cells from patients with AR. TRIM24 conditional knockout mice had more sever AR symptoms with elevated IL-4 production. TRIM24-knockout CD4+ T cells had similar proliferation and activation when compared to WT CD4+ T cells, while they had enhanced Th2 polarization. TRIM24-knockout CD4+ T cells had decreased acetylation of STAT6 and enhanced STAT6 activities after IL-4 stimulation. The regulation of STAT6 activities by TRIM24 depended on TRIM24 N terminal RIGN domain and Lys383 acetylation site of STAT6. CONCLUSIONS: TRIM24 suppresses Th2-mediated AR by regulating the acetylation of STAT6.

For patients with prior coronary artery bypass grafting and recurrent myocardial ischemia, percutaneous coronary intervention on bypass graft or native coronary artery?-A 5-year follow-up cohort study.

BACKGROUND: Real-world data on target vessel of percutaneous coronary intervention (PCI) for patients with prior coronary artery bypass grafting (CABG) was still limited. HYPOTHESIS: A prospective cohort was examined to determine the frequency and outcomes of native coronary artery PCI versus bypass graft PCI in patients with prior CABG. METHODS: A large-sample observational study enrolled a total of 10 724 patients with coronary artery disease (CAD) underwent PCI in 2013. Two- and five-year clinical outcomes were compared between graft PCI group and native artery PCI group in patients with prior CABG. RESULTS: A total of 438 cases had CABG history in the total cohort. Graft PCI group and native artery PCI group accounted for 13.7% and 86.3%, respectively. The rates of 2- and 5-year all-cause death and major adverse cardiovascular and cerebral events (MACCE) showed no significant difference between the two groups (p > .05). Two-year revascularization risk was lower in graft PCI group than native artery PCI group (3.3% and 12.4%, p < .05), but 5-year myocardial infarction (MI) risk was higher (13.3% and 5.0%, p < .05). In multivariate COX regression models, graft PCI group was independently associated with lower 2-year revascularization risk (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.05-0.88; p = .033), but higher 5-year MI risk than native artery PCI group (HR: 2.61; 95% CI: 1.03-6.57; p = .042). Five-year all-cause death and MACCE risk showed no difference between the two groups in model. CONCLUSIONS: In patients with prior CABG underwent PCI, patients in graft PCI group had higher 5-year MI risk than patients received native artery PCI. But, 5-year mortality and MACCE was not significantly different between graft PCI group and native artery PCI group.

Reconfigurable ultra-broadband mode converter based on a two-mode fiber with pressure-loaded phase-shifted long-period alloyed waveguide grating.

We present a reconfigurable ultra-broadband mode converter, which consists of a two-mode fiber (TMF) and pressure-loaded phase-shifted long-period alloyed waveguide grating. We design and fabricate the long-period alloyed waveguide gratings (LPAWG) with SU-8, chromium, and titanium via the photo-lithography and electric beam evaporation technique. With the help of the pressure loaded or released from the LPAWG onto the TMF, the device can realize reconfigurable mode conversion between the LP01 mode and the LP11 mode in the TMF, which is weak sensitive to the state of polarization. The mode conversion efficiency larger than 10 dB can be achieved with operation wavelength range of about 105 nm, which ranges from 1501.9 nm to 1606.7 nm. The proposed device can be further used in the large bandwidth mode division multiplexing (MDM) transmission and optical fiber sensing system based on few-mode fibers.

Three-dimensional mode multiplexer based on adiabatic-tapered waveguides forming vertical directional couplers over C + L band and beyond.

We present a mode multiplexer based on vertical directional couplers that are formed by adiabatic-tapered waveguides. We design and fabricate the device via the micro-fabrication processing to (de)multiplex the E11, E21, and E12 modes from the few-mode bus waveguide. Our experimental device shows a coupling ratio higher than 98.6% and 97.0% for the E21 and E12 modes, respectively, over the C + L band and beyond. The modal cross talk of this device can be lower than -17.1 dB, -18.4 dB, and -15.1 dB caused by the unintended E11, E21, and E12 modes, respectively. This mode multiplexer can work over a broader wavelength range with weak polarization sensitivity, which could be used in the mode-division-multiplexing systems where mode (de)multiplexing is required in the expanded communication wavelength window other than the C-band.

Diagnostic Methods of Global Developmental Delay Caused by 10q24.3 Heterozygous Loss： A Case Discussion / 中山大学学报(医学科学版)

ObjectiveTo discuss the diagnostic methods of global developmental delay caused by 10q24.3 heterozygous loss. MethodsA retrospective analysis was conducted on the clinical data of one child with global developmental delay， and the results of low depth whole-genome copy number variation sequencing （CNVseq） and family whole exome sequencing （WES） of the child and his parents. ResultsThe patient was a 10-month-old male with developmental retardation in four areas， with some special features （ocular hypertelorism， strabismus， flat nose bridge， protruding forehead， cleft palate， high palatal arch， etc.） and hypotonia of limbs. The CNVseq and WES test showed that the patient had new 10q24.3 heterozygosis loss. Because this region contains the gene SUFU associated with basal cell nevus syndrome and the gene CNNM2 associated with hypomagnesemia， seizures， and mental retardation， and the gene TRIM8 associated of Focal segmental glomerulosclerosis with neurodevelopmental syndrome， we speculated that the cause of the disease in the child was highly related to the heterozygosity deletion of SUFU gene and CNNM2 gene and TRIM8 gene. ConclusionGenetic testing should be improved as soon as possible for children with global developmental delay and special facial manifestations， so as to make clear diagnosis and to judge prognosis.

Intensity-interrogated hot-wire anemometer based on chirp effect of a fiber Bragg grating.

An intensity-interrogated optical fiber hot-wire anemometer based on the chirp effect of fiber Bragg grating (FBG) is presented. The FBG is coated with a silver film and heated optically by a 1480 nm laser beam, which is coupled into the fiber cladding by a long-period grating (LPG) and absorbed by the silver film to convert to thermal heat. Due to the gradual decrease of laser power along the length of the FBG, a temperature gradient is formed that induces a chirp effect to the FBG. Bandwidth of the FBG's reflection spectrum is therefore broadened that increases its reflected light power. The chirp rate of the FBG reduces with airflow velocity since the temperature gradient is weakened under the cooling effect of the airflow, resulting in a certain relationship between the reflected power of the FBG and airflow velocity. In the experiment, by detecting the reflected power of the FBG, airflow velocity measurement is achieved successfully with a high sensitivity up to -28.60 µW/(m·s-1) at airflow velocity of 0.1 m/s and a dynamic response time of under one second. The measurement range is up to 0 to 11 m/s. The intensity interrogation scheme of the FBG hot-wire anemometer reduces its cost greatly and makes it a promising solution for airflow velocity measurement in practical applications.

The Use of Thromboelastography in Percutaneous Coronary Intervention and Acute Coronary Syndrome in East Asia: A Systematic Literature Review.

Dual antiplatelet therapy (DAPT), alongside percutaneous coronary intervention (PCI), is central to the prevention of ischemic events following acute coronary syndrome (ACS). However, response to therapy can vary due to several factors including CYP2C19 gene variation, which shows increased prevalence in East Asian populations. DAPT responsiveness can be assessed using techniques such as light transmission aggregometry (LTA), VerifyNow® and thromboelastography with the PlateletMapping® assay, and there is increasing focus on the utility of platelet function testing to guide individualized treatment. This systematic literature review of one English and three Chinese language databases was conducted to evaluate the evidence for the utility of thromboelastography in ACS/PCI in East Asia. The search identified 42 articles from the English language and 71 articles from the Chinese language databases which fulfilled the pre-determined inclusion criteria, including 38 randomized controlled trials (RCTs). The identified studies explored the use of thromboelastography compared to LTA and VerifyNow in monitoring patient responsiveness to DAPT, as well as predicting ischemic risk, with some studies suggesting that thromboelastography is better able to detect low DAPT response than LTA. Other studies, including one large RCT, described the use of thromboelastography in guiding the escalation of DAPT, with some evidence suggesting that such protocols reduce ischemic events without increasing the risk of bleeding. There was also evidence suggesting that thromboelastography can be used to identify individuals with DAPT hyporesponsiveness genotypes and could potentially guide treatment by adjusting therapy in patients depending on responsiveness.

Ring core few-mode fiber sensor for curvature measurement.

An all-fiber Mach-Zehnder interferometer (MZI) using ring core few-mode fiber (RC-FMF) for curvature sensing is proposed and experimentally demonstrated. The MZI was fabricated by splicing a segment of RC-FMF between two pieces of single-mode fiber (SMF). With the benefit of a RC of the central axis of the RC-FMF, the sensor is more sensitive to curvature compared to other fiber sensors based on ordinary SMF or FMF. Curvature measurement can be achieved by monitoring the wavelength shift of interference dips. Experimental results have shown that the sensitivity of curvature sensing can reach up to -4.370nm/m-1, within the range of 1.199-1.549m-1. Also, the temperature sensing characteristics of the sensor are measured, and the maximum temperature sensitivity is 57.6 pm/°C, ranging from 25°C to 45°C. The proposed MZI sensor has excellent potential for curvature measurement of building structural health monitoring, bridge engineering, and more.

Ultra-broadband LP11 mode converter with high purity based on long-period fiber grating and an integrated Y-junction.

We report an ultra-broadband LP11 mode converter with high purity based on integrated two shunt-wound long-period fiber gratings (LPFGs) and an adiabatic Y-junction, together with a high-order-mode bandpass filter. Two shunt-wound LPFGs are inscribed by CO2 laser in a two-mode fiber to achieve a 10 dB bandwidth of 50 nm and 51 nm at resonance wavelengths of 1530 nm and 1570 nm, respectively. Meanwhile, the Y-junction fabricated by lithography can be operated over S + C+L band to combine the converted LP11 mode. The presented ultra-broadband mode converter is able to achieve a mode conversion efficiency of 95%, together with a wavelength-dependent loss of less than 3 dB over the S + C+L band. This device has low modal crosstalk of 17 dB between the LP01 and LP11 modes, because most of the residual LP01 mode is further filtered by a high-order-mode bandpass filter at the output port of the Y-junction. The insertion loss of mode converter is estimated to be lower than 2.7 dB, due to the use of low loss polymer material during the fabrication. The proposed ultra-broadband LP11 mode converter with high purity is promising for the application of ultra-broadband mode-division-multiplexing transmission systems.

Long-term effects of baseline on-treatment platelet reactivity in patients with acute coronary syndrome and thrombocytopenia undergoing percutaneous coronary intervention.

OBJECTIVE: To analyse the association between on-treatment platelet reactivity (TPR) and long-term outcomes of patients with acute coronary syndrome (ACS) and thrombocytopenia (TP) in the real world. METHODS: This prospective observational study enrolled patients with coronary artery disease (CAD) that underwent percutaneous coronary intervention (PCI). Patients with ACS and TP under dual antiplatelet therapy were selected for analysis. The 2- and 5-year clinical outcomes were evaluated among patients with high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) and normal on-treatment platelet reactivity (NTPR), as tested by thromboelastogram at baseline. RESULTS: A total of 10 724 patients with CAD that underwent PCI were identified. Of these, 474 patients with ACS and TP met the inclusion criteria: 124 (26.2%) with HTPR, 163 (34.4%) with LTPR and 187 (39.5%) with NTPR. The 5-year rates of all-cause death, major adverse cardiovascular and cerebrovascular events, cardiac death, myocardial infarction, revascularization, stroke and bleeding were not significantly different among the three groups. Multivariate Cox regression analysis demonstrated that patients with HTPR were not independently associated with any of the 5-year endpoints compared with patients with NTPR. CONCLUSIONS: TPR at baseline was not independently associated with long-term outcomes in patients with ACS and TP that underwent PCI.

All-optical light manipulation based on graphene-embedded side-polished fiber.

We present a study of all-optical light manipulation arising in a graphene-embedded side-polished fiber (SPF) with a Norland Optical Adhesives (NOA)-coated structure. With the help of the Pauli blocking effect, such an all-fiber device serves to manage the loss of transverse-electric-polarized light when the control light and the signal light are polarized along the direction parallel to the graphene surface. The insertion loss of this device can be effectively reduced with the NOA coating. An enhanced interaction between the graphene and the propagated light can be achieved via the strong evanescent field of the SPF and longer interaction length. This results in effective all-optical manipulation of light with a modulation depth of 10.4 dB (or modulation efficiency of ∼91%) and a modulation slope of ∼1.3, where the required control power is only about 14 dBm. The device has broadband operation wavelength. The insertion loss for both the signal light and the control light are only about 0.6 dB. The experimental results are well-fitting with the simulation study. Such an all-fiber device has the potential for all-optical signal processing.

High mobility group box 1 inhibition by BoxA attenuates ovalbumin-induced allergic rhinitis in mice.

This study was designed to evaluate the effects of BoxA on allergic rhinitis (AR). Ovalbumin (OVA)-induced AR mice model was employed and BoxA was administered to AR mice. AR symptoms, levels of cytokines and chemokines, and the expression of high mobility group box 1 (HMGB1), TLR2, and TLR4 were measured. BoxA treatment significantly ameliorated AR symptoms, decreased level of histamine, OVA-specific antibodies, suppressed the infiltration of immune cells in nasal tissues, inhibited the expression of IL-4, IL-6, IL-5, TNF-α, IL-13, IL-17, IL-2 while promoting the expression of IL-10, suppressed the expression of HMGB1, TLR2, and TLR4 in AR mice. BoxA ameliorated allergic rhinitis in mice by inhibiting HMGB1.

Low Power Consuming Mode Switch Based on Hybrid-Core Vertical Directional Couplers with Graphene Electrode-Embedded Polymer Waveguides.

We propose a mode switch based on hybrid-core vertical directional couplers with an embedded graphene electrode to realize the switching function with low power consumption. We designed the device with Norland Optical Adhesive (NOA) material as the guide wave cores and epoxy polymer material as cladding to achieve a thermo-optic switching for the E11, E21 and E12 modes, where monolayer graphene served as electrode heaters. The device, with a length of 21 mm, had extinction ratios (ERs) of 20.5 dB, 10.4 dB and 15.7 dB for the E21, E12 and E11 modes, respectively, over the C-band. The power consumptions of three electric heaters were reduced to only 3.19 mW, 3.09 mW and 2.97 mW, respectively, and the response times were less than 495 µs, 486 µs and 498 µs. Additionally, we applied such a device into a mode division multiplexing (MDM) transmission system to achieve an application of gain equalization of few-mode amplification among guided modes. The differential modal gain (DMG) could be optimized from 5.39 dB to 0.92 dB over the C-band, together with the characteristic of polarization insensitivity. The proposed mode switch can be further developed to switch or manipulate the attenuation of the arbitrary guided mode arising in the few-mode waveguide.

10-W power light co-transmission with optically carried 5G NR signal over standard single-mode fiber.

Efficient co-transmission of 10-W power light and optically carried 5G new radio (NR) signal over standard single-mode fiber (SSMF) is experimentally demonstrated, with an optical power transmission efficiency (OPTE) of power light up to 71.8%. This efficiency record is enabled by carefully manipulating the linewidth of the power light and appropriately adjusting the wavelength spacing between the power light and 5G NR optical signal to effectively mitigate the nonlinear effect arising in the SSMF. In the experiment, the optically carried 5G NR 64-level quadrature amplitude modulation orthogonal frequency division multiplexing signal at 1550 nm, with a data rate of 1.5 Gbit/s, is successfully co-propagated with 10-W power light at 1064 nm over 1-km SSMF. The error-vector magnitude (EVM) is 0.48% under a received electrical power of -25dBm. In comparison with back-to-back transmission, only slight EVM degradation of 0.02% is observed, showing that the 5G NR optical signal is almost unaffected by the existence of power light. Moreover, the power fluctuation of the collected power light is less than 0.2% over 6 h, while the EVM fluctuation is smaller than 0.01% within 30 min. Our scheme is promising to realize an optically powered remote antenna unit through the existing 5G fronthaul SSMF link.