Expert consensus on odontogenic maxillary sinusitis multi-disciplinary treatment

Odontogenic maxillary sinusitis (OMS) is a subtype of maxillary sinusitis (MS). It is actually inflammation of the maxillary sinus that secondary to adjacent infectious maxillary dental lesion. Due to the lack of unique clinical features, OMS is difficult to distinguish from other types of rhinosinusitis. Besides, the characteristic infectious pathogeny of OMS makes it is resistant to conventional therapies of rhinosinusitis. Its current diagnosis and treatment are thus facing great difficulties. The multi-disciplinary cooperation between otolaryngologists and dentists is absolutely urgent to settle these questions and to acquire standardized diagnostic and treatment regimen for OMS. However, this disease has actually received little attention and has been underrepresented by relatively low publication volume and quality. Based on systematically reviewed literature and practical experiences of expert members, our consensus focuses on characteristics, symptoms, classification and diagnosis of OMS, and further put forward multidisciplinary treatment decisions for OMS, as well as the common treatment complications and relative managements. This consensus aims to increase attention to OMS, and optimize the clinical diagnosis and decision-making of OMS, which finally provides evidence-based options for OMS clinical management.

Optimal interventional treatment for liver cancer:HAIC,TACE or iTACE?

Primary liver cancer is a common and lethal malignancy in China.Transcatheter arterial chemoembolization(TACE)is globally recognized as the preferred treatment modality for the non-surgical resection of hepatocellular carcinoma(HCC),while transcatheter arterial infusion(TAI)is another effective interventional treatment for HCC.In recent years,hepatic arterial infusion chemotherapy(HAIC)has gained increasing attention as an application-regulated modality for TAI.Owing to the current debate in the medical community regarding the use of HAIC and TACE for the treatment of HCC,the application of both approaches should be considered at a higher level,with a broader perspective and a more normative aspect.Accordingly,we aimed to define the rational combination of liver cancer TAI/HAIC with TACE as infusion transcatheter chemoembolization(iTACE),which suggests that the two interventions are not superior but lead to a mutually beneficial situation.In this review,we sought to discuss the development,specification,application,challenge and innovation,debate,and union of TAI/HAIC and TACE,and the clinical application and latest research on iTACE.We aimed to introduce new concepts of iTACE and expect new breakthroughs in the treatment of liver cancer owing to the combined use of the two major interventional tools.

神经节苷脂对脑外伤大鼠大脑皮质Nogo-A表达的影响

目的:观察神经节苷脂(GM1)对脑外伤大鼠大脑皮质中Nogo-A表达的影响,探讨GM1促进脑外伤神经修复的可能机制。方法:采用SPF级SD大鼠100只,随机分为空白对照组(n=10)、假手术组(n=20)、损伤后生理盐水组(n=35)和损伤后GM1组(n=35)。通过HE染色观察各组大鼠脑组织不同时间点病理情况;用免疫组化的方法观察Nogo-A阳性细胞数量。结果:通过免疫组化的方法观察损伤后生理盐水组:Nogo-A阳性细胞在造模24时即明显升高,至72h时仍呈升高的趋势;GMl组:Nogo-A的阳性细胞数早期逐渐升高,至24h时数量最多,之后开始减少,应用GMl后,Nogo-A的阳性细胞数量的增加较为延后。结论:Nogo-A在颅脑损伤后其阳性细胞数量显著增高,抑制中枢神经损伤后的再生,神经节苷脂GM1在脑损伤后可部分抑制Nogo-A的表达,机制可能通过稳定细胞膜、减轻细胞水肿,从而发挥对实验性脑外伤大鼠的神经保护作用。

阴/阳离子化羟乙基纤维素十二烷基缩水甘油醚的制备与应用

介绍一锅法合成一种羧基化的羟乙基纤维素(HEC)十二烷基缩水甘油醚(CHECGE)和一种季铵化的HEC十二烷基缩水甘油醚(QAHECGE)。利用红外光谱(FT-IR)和核磁共振氢谱(1 H-NMR)对产物进行结构表征及平均取代度(DS)的测定。产物的流变性能表征结果表明,CHECGE具有比HEC更强的凝胶行为,在稳态剪切下的表观黏度较HEC有所提高。虽然QAHECGE的凝胶行为和表观黏度小于HEC,但假塑性明显较HEC有所提高。以所得产物及其复合物将橄榄油(20%)在水相中进行乳化,结果显示分别在CHECGE、QAHECGE和CHECGE/QAHECGE(质量比为1∶3)复合物体系乳化下,均能制备出稳定的乳液(超过15d放置)。因此所得产物可以作为一种新型的大分子乳化剂。

Portal vein embolization in the treatment of portal vein bleeding after percutaneous transhepatic biliary drainage: A case report and literature review

Percutaneous transhepatic biliary drainage(PTBD)is an effective treatment for benign and malignant obstructive jaundice.Major bleeding complications occur in approximately 2–3%of patients after PTBD,which can result in death.A case involving a 63-year-old male with malignant obstructive jaundice,who experienced severe bleeding after PTBD,is reported.Emergency digital subtraction angiography,celiac trunk artery and superior mesenteric artery angiography were performed;however,no signs of arterial bleeding were found.To identify etiology,portal venography was performed under ultrasound guidance and portal vein bleeding was diagnosed.Ultimately,selective portal vein embolization successfully stopped the bleeding.

LSSVM Predictive Control for Calcination Zone Temperature in Rotary Kiln with IHS Algorithm

The calcination zone temperature control is an important problem in rotary kiln production process. In order to solve this problem,a predictive control method based on improved harmony search algorithm( IHS)and least square support vector machine( LSSVM) is proposed. LSSVM is utilized to bulid the nonlinear predictive model of calcination zone temperature in rotary kiln. The calcination zone temperature can be predicted through input control variable,the error and error correction of output feedback. The performance index function is established by deviation and control variable. An IHS algorithm with better fitness and faster convergence speed is proposed. The optimal control variable can be obtained by rolling optimization through this IHS algorithm. The stability of this predictive control method is proved to be feasible. The simulation and actual experiment results show that the proposed predictive control method has good control performance.

Objectives of China and the global mental health work plan

In June 2015,the office of the State Council transmitted‘the national mental health plan(2015-2020)'(abbreviated as ‘Plan’)drafted by the National Health and Family Planning Commission,the central comprehensive management office,the Development and Reform Commission and ten other departments.[1]The Plan clearly proposed that the comprehensive management and coordination of mental health

Effects of Different Seedling Raising Substrates on Quality of Rice Seedlings

Five different seedling raising substrates were used to take the place of the nutrient soil to cultivate rice seedling mechanical transplanting in Anqing,Anhui Province.The emergence rate,survival rate,quality of aboveground parts of seedlings,root system and dry weight and fresh weight were surveyed and analyzed.The results showed that the rice seedling raising substrates could significantly improve the seedling quality and survival rate of mechanically transplanted seedlings,especially the seedling raising substrates produced by Anhui Province Lufu Agriculture Science and Technology Stock Co.,Ltd.and Anhui Anqing Yike Seedling Material Co.,Ltd.Finally,it is recommended to promote the seedling raising substrate in large area,to lay a solid foundation for realizing high yield,high quality,and high efficiency of rice.

Optimization of Supercritical CO_(2) Extraction of Curcumin by Response Surface Methodology and Its Antioxidant Activity

[Objectives]This study was conducted to establish a mathematical model for supercritical CO_(2) extraction of curcumin.[Methods]With ginger as the experimental raw material,a quadratic polynomial mathematical model of the yield of curcumin extracted by supercritical CO_(2) was established by response surface methodology(RSM).The validity of the mathematical model was verified,and the effects of extraction temperature(60-70℃),pressure(30-50 MPa)and time(70-90 min)on curcumin yield were analyzed.[Results]According to the model,the process parameters were optimized.Taking curcumin yield as the index,the optimal process conditions for supercritical CO_(2) extraction obtained were:temperature 62.6℃,pressure 37.7 MPa,time 82.9 min,under which the yield of curcumin was as high as 7.34%.Under the optimal extraction conditions,curcumin had a certain reducing capacity,and showed strong scavenging capacities to·OH,O_(2)^(-)·and DPPH,and its IC_(50) values were 9.40,9.03 and 8.04 mg/ml,respectively.Therefore,it is feasible to extract curcumin from ginger using supercritical CO_(2).[Conclusions]This study provides a theoretical basis for the development and utilization of curcumin.

深时重大生物和气候事件与全球变化:进展与挑战

地球自5.4亿年前现代生态系统形成至今,发生了多次与碳循环扰动有关的重大气候事件.这些事件的触发机制、发展过程、环境变化及其伴随的生物响应型式为科学评估当今全球变化背景下生物多样性现状提供重要借鉴.然而,古-今生态系统变化时间尺度大不相同,高分辨率关键环境因子(温度、CO_(2)、降雨量、海洋氧化还原条件等)在深时记录中亦难以获取,深时海陆生物多样性模式尚缺乏高分辨率记录.因此,当今全球变化与深时记录对比存在巨大鸿沟.地球5.4亿年以来大部分时间处于两极无冰的温室状态,期间伴随多次极冷和极热气候事件,但地球深时重大生物演化和气候事件的关系复杂.生物多样性在变冷的奥陶纪早期、晚古生代大冰期、晚新生代大冰期以及中-晚三叠世和白垩纪热室期均呈现稳定增加,而在奥陶纪末冰期快速降温期间和二叠纪末、三叠纪末、白垩纪末火山排气作用导致的快速升温过程中急剧下降.地质时期生物多样性对气候变化的不同响应型式表明,生物多样性变化的根本驱动因素可能不是简单的温度、大气CO_(2)浓度等环境因子的背景值高或低,而是环境因子的变化速率(环境变率).变率较小,环境相对稳定,生物有足够的时间适应环境变化,生物多样性不会丧失,甚至繁盛.反之,若环境因子变率过大,超出了生态系统的承受力,生物来不及适应,生物多样性就会显著降低,甚至引发大灭绝.已有模拟和计算表明,当今地球碳排放的速度有可能超过了地质历史时期任何一次生物大灭绝事件.因此,避免环境突变事件和生物大灭绝的再次发生成为政界、科学界和普通民众关注的焦点.打通地球多圈层界限,开展古-今地质记录、冷-热极端气候、海-陆生态系统和长-短时间尺度的综合对比研究,并通过建立适用于深时的地球系统模型,模拟重大生物和环境事件的背景与发生过程,是地球系统科学未来发展的重要方向.

Carboniferous integrative stratigraphy,biotas,and paleogeographical evolution of the Qinghai-Tibetan Plateau and its surrounding areas

During the Carboniferous Period,the Qinghai-Tibetan Plateau and its surrounding areas were located in quite different paleogeographic positions with various sedimentary and biological types.It is important to systematically compile and summarize the Carboniferous strata and biotas of the Qinghai-Tibetan Plateau and its surrounding areas,to establish an integrated stratigraphic framework for correlation,and to reconstruct the paleogeography for correctly understanding the breakup of the Gondwana Continent and the evolution of the Paleo-Tethys Ocean in the Late Paleozoic.The Carboniferous of the Qinghai-Tibetan Plateau and its surrounding areas can be subdivided into the Gondwanan,Cimmerian,and Tethyan types.The Gondwanan-type Carboniferous are distributed in the North Himalayan,Kangmar-Lhunze,and Zanda-Zumba regions of the South Tibet Subprovince and northern India-Pakistan Area,where only the Mississippian is developed and the biota is of Gondwanan affinity.The Cimmerian-type Carboniferous,which are found in the Baoshan,Tengchong,Coqen-Xainza,LhasaZayu,Nagqu-Biru,and South Qiangtang regions,as well as Shan-Thai and South Afghanistan-Pamir areas,also represent only the Mississippian strata,but their biota is characterized by mixed characters of European,South China,Australian,and North American types.The Tethyan-type Carboniferous are distributed in the Tanggula Mountains,Hoh Xil-Bayanhar,ChamdoHengduanshan,Tiekelike,West Kunlun,Karakorum,East Kunlun-Central Qinling,and Qilian regions,where the Carboniferous succession is well developed,and the biota is of warm-water Tethyan affinity.The biostratigraphical correlation of the Gondwanan-type and Cimmerian-type Carboniferous is based mainly on conodonts and additionally on brachiopods and rugose corals.The Mississippian of the Tethyan-type Carboniferous is correlated mainly by using rugose corals and brachiopods,whereas in the Pennsylvanian foraminifera(fusuline)and conodonts are regarded as primary fossil groups,subordinated by rugose corals and brachiopods.Adhering to the International standard chronostratigraphy of the Carboniferous,we have reconstructed a framework of the litho-and biostratigraphic subdivision and correlation of the Qinghai-Tibetan Plateau and its surrounding areas.Further studies should focus on isotope geochronology,geochemistry,paleoclimates,and paleoenvironments of the Carboniferous in the Qinghai-Tibetan Plateau and its surrounding areas.

Preface to integrative stratigraphy,biotas,and paleogeographical evolution of the Qinghai-Tibetan Plateau and its surrounding areas

The Qinghai-Tibetan Plateau(QTP)is well known as the Roof of the World,the Third Pole and the Asian Water Tower.It spans a vast area from the Pamir Plateau in the west to the Longmenshan-Hengduan Mountains in the east,from the Himalaya Mountains in the south to the Kunlun-Qilian Mountains in the north.It stretches approximately 1,200 km from north to south and 2,500 km from east to west.When did the QTP start to uplift?This is still controversial between early and late Cenozoic scenarios.While some scholars advocated its uplift since the India-Asia continental collision at about 65 million years ago in the Paleogene(e.g.,Ding et al.,2017,2022),and the others suggested its uplift since the Miocene(Zheng and Wu,2018).

GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases

Partial endothelial-to-mesenchymal transition(EndMT)is an intermediate phenotype observed in endothelial cells(ECs)undergoing a transition toward a mesenchymal state to support neovascularization during(patho)physiological angiogenesis.Here,we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4(GTF2H4)as a positive regulator of this process.In addition,we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3(ERCC3)to co-regulate partial EndMT.Furthermore,by using phosphorylation proteomics and site-directed mutagenesis,we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3(NCOA3)at serine 1330,which promoted the interaction between NCOA3 and p65,resulting in the transcriptional activation of NF-κB and the NF-kB/Snail signaling axis during partial EndMT.In vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic injury.Collectively,our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases.

晚古生代大冰期碳-水循环回顾与展望

晚古生代大冰期(360~260 Ma)是地球上自动植物繁盛以来持续时间最长的冰期事件,记录了陆地自有高等植被和复杂陆地生态系统以来,唯一的一次从“冰室气候”向“温室气候”的转变.针对晚古生代大冰期的研究大多聚焦于全球碳循环以及冰川性海平面变化等方面,对大冰期的水循环研究相对较少,并且其主要基于气候模拟研究结果.随着单颗粒锆石精确测年技术的应用,高精度的综合地层框架使得冈瓦纳中高纬度地区冰川消长与低纬度地区沉积记录、生物多样性与演化及各种全球地球化学记录建立时序关系,为研究地球循环系统和反馈机制提供了基础条件.目前,对晚古生代大冰期碳同位素变化趋势已有较好认识,存在3次显著的碳同位素正漂事件,依次为杜内中期、巴什基尔早期和阿瑟尔早期,并且在时间上与冈瓦纳大陆识别的3次冰川高峰吻合.在宾夕法尼亚亚纪卡西莫夫末期发生了一次短暂的碳同位素负漂事件,引起显著的全球变暖和海洋缺氧.冰川体积与古热带区域气候动态在天文轨道周期尺度至1~8个百万年的冰期-间冰期时间尺度上都具有耦合关系.在各种时间尺度上,晚古生代大冰期地球表层系统各个圈层之间的反馈过程都非常复杂.因此,今后需在高精度综合地层框架下,开展不同复杂程度的生物地球化学循环和地球系统模型等的模拟工作,以全面地揭示晚古生代大冰期碳-水循环关联机制.

High-throughput deformation potential and electrical transport calculations

The deformation potential plays an important role in electrical transport properties, but in the context of high-throughputsearches requires a consistent and readily computable reference level. Here, we design a high-throughput method forcalculating the deformation potential for semiconductors in the MatHub-3d database. The deformation potential is obtainedfrom the volume-dependent band edge (valence band maximum and conduction band minimum) variations with respect tothe reference level. In order to adapt the calculation of reference level to a high-throughput manner, the average value of thefirst valence electron energy band associated with each compound is used as the reference level. Deformation potentials for11,993 materials are calculated using the above-mentioned method. By considering the calculated deformation potentials,electronic structures, and bulk moduli, 9957 compounds with converged electrical transport properties are obtained. 332promising p-type thermoelectric materials, and 321 n-type entries are then proposed. Among them, 156 compounds arescreened to having both potentially good n- and p-type thermoelectric transport properties. The band structures and chemicalbonding information for several typical compounds are further presented to reveal favorable band and bonding features forthermoelectrics.

重建深时地球生物多样性时空分布模式的思考

重建地球生物多样性演变历史是了解地球生命演化规律的关键.通过研究地质时期的生物多样性变化,能够追溯生命的起源、演化和灭绝过程,并探索其原因.然而,地球上曾经生活过的99%以上的生物都已经灭亡,其中只有一小部分保存为化石并被人类发现.因此,如何利用化石记录重建地球生物多样性变化的过程是一个非常复杂的科学难题.为了解决这一难题,需要从多方面入手.首先,建立含有时空信息的全球性大型综合数据库是研究深时生物多样性模式的必要条件,也是识别曾经发生过的重大生物事件的基础,以往的研究多集中在海洋无脊椎动物化石多样性的研究,目前仍然缺乏全球性的陆地生物多样性模式.其次,需要解决化石保存不完整和样本采集时空不均一的难题.近十几年来,随着海量数据的积累,大数据分析技术的发展,通过多学科交叉,在解决时空分辨率低和样本偏差等问题上发展了更有效的分析手段,但仍然任重道远.最后,新的大数据研究结果引发了对深时地球生物多样性变化的时空规律的许多新认识.随着研究的深入,五次生物大灭绝的灭绝幅度和灭绝率明显降低,需要以全球大数据为基础重新精确估算,其中二叠纪末生物大灭绝无疑仍是最大的一次,而泥盆纪晚期F/F和三叠纪末灭绝事件很可能算不上五大生物灭绝之二,白垩纪末生物大灭绝的持续时间和灭绝幅度也需要重新估算.此外,寒武纪-奥陶纪、石炭纪-二叠纪和新生代三大生物辐射事件也需要全球高分辨率化石数据验证.以人工智能和超级计算机等为手段建立的深时生态系统演变模型是实现古今对比的未来方向.这些研究将使我们对地球生物多样性历史有全方位的认识,也为现今的全球生态系统面临的问题提供深时参照.

Permian integrative stratigraphy and timescale of China

A series of global major geological and biological events occurred during the Permian Period. Establishing a highresolution stratigraphic and temporal framework is essential to understand their cause-effect relationship. The official International timescale of the Permian System consists of three series(i.e., Cisuralian, Guadalupian and Lopingian in ascending order) and nine stages. In China, the Permian System is composed of three series(Chuanshanian, Yansingian and Lopingian) and eight stages, of which the subdivisions and definitions of the Chuanshanian and Yangsingian series are very different from the Cisuralian and Guadalupian series. The Permian Period spanned ～47 Myr. Its base is defined by the First Appearance Datum(FAD) of the conodont Streptognathodus isolatus at Aidaralash, Kazakhstan with an interpolated absolute age 298.9±0.15 Ma at Usolka, southern Urals, Russia. Its top equals the base of the Triassic System and is defined by the FAD of the conodont Hindeodus parvus at Meishan D section, southeast China with an interpolated absolute age 251.902±0.024 Ma. Thirty-five conodont, 23 fusulinid, 17 radiolarian and 20 ammonoid zones are established for the Permian in China, of which the Guadalupian and Lopingian conodont zones have been served as the standard for international correlation. The Permian δ13 Ccarbtrend indicates that it is characterized by a rapid negative shift of 3–5‰ at the end of the Changhsingian, which can be used for global correlation of the end-Permian mass extinction interval, but δ13 Ccarbrecords from all other intervals may have more or less suffered subsequent diagenetic alteration or represented regional or local signatures only. Permian δ18 Oapatitestudies suggest that an icehouse stage dominated the time interval from the late Carboniferous to Kungurian(late Cisuralian). However, paleoclimate began to ameriolate during the late Kungurian and gradually shifted into a greenhouse-dominated stage during the Guadalupian.The Changhsingian was a relatively cool stage, followed by a globally-recognizable rapid temperature rise of 8–10°C at the very end of the Changhsingian. The87 Sr/86 Sr ratio trend shows that their values at the beginning of the Permian were between 0.70800,then gradually decreased to the late Capitanian minimum 0.70680–0.70690, followed by a persistent increase until the end of the Permian with the value 0.70708. Magenetostratigraphy suggests two distinct stages separated by the Illawarra Reversal in the middle Wordian, of which the lower is the reverse polarity Kiaman Superchron and the upper is the mixed-polarity Illawarra Superchron. The end-Guadalupian(or pre-Lopingian) biological crisis occurred during the late Capitanian, when faunal changeovers of different fossil groups had different paces, but generally experienced a relatively long time from the Jinogondolella altudensis Zone until the earliest Wuchiapingian. The end-Permian mass extinction was a catastrophic event that is best constrained at the Meishan section, which occurred at 251.941±0.037 Ma and persisted no more than 61±48 kyr. After the major pulse at Bed 25, the extinction patterns are displayed differently in different sections. The global end-Guadalupian regression is manifested between the conodont Jinogondolella xuanhanensis and Clarkina dukouensis zones and the endChanghsingian transgression began in the Hindeodus changxingensis-Clarkina zhejiangensis Zone. The Permian Period is also characterized by strong faunal provincialism in general, which resulted in difficulties in inter-continental and inter-regional correlation of both marine and terrestrial systems.

A comparison of the biological,geological events and environmental backgrounds between the Neoproterozoic-Cambrian and Permian-Triassic transitions

The Neoproterozoic-Cambrian(N-C) and Permian-Triassic(P-T) transitions have been regarded the two most critical transitions in earth history because of the explosive biological radiation in the early Cambrian(the Cambrian Explosion) and the largest mass extinction at the end-Permian.Previous studies suggest that these two critical transitions showed certain comparability in major evolutionary events.In other words,a series of biological,geological,and geochemical events that had happened in the N-C transition occurred repeatedly during the P-T transition.Those events included continental re-configuration related to the deep mantle dynamics,global-scale glaciations,large C-,Sr-,and S-isotope perturbations indicating atmospheric and oceanic changes,abnormal precipitation of carbonates,and associated multiple biological radiations and mass extinctions.The coupling of those events in both N-C and P-T transitions suggests that deep mantle dynamics could be a primary mechanism driving dramatic changes of environment on the earth's surface,which in turn caused major biological re-organizations.A detailed comparison of those events during the two critical transitions indicates that despite their general comparability,significant differences do exist in magnitude,duration,and frequency.The supercontinent Rodinia began to rift before the Snowball Earth time.By contrast,the supercontinent Pangea entered the dispersal stage after the greatest glaciation from the Late Carboniferous to Cisuralian.Quantitative data and qualitative analyses of different fossil groups show a more profound mass extinction during the N-C transition than at the end-Permian in terms of ecosystem disruption.This is indicated by the disappearance of the whole Ediacaran biota at the N-C boundary.The subsequent appearances of many new complex animals at phylum level in the early Cambrian mark the establishment of a brand new ecosystem.However,the end-Permian mass extinction is manifested mainly by the extinction of many different taxa at class and order levels.Although it caused the extinction of 95% of marine species and 75% of terrestrial species as well as complete cessation of coal and reef deposits after the mass extinction,this high-level biological re-organization still occurred within an established ecosystem,however drastic it may seem.Survived or Lazarus taxa re-occupied the existing ecospace in a relatively short duration after the end-Permian mass extinction.C-isotope excursions display large perturbations during both transitions,yet also in different magnitudes and frequencies,which suggest different atmospheric and oceanic conditions.The recurrent geological and geochemical events as well as the coupled major biological turnovers during the two transitions provide new clues to understanding the interplays among the earth-life system.Thus,it is essential to carry out multidisciplinary studies from the deep internal system to the surface of the Earth as a whole in order to unravel the interactions of different spheres of the earth.