bluuebunny/crossref_metadata_2025_split huggingface dataset:
Women with more feminine digit ratio (2D:4D) have higher reproductive success
Authors: Klimek Magdalena , Galbarczyk Andrzej , Nenko Ilona , Jasienska Grazyna 
Published: April 2016

ABSTRACTObjectivesPrenatal development has a long‐lasting influence on biological condition and health. Second‐to‐fourth digit ratio (2D:4D) is suggested as an indicator of sex hormone exposure during fetal development, and it is likely that women with a more feminine digit ratio were exposed to higher prenatal estrogen levels. Therefore, we tested if 2D:4D was related to a woman's reproductive characteristics.MethodsWe studied 319 women aged 46–92, who went through a natural menopause and whose husbands were alive at least until their menopause were studied. Women were recruited at the Mogielica Human Ecology Study Site located in rural Poland.ResultsWomen with more feminine 2D:4D had a higher number of children (P = 0.002), gave birth to their last child at a later age (P = 0.02), and had a longer reproductive lifespan (P = 0.04) than women with more masculine 2D:4D. Age and number of years of education were included as potential confounders in the analyses.ConclusionsThe results indicated that women with more feminine 2D:4D had higher reproductive success. While the exact mechanisms were not known, and the relationship between 2D:4D and adult sex hormone levels was questioned by previous studies, there might be other biological pathways explaining the observed results, that is, via behaviors that were indirectly related to fertility. Am J Phys Anthropol 160:549–553, 2016. © 2016 Wiley Periodicals, Inc.
Patterns of quadrupedal locomotion in a vertical clinging and leaping primate (Propithecus coquereli) with implications for understanding the functional demands of primate quadrupedal locomotion
Authors: Granatosky Michael C. , Tripp Cameron H. , Fabre Anne‐Claire , Schmitt Daniel 
Published: April 2016

ABSTRACTObjectivesMany primates exhibit a suite of characteristics that distinguish their quadrupedal gaits from non‐primate mammals including the use of a diagonal sequence gait, a relatively protracted humerus at touchdown, and relatively high peak vertical forces on the hindlimbs compared to the forelimbs. These characteristics are thought to have evolved together in early, small‐bodied primates possibly in response to the mechanical demands of navigating and foraging in a complex arboreal environment. It remains unclear, however, whether primates that employ quadrupedalism only rarely demonstrate the common primate pattern of quadrupedalism or instead use the common non‐primate pattern or an entirely different mechanical pattern from either group.Materials and MethodsThis study compared the kinematics and kinetics of two habitually quadrupedal primates (Lemur catta and Varecia variegata) to those of a dedicated vertical clinger and leaper (Propithecus coquereli) during bouts of quadrupedal walking.ResultsAll three species employed diagonal sequence gaits almost exclusively, displayed similar degrees of humeral protraction, and exhibited lower vertical peak forces in the forelimbs compared to the hindlimb.DiscussionFrom the data in this study, it is possible to reject the idea that P. coquereli uses a non‐primate pattern of quadrupedal walking mechanics. Nor do they use an entirely different mechanical pattern from either most primates or most non‐primates during quadrupedal locomotion. These findings provide support for the idea that this suite of characteristics is adaptive for the challenges of arboreal locomotion in primates and that these features of primate locomotion may be basal to the order or evolved independently in multiple lineages including indriids. Am J Phys Anthropol 160:644–652, 2016. © 2016 Wiley Periodicals, Inc.
Predictive significance of computed tomography in eosinophilic chronic rhinosinusitis with nasal polyps
Authors: Meng Yifan , Lou Hongfei , Wang Chengshuo , Zhang Luo 
Published: April 2016

BackgroundEosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP), characterized by eosinophil‐predominant inflammation in mucosa, is a subject of much investigation. However, no satisfactory atraumatic clinical parameter has been established to date for prediagnosis of this condition. The aim of this study was therefore to compare the use of computed tomography (CT) scans with other clinical parameters in prediagnosis of eCRSwNP.MethodsThis was a prospective cohort, single‐institution study. Two hundred consecutive CRSwNP patients (123 eCRSwNP and 77 non‐eosinophilic CRSwNP [neCRSwNP]) undergoing functional endoscopic sinus surgery in Beijing TongRen Hospital were recruited. Preoperative CT scan, skin‐prick test (SPT), and oral fractional exhaled nitric oxide (FENO) measurements were performed in each patient and full blood count with differential analysis under the patients’ regular condition was performed within 1 week before surgery. Logistic regression analysis and receiver operating characteristic (ROC) curve were used to assess the predictive value of clinical parameters.ResultsHistory of surgery, onset of asthma, history of allergy, total Lund‐Mackay scores, presence of osteoneogenesis, FENO, and blood eosinophil counts were all significantly higher in the eCRSwNP group, compared to the neCRSwNP group. The ratio of the CT scores for the ethmoid sinus and maxillary sinus (E/M ratio) had the highest predictive value, with an area under the ROC curve (AUC) of 0.938. The cutoff point of >2.59 for E/M ratio demonstrated a sensitivity of 94.2% and a specificity of 89.6% for eCRSwNP.ConclusionThe E/M ratio is a more useful predictor in diagnosis of eCRSwNP compared to the other clinical parameters.
Tumor necrosis factor‐α regulates interleukin‐33 expression through extracellular signal‐regulated kinase, p38, and nuclear factor–κB pathways in airway epithelial cells
Authors: Park Il‐Ho , Park Joo‐Hoo , Shin Jae‐Min , Lee Heung‐Man 
Published: April 2016

BackgroundInterleukin (IL)‐33 plays an important role in controlling immune responses in barrier tissues, and is a potent mediator of inflammatory diseases such as asthma, rheumatoid disease, and chronic rhinosinusitis. The aims of the present study were 2‐fold: (1) to determine the stimulatory effect of tumor necrosis factor‐α (TNF‐α) on IL‐33 production in nasal epithelial and A549 cells; and (2) to identify downstream pathways that activate IL‐33 production.MethodsPrimary nasal epithelial cells (PNECs) from 5 normal patients were isolated and cultured. To identify which cytokines stimulate IL‐33 production, we performed reverse‐transcription polymerase chain reaction (RT‐PCR), enzyme‐linked immunosorbent assay (ELISA), and immunofluorescence staining. Three mitogen‐activated protein kinases (MAPKs) (p38, extracellular signal‐regulated kinase [ERK], and c‐Jun N‐terminal kinase [JNK]) and nuclear factor κB (NF‐κB) were evaluated as downstream signaling molecules by RT‐PCR, ELISA, Western blot analysis, and luciferase reporter assay.ResultsThe IL‐33 messenger RNA (mRNA) and protein levels were increased significantly by TNF‐α in PNECs and A549 cells. TNF‐α stimulated the expression of IL‐33 in a dose‐ and time‐dependent manner in A549 cells. PNECs and A549 cells were treated with TNF‐α in the presence of specific inhibitors of p38, ERK, JNK, and NF‐κB. In both cell types, inhibitors of ERK, p38, and NF‐κB reversed TNF‐α–induced IL‐33 production. In the luciferase reporter assay, NF‐κB activity was inhibited not only by an NF‐κB inhibitor, but also by ERK and p38 inhibitors.ConclusionTNF‐α stimulated IL‐33 expression through ERK, p38, and NFκB pathways in PNECs and A549 cells.
Characterization of a novel high‐dose ovalbumin‐induced murine model of allergic sinonasal inflammation
Authors: Mendiola Michelle , Tharakan Anuj , Chen Mengfei , Asempa Tomefa , Lane Andrew P. , Ramanathan Murugappan 
Published: April 2016

BackgroundFew efficacious topical therapies exist for chronic rhinosinusitis (CRS). The lack of a reproducible mouse model of CRS limits the pilot testing of potential novel anti‐inflammatory therapies. Although the ovalbumin‐induced mouse model of sinonasal inflammation is commonly used, it is difficult to reproduce and can generate variable histologic results. In this study, we explore a variation of this model in different strains of mice and explore various inflammatory cytokines as reproducible molecular markers of inflammation.MethodsAllergic sinonasal inflammation was generated in BALB/c and C57BL/6 mice using intraperitoneal high‐dose injections of ovalbumin (Ova; Sigma Chemical Co.) followed by 10 days of high‐dose intranasal sensitization. Real‐time polymerase chain reaction (RT‐PCR) for eotaxin, interleukin 4 (IL‐4), and IL‐13 were measured from sinonasal mucosa. We also pilot tested a known topical budesonide to characterize the anti‐inflammatory response. Histological sections were analyzed for epithelial thickness and eosinophilia.ResultsBoth BALB/c and C57BL/6 mice consistently showed increases in T helper 2 (Th2) cytokines after sensitization with high‐dose Ova (p < 0.0001) when compared to controls. There were also significant increases in epithelial thickening in Ova‐sensitized mice and eosinophilia in both BALB/c and C57BL/6 strains. In addition, topical budesonide significantly reduced anti‐inflammatory cytokines, eosinophilia, and epithelial thickness.ConclusionOur variation of the ovalbumin‐induced mouse model of sinonasal inflammation in both BALB/c and C57BL/6 mice provides an efficacious model for testing potential topical anti‐inflammatory therapies for CRS. The utilization of sinonasal mucosal Th2 cytokines along with histologic markers provides a consistent and quantifiable marker of inflammation in assessing the efficacy of candidate drugs.
Computergestützte Syntheseplanung: Das Ende vom Anfang
Authors: Szymkuć Sara , Gajewska Ewa P. , Klucznik Tomasz , Molga Karol , Dittwald Piotr , Startek Michał , Bajczyk Michał , Grzybowski Bartosz A. 
Published: April 2016

AbstractSeit der Einführung des ersten dokumentierten Forschungsprojekts (Dendral, 1965) zur rechnergestützten organischen Synthese ist ein halbes Jahrhundert vergangen. In den 1970er und 1980er Jahren wurden viele weitere Programme entwickelt, doch bis zu den 2000er Jahren war der Enthusiasmus dieser Pionierzeit weitgehend verschwunden, und wegen der schwierigen Aufgabe, die Planung organischer Synthesen in Computer einzugeben, erhielt sie den Ruf einer “Mission impossible”. Das ist recht merkwürdig angesichts der Tatsache, dass Computer in der Zwischenzeit viele andere Fähigkeiten “gelernt” haben, die als alleinige Domänen von Intellekt und Kreativität des Menschen betrachtet wurden – so können Rechner heutzutage besser Schach spielen als menschliche Weltmeister, und sie können klassische Musik komponieren, die für das menschliche Ohr angenehm ist. In der organischen Synthese hat es zwar keine vergleichbaren Leistungen gegeben, aber dieser Aufsatz behauptet, dass es verfrüht wäre, eine Niederlage einzugestehen. Tatsächlich kann dem Computer schließlich “beigebracht” werden, die Synthesen von komplizierten organischen Verbindungen in Sekunden‐ bis Minutenschnelle zu planen, indem die Kombination aus moderner Rechenleistung und Algorithmen aus der Graphen‐/Netzwerktheorie zusammengeführt wird mit in geeigneten Formaten codierten chemischen Regeln (mit vollständiger Stereo‐ und Regiochemie) und Elementen der Quantenmechanik. Der Aufsatz beginnt mit einem Überblick über theoretische Grundkonzepte, die essenziell sind für die Analyse der großen Datenmengen chemischer Synthesen. Im Anschluss daran wird auf die Optimierung von Synthesewegen unter Einbeziehung bekannter Reaktionen eingegangen. Einen Schwerpunkt bildet die anschließende Besprechung der Algorithmen, die eine vollständig neue und automatisierte Planung der Synthesen für komplizierte Zielverbindungen ermöglichen, darunter auch solche, die noch nicht hergestellt wurden. Es gibt natürlich noch Verbesserungsmöglichkeiten, letztendlich aber werden Computer für die praktische Planung der organischen Synthese wichtig und hilfreich sein. Churchills berühmte Worte nach dem ersten wichtigen Sieg der Alliierten über die Achsenmächte paraphrasierend, ist es für die computergestützte Syntheseplanung nicht das Ende, nicht einmal der Anfang vom Ende, sondern das Ende vom Anfang. Der Computer ist da und wird bleiben.
Modulare zweizähnige NHC‐Thioether‐Hybridliganden zur Stabilisierung von Palladium‐Nanopartikeln in diversen Lösungsmitteln
Authors: Rühling Andreas , Schaepe Kira , Rakers Lena , Vonhören Benjamin , Tegeder Patricia , Ravoo Bart Jan , Glorius Frank 
Published: April 2016

AbstractDie Synthese von vier zweizähnigen NHC‐Thioether‐Hybridliganden wird vorgestellt. Mit diesen Liganden modifizierte Palladium‐Nanopartikel sind, in Abhängigkeit des verwendeten Liganden, in verschiedenen Lösungsmitteln stabil und zeigen eine hohe Chemoselektivität in der Hydrierung von Olefinen. Die Löslichkeit der Nanopartikel konnte je nach pH‐Wert des Lösungsmittels mehrfach geschaltet werden. Röntgen‐Photoelektronenspektroskopie (die eine feine Verschiebung in der Bindungsenergie zeigt) wurde als praktische Analysemethode zur Bestimmung des Bindungsmodus des NHC‐Liganden identifiziert.
Die spezifische enzymatische Halogenierung – von der Entdeckung halogenierender Enzyme bis zu deren Anwendung in vitro und in vivo
Authors: Weichold Veit , Milbredt Daniela , van Pée Karl‐Heinz 
Published: April 2016

AbstractIm Verlauf der letzten 20 Jahre hat sich der Fokus von den Haloperoxidasen in Richtung der Flavin‐abhängigen und der Nicht‐Häm‐Eisen‐abhängigen Halogenasen verschoben. Für diese konnte in verschiedenen Organismen die Beteiligung an der Biosynthese halogenierter Metaboliten nachgewiesen werden. Während der ersten 10–12 Jahre lag der Fokus auf dem Nachweis von Halogenasen sowie der Aufklärung der dreidimensionalen Struktur und des Reaktionsmechanismus. In diesem Aufsatz werden hauptsächlich Arbeiten über halogenierende Enzyme mit einem Veröffentlichungsdatum zwischen 2010 und 2015 besprochen. Sein Schwerpunkt liegt auf Arbeiten zur Aufklärung der Beteiligung halogenierender Enzyme an den Biosynthesen halogenierter Metaboliten, der Anwendung von Halogenasen in In‐vivo‐ und In‐vitro‐Systemen, der In‐vivo‐Veränderung von Biosynthesewegen in Bakterien und Pflanzen, der Verbesserung der Enzymstabilität, der Erweiterung des Substratspektrums und der Verknüpfung von Biokatalyse mit chemischer Synthese zur Bildung neuer Verbindungen.
Hierarchical Tubular Structures Composed of Co3O4 Hollow Nanoparticles and Carbon Nanotubes for Lithium Storage
Authors: Chen Yu Ming , Yu Le , Lou Xiong Wen (David) 
Published: April 2016

AbstractHierarchical tubular structures composed of Co3O4 hollow nanoparticles and carbon nanotubes (CNTs) have been synthesized by an efficient multi‐step route. Starting from polymer‐cobalt acetate (Co(Ac)2) composite nanofibers, uniform polymer‐Co(Ac)2@zeolitic imidazolate framework‐67 (ZIF‐67) core–shell nanofibers are first synthesized via partial phase transformation with 2‐methylimidazole in ethanol. After the selective dissolution of polymer‐Co(Ac)2 cores, the resulting ZIF‐67 tubular structures can be converted into hierarchical CNTs/Co‐carbon hybrids by annealing in Ar/H2 atmosphere. Finally, the hierarchical CNT/Co3O4 microtubes are obtained by a subsequent thermal treatment in air. Impressively, the as‐prepared nanocomposite delivers a high reversible capacity of 1281 mAh g−1 at 0.1 A g−1 with exceptional rate capability and long cycle life over 200 cycles as an anode material for lithium‐ion batteries.
Gold Doping of Silver Nanoclusters: A 26‐Fold Enhancement in the Luminescence Quantum Yield
Authors: Soldan Giada , Aljuhani Maha A. , Bootharaju Megalamane S. , AbdulHalim Lina G. , Parida Manas R. , Emwas Abdul‐Hamid , Mohammed Omar F. , Bakr Osman M. 
Published: April 2016

AbstractA high quantum yield (QY) of photoluminescence (PL) in nanomaterials is necessary for a wide range of applications. Unfortunately, the weak PL and moderate stability of atomically precise silver nanoclusters (NCs) suppress their utility. Herein, we accomplished a ≥26‐fold PL QY enhancement of the Ag29(BDT)12(TPP)4 cluster (BDT: 1,3‐benzenedithiol; TPP: triphenylphosphine) by doping with a discrete number of Au atoms, producing Ag29−xAux(BDT)12(TPP)4, x=1–5. The Au‐doped clusters exhibit an enhanced stability and an intense red emission around 660 nm. Single‐crystal XRD, mass spectrometry, optical, and NMR spectroscopy shed light on the PL enhancement mechanism and the probable locations of the Au dopants within the cluster.
All‐Metal Antiaromaticity in Sb4‐Type Lanthanocene Anions
Authors: Min Xue , Popov Ivan A. , Pan Fu‐Xing , Li Lei‐Jiao , Matito Eduard , Sun Zhong‐Ming , Wang Lai‐Sheng , Boldyrev Alexander I. 
Published: April 2016

AbstractAntiaromaticity, as introduced in 1965, usually refers to monocyclic systems with 4n π electrons. This concept was extended to all‐metal molecules after the observation of Li3Al4− in the gas phase. However, the solid‐phase counterparts have not been documented to date. Herein, we describe a series of all‐metal antiaromatic anions, [Ln(η4‐Sb4)3]3−(Ln=La, Y, Ho, Er, Lu), which were isolated as the K([2.2.2]crypt) salts and identified by single‐crystal X‐ray diffraction. Based on the results obtained from the chemical bonding analysis, multicenter indices, and the electron‐counting rule, we conclude that the core [Ln(η4‐Sb4)3]3− fragment of the crystal has three locally π‐antiaromatic Sb4 fragments. This complex represents the first locally π‐antiaromatic all‐metal system in the solid state, which is stabilized by interactions of the three π‐antiaromatic units with the central metal atom.
The Origin of the Catalytic Activity of a Metal Hydride in CO2 Reduction
Authors: Kato Shunsuke , Matam Santhosh Kumar , Kerger Philipp , Bernard Laetitia , Battaglia Corsin , Vogel Dirk , Rohwerder Michael , Züttel Andreas 
Published: April 2016

AbstractAtomic hydrogen on the surface of a metal with high hydrogen solubility is of particular interest for the hydrogenation of carbon dioxide. In a mixture of hydrogen and carbon dioxide, methane was markedly formed on the metal hydride ZrCoHx in the course of the hydrogen desorption and not on the pristine intermetallic. The surface analysis was performed by means of time‐of‐flight secondary ion mass spectroscopy and near‐ambient pressure X‐ray photoelectron spectroscopy, for the in situ analysis. The aim was to elucidate the origin of the catalytic activity of the metal hydride. Since at the initial stage the dissociation of impinging hydrogen molecules is hindered by a high activation barrier of the oxidised surface, the atomic hydrogen flux from the metal hydride is crucial for the reduction of carbon dioxide and surface oxides at interfacial sites.
An Electron‐Poor C64 Nanographene by Palladium‐Catalyzed Cascade C−C Bond Formation: One‐Pot Synthesis and Single‐Crystal Structure Analysis
Authors: Seifert Sabine , Shoyama Kazutaka , Schmidt David , Würthner Frank 
Published: April 2016

AbstractHerein, we report the one‐pot synthesis of an electron‐poor nanographene containing dicarboximide groups at the corners. We efficiently combined palladium‐catalyzed Suzuki–Miyaura cross‐coupling and dehydrohalogenation to synthesize an extended two‐dimensional π‐scaffold of defined size in a single chemical operation starting from N‐(2,6‐diisopropylphenyl)‐4,5‐dibromo‐1,8‐naphthalimide and a tetrasubstituted pyrene boronic acid ester as readily accessible starting materials. The reaction of these precursors under the conditions commonly used for Suzuki–Miyaura cross‐coupling afforded a C64 nanographene through the formation of ten C−C bonds in a one‐pot process. Single‐crystal X‐ray analysis unequivocally confirmed the structure of this unique extended aromatic molecule with a planar geometry. The optical and electrochemical properties of this largest ever synthesized planar electron‐poor nanographene skeleton were also analyzed.
Das Bis(pentafluorethyl)germylen‐Trimethylphosphan‐Addukt, (C2F5)2Ge⋅PMe3 – Charakterisierung, Ligandeigenschaften und Reaktivität
Authors: Pelzer Stefanie , Neumann Beate , Stammler Hans‐Georg , Ignat'ev Nikolai , Hoge Berthold 
Published: April 2016

AbstractWir beschreiben hier die Synthese des Germylen‐Phosphan‐Adduktes (C2F5)2Ge⋅PMe3 ausgehend von (C2F5)3GeH; dabei wurde dieses in überschüssigem PMe3 erhitzt, was zur reduktiven Eliminierung von C2F5H führte. Die Molekülstruktur des Addukts im Festkörper wurde röntgenographisch bestimmt und mit Ergebnissen quantenmechanischer Rechnungen verglichen. Die Eigenschaften als Ligand wurden mithilfe IR‐spektroskopischer Untersuchungen des CO‐Bereichs von [Ni0(CO)3{Ge(C2F5)2(PMe3)}] abgeleitet. Damit wurde (C2F5)2Ge⋅PMe3 anhand des elektronischen Parameters nach Tolman als ein mit PMe3 vergleichbarer π‐Akzeptorligand eingeordnet. Des Weiteren wurden eine [2+4]‐Cycloaddition mit 2,3‐Dimethyl‐1,3‐butadien sowie Insertionsreaktionen in σ‐Bindungen beobachtet. Ein Beispiel für die letztgenannten Reaktionen ist die Aktivierung der C‐Cl‐Bindung in Dichlormethan unter Bildung des Phosphoniumylidkomplexes [(C2F5)2Cl2Ge‐CH2PMe3], der vollständig röntgenographisch charakterisiert wurde.
Enzyme‐ and Ruthenium‐Catalyzed Enantioselective Transformation of α‐Allenic Alcohols into 2,3‐Dihydrofurans
Authors: Yang Bin , Zhu Can , Qiu Youai , Bäckvall Jan‐E. 
Published: April 2016

AbstractAn efficient one‐pot method for the enzyme‐ and ruthenium‐catalyzed enantioselective transformation of α‐allenic alcohols into 2,3‐dihydrofurans has been developed. The method involves an enzymatic kinetic resolution and a subsequent ruthenium‐catalyzed cycloisomerization, which provides 2,3‐dihydrofurans with excellent enantioselectivity (up to >99 % ee). A ruthenium carbene species was proposed as a key intermediate in the cycloisomerization.
Enzymatic Macrocyclization of 1,2,3‐Triazole Peptide Mimetics
Authors: Oueis Emilia , Jaspars Marcel , Westwood Nicholas J. , Naismith James H. 
Published: April 2016

AbstractThe macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme‐mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4‐substituted 1,2,3‐triazole moieties. The introduction of non‐peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non‐natural triazole‐containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.
Astringent Mouthfeel as a Consequence of Lubrication Failure
Authors: Ma Shuanhong , Lee Haeshin , Liang Yongmin , Zhou Feng 
Published: April 2016

AbstractHerein, we systematically investigate the origin of astringent mouthfeel when we eat unripe fruits, drink coffee or tea, from the perspective of lubrication by simulating the dynamic weak interaction on the tongue with model protein (mucoprotein, MP) and polyphenolic compounds (tannic acid, TA). Astringency was due to the protein‐mediated lubrication failure when encountering polyphenolic molecules that normally exist, for example in unripe fruits, coffee, tea. The underlying molecular mechanism of oral tribology is widely present in nature and enables us to engineer a tongue‐like polyacrylamide composite hydrogel that exhibits high TA sensitivity and to develop a scientific strategy for catching slippery fish using TA‐containing gloves. These results provide novel and useful insights into the failure of biological boundary lubrication on soft tissue surface with the adsorbed proteins.