Targeted treatment of cancer with monoclonal antibodies increases the benefit for patients. In order to improve the anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research fie...Targeted treatment of cancer with monoclonal antibodies increases the benefit for patients. In order to improve the anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research field. The emergence of various techniques to produce multi-specific recombinant antibody molecules has led to the selection of target combinations in various forms. To date, only a few multi-specific constructs have entered phase III clinical trials, in contrast to classical monoclonal antibodies. Some of the format options are outlined from a technical point of view. We focus on the achievements and prospects of the underlying technologies for generating biand multispecific antibodies.展开更多
1.Introduction Because of the joint efforts of Active Healthy Kids Global Alliance,the results from the Global Matrix 2.0,involving 38countries,provide a timely insight into physical activity(PA)in children and adoles...1.Introduction Because of the joint efforts of Active Healthy Kids Global Alliance,the results from the Global Matrix 2.0,involving 38countries,provide a timely insight into physical activity(PA)in children and adolescents worldwide.1All the 38 countries,including China,published a report card on 9 PA indicators.1,2Surprisingly,92%of the countries had average grades of C or展开更多
Dear editor, In 2015, a national reform plan was implemented by the central government that covers not only professional clubs and leagues but also campus and grassroots football, to develop football (soccer) in Chi...Dear editor, In 2015, a national reform plan was implemented by the central government that covers not only professional clubs and leagues but also campus and grassroots football, to develop football (soccer) in China.r According to the plan of China's Ministry of Education (MOE),2 football will be nationally pro- moted among school students and youth. Furthermore, MOE plans to select 20,000 primary or middle schools in which the sport would have been promoted by 2020. Then, this number would be increased to 50,000 by 2025.展开更多
Objective:To explore the effectiveness and safety of cardiac rehabilitation qigong exercise in stable coronary artery disease(CAD)patients undergoing phaseⅢrehabilitation.Methods:This was a randomized controlled tria...Objective:To explore the effectiveness and safety of cardiac rehabilitation qigong exercise in stable coronary artery disease(CAD)patients undergoing phaseⅢrehabilitation.Methods:This was a randomized controlled trial.A total of 59 stable CAD patients undergoing phaseⅢrehabilitation treated in Sports Medicine Hospital from March 2017 to September 2017 were enrolled after meeting the inclusion criteria and then divided into cardiac rehabilitation qigong exercise group(n=30)receiving a 12-week intervention and control group(n=29).All participants were assessed at baseline and at 12-week intervention for the primary outcome,that was treadmill test parameter and the secondary outcomes including physical fitness,body composition,bone mineral density,and cardiac ultrasound B-mode imaging.Results:There were no significant differences in baseline demographics between the two groups.After a 12-week cardiac rehabilitation qigong exercise intervention,compared with the control group,ΔV02(initial 1352.63±340.95 vs 12 weeks 1594.57±467.14)vs(initial 1363.83±322.90 vs 12 weeks 1323.76±318.92)(P=.003),ΔVO2/kg(initial 21.23±3.56 vs 12 weeks 24.75±5.11)vs(initial 21.01±3.71 vs 12 weeks 20.35±3.66)(P=.002),ΔMETS(initial 6.19±1.12 vs 12 weeks 7.16±1.60)vs(initial 6.00±1.19 vs 12 weeks 5.86±1.23)(P=.001),ΔVO2/HR(P=.027),ΔSV(P=.014),ΔOUES(P=.012),Δhand-grip strength(P=.002),Δflexibility(P=.001),Δbalance(P=.002),ΔT-score(P=.042),ΔBQI(P=.018).However,Δresting systolic blood pressure(P=.004)andΔresting diastolic pressure(P=.012)decreased in the cardiac rehabilitation qigong exercise group.Conclusion:Cardiac rehabilitation qigong exercise can improve cardiopulmonary aerobic capacity,physical fitness,bone mineral density in patients with stable CAD,suggesting that certain effect and safety for stable CAD patients undergoing phaseⅢrehabilitation can be obtained.展开更多
1.Introduction Physical inactivity has been identified as the fourth leading risk factor for global mortality.~1Globally,it accounts for about6%of deaths,21%–25%of breast and colon cancers,27%of diabetes,and 30%of is...1.Introduction Physical inactivity has been identified as the fourth leading risk factor for global mortality.~1Globally,it accounts for about6%of deaths,21%–25%of breast and colon cancers,27%of diabetes,and 30%of ischemic heart disease.~1In China,the economic costs of health diseases due to physical inactivity had reached 6.7 billion US dollars in 2007,which accounted展开更多
Organic light-emitting transistors(OLETs)are miniaturized electroluminescent devices,and they simultaneously integrate the dual functionality of switching in organicfield-effect transistors and emission in organic ligh...Organic light-emitting transistors(OLETs)are miniaturized electroluminescent devices,and they simultaneously integrate the dual functionality of switching in organicfield-effect transistors and emission in organic light-emitting diodes,which have recently aroused interest from scientists for the next-generation of display applications[1–3].Notably,white organic light-emitting transistors(WOLETs)have gained much attention for their potential applications in sensors,switches,and light sources,including indoor lighting,street lighting andflood lighting[4].Moreover,the Commission Internationale de l’Elcairage(CIE)standard coordinates are precisely defined as(0.33,0.33)of pure white emission,providing a universal reference for evaluating white light accuracy and consistency across lighting and display technologies[5].To meet the requirements of high color-purity,most of the reported white emissive materials and WOLETs have been achieved by rational combination of red,green,blue for three primary colors or blue and orange for two complementary colors emitters[6],such as doping an emitter into an appropriate host and employing the multi-component active layers with a stacked configuration[7].Although a minority of doped electroluminescent devices have the capability of good exciton utilization to realize the white emission,the multi-component active layer is inherently prone to phase separation,which is harmful for the optoelectronic devices[4].Therefore.展开更多
High-efficiency electroluminescent devices featuring simplified architecture have received considerable attention due to significant advantages in construction procedures and commercialized applications.However,there ...High-efficiency electroluminescent devices featuring simplified architecture have received considerable attention due to significant advantages in construction procedures and commercialized applications.However,there still remains a critical challenge with regard to the lack of organic semiconductors that simultaneously possess high luminescent efficiency and balanced carrier-transporting abilities.Herein,we design a thermally activated delayed fluorescence(TADF)emitter 4-(9,9-dimethyl-9,10-dihydroacridine)-4′-triphenylphosphineoxide-benzophenone(DMAC-BPTPO)by incorporating triphenylphosphine oxide into the donor–acceptor skeleton.The accessional electrontransporting moiety,rod-like dimer,and horizontally packing model synergistically enable DMAC-BP-TPO which possesses an excellent photoluminescence quantum yield of nearly 90%with a reverse intersystem crossing rate constant of 2.0×106 s−1,horizontal dipole ratio of 89%,and a balanced electron and hole mobilities with a small constrast ratio of 1.08.Eventually,simplified electroluminescent devices including organic lightemitting diodes(OLEDs)and organic light-emitting transistors(OLETs)incorporating DMAC-BP-TPO-based nondoped film are demonstrated due to their superior integrated optoelectronic properties along with preferable horizontal dipole orientation.A record-high external quantum efficiency value of 21.7%and 4.4%are finally achieved in the simplified nondoped OLED and OLET devices,which are among the highest values in the related research fields.This work provides a new avenue to develop a high-efficiency bipolar TADF emitter to advance the simplified electroluminescent devices.展开更多
Introduction of asymmetric units into conjugated polymers is an important strategy to regulate the photophysical and electronic properties of polymers,as asymmetric units can not only regulate solubility and energy le...Introduction of asymmetric units into conjugated polymers is an important strategy to regulate the photophysical and electronic properties of polymers,as asymmetric units can not only regulate solubility and energy levels,but also molecular stacking and orientation,thus giving much higher optoelectronic properties.However,very few studies have been reported in this field.The semiconducting properties of conjugated polymers could be regulated through regioregularity adjustment.Here,we took the asymmetric thiophene/pyridine side group DPP as core and developed the regioregular monomer T-Py-DPP through three steps:alkyl chain introduction,tin monomer coupling and NBS double bromination.The T-Py-DPP monomer was polymerized into reg-PPy TDPP-2FBT with a head-to-head structure.The regioregularity of T-Py-DPP unit endowed reg-PPy TDPP-2FBT with backbone planarity,self-assembly orientation,network-like morphology and high crystallinity in films,thus the superior bipolar transport properties.The highest hole and electron mobilities of reg-PPy TDPP-2FBT were 0.93 and 0.57 cm^(2)·V^(-1)·s^(-1),respectively,with 40%improvement relative to the regiorandom polymer.展开更多
Dear Editor,Depending on the perceived threat in the environment,organisms can express a broad spectrum of behaviors,ranging from exploration to defensive behaviors[1,2],such as fear response and avoidance.Generalizat...Dear Editor,Depending on the perceived threat in the environment,organisms can express a broad spectrum of behaviors,ranging from exploration to defensive behaviors[1,2],such as fear response and avoidance.Generalization of fear memory can generate anxiety-related disorders that afflict 10%-30%of individuals worldwide,especially during the epidemic situation[3,4].展开更多
Semiconducting two-dimensional conjugated polymers(2DCPs)with strong fluorescence emission have great potential for various optoelectronic applications.However,it is enormously challenging to achieve this goal due to ...Semiconducting two-dimensional conjugated polymers(2DCPs)with strong fluorescence emission have great potential for various optoelectronic applications.However,it is enormously challenging to achieve this goal due to the significant compact interlayerπ-πstacking-induced quenching effect in these systems.In this work,we found that highly fluorescent semiconducting 2DCPs can be prepared through an effective side-chain engineering approach in which interlayer spacers are introduced to reduce the fluorescence quenching effect.The obtained two truxene-based 2DCP films that,along with-C6H13 and-C_(12)H_(25)alkyl side chains as interlayer spacers both demonstrate superior fluorescence properties with a high photoluminescence quantum yield of 5.6%and 14.6%,respectively.These are among the highest values currently reported for 2DCP films.Moreover,an ultralong isotropic quasi-twodimensional exciton diffusion length constrained in the plane with its highest value approaching 110 nm was revealed by the transient photoluminescence microscopy technique,suggesting that theπ-conjugated structure in these truxene-based 2DCP films has effectively been extended.This work can enable a broad exploration of highly fluorescent semiconducting 2DCP films for more deeply fundamental properties and optoelectronic device applications.展开更多
Some semelparous organisms in nature mate as many times as they can in a single reproductive episode before death,while most iteroparous species including humans avoid such suicidal reproductive behavior.Animals natur...Some semelparous organisms in nature mate as many times as they can in a single reproductive episode before death,while most iteroparous species including humans avoid such suicidal reproductive behavior.Animals naturally pursue more sex and the possible fatal consequence of excessive sex must be orchestrated by negative feedback signals in iteroparous species,yet very little is known about the regulatory mechanisms.Here we used Drosophila male sexual behavior as a model system to study how excessive sex may kill males and how the nervous system reacts to prevent death by sex.We found that continuous sexual activity by activating the fruitlessexpressing neurons induced a fixed multi-step behavioral pattern ending with male death.We further found negative feedback in the fly brain to prevent suicidal sexual behavior by expression changes of the neurotransmitters acetylcholine and gamma-aminobutyric acid,and neuropeptide F.These findings are crucial to understand the molecular underpinnings of how different organisms choose reproductive strategies and balance reproduction and survival.展开更多
文摘Targeted treatment of cancer with monoclonal antibodies increases the benefit for patients. In order to improve the anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research field. The emergence of various techniques to produce multi-specific recombinant antibody molecules has led to the selection of target combinations in various forms. To date, only a few multi-specific constructs have entered phase III clinical trials, in contrast to classical monoclonal antibodies. Some of the format options are outlined from a technical point of view. We focus on the achievements and prospects of the underlying technologies for generating biand multispecific antibodies.
基金supported by the General Administration of Sport of China(No.2015B050)Ministry of Human Resources and Social Security of the People’s Republic of China(No.2016-19)+1 种基金the Fundamental Research Funds of Ministry of Finance of the People’s Republic of China(No.2016-20)Chinese Football Association(2016-6)
文摘1.Introduction Because of the joint efforts of Active Healthy Kids Global Alliance,the results from the Global Matrix 2.0,involving 38countries,provide a timely insight into physical activity(PA)in children and adolescents worldwide.1All the 38 countries,including China,published a report card on 9 PA indicators.1,2Surprisingly,92%of the countries had average grades of C or
基金supported by General Administration of Sport of China(No.2015B050)the National Natural Science Foundation of China(No.31371195)
文摘Dear editor, In 2015, a national reform plan was implemented by the central government that covers not only professional clubs and leagues but also campus and grassroots football, to develop football (soccer) in China.r According to the plan of China's Ministry of Education (MOE),2 football will be nationally pro- moted among school students and youth. Furthermore, MOE plans to select 20,000 primary or middle schools in which the sport would have been promoted by 2020. Then, this number would be increased to 50,000 by 2025.
文摘Objective:To explore the effectiveness and safety of cardiac rehabilitation qigong exercise in stable coronary artery disease(CAD)patients undergoing phaseⅢrehabilitation.Methods:This was a randomized controlled trial.A total of 59 stable CAD patients undergoing phaseⅢrehabilitation treated in Sports Medicine Hospital from March 2017 to September 2017 were enrolled after meeting the inclusion criteria and then divided into cardiac rehabilitation qigong exercise group(n=30)receiving a 12-week intervention and control group(n=29).All participants were assessed at baseline and at 12-week intervention for the primary outcome,that was treadmill test parameter and the secondary outcomes including physical fitness,body composition,bone mineral density,and cardiac ultrasound B-mode imaging.Results:There were no significant differences in baseline demographics between the two groups.After a 12-week cardiac rehabilitation qigong exercise intervention,compared with the control group,ΔV02(initial 1352.63±340.95 vs 12 weeks 1594.57±467.14)vs(initial 1363.83±322.90 vs 12 weeks 1323.76±318.92)(P=.003),ΔVO2/kg(initial 21.23±3.56 vs 12 weeks 24.75±5.11)vs(initial 21.01±3.71 vs 12 weeks 20.35±3.66)(P=.002),ΔMETS(initial 6.19±1.12 vs 12 weeks 7.16±1.60)vs(initial 6.00±1.19 vs 12 weeks 5.86±1.23)(P=.001),ΔVO2/HR(P=.027),ΔSV(P=.014),ΔOUES(P=.012),Δhand-grip strength(P=.002),Δflexibility(P=.001),Δbalance(P=.002),ΔT-score(P=.042),ΔBQI(P=.018).However,Δresting systolic blood pressure(P=.004)andΔresting diastolic pressure(P=.012)decreased in the cardiac rehabilitation qigong exercise group.Conclusion:Cardiac rehabilitation qigong exercise can improve cardiopulmonary aerobic capacity,physical fitness,bone mineral density in patients with stable CAD,suggesting that certain effect and safety for stable CAD patients undergoing phaseⅢrehabilitation can be obtained.
基金supported by General Administration of Sport of China(No.2015B050)Ministry of Human Resources and Social Security of the People’s Republic of China(No.2016–19)the Fundamental Research Funds of Ministry of Finance of the People’s Republic of China(No.2016–20)
文摘1.Introduction Physical inactivity has been identified as the fourth leading risk factor for global mortality.~1Globally,it accounts for about6%of deaths,21%–25%of breast and colon cancers,27%of diabetes,and 30%of ischemic heart disease.~1In China,the economic costs of health diseases due to physical inactivity had reached 6.7 billion US dollars in 2007,which accounted
基金supported by the National Natural Science Foundation of China(52233010,52103245,22021002,and 22305252)the CAS Project for Young Scientists in Basic Research(YSBR053)+4 种基金the Beijing National Laboratory for Molecular Sciences(BNLMS-CXXM-202012)China Postdoctoral Science Foundation(2023M733555)Postdoctoral Fellowship Program of CPSF(GZB20230771)the International Cooperation Program of the Chinese Academy of Sciences(121111KYSB20200004)The authors also acknowledge Dr.Xun Tang(Kyushu University)for the optical discussion and Zhenling Liu(Institute of Chemistry,Chinese Academy of Sciences)for the ESP calculated.
文摘Organic light-emitting transistors(OLETs)are miniaturized electroluminescent devices,and they simultaneously integrate the dual functionality of switching in organicfield-effect transistors and emission in organic light-emitting diodes,which have recently aroused interest from scientists for the next-generation of display applications[1–3].Notably,white organic light-emitting transistors(WOLETs)have gained much attention for their potential applications in sensors,switches,and light sources,including indoor lighting,street lighting andflood lighting[4].Moreover,the Commission Internationale de l’Elcairage(CIE)standard coordinates are precisely defined as(0.33,0.33)of pure white emission,providing a universal reference for evaluating white light accuracy and consistency across lighting and display technologies[5].To meet the requirements of high color-purity,most of the reported white emissive materials and WOLETs have been achieved by rational combination of red,green,blue for three primary colors or blue and orange for two complementary colors emitters[6],such as doping an emitter into an appropriate host and employing the multi-component active layers with a stacked configuration[7].Although a minority of doped electroluminescent devices have the capability of good exciton utilization to realize the white emission,the multi-component active layer is inherently prone to phase separation,which is harmful for the optoelectronic devices[4].Therefore.
基金financial support from the National Natural Science Foundation of China(grant nos.52103220,52273164,and 52233010)the Shandong Provincial Natural Science Foundation(grant nos.ZR2022ZD37 and ZR2023QE078)+4 种基金the Ministry of Science and Technology of China(grant nos.2022YFB3603800 and 2018YFA0703200)the Fundamental Research Funds for the Central Universities(grant no.QNTD20)the Beijing National Laboratory for Molecular Sciences(grant no.BNLMS-CXXM-202012)the Natural Science Foundation of Qingdao(grant no.23-2-1-75-zyyd-jch)the Shandong Provincial Regular Undergraduate University Teacher Visiting and Training Fund.
文摘High-efficiency electroluminescent devices featuring simplified architecture have received considerable attention due to significant advantages in construction procedures and commercialized applications.However,there still remains a critical challenge with regard to the lack of organic semiconductors that simultaneously possess high luminescent efficiency and balanced carrier-transporting abilities.Herein,we design a thermally activated delayed fluorescence(TADF)emitter 4-(9,9-dimethyl-9,10-dihydroacridine)-4′-triphenylphosphineoxide-benzophenone(DMAC-BPTPO)by incorporating triphenylphosphine oxide into the donor–acceptor skeleton.The accessional electrontransporting moiety,rod-like dimer,and horizontally packing model synergistically enable DMAC-BP-TPO which possesses an excellent photoluminescence quantum yield of nearly 90%with a reverse intersystem crossing rate constant of 2.0×106 s−1,horizontal dipole ratio of 89%,and a balanced electron and hole mobilities with a small constrast ratio of 1.08.Eventually,simplified electroluminescent devices including organic lightemitting diodes(OLEDs)and organic light-emitting transistors(OLETs)incorporating DMAC-BP-TPO-based nondoped film are demonstrated due to their superior integrated optoelectronic properties along with preferable horizontal dipole orientation.A record-high external quantum efficiency value of 21.7%and 4.4%are finally achieved in the simplified nondoped OLED and OLET devices,which are among the highest values in the related research fields.This work provides a new avenue to develop a high-efficiency bipolar TADF emitter to advance the simplified electroluminescent devices.
基金financially supported by the Ministry of Science and Technology of China(Nos.2018YFA0703200 and 2022YFB3603800)the National Natural Science Foundation of China(Nos.21875259,52233010,51725304,61890943,52103245 and 22021002)+2 种基金the CAS Project for Young Scientists in Basic Research(No.YSBR-053)the Youth Innovation Promotion Association of the Chinese Academy of Sciences,the National Program for Support of Top-notch Young Professionals,the Beijing National Laboratory for Molecular Sciences(No.BNLMS-CXXM-202012)the Key Research Program of the Chinese Academy of Sciences(Nos.XDPB13 and 121111KYSB20200004)。
文摘Introduction of asymmetric units into conjugated polymers is an important strategy to regulate the photophysical and electronic properties of polymers,as asymmetric units can not only regulate solubility and energy levels,but also molecular stacking and orientation,thus giving much higher optoelectronic properties.However,very few studies have been reported in this field.The semiconducting properties of conjugated polymers could be regulated through regioregularity adjustment.Here,we took the asymmetric thiophene/pyridine side group DPP as core and developed the regioregular monomer T-Py-DPP through three steps:alkyl chain introduction,tin monomer coupling and NBS double bromination.The T-Py-DPP monomer was polymerized into reg-PPy TDPP-2FBT with a head-to-head structure.The regioregularity of T-Py-DPP unit endowed reg-PPy TDPP-2FBT with backbone planarity,self-assembly orientation,network-like morphology and high crystallinity in films,thus the superior bipolar transport properties.The highest hole and electron mobilities of reg-PPy TDPP-2FBT were 0.93 and 0.57 cm^(2)·V^(-1)·s^(-1),respectively,with 40%improvement relative to the regiorandom polymer.
基金supported by grants from the National Natural Science Foundation of China(81870852 and 82171199)the Qing Lan Project of Jiangsu Province,the Education Department of Jiangsu Province(18KJA320007)+3 种基金the Natural Science Foundation of Jiangsu Province(BK20181146 and BK20210911)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX21_2706,KYCX21_2703,and YCX21_2717)the Program on Basic Research Projects of Xuzhou City(KC21048)the Special Funds for Anesthesia Medical Research of Jiangsu Medical Association SYH-32021-0040(2021035).
文摘Dear Editor,Depending on the perceived threat in the environment,organisms can express a broad spectrum of behaviors,ranging from exploration to defensive behaviors[1,2],such as fear response and avoidance.Generalization of fear memory can generate anxiety-related disorders that afflict 10%-30%of individuals worldwide,especially during the epidemic situation[3,4].
基金supported by the Ministry of Science and Technology of China(grant nos.2018YFA0703200 and 2022YFB3603800)the Natural Science Foundation of China(grant nos.21875259,52233010,51725304,61890943,and 22021002)+3 种基金the CAS Project for Young Scientists in Basic Research(grant no.YSBR-053)the Youth Innovation Promotion Association of the Chinese Academy of Sciences,the National Program for Support of Top-notch Young Professionals,the Beijing National Laboratory for Molecular Sciences(grant no.BNLMS-CXXM-202012)the Key Research Program of the Chinese Academy of Sciences(grant no.XDPB13)K.C.Wong Education Foundation(grant no.GJTD-2020-02).
文摘Semiconducting two-dimensional conjugated polymers(2DCPs)with strong fluorescence emission have great potential for various optoelectronic applications.However,it is enormously challenging to achieve this goal due to the significant compact interlayerπ-πstacking-induced quenching effect in these systems.In this work,we found that highly fluorescent semiconducting 2DCPs can be prepared through an effective side-chain engineering approach in which interlayer spacers are introduced to reduce the fluorescence quenching effect.The obtained two truxene-based 2DCP films that,along with-C6H13 and-C_(12)H_(25)alkyl side chains as interlayer spacers both demonstrate superior fluorescence properties with a high photoluminescence quantum yield of 5.6%and 14.6%,respectively.These are among the highest values currently reported for 2DCP films.Moreover,an ultralong isotropic quasi-twodimensional exciton diffusion length constrained in the plane with its highest value approaching 110 nm was revealed by the transient photoluminescence microscopy technique,suggesting that theπ-conjugated structure in these truxene-based 2DCP films has effectively been extended.This work can enable a broad exploration of highly fluorescent semiconducting 2DCP films for more deeply fundamental properties and optoelectronic device applications.
基金the National Key R&D Program of China(2019YFA0802400)the National Natural Science Foundation of China(31970943,31622028,and 31700920)the Jiangsu Innovation and Entrepreneurship Team Program。
文摘Some semelparous organisms in nature mate as many times as they can in a single reproductive episode before death,while most iteroparous species including humans avoid such suicidal reproductive behavior.Animals naturally pursue more sex and the possible fatal consequence of excessive sex must be orchestrated by negative feedback signals in iteroparous species,yet very little is known about the regulatory mechanisms.Here we used Drosophila male sexual behavior as a model system to study how excessive sex may kill males and how the nervous system reacts to prevent death by sex.We found that continuous sexual activity by activating the fruitlessexpressing neurons induced a fixed multi-step behavioral pattern ending with male death.We further found negative feedback in the fly brain to prevent suicidal sexual behavior by expression changes of the neurotransmitters acetylcholine and gamma-aminobutyric acid,and neuropeptide F.These findings are crucial to understand the molecular underpinnings of how different organisms choose reproductive strategies and balance reproduction and survival.