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Comprehensive Assessment of Anxiolytic Properties in 4-HPAA Derivatives: Bridging in Vivo Validation and Molecular Docking Analyses

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Open Journal of Medicinal Chemistry 2024年第3期14卷 29-44页

作者： Kawthar Alhussieni Rami Ayoub Jamal Jilani Qais Jarrar Othman Alhussinei Vetriselvan Subramaniyan Esra Nasraldin Khalil Sharafaldin Harshini Muruganantham Jureerat Kijsomporn ling shing wong Department of Applied Pharmaceutical Sciences and Clinical Pharmacy Faculty of Pharmacy Isra University Amman Jordan Department of Pharmaceutical Chemistry Faculty of Pharmacy Universiti Malaya Kuala Lumpur Malaysia Department of Medicinal Chemistry and Pharmacognosy Faculty of Pharmacy Jordan University of Science and Technology Irbid Jordan Department of Allied Medical Sciences Zarqa Private University Zarqa Jordan Department of Medical Sciences School of Medical and Life Sciences Sunway University Bandar Sunway Malaysia Department of Clinical Pharmacy and Pharmacy Practice Faculty of Pharmacy Universiti Malaya Kuala Lumpur Malaysia Center for Global Research Saveetha Medical College Saveetha Institute of Medical and Technical Sciences Saveetha University Chennai India School of Nursing Metharath University Bangtoey Thailand Faculty of Health and Life Sciences INTI International University Nilai Malaysia

Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HPAA) is identified in brain cells as a physiological byproduct of tyramine. This study hypothesizes that 4-HPAA may regulate anxiety due to its anxiolytic properties, acting as a modulator of the GABAergic system, which plays a crucial role in the pathophysiology of anxiety disorders. Our study aims to enhance the anxiolytic effects of 4-HPAA through chemical modification to improve its pharmacokinetic properties. Three derivatives, namely Isopropyl-4-hydroxy-[phenyl] acetate (IHPA), Isopropyl-4-hydroxy-[phenyl] acetate (MPAA), and 4-methoxyphenyl acetate (MPHA), have been synthesized from 4-HPAA. This assessment will use well-established animal models, specifically the Elevated Plus-Maze (EPM) and Zero Maze (EZM) tests, selected for their validity in replicating anxiety-like symptoms in animals. Chronic caffeine administration via drinking water (0.3 g/l for 14 days) was employed to induce an anxiety state for testing purposes. IHPA and MPAA demonstrated significant anxiolyticactivity when tested in the EPM and EZM experiments. Molecular docking simulations using AutoDock Vina indicated that 4-HPAA derivatives had docking scores ranging from −5.8 to −4.8 kcal/mol, compared to the standard anxiolytic medication Diazepam, which scored −7.1 kcal/mol. These scores suggest a potential for 4-HPAA derivatives to interact effectively with the Gamma-aminobutyric acid (GABA_A) receptor. In conclusion, our in vivo and in silico analyses indicate a promising anxiolytic potential for 4-HPAA derivatives.

关键词： Anxiolytics 4-HPAA Molecular Docking Elevated Plus-Maze Zero Maze Tests

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Overview of Jute Fibre as Thermoplastic Matrix Polymer Reinforcement

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Journal of Renewable Materials 2024年第3期12卷 457-483页

作者： Tezara Cionita Mohammad Hazim Mohamad Hamdan Januar Parlaungan Siregar Deni Fajar Fitriyana Ramli Junid wong ling shing Jamiluddin Jaafar Agustinus Purna Irawan Teuku Rihayat Rifky Ismail Athanasius Priharyoto Bayuseno Emilianus Jehadus Faculty of Engineering and Quantity Surveying INTI International UniversityNilaiNegeri Sembilan71800Malaysia Technical Department Dyna Forming Engineering Technology(DFETECH)SDN.BHD.SerembanNegeri Sembilan70300Malaysia Faculty of Mechanical and Automotive Engineering Technology UniversitiMalaysia Pahang Al-Sultan Abdullah(UMPSA)PekanPahang26600Malaysia Automotive Engineering Center(AEC) UniversitiMalaysia Pahang Al-Sultan Abdullah(UMPSA)PekanPahang26600Malaysia Department of Mechanical Engineering Universitas Negeri SemarangKampus SekaranGunungpatiSemarang50229Indonesia Faculty of Manufacturing and Mechatronic Engineering Technology Universiti Malaysia Pahang Al-Sultan AbdullahPekanPahang26600Malaysia Faculty of Health and Life Sciences INTI International UniversityNilai71800Malaysia Faculty of Mechanical and Manufacturing Engineering Universiti Tun Hussein Onn MalaysiaParit RajaBatu PahatJohor86400Malaysia Faculty of Engineering Universitas TarumanagaraJakarta Barat11440Indonesia Department of Chemical Engineering Politeknik Negeri LhokseumaweLhokseumawe24301Indonesia Department of Mechanical Engineering Faculty of EngineeringDiponegoro UniversitySemarang50275Indonesia Department of Mathematics Education Universitas Katolik Indonesia Santu Paulus RutengNusa Tenggara Timur8651Indonesia

Recent decades have seen a substantial increase in interest in research on natural fibres that is aligned with sustainable development goals(SDGs).Due to their renewable resources and biodegradability,natural fiberreinforced composites have been investigated as a sustainable alternative to synthetic materials to reduce the usage of hazardous waste and environmental *** the natural fibre,jute fibre obtained from a bast plant has an increasing trend in the application,especially as a reinforcement *** research works have been performed on jute fibre with regard to reinforced thermoset and thermoplastic ***,current demands on sustainable materials have required new developments in thermoplastic *** this paper,the author reviews jute plants as reinforcement materials for thermoplastic matrix *** review provides an overview of the sustainability of jute plants as reinforcement material for thermoplastic matrix *** overview on jute based thermoplastic composites focused on the thermal behavior and mechanical *** from physical,chemical,and mechanical properties,the study also covers the current and perspectives for future research challenges faced by the researchers on jute fibre reinforced thermoplastic composites.

关键词： Jute fibre sustainable development goals(SDGs) natural fibre thermoplastic composite sustainable manufacturing

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Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease

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World Journal of Hepatology 2024年第2期16卷 211-228页

作者： Lung-Yi Mak Matthew shing Hin Chung Xue Li Francisco Tsz Tsun Lai Eric Yuk Fai Wan Celine Sze ling Chui Franco Wing Tak Cheng Esther Wai Yin Chan Ching Lung Cheung Ivan Chi Ho Au Xi Xiong Wai-Kay Seto Man-Fung Yuen Carlos King Ho wong Ian Chi Kei wong Department of Medicine The University of Hong KongHong KongChina State Key Laboratory of Liver Research The University of Hong KongHong KongChina Department of Pharmacology and Pharmacy The University of Hong KongHong KongChina Laboratory of Data Discovery for Health(D24H) Hong Kong Science and Technology ParkHong KongChina Department of Family Medicine and Primary Care The University of Hong KongHong KongChina School of Nursing The University of Hong KongHong KongChina School of Public Health The University of Hong KongHong KongChina Research Department of Practice and Policy University College LondonLondon WC1E 6BTUnited Kingdom Aston School of Pharmacy Aston UniversityBirmingham B47ETUnited Kingdom

BACKGROUND Chronic liver disease(CLD)was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)*** To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma(HCC)among patients with *** A retrospective,territory-wide cohort of CLD patients was identified from an electronic health database in Hong *** with confirmed SARS-CoV-2 infection[coronavirus disease 2019(COVID-19)+CLD]between January 1,2020 and October 25,2022 were identified and matched 1:1 by propensity-score with those without(COVID-19-CLD).Each patient was followed up until death,outcome event,or November 15,*** outcome was incidence of *** outcomes included all-cause mortality,adverse hepatic outcomes,and different treatment strategies to HCC(curative,non-curative treatment,and palliative care).Analyses were further stratified by acute(within 20 d)and post-acute(21 d or beyond)phases of SARS-CoV-2 *** rate ratios(IRRs)were estimated by Poisson regression *** Of 193589 CLD patients(>95%non-cirrhotic)in the cohort,55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score *** 249-d median follow-up,COVID-19+CLD was not associated with increased risk of incident HCC(IRR:1.19,95%CI:0.99-1.42,P=0.06),but higher risks of receiving palliative care for HCC(IRR:1.60,95%CI:1.46-1.75,P<0.001),compared to *** both acute and post-acute phases of infection,COVID-19+CLD were associated with increased risks of allcause mortality(acute:IRR:7.06,95%CI:5.78-8.63,P<0.001;post-acute:IRR:1.24,95%CI:1.14-1.36,P<0.001)and adverse hepatic outcomes(acute:IRR:1.98,95%CI:1.79-2.18,P<0.001;post-acute:IRR:1.24,95%CI:1.13-1.35,P<0.001),compared to *** Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC,they

关键词： SARS-CoV-2 infection Chronic liver disease Long COVID Post-COVID-19 syndrome Cirrhosis Hepatocellular carcinoma

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Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

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Acupuncture and Herbal Medicine 2024年第1期4卷 102-112页

作者： Yu-Xin Zhu Zi-ling Tang Lu Lu Zuo-Cheng Qiu Dabo Pan Yang Yu Hui-Hui Xiao Man-Sau wong State Key Laboratory of Chinese Medicine and Molecular Pharmacology(Incubation) The Hong Kong Polytechnic University Shenzhen Research InstituteShenzhenChina Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine School of Traditional Chinese MedicineJinan UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of PharmacyJinan UniversityGuangzhouChina Department of Food Science and Nutrition The Hong Kong Polytechnic UniversityHong KongChina Research Center for Chinese Medicine Innovation The Hong Kong Polytechnic UniversityHong KongChina

Objective:Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast *** previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance,a folk herbal medicine used to treat bone fractures and joint diseases in China,exerted bone-protective effects,and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1(TPH-1).However,there is no direct evidence for the action of lignans on *** study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone ***:Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to *** cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 *** serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were ***:The lignans showed high binding scores and binding affinities to TPH-1,inhibited the activity and protein expression of TPH-1,suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral ***:This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases,including osteoporosis.

关键词： Lignan Osteoporosis Sambucus williamsii Hance Serotonin TPH-1 inhibitor

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Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice

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Chinese Journal of Integrative Medicine 2024年第4期30卷 311-321页

作者： Lea ling-Yu Kan Ben Chung-Lap Chan Grace Gar-Lee Yue LI Pei-ting Sharon Sze-Man Hon HUANG Dan-qi Miranda Sin-Man Tsang Clara Bik-San Lau Ping-Chung Leung Chun-Kwok wong Institute of Chinese Medicine The Chinese University of Hong KongHong Kong SARChina State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Chemical Pathology The Chinese University of Hong KongHong Kong SARChina China-Australia International Research Centre for Chinese Medicine School of Health and Biomedical SciencesSTEM CollegeRMIT UniversityBundooraVictoriaAustralia Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong Kong SARHong KongChina

Objective To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula(4HF)and doxorubicin in triple-negative breast cancer(TNBC).Methods Murine-derived triple-negative mammary carcinoma cell line,4T1 cells,was cultured and inoculated into mouse mammary ***-six mice were randomly assigned into 6 groups(n=11 in ench):naive,control,LD 4HF(low dose 4HF),HD 4HF(high dose 4HF),LD 4HF+D(low dose and doxorubicin),and D(doxorubicin).Apart from the naive group,each mouse received subcutaneous inoculation with 5×10^(5)4T1 cells resuspended in 100µL of normal saline in the mammary fat *** from the day of tumor cell inoculation,tumors were grown for 6 *** LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF,*** LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin(5 mg/kg).The D group received weekly intraperitoneal injections of doxorubicin(5 mg/kg).The treatment naive mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a *** control group received daily oral gavage of 0.2 mL double-distilled *** treatment period was 30 *** the end of treatment,mice organs were harvested to analyze immunological activities via immunophenotyping,gene and multiplex analysis,histological staining,and gut microbiota *** Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens(P<0.05),altered the hypoxia and overall immune lymphocyte landscape,and manipulated gut microbiota to favor the anti-tumor immunological ***,immunosuppressive genes,cytokines,and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated(P<0.05).4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective

关键词： adjunctivetherapy breast cancer cytokines Chinese medicine tumor microenvironment

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Caseinolytic mitochondrial matrix peptidase X is essential for homologous chromosome synapsis and recombination during meiosis of male mouse germ cells

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Asian Journal of Andrology 2024年第2期26卷 165-174页

作者： Hai-Wei Feng Yu Zhao Yan-ling Gao Dong-Teng Liu Li-Jun Huo Key Laboratory of Agricultural Animal Genetics Breeding and ReproductionEducation Ministry of ChinaCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan 430070China Shenzhen Key Laboratory of Fertility Regulation Reproductive Medicine CenterThe University of Hong Kong-Shenzhen HospitalShenzhen 518053China Maternal-Fetal Medicine Institute Department of Obstetrics and GynaecologyShenzhen Baoan Women's and Children's HospitalJinan UniversityShenzhen 518100China Department of Obstetrics and Gynaecology Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina

Meiosis is the process of producing haploid gametes through a series of complex chromosomal events and the coordinated action of various *** mitochondrial protease complex(ClpXP),which consists of caseinolytic mitochondrial matrix peptidase X(ClpX)and caseinolytic protease P(ClpP)and mediates the degradation of misfolded,damaged,and oxidized proteins,is essential for maintaining mitochondrial *** has been implicated in meiosis regulation,but its precise role is currently *** this study,we engineered an inducible male germ cell-specific knockout caseinolytic mitochondrial matrix peptidase X(Clpx^(cKO))mouse model to investigate the function of ClpX in *** found that disrupting Clpx in male mice induced germ cell apoptosis and led to an absence of sperm in the ***,it caused asynapsis of homologous chromosomes and impaired meiotic recombination,resulting in meiotic arrest in the zygotene-to-pachytene transition *** loss of ClpX compromised the double-strand break(DSB)repair machinery by markedly reducing the recruitment of DNA repair protein RAD51 homolog 1(RAD51)to DSB *** dysfunction may be due to an insufficient supply of energy from the aberrant mitochondria in Clpx^(cKO) spermatocytes,as discerned by electron ***,ubiquitination signals on chromosomes and the expression of oxidative phosphorylation subunits were both significantly attenuated in Clpx^(cKO) *** together,we propose that ClpX is essential for maintaining mitochondrial protein homeostasis and ensuring homologous chromosome pairing,synapsis,and recombination in spermatocytes during meiotic prophase I.

关键词： ClpX homologous chromosome meiosis mitochondrial recombination synapsis

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Effects of NO_(2) and SO_(2) on the secondary organic aerosol formation fromβ-pinene photooxidation

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Journal of Environmental Sciences 2024年第2期136卷 151-160页

作者： Xiangyu Zang Zhaoyan Zhang Yingqi Zhao Gang Li Hua Xie Weiqing Zhang Guorong Wu Xueming Yang ling Jiang Zhang Dayu School of Chemistry Dalian University of TechnologyDalian 116024China State Key Laboratory of Molecular Reaction Dynamics Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian 116023China University of Chinese Academy of Sciences Beijing 100049China Department of Chemistry School of ScienceSouthern University of Science and TechnologyShenzhen 518055China

Elucidating the effects of anthropogenic pollutants on the photooxidation of biogenic volatile organic compounds is crucial to understanding the fundamental mechanisms of secondary organic aerosol(SOA)***,the impacts of NO_(2)and SO_(2)on SOA formation from the photooxidation of a representative monoterpene,β-pinene,were investigated by a number of laboratory *** results indicated NO_(2)enhanced the SOA mass concentrations and particle number concentrations under both low and highβ-pinene *** could be rationalized that the increased O_(3)concentrations upon the NO_(x)photolysis was helpful for the generation of more amounts of O_(3)-oxidized products,which accelerated the SOA nucleation and *** with NO_(2),the promotion of the SOA yield by SO_(2)was mainly reflected in the increase of mass concentration,which might be due to the elimination of the newly formed particles by the initially formed *** observed low oxidation degree of SOA might be attributed to the fast growth of SOA,resulting in the uptake of less oxygenated gas-phase species onto the particle *** present findings have important implications for SOA formation affected by anthropogenic–biogenic interactions in the ambient atmosphere.

关键词： Secondary organic aerosol Volatile organic compound Anthropogenic pollutant Beta-pinene Photooxidation

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Indications of pro-inflammatory cytokines in laparoscopic and open liver resection for early-stage hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 257-264页

作者： Kevin Tak-Pan Ng Li Pang Jia-Qi Wang wong Hoi She Simon Hing-Yin Tsang Chung Mau Lo Kwan Man Tan To Cheung Department of Surgery HKU-SZH&School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina State Key Laboratory of Liver Research The University of Hong KongHong KongChina

Background:Our clinical practice of laparoscopic liver resection(LLR)had achieved better short-term and long-term benefits for patients with hepatocellular carcinoma(HCC)over open liver resection(OLR),but the underlying mechanisms are not *** study was to find out whether systemic inflammation plays an important ***:A total of 103 patients with early-stage HCC under liver resection were enrolled(LLR group,n=53;OLR group,n=50).The expression of 9 inflammatory cytokines in patients at preoperation,postoperative day 1(POD1)and POD7 was quantified by Luminex Multiplex *** relationships of the cytokines and the postoperative outcomes were compared between LLR and ***:Seven of the circulating cytokines were found to be significantly upregulated on POD1 after LLR or OLR compared to their preoperative *** to OLR,the POD1 levels of granulocytemacrophage colony-stimulating factor(GM-CSF),interleukin-6(IL-6),IL-8,and monocyte chemoattractant protein-1(MCP-1)in the LLR group were significantly *** POD1 levels of these cytokines were significantly correlated with longer operative time and higher volume of blood loss during *** levels of these cytokines were positively associated with postoperative liver injury,and the length of hospital ***,a high level of IL-6 at POD1 was a risk factor for HCC recurrence and poor disease-free survival after liver ***:Significantly lower level of GM-CSF,IL-6,IL-8,and MCP-1 after liver resection represented a milder systemic inflammation which might be an important mechanism to offer better short-term and long-term outcomes in LLR over OLR.

关键词： Laparoscopic liver resection Open liver resection Hepatocellular carcinoma Postoperative cytokines Inflammatory responses

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Inferior vena cava reconstruction in extended right hepatectomy

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Hepatobiliary & Pancreatic Diseases International 2024年第5期23卷 533-534页

作者： Karin KY Ho Sui ling Sin Kin Pan Au Henry HY Lee Daniel TL Chan Albert Chan Department of Surgery The University of Hong Kong102 Pok Fu Lam RoadHong KongChina Department of Surgery Yan Chai Hospital7 Yan Chai StreetHong KongChina State Key Laboratory of Liver Research(Li Ka shing Faculty of Medicine The University of Hong Kong)102 Pok Fu Lam RoadHong KongChina

To the Editor : Barcelona Clinic Liver Cancer(BCLC) Stage C hepatocellular carcinoma(HCC) with vascular invasion has been considered unresectable. However, the curative rate from systemic treatment is rather dismal. Even with the use of immunotherapy, complete remission is less than 10% [ 1 ]. On the contrary, recent advances in transplant oncology, especially in the application of liver transplant-related surgical techniques in complex liver resections, make the operation possible for patients with locally advanced HCC who were previously considered to be unresectable [ 2 ]. We hereby present the surgical management of a patient with giant HCC in right liver lobe with inferior vena cava(IVC) invasion.

关键词： invasion vena Liver

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设计消亡中的咸海——人类世背景下景观美学与效能的融合

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景观设计学（中英文） 2024年第1期12卷 96-105页

作者：王爱玲美国哈佛大学设计研究生院剑桥02138

本文以咸海作为景观设计干预的场地,探索在不可逆的人为损害环境的背景下,景观设计师应该如何巧妙地融合美学与效能,使逐渐消逝的湖泊在人类世背景下以尊严和美感谢幕。文章提出,针对咸海的设计方案不仅旨在保留其现有部分,更在于赋予... 详细信息

本文以咸海作为景观设计干预的场地,探索在不可逆的人为损害环境的背景下,景观设计师应该如何巧妙地融合美学与效能,使逐渐消逝的湖泊在人类世背景下以尊严和美感谢幕。文章提出,针对咸海的设计方案不仅旨在保留其现有部分,更在于赋予正在消失的景观新的生态价值和意义。本研究认为,在对遭遇人为破坏的景观进行设计时,应着重思考如何使人类清晰地认识到自身对土地的影响,并通过设计手段来纾解人们因环境退化而产生的生态悲伤。本文强调,设计过程必须考量“非人类因素”及其作用,从而更全面地应对挑战。在针对咸海的设计方案中,本文提出了一系列创新措施,包括构建盐池系统、实施耕作措施、建造捕沙沙丘和设置生态标识。设计拟采用场地中的自然资源(如沙石和自然盐等无机材料)和植被等有机材料,以减缓咸海的消亡。本文深入探讨了应对咸海生态悲伤的设计策略,倡导景观设计不仅要从解决问题的角度出发,还应深刻理解非人类因素对于景观效能的影响。文章突出了人类世背景下与环境和物质共存的必要性,通过探讨场地中的物质作为非人类因素在景观效能中的角色,推动从以人类为中心的景观保护观念向感激自然界所有组成部分的态度转变,消解对生态破坏的罪责感及人类作为环境保护唯一媒介的无力感。设计中采用的地球工程学方法和对沙漠材料性能的研究,展现了景观设计如何能与咸海的自然元素和材料互动,以营造一种超越人类中心主义的美学视角。文章的核心目标在于通过设计激发人们对生态的新认知,使人们在人类世背景下深刻体会咸海的消逝,并通过突出自然元素的效能来缓和这一消逝过程,开辟新的生态可能性。

关键词：人类世景观景观美学非人类纠缠咸海沙漠化生态意识生态悲伤

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