Translocator protein and neurodegeneration: insights from Alzheimer’s disease

The 18 kDa translocator protein(TSPO)located on the outer mitochondrial membrane regulates several key cellular processes including mitochondrial homeostasis,cholesterol transport,apoptosis,cell proliferation,and maintenance of mitochondrial health(Rupprecht et al.,2022,2023).TSPO is expressed in both peripheral organs and the central nervous system,with a more pronounced expression in tissues that produce steroids.The main reason why TSPO has garnered so much attention is because it plays a key role in neurosteroidogenesis by transferring cholesterol from the outer to the inner mitochondrial membrane,which is the rate-limiting step in neurosteroid synthesis.A cholesterol-recognizing amino acid consensus domain has been identified in the cytosolic C terminus of the TSPO protein by both in vitro and site-directed mutagenesis experiments(Li et al.,2001).However,the role of TSPO in the process of neurosteroid synthesis has been challenged by several studies,particularly TSPO knockout models,which suggest that TSPO removal does not affect the phenotype or the system’s viability(Tu et al.,2014).However,ligands targeting TSPO have been shown to enhance levels of neurosteroids which suggests that neurosteroidogenesis is one of the major functional roles mediated by the TSPO protein.

Global transplantation:Lessons from organ transplantation organizations worldwide

Although national transplant organizations share common visions and goals,the creation of a unified global organization remains impractical.Differences in ethnicity,culture,religion,and education shape local practices and infrastructure,making the establishment of a single global entity unfeasible.Even with these social disparities aside,logistical factors such as time and distance between organ procurement and transplantation sites pose significant challenges.While technological advancements have extended organ preservation times,they have yet to support the demands of transcontinental transplantations effectively.This review presents a comparative analysis of the structures,operational frameworks,policies,and legislation governing various transplant organizations around the world.Key differences pertain to the administration of these organizations,trends in organ donation,and organ allocation policies,which reflect the financial,cultural,and religious diversity across different regions.While a global transplant organization may be out of reach,agreeing on best practices for the benefit of patients is essential.

Lesson learnt from 60 years of liver transplantation:Advancements,challenges,and future directions

Over the past six decades,liver transplantation(LT)has evolved from an experimental procedure into a standardized and life-saving intervention,reshaping the landscape of organ transplantation.Driven by pioneering breakthroughs,technological advancements,and a deepened understanding of immunology,LT has seen remarkable progress.Some of the most notable breakthroughs in the field include advances in immunosuppression,a revised model for end-stage liver disease,and artificial intelligence(AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT,paired with ever-evolving technological advances.Additionally,the refinement of transplantation procedures,resulting in the introduction of alternative transplantation methods,such as living donor LT,split LT,and the use of marginal grafts,has addressed the challenge of organ shortage.Moreover,precision medicine,guiding personalized immunosuppressive strategies,has significantly improved patient and graft survival rates while addressing emergent issues,such as short-term complications and early allograft dysfunction,leading to a more refined strategy and enhanced postoperative recovery.Looking ahead,ongoing research explores regenerative medicine,diagnostic tools,and AI to optimize organ allocation and posttransplantation car.In summary,the past six decades have marked a transformative journey in LT with a commitment to advancing science,medicine,and patient-centered care,offering hope and extending life to individuals worldwide.

Safety Evaluation of Myricetin and Crude Extract from Myrica rubra Leaves on Non-target Organisms

[ Objective] The study aimed to supply important basis for developing environment-friendly pesticides with myricetin and crude extract of Myrica rubra leaves as effective components. [ Method] According to ＂Test guidelines for environmental safety evaluation on chemical pesticides＂, the toxicity of myricetin and crude extract of M. rubra leaves on non-target organisms was determined and the safety evaluation was carried out. [Result] MyriceUn and crude extract of M. rubra leaves had low toxicity on non-target organisms, such as earthworm, silkworm and soil microbes. Myricetin showed low toxicity and the crude extract of M. rubra leaves showed middle toxicity on tadpole. The high-concentration crude extract of M. rubra leaves had some antifeedant effect on silkworm. [ Conclusion] Myricetin and crude extract of M. rubra leaves had low toxicity on non-tar- get organisms in environment and they were relatively safe.

Removal of Nitrogen, Phosphorus, and Organic Pollutants From Water Using Seeding Type Immobilized Microorganisms

Objective To study the possibility of removing nitrogen, phosphorus, and organic pollutants using seeding type immobilized microorganisms. Methods Lakes P and M in Wuhan were chosen as the objects to study the removal of nitrogen, phosphorus, and organic pollutants with the seeding type immobilized microorganisms. Correlations between the quantity of heterotrophic bacteria and the total nitrogen （TN）, total phosphorus （TP）, and total organic carbon （TOC） in the two lakes were studied. The dominant bacteria were detected, inoculated to the sludge and acclimated by increasing nitrogen, phosphorus and decreasing carbon source in an intermittent, time-controlled and fixed-quantity way. The bacteria were then used to prepare the seeding type immobilized microorganisms, selecting diatomite as the adsorbent cartier. The ability and influence factors of removing nitrogen, phosphorus, and organic pollutant from water samples by the seeding type immobilized microorganisms were studied. Results The coefficients of the heterotrophic bacterial quantity correlated with TOC, TP, and TN were 0.9143, 0.8229, 0.7954 in Lake P and 0.9168, 0.7187, 0.6022 in Lake M. Ten strains of dominant heterotrophic bacteria belonging to Pseudomonas, Coccus, Aeromonas, Bacillus, and Enterobateriaceae, separately, were isolated. The appropriate conditions for the seeding type immobilized microorgansims in purifying the water sample were exposure time=24 h, pH=7.0-8.0, and quantity of the immobilized microorganisms=0.75-1g/50 mL. The removal rates of TOC, TP, and TN under the above conditions were 80.2%, 81.6%, and 86.8%, respectively. Conclusion The amount of heterotrophic bacteria in the two lakes was correlated with TOC, TP, and TN. These bacteria could be acclimatized and prepared for the immobilized microorganisms which could effectively remove nitrogen, phosphorus, and mixed organic pollutants in the water sample.

HEAVY METAL CONCENTRATION AND ITS EVALUATION IN THE ORGANISMS FROM MEIZHOU BAY

The present paper reports Zn,Cu,Pb,Cd,Ni,Fe,Mn and Co contents in the tissues of oyster,solen,red-tail prawn,sea eel and kelp,taken from Meizhou Bay(and analysed by flame atomicabsorption spectrophotometry after wet digestion)in June 1992,and also the concentration factors esti-mated from the mean metal concentrations in the organisms and water there.Heavy metal concentrationsin every species of the organisms followed the pattern:Fe,Mn,Cu,Zn】Pb,Cd,Ni,Co and in variousorganisms showed considerable variation.In general,levels of most of these metals were in the order:softtissues of the bivalves】the kelp】muscles of the red-tail prawn,the sea eel.The greatest concentrationof most metals was found in the gill or viscera of the sea eel,whereas the muscle tissues,in general,con-tained only low concentrations of them.The Cu,Zn concentration factors of the oyster were higher by1—2 orders of magnitude than that of the other organisms.The observed heavy metal levels were closeto those reported from various

Unveiling Organic Electrode Materials in Aqueous Zinc-Ion Batteries:From Structural Design to Electrochemical Performance

Aqueous zinc-ion batteries(AZIBs)are one of the most compelling alternatives of lithium-ion batteries due to their inherent safety and economics viability.In response to the growing demand for green and sustainable energy storage solutions,organic electrodes with the scalability from inexpensive starting materials and potential for biodegradation after use have become a prominent choice for AZIBs.Despite gratifying progresses of organic molecules with electrochemical performance in AZIBs,the research is still in infancy and hampered by certain issues due to the underlying complex electrochemistry.Strategies for designing organic electrode materials for AZIBs with high specific capacity and long cycling life are discussed in detail in this review.Specifically,we put emphasis on the unique electrochemistry of different redox-active structures to provide in-depth understanding of their working mechanisms.In addition,we highlight the importance of molecular size/dimension regarding their profound impact on electrochemical performances.Finally,challenges and perspectives are discussed from the developing point of view for future AZIBs.We hope to provide a valuable evaluation on organic electrode materials for AZIBs in our context and give inspiration for the rational design of high-performance AZIBs.

Significant contributions of the petroleum industry to volatile organic compounds and ozone pollution:Insights from year-long observations in the Yellow River Delta

The petroleum industry is a significant source of anthropogenic volatile organic compounds(VOCs),but up to now,its exact impact on urban VOCs and ozone(O_(3))remains unclear.This study conducted year-long VOC ob-servations in Dongying,China,a petroleum industrial region.The VOCs from the petroleum industry(oil and gas volatilization and petrochemical production)were identified by employing the positive matrix factorization model,and their contribution to O_(3) formation was quantitatively evaluated using an observation-based chemical box model.The observed annual average concentration of VOCs was 68.6±63.5 ppbv,with a maximum daily av-erage of 335.3 ppbv.The petroleum industry accounted for 66.5%of total VOCs,contributing 54.9%from oil and gas evaporation and 11.6%from petrochemical production.Model results indicated that VOCs from the petroleum industry contributed to 31%of net O_(3) production,with 21.3%and 34.2%contributions to HO_(2)+NO and RO_(2)+NO pathways,respectively.The larger impact on the RO_(2) pathway is primarily due to the fact that OH+VOCs ac-count for 86.9%of the primary source of RO_(2).This study highlights the critical role of controlling VOCs from the petroleum industry in urban O_(3) pollution,especially those from previously overlooked low-reactivity alkanes.

Chlorophenols in marine organisms from the southern coast of Hangzhou Bay,China,and an assessment of risks posed to human health

The composition of chlorophenols in marine organisms from the southern coast of Hangzhou Bay, China, was analyzed and the health risks posed to humans assessed. A total of 19 chlorophenols from 16 types of marine organism were analyzed across nine survey sections in Hangzhou Bay. The chlorophenols were analyzed by gas chromatography-mass spectrometry using a DB-5MS quartz capillary column. The concentrations of monochlorophenol, dichlorophenol, trichlorophenol, tetrachlorophenol, and pentachlorophenol ranged from below the detection limit(ND) to 132 μg/kg, ND–51.0 μg/kg, ND–42.5 μg/kg, ND–69.0 μg/kg, and ND–9.06 μg/kg, respectively. Additionally, concentration differences between each type of chlorophenol were not significant( P >0.05). However, significant differences were found between monochlorophenol( F =8.13, P <0.01) and total chlorophenol(F =5.19, P <0.01) concentrations. As the noncarcinogenic risk indices were <0.1(10-5 –10-2) for all of the organisms, no high risk was posed by 2-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol, 2,4,5-trichlorophenol, 2,3,4,6-tetrachlorophenol, and pentachlorophenol to humans consuming marine organisms from the study area. Furthermore, the carcinogenic risks posed by 2,4,6-trichlorophenol and pentachlorophenol were lower than limits set by the International Commission on Radiological Protection and the US Environmental Protection Agency. However, the noncarcinogenic and carcinogenic risks posed by chlorophenols in marine organisms from four of the survey sections(Sizaopu, Niluoshan, Longshan Town and Xinhong zha) were higher than the other survey sections.

Statistical Study of Trace Elemental Concentrations in Major Types of Organisms from Typical Chinese Coastal Waters

Frequency distribution characteristics of trace elements Fe, Mn, Zn, Cu, Sr and Ba are studied for the marine organisms collected from typical Chinese coastal waters and compared with those of major elements Ca and Mg. Nearly all the distributions for trace elements in macroalgae, benthic molluscs, crustaceans, cephalopods and different tissues of fish ( muscle, liver and bone ) are found to show some degree of positive skewness, indicating a relatively large number of marine organisms with low concentrations for a particular element and only a few organisms with disproportionately high concentrations. Their distribution types are generally logarithmic normal distribution or nearly logarithmic normal distribution. Distribution of Ca is similar to that of trace elements, while Mg shows normal distribution. Average elemental concentrations of major types of organisms are calculated based on their frequency distributions.

PI3K/Akt/mTOR Signaling as Targets for Developing Anticancer Agents from Marine Organisms

The PI3K/Akt/mTOR signaling pathway is one of the most frequently dysregulated pathways in cancer.Targeting the PI3K-mediated pathway has been an important strategy for developing novel anticancer agents.In the past decades,more than 40 inhibitors of the PI3K/Akt/mTOR pathway have been developed at different clinical stages.Temsirolimus,everolimus,idelalisib,and copanlisib have been approved for clinical use by the Food and Drug Administration of the United States(FDA).However,the toxic-ity and drug resistance limit their efficiency in the treatment.Novel compounds with greater potency and selectivity,as well as im-proved therapeutic indices with reduced toxicity,are clearly required.Over the past three decades,a lot of bioactive ingredients with anticancer effects by affecting the PI3K-mediated pathways have been found from marine organisms.In the present mini-review,anticancer compounds from marine source that target the PI3K/Akt/mTOR signaling were reviewed.The molecular entities and their modes of action were presented.The marine compounds targeting special factors of the PI3K/Akt/mTOR were highlighted.

An Analysis of the Dilemmas in Rural Modernization From the Perspective of Organism Philosophy

The process of modernization first took place in the city and then gradually extended to the countryside.Therefore the rural modernization has followed development path with the characteristics of urban modernization in many aspects,using modern scientific and technological means to carry out intensive management of enterprises and pursue the high efficient of market economy,and the dominant value evaluation is carried out from the perspective of utilitarianism,which makes some negative effects in the process of urban development gradually shift to the countryside,and brings some“dilemma”problems in rural modernization.The Chinese philosophy of organism pays attention to the study of the vitality of all kinds of organisms.According to the viewpoint of the philosophy of organism under the background of Chinese culture,both urban and rural regions are complex systems,in which coupled by living organism,artificial organism,social organism,and spiritual organism in a number of ways.The“dilemmas”of the process of rural modernization stem from the uncoordinated relations among those organisms.To solve the dilemmas of rural modernization,it is necessary to eliminate the excessive squeeze of technical artifacts(“artificial organism”,in Chinese philosophy of organism)on the human life organism and ecological environment and enhance the vitality of rural development.The philosophy of organism advocates a holistic and organic perspective on the relationship between rural and urban areas,fully aware of organic links in the process of urban and rural development and even the modernization of the country,in terms of people’s concepts and management models.Only when people’s concepts and management patterns change substantially will it be possible to solve the dilemmas of rural modernization.

A New Discovery of Deep-Water Benthic Organisms from the Southwestern Dongsha Area,South China Sea

Dongsha waters are poorly studied for gas hydrates. Previous multi-channel seismic reflection and Chirp sub- bottom profiles show that numerous submarine mounds stand up to 100 m high above the seafloor over the continental slope of the SW Dongsha Island in northern margin of the South China Sea （SCS）. These mounds are characterized by hardened seabed, seafloor gas venting and folded structures, which implies the existence of active mud volcanoes. This work aims to confirm this speculation by seafloor sample dredging and to explore the potential of gas hydrates.

Species Identification of Mealie Meal Spoilage Organisms and Pathogenic Bacteria from Selected Food Stores in Lusaka District of Zambia

Background: Mealie Meal is one of the by-products of maize from dry milling. It constitutes more significant part of the daily diet of growing population of the Lusaka District of Zambia. However, reported cases of a cholera outbreak in October 2017-May 2018 were attributed to water contamination in the households of Lusaka. Hitherto there is no previous study or documented data for gastroenteritis caused by microbial contamination from food stores. Aim: The main objective of the study was to carry out species identification of Mealie meal spoilage organisms and pathogenic bacteria from selected food stores in Lusaka district from September 2019-March 2020. Crosssectional survey was conducted for food spoilage organisms and pathogenic bacteria of packaged maize meal flour from a selected food store. The number of packaged Mealie meal samples from selected food stores included in the study was 143 samples. Samples were obtained by a simple stratified random selection from food stores in Lusaka District. Thus Mealie Meal samples bought from Street food vendors were 96 (67%), Shops—30 (21%), Malls—17 (11.9%). Subsequently isolation by spread and pour plate methods, and species identification of microbial contamination by Cell Culture processes coupled to microbial morphological and biochemical characterization was performed. Microsoft Office Excel (version 2007) Spreadsheet was employed for the categorical data analysis and summarized graphical presentation of data. Laboratory findings revealed: Spoilage organisms—Aspergillum species, Mucor Species, Candida Species, Clostridium Species and Bacillus Species;Pathogenic Bacteria Species—Clostridium perfringens, Staphylococcus aureus, Clostridium tetani, Bacillus, Escherichia coli, Pseudomonas aeruginosa and Yesinia pestis. It can be established from the laboratory results earlier mentioned that the food poisoning outbreak could evolve from food stores in Lusaka district apart from water contamination.

Prevalence of Some World Health Organization Priority Organisms from an Abattoir at Kwata, Anambra State, Nigeria

The abattoir is one of the important sectors in the food industry, therefore the need for close monitoring of everything concerning it to minimize microbial contamination. The aim of the study is to identify bacteria listed as WHO priority organisms associated with meat from Kwata abattoir in Awka, Anambra state. The study was carried out over a three (3) months period from September to December 2022. Thirteen samples were collected from the floor, table, water, meat, knife and soil in the abattoir. The samples were cultured using streak and spread plate methods on MacConkey and Cetrimide agar. The isolates were identified with the following biochemical tests: catalase, oxidase, citrate and indole tests. Ampiclox levofloxacin, gentamicin, ofloxacin impenem ceftraixone, cefixime, cefuroxime and nitrofurantoin were used for sensitivity test following Kirby Bauer disc diffusion method and biofilm formation was determined using the tube method. The 75 isolates obtained were identified as follows;29.3% E. coli, 26.7% Klebsiella spp., 16% Proteus spp., and 28% Pseudomonas spp. The result of antibiotics sensitivity test interpreted using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints showed that (98%) of the isolates were resistant to the antibiotics used. Test for biofilm formation with 52 isolates showed 31 strong, 12 moderate and 9 weak biofilm formers. The result of this study confirms the presence of bacteria contaminants within the WHO priority list in the abattoir, as such there is need for improved handling of animals. Slaughtering, cleaning and distribution of meat should be done using aseptic procedures. .

Bioleaching of vanadium from stone coal vanadium ore by Bacillus mucilaginosus:Influencing factors and mechanism

Vanadium and its derivatives are used in various industries,including steel,metallurgy,pharmaceuticals,and aerospace engineering.Although China has massive reserves of stone coal resources,these resources have low grades.Therefore,the effective extraction and recovery of metallic vanadium from stone coal is an important way to realize the efficient resource utilization of stone coal vanadium ore.Herein,Bacillus mucilaginosus was selected as the leaching strain.The vanadium leaching rate reached 35.5%after 20 d of bioleaching under optimal operating conditions.The cumulative vanadium leaching rate in the contact group reached 35.5%,which was higher than that in the noncontact group(9.3%).The metabolites of B.mucilaginosus,such as oxalic,tartaric,citric,and malic acids,dominated in bioleaching,accounting for 73.8%of the vanadium leaching rate.Interestingly,during leaching,the presence of stone coal stimulated the expression of carbonic anhydrase in bacterial cells,and enzyme activity increased by 1.335-1.905 U.Enzyme activity positively promoted the production of metabolite organic acids,and total organic acid content increased by 39.31 mg·L^(-1),resulting in a reduction of 2.51 in the pH of the leaching system with stone coal.This effect favored the leaching of vanadium from stone coal.Atomic force microscopy illustrated that bacterial leaching exacerbated corrosion on the surface of stone coal beyond 10 nm.Our study provides a clear and promising strategy for exploring the bioleaching mechanism from the perspective of microbial enzyme activity and metabolites.

Accelerating the practical application of MOFs for hydrogen storage-from performance-driven to application-oriented

Metal–organic frameworks(MOFs)are highly promising porous materials known for their exceptional porosity,extensive surface area,and customizable pore structures,making them an ideal solution for hydrogen storage.However,most MOFs research remains confined to the laboratory,lacking practical applications.To address this,the author proposes a shift towards practical applications,the creation of a comprehensive MOFs database,alignment of synthesis with practical considerations,and diversification of MOFs applications.These steps are crucial for harnessing the full potential of MOFs in real-world energy challenges.

Environmental dynamics of nitrogen and phosphorus release from river sediments of arid areas

Human activities lead to the accumulation of a large amount of nitrogen and phosphorus in sediments in rivers.Simultaneously,nitrogen and phosphorus can be affected by environment and re-enter the upper water body,causing secondary pollution of the river water.In this study,laboratory simulation experiments were conducted initially to investigate the release of nitrogen and phosphorus from river sediments in Urumqi City and the surrounding areas in Xinjiang Uygur Autonomous Region of China and determine the factors that influence their release.The results of this study showed significant short-term differences in nitrogen and phosphorus release characteristics from sediments at different sampling points.The proposed secondary kinetics model(i.e.,pseudo-second-order kinetics model)better fitted the release process of sediment nitrogen and phosphorus.The release of nitrogen and phosphorus from sediments is a complex process driven by multiple factors,therefore,we tested the influence of three factors(pH,temperature,and disturbance intensity)on the release of nitrogen and phosphorus from sediments in this study.The most amount of nitrate nitrogen(NO_(3)^(–)-N)was released under neutral conditions,while the most significant release of ammonia nitrogen(NH_(4)^(+)-N)occurred under acidic and alkaline conditions.The release of nitrite nitrogen(NO_(2)^(-)-N)was less affected by pH.The dissolved total phosphorus(DTP)released significantly in the alkaline water environment,while the release of dissolved organic phosphorus(DOP)was more significant in acidic water.The release amount of soluble reactive phosphorus(SRP)increased with an increase in pH.The sediments released nitrogen and phosphorus at higher temperatures,particularly NH_(4)^(+)-N,NO_(3)^(–)-N,and SRP.The highest amount of DOP was released at 15.0℃.An increase in disturbance intensity exacerbated the release of nitrogen and phosphorus from sediments.NH_(4)^(+)-N,DTP,and SRP levels increased linearly with the intensity of disturbance,while NO_(3)^(–)-N and NO_(2)^(–)-N were more stable.This study provides valuable information for protecting and restoring the water environment in arid areas and has significant practical reference value.

Multifaceted functions of Drp1 in hypoxia/ischemia- induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy

Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings.Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia.Dynamin-related protein 1(Drp1)regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications,which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury.However,there is active controversy and gaps in knowledge regarding the modification,protein interaction,and functions of Drp1,which both hinder and promote development of Drp1 as a novel therapeutic target.Here,we summarize recent findings on the oligomeric changes,modification types,and protein interactions of Drp1 in various hypoxic-ischemic diseases,as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia.Additionally,potential clinical translation prospects for targeting Drp1 are discussed.This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.

Laser-forged transformation and encapsulation of nanoalloys:pioneering robust wideband electromagnetic wave absorption and shielding from GHz to THz

The emergence of the internet of things has promoted wireless communication’s evolution towards multi-band and multi-area utilization.Notably,forthcoming sixth-generation(6G)communication standards,incorporating terahertz(THz)frequencies alongside existing gigahertz(GHz)modes,drive the need for a versatile multi-band electromagnetic wave(EMW)absorbing and shielding material.This study introduces a pivotal advance via a new strategy,called ultrafast laser-induced thermal-chemical transformation and encapsulation of nanoalloys(LITENs).Employing multivariate metal-organic frameworks,this approach tailors a porous,multifunctional graphene-encased magnetic nanoalloy(GEMN).By fine-tuning pulse laser parameters and material components,the resulting GEMN excels in low-frequency absorption and THz shielding.GEMN achieves a breakthrough of minimum reflection loss of−50.6 dB in the optimal C-band(around 4.98 GHz).Computational evidence reinforces GEMN’s efficacy in reducing radar cross sections.Additionally,GEMN demonstrates superior electromagnetic interference shielding,reaching 98.92 dB under THz band(0.1–2 THz),with the mean value result of 55.47 dB.These accomplishments underscore GEMN’s potential for 6G signal shielding.In summary,LITEN yields the remarkable EMW controlling performance,holding promise in both GHz and THz frequency domains.This contribution heralds a paradigm shift in EM absorption and shielding materials,establishing a universally applicable framework with profound implications for future pursuits.