86 research outputs found
The effect of long-term dietary restriction on insulin signaling pathway in rat brain during aging
No full textStarenje je normalan, fiziološki proces koji obuhvata sve organe i organske sisteme i tokom koga se organizam suočava sa nizom strukturnih i funkcionalnih promena. Starenje mozga je izrazito kompleksan proces, predstavljen nizom sukcesivnih događaja koji postepeno rezultiraju gubitkom kognitivnih i motornih funkcija. Postoji niz farmakoloških i sredinskih faktora koji su u stanju da odlože i/ili uspore mnoge od starosno-zavisnih procesa, a dijetalna restrikcija (DR) je jedna od najviše i najduže istraživanih. Mnogobrojni su eksperimentalni i epidemiološki podaci koji govore u prilog korisnih efekata restriktivnog režima ishrane, bez obzira da li se radi o svakodnevnoj, ili intermitentnoj dijeti, smanjenju količine hrane ili kalorija. Međutim, u poslednje vreme se sve više pojavljuju podaci koji dovode u pitanje univerzalnost korisnog dejstva dijete. Da bi ovakva intervencija postigla svoj optimalni efekat, neophodno je povesti računa o određenim specifičnostima prilikom uspostavljanja restriktivnog režima ishrane. Pre svega, pokazano je da stepen restrikcije igra bitnu ulogu u efektima koje ona proizvodi i da previše restriktivan režim ishrane može imati negativne posledice po organizam. Takođe, postoje indicije da nisu svi organski sistemi podjednako podložni procesima starenja, kao ni dejstvu dijete. Efekat dijete se može veoma razlikovati u zavisnosti od stepena i tipa restrikcije, pola i organa gde se efekat očekuje, kao i od starosti jedinke na koju se restriktivni režim primenjuje. Prvi korak u istraživanju korisnih efekata restrikcije hrane koja je iznosila 60% prosečnog dnevnog unosa hrane, bio je ispitati efekat različitih dijetalnih režima, odnosno efekte DR koja je različito trajala i koja je započeta u različitim životnim dobima kod mužjaka Wistar soja pacova. Praćen je čitav niz parametara u aktivnosti životinja i detektovane su značajne razlike u njihovim fizičkim i kognitivnim preformansama, kako tokom starenja, tako i pod uticajem različitih režima ishrane. Dugotrajna dijetalna restrikcija otpočeta u adultnom dobu je dovela do poboljšanja u izvođenju motoričkih i kognitivnih testova i do sveukupnog poboljšanog stanja organizma, što se ogledalo u smanjenoj krhkosti ovih životinja. Nasuprot tome, restriktivni režimi istog tipa, ali kasnijeg početka i/ili kraćeg trajanja, pokazali su se kao neuspešni u pokušaju da se izazovu korisni efekti i poboljša stanje organizma. Dijeta sa izrazito kasnim početkom i kratkog trajanja je dovela čak i do negativnih posledica po organizam, izazivajući dodatne poteškoće u habituaciji životinja i povečavajući njihovu krhkost. Shodno detektovanim rezultatima, za dalji nastavak istraživanja je izabrana dijeta za koju je pokazano da daje nedvosmisleno dobar efekat i dalje je ispitivan njen uticaj na energetski metabolizam mozga. Smatra se da je narušavanje homeostaze energetskog metabolizma jedan od vodećih uzroka koji leži u osnovi brojnih neurodegenerativnih bolesti koje se javljaju tokom starenja. Ključnu ulogu u metabolizmu glukoze i održavanju energetske homeostaze imaju proteini insulinskog signalnog puta koji su odgovorni za regulaciju unosa hranjivih materija, zatim AMPK kao glavni energetski senzor ćelije i glukozni transporteri koji omogućavaju ulazak glukoze u mozak i nervne ćelije. Novija istraživanja ukazuju da pomenuti proteini imaju važnu ulogu u procesima koji leže u osnovi efekata DR na starosno-zavisne promene. Upravo zato, važan aspekt ove doktorske disertacije predstavljao je ispitivanje promena u ekspresiji glukoznih transportera, AMPK proteina, Neuropeptida Y, insulina, insulinskog receptora, supstrata insulinskog receptora i protein kinaze B. Ispitivanja su sprovedena na nivou kore prednjeg mozga, hipokampusa i hipotalamusa, struktura u kojima je pokazano da dolazi do znatnog narušavanja energetske homeostaze tokom starenja. Dobijene promene su sagledane u odnosu na promene relevantnih biohemijskih parametara u serumu, kao što su glukoza, insulin, holesterol i trigliceridi. Zaključeno je da dugotrajna dijetalna restrikcija dovodi do niza promena, koje uključuju povećanje nivoa NPY proteina i insulina, utišavanje insulinskog signalnog puta u hipotalamusu i hipokampusu, kao i do bolje snabdevenost kore velikog mozga i hipokampusa dovoljnom količinom energije. Sve ove promene su zajedno doprinele poboljšanju kognitivnih i motoričkih performansi životinja u dubokoj starosti. Rezultati ove doktorske disertacije upućuju na korisnost restriktivnog režima ishrane, ali istovremeno nameću limite u pogledu trenutka uvođenja ovakvog režima ishrane i dužine trajanja, uzimajući u obzir negativne efekte do kojih DR može dovesti u određenim slučajevima.Aging is a normal, physiological process that involves all organs and organic systems, and during which the organism faces a number of structural and functional changes. Brain aging is an extremely complex process, represented by a series of successive events that gradually result in loss of cognitive and motor functions. There are a number of pharmacological and environmental factors that are able to postpone and / or slow down many of the age-dependent processes, and dietary restriction (DR) is one of the most investigated and most widely used experimental intervention in aging research. There are numerous experimental and epidemiological data that support the beneficial effects of a restrictive diet, regardless of the type: a daily reduction or intermittent diet, reduction in food or in calories, all of those approaches seem beneficial. Nevertheless, there is a body of data that challenges current premise about comprehensive DR usefulness. In order for DR to achieve its optimal effect, it is necessary to take certain specificities into account while establishing a restrictive dietary regime. First of all, it has been shown that the percentage of restriction plays an important role in the effects it induces, and that a very restrictive diet may have negative consequences for the organism. In addition, not all the body systems are equally susceptible to aging processes, nor to the beneficial effects of DR. The effect of the restrictive diet can vary greatly, depending on the degree and type of restriction, gender and organs examined, as well as the age of the individual to which the restrictive regimen is applied. In order to investigate the effect of 60% DR on the energy homeostasis and insulin signaling in the brain, we first examined the effects of three different types of dietary restriction that varied in length and onset, on rat behavior during aging. The experiments were performed on 12-, 18- and 24-month-old male Wistar rats exposed to AL or DR type of feeding (60% of AL daily intake). A variety of parameters were monitored in the activities of animals and significant differences in their physical and cognitive performance were detected, both during aging and under the influence of different dietary regimes. Long-term dietary restriction that started in young adulthood led to the improvement of motor and cognitive performances and to the reduced frailty. By contrast, restrictive regimes of the same type, but with late-onset and/or the shorter duration, have a less pronounced positive impact on motor and cognitive functions during aging. A diet that started at old age and had the shortest duration has even led to negative consequences, causing additional difficulties in the habituation of animals, and increased their frailty score. Based on results mentioned above and the most favorable outcome of DR, we continued to investigate the longest dietary regime and its effect on brain metabolism during aging. Disruption of homeostasis in the brain energy metabolism is considered to be one of the leading causes that lie behind many age-related neurodegenerative diseases. The key proteins that regulate processes of glucose metabolism and energy homeostasis are: AMPK, as the main energy cell sensor, glucose transporters that facilitate glucose transport across the blood-brain-barrier and plasma membrane, and proteins involved in insulin signaling pathway, responsible for the regulation of nutrient intake. These proteins play an important role in processes involved in the effects of DR on age-dependent changes. For this reason, we examined changes in the expression of glucose transporters, AMPK protein, Neuropeptide Y, insulin, Insulin Receptor, Insulin Receptor Substrate, and Protein Kinase B. The analysis was performed in cerebral cortex, hippocampus and hypothalamus, structures most severely affected by process of aging and also with important role in energy homeostasis. Relevant biochemical parameters in the serum were also investigated, such as glucose, insulin, cholesterol, and triglycerides. The most pronounced changes elicited by long-term restrictive regime were related to increased levels of insulin and NPY proteins, as well as attenuation of the insulin signal pathway in the hypothalamus and the hippocampus, and improved energy supply of cortex and hippocampus. All the above changes resulted in a significant improvement of cognitive and motor performances of 24 month-old animals. The results of this doctoral dissertation point to the usefulness of a restrictive diet, but at the same time impose certain limits, regarding the time point when the diet should be applied and also the duration of diet, taking into account the negative effects that DR may have in certain cases.
Impact of fermented foods consumption on gastrointestinal wellbeing in healthy adults: a systematic review and meta-analysis
No full textObjective: In recent years, the consumption of fermented foods (FFs) has been
linked with gastrointestinal health and wellbeing. Here, we systematically review
and meta-analyse the currently available evidence relating to this as part of
the COST Action PIMENTO and guided by the European Food Safety Authority
(EFSA) health claim dossiers.
Methods: MEDLINE, Scopus and Cochrane CENTRAL bibliographic libraries
were searched for relevant literature up to 31st January 2025. All eligible
studies were included for narrative review as per EFSA guidelines, but only
randomised controlled trials (RCTs) were considered for meta-analyses. Risk of
bias, mechanisms of action, bioactive compounds and safety were additionally discussed. Data was pooled using mean difference (MD)/standardized MD for continuous data and relative risk (RR) for dichotomous data. Certainty of evidence was evaluated through GRADE assessment.
Results: A total of 25 studies (19 RCTs included in meta-analysis) with 4,328 participants were included in the systematic review. Meta-analysis demonstrated the beneficial impact of FF consumption on frequency of bowel movements (MD 0.60, CI 0.04, 1.16, p = 0.04, I2 = 74%), stool consistency (Bristol Stool Form Scale) (MD 0.25, CI 0.03, 0.47, p = 0.03, I2 = 72%), gastrointestinal symptoms (SMD −0.60, CI −1.05, −0.15, p = 0.009, I2 = 90%) and intestinal transit time (−13.65 CI −21.88, −5.43, p = 0.001, I2 = 95%), among others. Certainty of evidence was highly variable and mostly low.
Conclusion: Our analysis suggests that FF consumption beneficially impacts the frequency of bowel movements, stool consistency, incidence of hard stools, intestinal transit time, abdominal symptoms, bloating, borborygmi, flatulence and degree of constipation.
Systematic review registration: This study was registered at the Open Science Framework (osf.io, registration number: q8yzd)
The role of fermented foods in managing food allergies in children and adults: a systematic review
No full textIntroduction: Fermented foods are among the oldest foods produced, and
several different health benefits are attributed to their consumption even in the
absence of concrete clinical evidence. To address this gap, this systematic review
focuses on the effects of the consumption of fermented foods on food allergies. Methods: This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the relevant European Food Safety Authority guidelines. A systematic search strategy was established and registered in a study protocol in Open Science Framework. Scopus, MEDLINE, and Cochrane Library were searched with specific strings targeting human studies focusing on Fermented food and food allergies. Inclusion and exclusion criteria were defined based on the People Intervention Comparison Outcome elements. The Cadima tool was used to perform screening and selection of articles. A standard template was used for data extraction. Risk of bias assessment was performed using the Risk of Bias 2.0 Tool, Risk of Bias in Non-randomized Studies - of Interventions, or Newcastle–Ottawa Scale protocols. Additionally, a narrative section was written based on the European Food Safety Authority guidelines for the mechanism of action and product characteristics for evidence support.Results: From a total of 558 initial records, 10 studies were finally selected. Fermented foods evaluated were fermented soy products, baked goods, fruit-based beverages, vinegar-treated foods, oat-based drinks, and dairy products (yogurt, cheese). In several studies, a reduced allergenicity was reported that was related to fermentation-mediated hydrolysis of allergenic proteins of gluten or soy. Additional mechanisms were related to anti-allergic immunomodulatory effects or favorable shifts in gut microbiota composition. In one case, fermented food consumption led to aggravation of the allergic response, presumably due to the compounds generated during soy fermentation. Risk of bias assessment revealed that most studies were performed with important methodological limitations. Conclusion: While fermented foods hold promise in reducing food allergenicity and promoting tolerance, current evidence is limited to draw solid conclusions. Rigorous, well-designed human clinical trials, complemented by mechanistic studies in vitro and in vivo, are needed to clarify the role of fermented foods as dietary or even clinical tools to combat food allergies
The effect of a restricted feeding regimen of different duration on behavior and the mTOR signaling pathway in the cortex and hippocampus of aging male and female Wistar rats
No full textStarenje je složen biološki proces praćen postepenim gubitkom fizoloških funkcija i promenama u strukturi i funkciji svih sistema, pa i nervnog. Kao jedna od najefikasnijih intervencija u produženju životnog veka i odlaganju starosno zavisnih promena se pokazala dijetalna restrikcija (DR), definisana kao smanjenje kalorijskog unosa bez pothranjenosti. Međutim, o uticaju koji ima starost organizma i dužina trajanja DR na korisne efekte po kojima je DR poznata, se malo zna.
U ovoj studiji ispitan je uticaj 40% DR različitog trajanja i početka na promene telesne mase, preživljavanje, krhkost, ponašanje, ekspresiju dopaminskih receptora i mTOR signalizaciju kod mužjaka i ženki Wistar pacova. Kod 18-mesečnih ženki, DR je smanjila smrtnost, poboljšala memoriju i smanjila anksiozno ponašanje, bez obzira na to da li je započeta u ranom ili kasnom periodu života, dok je kod starih ženki efekat zavisio od trenutka otpočinjanja DR. Kod mužjaka, DR je povećala preživljavanje i smanjila krhkost, ali nije poboljšala memoriju, dok je anksioznost bila povećana u svim grupama. Ekspresija proteina mTOR signalnog puta se menjala u zavisnosti od pola, starosti organizma i dužune trajanja DR. Rezultati ističu ključnu ulogu pola i vremena otpočinjanja DR. Iako rezultati potvrđuju da je DR moćna strategija za zdravo starenje negativni efekti kasno započete DR naglašavaju važnost definisanja optimalnog vremenskog okvira za uvođenje DR, ukazujući na potrebu za personalizovanim pristupom u u intervencijama za odlaganje starosnih promena.Aging is a complex biological process characterized by a gradual loss of physiological functions accompanied with changes in the structure and function of all systems, including the nervous system. Dietary restriction (DR), defined as a reduction in caloric intake without malnutrition, has proven to be one of the most effective interventions for extending lifespan and delaying age-related changes. However, data are lacking on how the onset and duration of DR, as well as sex, influence its beneficial effects.
This study examined the effects of 40% DR of various duration and onset on body weight, survival, frailty, behavior, dopamine receptor expression, and mTOR signaling in male and female Wistar rats. In 18-month-old females, DR reduced mortality, improved memory, and decreased anxiety-related behavior, regardless of whether it was initiated early or late in life, while the effect in older females depended on the timing of when DR was initiated. In males, DR increased survival and reduced frailty, but did not improve memory, whereas anxiety was heightened in all groups. The expression of proteins in the mTOR signaling pathway varied depending on sex, age, and the duration of DR.
The results highlight the critical roles of sex and the timing of DR initiation. Although the findings confirm that DR is a powerful strategy for healthy aging, the negative effects of late-started DR emphasize the importance of defining an optimal timeframe for implementing DR, indicating the need for a personalized approach in interventions aimed at delaying age-related changes
The effect of a restricted feeding regimen of different duration on behavior and the mTOR signaling pathway in the cortex and hippocampus of aging male and female Wistar rats
No full textStarenje je složen biološki proces praćen postepenim gubitkom fizoloških funkcija i promenama u strukturi i funkciji svih sistema, pa i nervnog. Kao jedna od najefikasnijih intervencija u produženju životnog veka i odlaganju starosno zavisnih promena se pokazala dijetalna restrikcija (DR), definisana kao smanjenje kalorijskog unosa bez pothranjenosti. Međutim, o uticaju koji ima starost organizma i dužina trajanja DR na korisne efekte po kojima je DR poznata, se malo zna.
U ovoj studiji ispitan je uticaj 40% DR različitog trajanja i početka na promene telesne mase, preživljavanje, krhkost, ponašanje, ekspresiju dopaminskih receptora i mTOR signalizaciju kod mužjaka i ženki Wistar pacova. Kod 18-mesečnih ženki, DR je smanjila smrtnost, poboljšala memoriju i smanjila anksiozno ponašanje, bez obzira na to da li je započeta u ranom ili kasnom periodu života, dok je kod starih ženki efekat zavisio od trenutka otpočinjanja DR. Kod mužjaka, DR je povećala preživljavanje i smanjila krhkost, ali nije poboljšala memoriju, dok je anksioznost bila povećana u svim grupama. Ekspresija proteina mTOR signalnog puta se menjala u zavisnosti od pola, starosti organizma i dužune trajanja DR. Rezultati ističu ključnu ulogu pola i vremena otpočinjanja DR. Iako rezultati potvrđuju da je DR moćna strategija za zdravo starenje negativni efekti kasno započete DR naglašavaju važnost definisanja optimalnog vremenskog okvira za uvođenje DR, ukazujući na potrebu za personalizovanim pristupom u u intervencijama za odlaganje starosnih promena.Aging is a complex biological process characterized by a gradual loss of physiological functions accompanied with changes in the structure and function of all systems, including the nervous system. Dietary restriction (DR), defined as a reduction in caloric intake without malnutrition, has proven to be one of the most effective interventions for extending lifespan and delaying age-related changes. However, data are lacking on how the onset and duration of DR, as well as sex, influence its beneficial effects.
This study examined the effects of 40% DR of various duration and onset on body weight, survival, frailty, behavior, dopamine receptor expression, and mTOR signaling in male and female Wistar rats. In 18-month-old females, DR reduced mortality, improved memory, and decreased anxiety-related behavior, regardless of whether it was initiated early or late in life, while the effect in older females depended on the timing of when DR was initiated. In males, DR increased survival and reduced frailty, but did not improve memory, whereas anxiety was heightened in all groups. The expression of proteins in the mTOR signaling pathway varied depending on sex, age, and the duration of DR.
The results highlight the critical roles of sex and the timing of DR initiation. Although the findings confirm that DR is a powerful strategy for healthy aging, the negative effects of late-started DR emphasize the importance of defining an optimal timeframe for implementing DR, indicating the need for a personalized approach in interventions aimed at delaying age-related changes
Evaluating frailty scores across experimental groups in rodent models: Bridging physical and cognitive domains
No full textFrailty, a reversible clinical geriatric syndrome, impairs the ability to maintain homeostasis,
leading to severe consequences such as hospitalization and death. Cognitive frailty, characterized
by the co-occurrence of physical frailty and cognitive impairment, has garnered increasing
attention in recent years. Preclinical models, especially rodent studies, are essential for
understanding frailty and developing interventions to mitigate associated conditions. Traditionally,
animal studies have focused solely on physical frailty. We have pioneered the inclusion of
cognitive parameters by developing a novel physical-cognitive frailty score (FS) in animal
research, in order to assess the effectiveness of anti-aging interventions. Here, we provide a
detailed example of the FS calculation at the group level, which can serve as a guide for other
studies. This dual-focus approach also helps in understanding how physical frailty and cognitive
impairment interact to exacerbate adverse health outcomes and provides an opportunity to evaluate
potential interventions that target both physical and cognitive dimensions of frailty more reliably
The role of the author in the hagiographic narrative: Selected examples of Serbian lives
No full textThe theoretical and historical questions discussed in this paper concern the
relationship between the hagiographical text, its author and its audience.
Within the overall structure of the work, the author’s role as the direct or
indirect witness to the story of the holy man and his deeds is analyzed by
using characteristic examples from Serbian hagiographies and their models
belonging to the Byzantine hagiographical tradition
The Role of Nutrition in Brain Aging: Modulating Neural Health through Diet
No full textNutrition plays an important role in maintaining brain health, particularly during
aging, by supporting cognitive function, preserving synaptic plasticity, reducing
inflammation and oxidative stress, and enhancing the brain's resilience to agerelated
decline. Over the past two decades, our laboratory has systematically
investigated the impact of nutritional interventions, primarily dietary/caloric
restriction (DR/CR) on the aging brain. Our findings demonstrate that both lifelong
and late-onset dietary restriction have robust effects on neuronal structure,
function and behavior. We demonstrated that CR consistently influences general
activity, cognitive performance, and frailty level in aged rodent models, with lifelong
regimens showing the most profound effects. Structurally, CR preserves synaptic
integrity and plasticity in key brain regions by maintaining the expression of key
presynaptic and postsynaptic components. Metabolically, different feeding
schedules modulate energy homeostasis in specific brain regions and show regiondependent
resilience to aging. Importantly, our studies reveal that the timing and
duration of dietary restriction are critical: early initiation (young adulthood) of the
restricted diet leads to more pronounced benefits, while application later in life still
provides neuroprotective but less consistent benefits. However, late-onset and
short-term restriction lead to adverse effects on several levels, which has to be
taken into account when choosing caloric restriction as an antiaging strategy.
Overall, our work emphasizes that strategic dietary modulation supports synaptic
maintenance, metabolic health and resilience in the aging brain. These findings
provide a solid foundation for the implementation of nutritional strategies in human
interventions aimed at preserving cognitive health and delaying neurodegenerative
processes across the lifespan.Dragić M, editor. Book of abstracts: 9th Congress of Serbian Neuroscience Society; 2025 Oct 6-8; Belgrade, Serbia. Belgrade: Serbian Neuroscience Society; 2025
The effects of food restriction on anxiety level and dopaminergic system during aging in male Wistar rats
No full textAims: Food restriction (FR) ¬is well known as an environmental intervention efficient in delaying aging and age-related disorders. Important role in the regulation of food intake plays the gut-brain dopamine (DA) axis. Dopamine is a neurotransmitter involved in regulation of brain’s rewarding and pleasure centers, who’s signaling is indispensable to survival and maintenance of eating patterns. Reversely, reduced food intake affects DA circuits and behaviors controlled by DA, including anxiety. Herein we investigated mechanisms through which FR affects anxiety and the role of dopaminergic system in this process.
Methods: 60% FR of various onset and duration (FR1, FR2 and FR3) was implemented as a feeding regime for aging male Wistar rats. Open field test and light-dark box were used to investigate effects of age and food restriction on anxiety-like behavior. Western blot and PCR were used to determine the changes at the transcriptional and translational level.
Results: Open field test showed an increased general activity of animals under FR1 in comparison to the controls, while FR2 and FR3 seemed to have deleterious effect on anxiety level. Light-dark box confirmed deleterious effect of FR2 and FR3 regimens. Changes detected on behavioral level were accompanied with the specific changes in the level of dopaminergic receptors.
Conclusions: Our results showed that food restriction is not universally beneficial, but depends on age when implemented. We showed that FR-induced effects can vary from anxiolytic to anxiogenic, while the components of DA circuits in the brain show region-specific response to FR.Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book: 2019 Dec 6-8; Belgrade, Serbia. Belgrade: Institute for Biological Research "Siniša Stanković", University of Belgrade; Immunological Society of Serbia; 2019. p. 73
The effects of different dietary regimens on cholesterol metabolism in the cerebellum of aging rats
No full textAims: Dietary restriction (DR) has numerous beneficial effects on organism, starting from positive effect on life expectancy, to protective effects on cardiovascular system, blood lipid levels, immune response, glucoregulation, and neurological functions. Previously it has been shown that DR changes expression of genes and proteins involved in cholesterol metabolism, in both cerebral cortex and hippocampus. Herein we investigated cholesterol homeostasis in cerebellum, as a brain structure involved in motor and cognitive functions.
Methods: We examined the effect of 4 different DR regimens (intermittent fasting and limited daily feeding of various onset and duration), on cholesterol metabolism in cerebellum of aging male Wistar rats. We used western blot to examine changes in the level of proteins playing the major roles in cholesterol biosynthesis (SREBP1 and HMGCR), transport (ApoE and LRP1) and elimination from the brain (CYP46).
Results: Detected changes in the expression level of selected proteins indicated that the effect of DR is highly dependent on the type of dietary regimen and the age when implemented. Positive effect is mainly noticed in the group of 18 months old rats.
Conclusions: This study showed the potential of dietary restriction as an alternative to pharmacological treatment of high blood cholesterol levels and confirmed beneficial effects of DR as a healthy lifestyle in prevention of age related disorders.Isaković A, editor. Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. Belgrade: Serbian Neuroscience Society; 2019. p. 497
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