scholarly journals Single-dose Levodopa Administration and Aging Independently Disrupt Time Production

2006 ◽  
Vol 18 (3) ◽  
pp. 376-387 ◽  
Author(s):  
Brian C. Rakitin ◽  
Nikolaos Scarmeas ◽  
Tina Li ◽  
Chariklia Malapani ◽  
Yaakov Stern
Keyword(s):  
Aging Effects ◽  
Psychomotor Speed ◽  
Time Intervals ◽  
Double Blind ◽  
Time Production ◽  
Target Time ◽  
Timing Errors ◽  
Timing Effect ◽  
Age Related ◽  
Recall Time

We tested the hypothesis that age-related time production deficits are dopamine-mediated. The experiment was conducted double-blind, and with random assignment of 32 healthy aged and 32 healthy young participants to either inert placebo or levodopa (200 mg) groups. The procedure included training participants to produce two target time intervals (6 and 17 sec) in separate blocks, drug/placebo administration, a 1-hr delay, and then delayed free-recall time production retesting without feedback. Participants also performed a speeded choice reaction time (RT) task, as a control for potential dopaminergic and aging effects on attention and psychomotor speed. Results indicate that during retesting, aged participants show duration-dependent timing errors that are larger than those shown by the young participants. Levodopa administration yielded lengthened time production of both target intervals. The aging and levodopa effects did not interact. Also, aging slowed RT and increased RT variability, but levodopa had no effect on the RT. These results suggest that at this dosage and under these specific conditions, timing is dopamine-mediated but the effect of aging on time production is not. Moreover, the levodopa timing effect cannot be attributed to the effects of dopaminergic function on psychomotor speed.

scholarly journals Strategies and cognitive reserve to preserve lexical production in aging

GeroScience ◽  
2021 ◽  
Author(s):  
Monica Baciu ◽  
Sonja Banjac ◽  
Elise Roger ◽  
Célise Haldin ◽  
Marcela Perrone-Bertolotti ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Aging ◽  
Individual Variability ◽  
Future Research ◽  
Aging Effects ◽  
Main Hypothesis ◽  
Compensatory Strategies ◽  
Age Related ◽  
Complementary Domain

AbstractIn the absence of any neuropsychiatric condition, older adults may show declining performance in several cognitive processes and among them, in retrieving and producing words, reflected in slower responses and even reduced accuracy compared to younger adults. To overcome this difficulty, healthy older adults implement compensatory strategies, which are the focus of this paper. We provide a review of mainstream findings on deficient mechanisms and possible neurocognitive strategies used by older adults to overcome the deleterious effects of age on lexical production. Moreover, we present findings on genetic and lifestyle factors that might either be protective or risk factors of cognitive impairment in advanced age. We propose that “aging-modulating factors” (AMF) can be modified, offering prevention opportunities against aging effects. Based on our review and this proposition, we introduce an integrative neurocognitive model of mechanisms and compensatory strategies for lexical production in older adults (entitled Lexical Access and Retrieval in Aging, LARA). The main hypothesis defended in LARA is that cognitive aging evolves heterogeneously and involves complementary domain-general and domain-specific mechanisms, with substantial inter-individual variability, reflected at behavioral, cognitive, and brain levels. Furthermore, we argue that the ability to compensate for the effect of cognitive aging depends on the amount of reserve specific to each individual which is, in turn, modulated by the AMF. Our conclusion is that a variety of mechanisms and compensatory strategies coexist in the same individual to oppose the effect of age. The role of reserve is pivotal for a successful coping with age-related changes and future research should continue to explore the modulating role of AMF.

scholarly journals Lipid Lowering Therapy with Combination of Niacin and Statin in Women: Age-Related Endothelial Effects

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Beth Parker ◽  
Kamlesh Kothawade ◽  
Namee Kim ◽  
Maura Paul-Labrador ◽  
Noel Bairey Merz ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Vascular Function ◽  
Controlled Trial ◽  
Pearson Correlation ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cardiac Events ◽  
Double Blind ◽  
Lowering Therapy ◽  
Age Related

Background. Many women remain at risk for cardiac events despite treatment to reduce low-density lipoprotein cholesterol (LDL-C). We hypothesized that for postmenopausal women treated with niacin in addition to statin vascular function will improve. Methods. We conducted a randomized, double-blind, placebo-controlled trial of 16 weeks of niacin (N) versus placebo (PL) in 43 women (mean age, 67±9 years) previously on statin therapy. Study outcomes included lipoprotein levels, vascular inflammation assessed by high sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and endothelial function, assessed as brachial artery flow mediated dilation (FMD). Results. The N group significantly increased HDL-C and decreased LDL-C cholesterol relative to PL (both P<0.01). FMD improved in both groups (P=0.02) irrespective of niacin (P=0.21). Age influenced change in FMD (P=0.01) such that improved FMD (before to after) with lipid lowering therapy was greater with older age (P=0.03 Pearson correlation = 0.34), independent of treatment group. Conclusions. Lipid lowering therapy with combination of niacin and statin does not improve inflammation or endothelial function compared to statin alone. However, older women demonstrate relatively greater endothelial benefit of lipid lowering therapy over 4 months. This trial is registered with Clinicaltrials.gov NCT00590629.

Endokrinológiai tényezők és metabolikus folyamatok szerepe az élettartam szabályozásában

2021 ◽  
Vol 162 (33) ◽  
pp. 1318-1327
Author(s):  
Tamás Halmos ◽  
Ilona Suba
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Life Expectancy ◽  
Significant Risk ◽  
Low Grade ◽  
Aging Effects ◽  
Protective Function ◽  
Beneficial Effects ◽  
Age Related

Összefoglaló. Az emberek a lehető leghosszabb ideig akarnak élni, jó egészségben. Ha kiküszöbölnénk a kedvezőtlen külső körülményeket, a várható élettartam meghaladhatná a 100 évet. A 20. és 21. században a jóléti társadalmakban a várható élettartam jelentősen megnőtt, így Magyarországon is. Az áttekintett irodalom alapján megvizsgáltuk, hogy a genetika és az öröklődés mellett milyen endokrinológiai és metabolikus tényezők játszanak szerepet az élet meghosszabbításában. Megvizsgáltunk minden endogén tényezőt, amely pozitívan vagy negatívan befolyásolhatja az életkorral összefüggő betegségeket (Alzheimer-kór, szív- és érrendszeri betegségek, rák) és az élettartamot. Kiemeltük a hyperinsulinaemia, az inzulinrezisztencia, a metabolikus szindróma öregedést gyorsító hatását, az inzulinszerű növekedési hormon-1 ellentmondásos szerepét, valamint az élet meghosszabbításában részt vevő, újabban felfedezett peptideket, mint a klotho és a humanin. Ismertettük a mitochondriumok szerepét az élettartam meghatározásában, bemutattuk a mitohormesis folyamatát és annak stresszvédő funkcióját. Bemutattuk a rapamicin célszervét, az mTOR-t, amelynek gátlása meghosszabbítja az élettartamot, valamint a szirtuinokat. Kitértünk az autophagia folyamatára, és ismertettük a szenolitikumok szerepét az öregedésben. Az időskori autoimmunitás csökkenése hozzájárul az élettartam rövidüléséhez, utaltunk a thymus koordináló szerepére. Kiemeltük a bélmikrobiom fontos szerepét az élettartam szabályozásában. Hivatkoztunk a „centenáriusok” megfigyeléséből nyert humánadatokra. Megvizsgáltuk, milyen beavatkozási lehetőségek állnak rendelkezésre az egészségben tölthető élettartam meghosszabbításához. Az életmódbeli lehetőségek közül kiemeltük a kalóriabevitel-csökkentés és a testmozgás jótékony szerepét. Megvizsgáltuk egyes gyógyszerek feltételezett hatásait. Ezek közé tartozik a metformin, az akarbóz, a rezveratrol. E gyógyszerek mindegyikének hatása hasonló a kalóriamegszorításéhoz. Nincs olyan „csodaszer”, amely igazoltan meghosszabbítja az élettartamot emberben. Egyes géneknek és génmutációknak jótékony hatásuk van, de ezt környezeti tényezők, betegségek, balesetek és más külső ártalmak módosíthatják. Kiemeljük az elhízás, az alacsony fokozatú gyulladás és az inzulinrezisztencia öregedésre gyakorolt gyorsító hatását. A metabolikus szindróma elterjedtsége miatt ez jelentős népegészségügyi kockázatot jelent. Az inzulin, a növekedési hormon és az inzulinszerű növekedési faktorok hatásainak értékelése továbbra is ellentmondásos. Az egészséges, szellemileg és fizikailag aktív életmód, a kalóriacsökkentés mindenképpen előnyös. Az életet meghosszabbító szerek értékelése még vitatott. Orv Hetil. 2021; 162(33): 1318–1327. Summary. People want to live as long as possible in good health. If we eliminate the unfavorable external conditions, the life expectancy could exceed 100 years. In the 20th and 21th centuries, life expectancy in welfare societies increased significantly, including in Hungary. Based on the reviewed literature, we examined what endocrinological and metabolic factors play a role in prolonging life in addition to genetics and inheritance. We examined all endogenous factors that can positively or negatively affect age-related diseases (Alzheimer’s disease, cardiovascular disease, cancer) and longevity. We highlighted the aging effects of hyperinsulinemia, insulin resistance, metabolic syndrome, the controversial role of insulin-like growth factor-1, and more recently discovered peptides involved in prolonging lifespan, such as klotho and humanin. We described the role of mitochondria in determining longevity, we demonstrated the process of mitohormesis and its stress-protective function. We presented the target organ of rapamycin, mTOR, the inhibition of which prolongs lifespan, as well as sirtuins. We covered the process of autophagy and described the role of senolytics in aging. The decrease in autoimmunity in old age contributes to the shortening of life expectancy, we referred to the coordinating role of the thymus. We highlighted the important role of intestinal microbiome in the regulation of longevity. We referred to human data obtained from observations on “centenarians”. We examined what intervention options are available to prolong healthy life expectancy. Among the lifestyle options, we highlighted the beneficial role of calorie reduction and exercise. We examined the putative beneficial effects of some drugs. These include metformin, acarbose, resveratrol. The effect of each of these drugs is similar to calorie restriction. There is no “miracle cure” that has been shown to prolong life-span in humans. Some genes and gene mutations have beneficial effects, but this can be modified by environmental factors, diseases, accidents, and other external harms. We highlight the accelerating effects of obesity, low-grade inflammation, and insulin resistance on aging. Due to the prevalence of metabolic syndrome, this poses a significant risk to public health. The assessment of the effects of insulin, growth hormone, and insulin-like growth factors remains controversial. A healthy, mentally and physically active lifestyle, calorie reduction is definitely beneficial. The evaluation of life-prolonging agents is still controversial. Orv Hetil. 2021; 162(33): 1318–1327.

scholarly journals Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men

2010 ◽  
Vol 299 (4) ◽  
pp. E675-E682 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Paul Y. Takahashi ◽  
Daniel M. Keenan ◽  
Peter Y. Liu ◽  
Kristi L. Mielke ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Negative Feedback ◽  
Pulse Frequency ◽  
Analysis Of Covariance ◽  
Double Blind ◽  
Healthy Men ◽  
Age Related ◽  
Lh Release ◽  
Lh Secretion ◽  
Double Blind Crossover Study

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20–73 yr, BMI 21–32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion ( P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts ( P = 0.025), 3) suppressed incremental GnRH-induced LH release ( P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release ( P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH ( P = 0.002) and T ( P = 0.017) concentrations, 2) accelerating LH pulse frequency ( P = 0.013), 3) amplifying total (basal plus pulsatile) LH ( P = 0.002) and T ( P < 0.001) secretion, 4) shortening LH secretory bursts ( P = 0.032), and 5) reducing LH secretory regularity ( P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion ( P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.

scholarly journals Effects of Dehydroepiandrosterone and Atamestane Supplementation on Frailty in Elderly Men

2006 ◽  
Vol 91 (10) ◽  
pp. 3988-3991 ◽  
Author(s):  
Majon Muller ◽  
Annewieke W. van den Beld ◽  
Yvonne T. van der Schouw ◽  
Diederick E. Grobbee ◽  
Steven W. J. Lamberts
Keyword(s):  
Controlled Trial ◽  
Hormone Replacement ◽  
Subjective Quality Of Life ◽  
Double Blind ◽  
Specific Test ◽  
Age Related ◽  
Strength Tests ◽  
Leg Extensor Power ◽  
General Community

Abstract Background: It has been suggested that the age-related decline of androgens in men plays a distinct role in the development of several aspects of frailty. Therefore, hormone replacement might improve the course of frailty by increasing lean body mass and muscle strength, decreasing fat mass, and improving the subjective quality of life. Objective: The objective of the study was to assess whether hormone replacement with dehydroepiandrosterone (DHEA) and/or atamestane might improve the course of frailty. Design: This was a double-blind, randomized, controlled trial. Setting: The study was conducted in the general community. Participants: Participants included 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength tests. Seventeen participants did not complete the trial. Intervention: Subjects were randomly assigned to one of four intervention arms: atamestane (100 mg/d) and placebo, DHEA (50 mg/d) and placebo, a combination of atamestane (100 mg/d) and DHEA (50 mg/d), or two placebo tablets for 36 wk. Main Outcome Measures: Physical frailty was measured by means of a specific test battery, including isometric grip strength, leg extensor power, and physical performance. Results: The randomization was successful, and 83 (83%) men completed the intervention. There were no differences between the treatment arms and placebo group in any of the outcome measurements after intervention. Conclusions: The results of this double-blind, randomized trial do not support the hypothesis that hormone replacement with DHEA and/or atamestane might improve the course of frailty.

Evaluation of Representative Piping Systems Designed by Implicit Fatigue Concept

2008 ◽  
Author(s):  
Shin-Beom Choi ◽  
Sun-Hye Kim ◽  
Yoon-Suk Chang ◽  
Jae-Boong Choi ◽  
Young-Jin Kim ◽  
...  
Keyword(s):  
Fatigue Life ◽  
Nuclear Power ◽  
Heat Removal ◽  
Environmental Water ◽  
Lessons Learned ◽  
Metal Fatigue ◽  
Aging Effects ◽  
Age Related ◽  
Piping Systems ◽  
Surge Line

NUREG-1801 provides generic aging lessons learned to manage aging effects that may occur during continued operation beyond the design life of nuclear power plant. According to this report, the metal fatigue, among several age-related degradation mechanisms, is identified as one of time-limited aging analysis item. The objective of this paper is to introduce fatigue life evaluation of representative surge line and residual heat removal system piping which was designed by implicit fatigue concept. For the back-fitting evaluation employing explicit fatigue concept, detailed parametric CFD as well as FE analyses results are used. The well-known ASME Section III NB-3600 procedure is adopted for the metal fatigue and NUREG/CR-5704 procedure is further investigated to deal with additional environmental water effects. With regard to the environmental effect evaluation, two types of fatigue life correction factors are considered, such as maximum Fen and individual Fen. As a result, it was proven that a thermal stratification phenomenon is the governing factor in metal fatigue life of the surge line and strain rate is the most important parameter affecting the environmental fatigue life of both piping. The evaluation results will be used as technical bases for continued operation of OPR 1000 plant.

scholarly journals A pilot study of clinical cell therapy for patients with vascular dementia

2021 ◽  
Vol 9 (2) ◽  
pp. 137-150
Author(s):  
Yunliang Wang ◽  
Xiaoling Guo ◽  
Yanqiu Liu ◽  
Yan Li ◽  
Ying Liu ◽  
...  
Keyword(s):  
Pilot Study ◽  
Cell Therapy ◽  
Vascular Dementia ◽  
Clinical Dementia Rating ◽  
Double Blind ◽  
Cell Therapies ◽  
Group Patient ◽  
Verbal Recall ◽  
Human Lifespan ◽  
Age Related

Background:Vascular dementia (VD) is a series of clinical and neurophysiological manifestations caused by cerebrovascular disease. As the human lifespan increases, the number of people affected by age-related dementia is growing at an alarming pace, but no proved therapeutic methods can stop it from getting worse.Objective:To investigate the neurorestorative effects of injecting olfactory ensheathing cells (OECs), Schwann cells (SCs), and olfactory receptor neurons (ORNs) into olfactory sub-mucosa in VD patients.Methods:A pilot study of double-blind randomized controlled cell therapies was conducted in VD patients (n = 5). Cells were injected into the patients’ olfactory sub-mucosa. Two patients received OEC treatment, one received SC treatment, one ORN treatment, and one OEC combined with ORN. Mental state and cognitive function were observed before treatment and 1, 3, 6, and 12 months after treatment. magnetic resonance imaging (MRI) or computed tomography (CT) was performed before treatment and 12 months after treatment.Results:The directional function score on the Mini-Mental Status Examination (MMSE) in the patient who received SC treatment had increased slightly 1 and 3 months after treatment. The scores for orientation, attention, delayed verbal recall, and repetition increased in the ORN group patient 1 month after treatment. The orientation and repetition scores of the ORN group patient continued to increase 3 months after treatment. The scores for attention, delayed verbal recall, and phase 3 command decreased in the OEC and the OEC + ORN group patients after treatment assessment Scores on the Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating (CDR) scale also improved in the ORN group patient. Clinical and MRI or CT examinations did not find any side effects from the cell therapy or transplanting procedure.Conclusion:All of the cell transplantations were found to be safe. ORN was shown to be a promising therapy for VD patients. Phase II clinical trials of ORN, SC, and OEC therapy are required to verify their effects on VD symptoms, especially ORNs.

scholarly journals Sex-dependent Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment

2021 ◽  
Author(s):  
Zhengshi Yang ◽  
Jessica Z.K. Caldwell ◽  
Jeffrey L. Cummings ◽  
Aaron Ritter ◽  
Jefferson W. Kinney ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Functional Connectivity ◽  
Aging Effect ◽  
Analysis Of Covariance ◽  
Aging Effects ◽  
Mixed Effect ◽  
Effect Analysis ◽  
Pathological Aging ◽  
Age Related

Abstract Purpose To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Materials and Methods 277 functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson’s correlation was used to characterize the functional connectivity (FC) between caudate and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4 and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region’s connectivity with caudate. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. Results The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P=6.23x10−7, right: P=3.37x10−8), but not for men (P>0.3 for bilateral caudate). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Conclusion Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

The Storage of Time Intervals Using Oscillating Neurons

1989 ◽  
Vol 1 (3) ◽  
pp. 359-371 ◽  
Author(s):  
Christopher Miall
Keyword(s):  
Nervous System ◽  
Small Group ◽  
Output Unit ◽  
Pacemaker Cells ◽  
Time Intervals ◽  
Common Multiple ◽  
Pacemaker Neurons ◽  
Encoding Scheme ◽  
Output Neuron ◽  
Recall Time

A mechanism to store and recall time intervals ranging from hundreds of milliseconds to tens of seconds is described. The principle is based on beat frequencies between oscillating elements; any small group of oscillators codes specifically for an interval equal to the lowest common multiple of their oscillation periods. This mechanism could be realized in the nervous system by an output neuron, excited by a group of pacemaker neurons, and able to select via a Hebbian rule a subgroup of pacemaker cells to encode any given interval, or small number of intervals (for example, a pattern of pulses). Recall could be achieved by resetting the pacemaker cells and setting a threshold for activation of the output unit. A simulation is described and the main features of such an encoding scheme are discussed.

scholarly journals Aging Effects on Esophageal Transit Time in the Upright Position During Videofluoroscopy

2020 ◽  
Vol 129 (6) ◽  
pp. 618-624
Author(s):  
Kendrea L. (Focht) Garand ◽  
Lindsey Culp ◽  
Bin Wang ◽  
Kate Davidson ◽  
Bonnie Martin-Harris
Keyword(s):  
Age Groups ◽  
Normative Values ◽  
Barium Swallow ◽  
Aging Effects ◽  
Esophageal Function ◽  
Modified Barium Swallow ◽  
Esophageal Transit ◽  
Esophageal Clearance ◽  
Age Related ◽  
Modified Barium Swallow Study

Objectives: The purpose of this study was to examine age-related effects on esophageal transit times (ETT) among healthy adult participants. Methods: A total of 175 healthy, non-dysphagic participants underwent a modified barium swallow study (MBSS), and ETT was recorded for two standardized swallowing tasks. Differences across age groups were determined using Kruskal–Wallis test. Relationships between an Esophageal Clearance (Modified Barium Swallow Impairment Profile Component 17) score and ETT were also explored. Results: No significant differences were observed in ETT across age groups for nectar-thickened liquid ( P = .335) or pudding ( P = .231) consistencies. No significant differences were observed between males and females in ETT for either the nectar ( P = .112) or pudding trial ( P = .817). For nectar, the mean ETT for patients with Component 17 scores of 2 or greater were significantly higher than that of participants with a score of 0 ( P < .0001). For pudding, participants with a score >0 demonstrated significantly higher mean ETT compared to participants with a score of 0 (with P = .0008 and P < .0001, respectively). Conclusion: Study findings failed to support age-related or sex-related differences in ETT for two standardized swallowing tasks administered during a MBSS in healthy individuals. The normative values following a standardized protocol in this study provide guidance in clinical interpretation of esophageal function.

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