Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries
1Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027, Australia
2School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, 6009, Australia
3McCusker Alzheimer's Research Foundation, Hollywood Medical Centre, 85 Monash Avenue, Suite 22, Nedlands, 6009, Australia
- Corresponding Author:
- Dr. Ian Martins
School of Medical Sciences
Edith Cowan University
270 Joondalup Drive, Joondalup
Western Australia 6027, Australia
E-mail: [email protected]
Received Date: September 04, 2013; Accepted Date: October 04, 2013; Published Date: October 07, 2013
Citation: Martins IJ (2013) Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries. J Mol Genet Med S1:001.
Copyright: © 2013 Martins IJ. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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The incidence of global obesity and Type 2 diabetes has increased and is predicted to rise to 30% of the global population. Diet and lifestyle factors are incapable to resolve the increased incidence for obesity and diabetes in various populations of the world. Developing countries have come to the forefront because of the higher diabetic epidemic. The urbanization may possibly provide an explanation for the global diabetic epidemic. In Western countries the metabolic syndrome and non alcoholic fatty liver disease (NAFLD) have reached 30 % of the population and now at present NAFLD afflicts 20% of developing populations. Western diets and sedentary lifestyles cause metabolic disorders in developing countries which may increase neurodegenerative diseases by the disrupted metabolism of xenobiotics in urban populations. In developing countries access to high calorie diets in urban areas down regulate
liver nuclear receptors that are responsible for glucose, lipid and toxicological sensing and interrupt the metabolism of xenobiotics that become toxic to various tissues such as the pancreas, heart, kidney, brain and liver. Xenobiotics in urban areas induce epigenetic changes that involve chromatin remodelling by alterations in transcriptional regulators with modification of histones. Dysfunction of nuclear receptors such as the calorie sensitive sirtuin 1 (Sirt 1) gene involves abnormal nutrient metabolism with insulin resistance, NAFLD, energy balance and circadian rhythm disorders. In obesity and diabetes insulin resistance has been connected to poor xenobiotic metabolism
with the toxic affects of increased xenobiotic transport to the brain associated with neurodegeneration. Dietary interventions to increase xenobiotic metabolism are likely to reduce oxidative stress and neuroendocrine disease in developing countries. Prevention programs are an important goal of international health organizations and in developing countries the plans to adapt a healthy diet, active lifestyle and reduced exposure to xenobiotics are important to manage the global epidemic for obesity and diabetes.
Diabetes; Genomic instability; Xenobiotic; Non alcoholic
fatty liver disease; Nuclear receptors; Developing countries
Developing countries are important to the understanding of disease
processes related to the molecular basis of cell dysfunction and these
populations can be used to test the hypothesis of the origins and cause of
the metabolic syndrome, accelerated obesity and cardiovascular disease
in Western populations. In previous studies disorders such as obesity
and diabetes were lower in developing countries and were related to
diet, lifestyle and exercise. In developing countries the rapid migration
from the rural to urban areas can be used as a model [1,2] and may be
an important factor that has accelerated the global diabetic epidemic
which has spread to developing countries. The global rise in obesity
and severity of diabetes may allow the interpretation of risk factors in
developing countries that may possibly explain the cause of early nuclear
and cellular dysfunction in Western communities. Interests in the
gene environment interactions that change gene expression that affect
cellular glucose and lipid metabolism are of considerable interest. Diets
high in calories with alcohol consumption in developing countries may
affect gene-environment interactions. Developing countries in urban
areas may differ from developed countries in relation not only to the
calorie content of the diet but also the presence of specific chemicals
such as xenobiotics and xenometals. In developing countries (urban
areas) access to high calorie diets may downregulate liver nuclear
receptors that are responsible for toxicological sensing and interrupt
the metabolism of xenobiotics which may rise in the blood plasma
with transport to various cells and tissues such as the pancreas, heart,
kidney, brain, liver and lungs. The relationship between the food intake
and equilibration of xenobiotics or xenometals to various tissues has
now become important to the development of insulin resistance and may explain the rise in obesity in developing countries with relevance
to the global diabetes epidemic and neurodegeneration (Figure 1) [3-5].
Figure 1: Western diets induce the metabolic syndrome, NAFLD and disrupt
Developing countries may now consume saturated fat similar to
Western countries that may lead to hyperphagia, obesity and diabetes
[3,4] being the major disorders in Western communities. In urban
areas access to high calorie foods may possibly explain the rise (20%)
in non alcoholic fatty liver disease (NAFLD) in developing countries
with NAFLD as high as 30% in Western countries [6-8]. The effects
of alterations in diets and lifestyle in developing countries possibly
promote highly reactive intermediates that are toxic to the cell (nuclear
apoptosis) with insulin resistance, abnormal liver lipid metabolism
and the development of the metabolic syndrome in these countries.
Epigenetic alterations in cells possibly lead to various other diseases
such as cardiovascular disease, gall bladder disease, Parkinson’s disease
(PD) and Alzheimer’s disease (AD) that are associated with severity of
diabetes and accelerated aging. The global obesity and diabetic epidemic
in developing countries require special attention for the understanding
of various molecular mechanisms that are involved in the induction or
prevention of chronic disease manifestation.
Increased Global Obesity and Diabetes with the
Metabolic Syndrome, NAFLD and Neurodegeneration
The global metabolic syndrome that now includes the under
developed countries indicates that the major endocrine disorder is
insulin resistance. The metabolic syndrome and NAFLD have affected
60% of individuals in developed and developing countries [6-8]. These
insulin resistant individuals become hypercholesterolemic with hepatic
insulin resistance playing a pivotal role in lipoprotein abnormalities.
Lipoprotein metabolism is disturbed in these individuals with increased
lipid accumulation and excess lipids that are stored in adipose tissue. In
obese individuals the classification of obesity is with a body mass index
that is greater than 30.0 Kg/m2. The liver and its disease progression
(NAFLD) with poor lipid metabolism may responsible for the increased
adiposity in obese individuals [9,10] and associated with the induction
of the severity of the metabolic syndrome and diabetes in developing
Developing countries are referred to as the countries of Africa,
Asia, Latin America and Oceania. In developing countries by 2025
individuals with obesity and diabetes are projected to increase to
115 million and the diabetic epidemic will affect countries such as in
Asia and Oceania (Samoa) [11,12]. Extensive literature search by the
World Health Organization conducted with terms such as obesity,
insulin resistance, the metabolic syndrome, diabetes, dyslipidemia,
nutrition and physical activity in developing countries between 1966
to June 2008 indicate that the improved economic situation in these
developing countries is associated with increasing prevalence of obesity
and the metabolic syndrome in adults and children. The number of
people with diabetes is projected to double in developing regions such
as Africa, Asia, and India [12,13]. In Asia the diabetic epidemic has
escalated and accounts for 60% of the world diabetic population .
The diabetic epidemic has been associated with NAFLD in developing
countries of Latin America, Asia, India and Africa with prevalence (20-
40 %) similar to developed countries [15-17]. Evidence from various
studies indicate that environmental factors are the major determinants
of the increasing rates of diabetes with the development of diabetes at a
younger age in Asian populations. Rapid urbanization from 20 to 60%
has occurred in Africa, India, China and Asia and possibly involved
with the large global diabetic population in these developing countries
[17-21]. Poor nutrition transition with increased consumption of
energy dense foods and edible oils, sedentary lifestyles, alcohol,
polluted environments, poor physical activity and overcrowding possibly contribute to increased social stress that may be responsible
for the dramatic increase in these chronic diseases [21-23].
Polluted environments contain chemical compounds foreign to
animals and humans are referred to as xenobiotics that include drugs,
drug metabolites, and environmental compounds such as pollutants
that are not produced by the body. In the environment xenobiotics
include synthetic pesticides, herbicides, chemicals and industrial
pollutants that pollute the air and water [24-26]. Global disability
adjusted life years (DALYS) attributable to air pollution from industry
in these developing countries is estimated to be 17 million . Several
studies show that air and water environmental pollution in developing
countries especially in densely populated urban areas may contribute
to at least 20% of chronic diseases and possibly to deaths of millions of
people annually in these countries. Alcohol ingestion has been shown
to be increased in developing communities that corrupt xenobiotic
metabolism . Increased cigarette smoking (tobacco) allow the entry
of xenometals such as heavy metals (lead, cadmium, manganese, iron,
copper, strontium, rubidium, nickel, zinc, zirconium and chromium)
and chemical elements such as (sulfur, chlorine, potassium, calcium
and bromine) into the body with toxic effects to the liver and brain
Chronic neurodegenerative diseases associated with Type 2
diabetes have been shown to increase with age in developed countries
and recent studies indicate that obesity and diabetes are associated with
these neurodegenerative diseases especially those related to AD and PD
[27-29]. Studies have concluded that AD is now referred to as Type 3
diabetes and is primarily involved with neurodegeneration and insulin
resistance. Neurodegenerative diseases that involve diabetes include
ataxia-telangiectasia, Friedreich ataxia, Huntington disease, Prader-
Willi syndrome, Werner syndrome, Wolfram syndrome, myotonic
dystrophy and Down syndrome/trisomy 21 . In developing
countries neurodegenerative disorders such as AD, dementias,
epilepsy, PD and acute ischemic stroke stand as emerging public health
standards and are closely associated with the increased prevalence in
obesity and the metabolic syndrome in these developing communities
Gene Environment Interactions induce Epigenetic
Alterations in Obesity and Diabetes
The gene-environment interaction in developing countries
indicates that urbanization facilitates increased access to food which
leads to induction of epigenetic alterations that are associated with
lipid and glucose dyshomeostasis as well as greater adiposity in obese
individuals. High calorie diets regulate transcriptional responses with
DNA modifications that include DNA methylation, histone tails,
chromatin and micro RNA alterations that regulate DNA expression
and promote chronic disease susceptibility. Urban environments
may contain xenobiotics (soil, water, air) that may also contribute to
epigenetic modifications and contribute to the global rise in obesity in
these developing countries [32-41].
The alterations in glucose and lipid metabolism in obese individuals
involve nuclear receptor dysfunction that promotes liver disease [42-46]. Altered glucose and lipid metabolism in obesity are associated with
liver nuclear receptor dysfunction with an increase in lipid storage in
adipose tissue. Alterations in the transcriptional regulation of nuclear
receptors are responsible for changes in energy and glucose metabolism
and involve the peroxisome proliferator-activated receptor gamma
(PPAR gamma) and PPARalpha, beta/delta that are responsible for
fatty acid, triglyceride, and lipoprotein metabolism . The liver X receptors (LXR)/ liver receptor homolog-1 (LRH-1) is responsible
for reverse cholesterol transport, cholesterol absorption and bile acid
metabolism regulated by the farnesol X receptor (FXR), LXRs, and
LRH-1 receptors. Pregnane X receptor (PXR) and the constitutive
androstane receptor (CAR) have endobiotic functions that impact on
glucose and lipid metabolism with affects on the metabolic syndrome
associated with the pathogenesis of metabolic diseases [48-51]. The
nuclear receptor aryl hydrocarbon receptor has also been closely
associated with NAFLD . Liver nuclear receptors such as PXR,
CAR and xenobiotic sensing nuclear receptor (SXR) are responsible
for the detection of foreign toxic substances (xenobiotics) and respond
by the expression of cytochrome p 450 (CYP 450) enzymes involved
in the defense against xenobiotics (drugs) for rapid clearance by the
liver [53,54]. Liver nuclear receptors are involved in the metabolism
of nutrients (glucose, fatty acid and cholesterol), bile acid and drug
metabolism [54-58] and closely involved in the pathogenesis of chronic
diseases such as NAFLD, obesity, diabetes, atherosclerosis, gall bladder
disease [59-61] and neurodegeneration.
The gene environment interactions induce epigenetic changes
involve alterations in nuclear receptors with chromatin remodelling
that are linked to obesity and diabetes. High fat and high cholesterol
diets interfere with nuclear receptors and chromatin remodelling
that are linked to oxidative stress, insulin resistance and NAFLD.
Interest in calorie restriction and transcriptional regulation of nuclear
receptors has increased and these receptors are closely involved
with insulin resistance. Dietary regulation of the nuclear receptors
involves the calorie sensitive anti-aging gene Sirtuin 1 (Sirt 1) that is
principally involved in obesity, liver lipid metabolism (NAFLD) and
brain neuronal proliferation with close links to the development of AD
[61,62]. Sirt1 is a NAD+ dependent protein deacetylase and is involved
in the deacetylation of the nuclear receptors (Figure 2) with its critical
involvement in insulin resistance [63,64].
Figure 2: Sirtuin 1 regulation of chromatin structure and gene expression with
effects on obesity and diabetes.
Sirt 1 is involved in metabolic regulation and in the repair of
deoxyribonucleic acid (DNA) damage with epigenetic alterations
involving histone deacetylation in chromatin [65,66]. Sirt 1
involvement in PXR activation occurs by deacetylation of the PXR liver
receptor [67,68] and is linked to protection of DNA by xenobiotics
with epigenetic alterations involving histone deacetylation [69-71].
Sirt1 maintains the DNA to prevent gene modification of various
genes including CYP 450 enzymes  and allows rapid metabolism
of xenobiotics that enter the organism. In under developed countries
urbanization and Western diet changes involve Sirt 1dysregulation
caused by alterations in transcriptional regulators and modification of
chromatin that contribute to endocrine abnormalities such as insulin
resistance, NAFLD and energy balance disorders [73-79].
Interests in calorie restriction and neurodegeneration involve
Sirt 1 mediated deacetylation of the transcriptional factor FoxO3a
that represses Rho-associated protein kinase-1 gene expression and
activation of the non amyloidogenic α-secretase processing of the
amyloid precursor protein (APP) with the reduction of amyloid
beta (Aβ) generation . Environmental changes with dietary
consumption of xenobiotics affect chromatin remodelling that
regulate gene expression with affects on appetite and hyperphagia
that promotes obesity, diabetes and neurodegeneration [81,82].
Interests in transcriptional factors (co-regulator complexes) modify
Sirt 1chromatin interactions and nutrient, drug and toxin metabolism
[81-83]. Environmental inhibitors modify Sirt1 and its regulators with
modifications in chromatin structure and prevent activators of Sirt1
that regulate appetite and food intake . In developing countries movement of populations from rural to urban regions alter Sirt1 and
nuclear receptor interactions that act as metabolic and toxicological
sensors that allow populations to adapt to environmental changes.
High calorie diets down regulate nuclear Sirt 1 activity disrupted
xenobiotic or xenometal metabolism that alters gene expression with
the acceleration in aging and the development of obesity and diabetes
in these populations.
Metabolic Disorders Affect the Metabolism of Xenobiotics and Increase the Concentration of Neurotoxins
Major threats of xenobiotics such as environmental pollutants
(Figure 3) may increase with age in individuals from developing
countries [85-89]. These xenobiotics allow induction of various
chronic illnesses such as obesity and diabetes by alteration in liver
and brain function. The global obesity epidemic (30%) now includes
the developing countries (20%) and is possibly connected to the large
diabetic population in developing countries with unhealthy diets and
poor liver xenobiotic metabolism involved in the severity of diabetes
[90-94]. In obesity and diabetes the liver and brain have been found
to be diseased with insulin resistance connected to the peripheral
organ disease progression . Obese and diabetic individuals have
blood brain barrier (BBB) disorders  and loss of BBB trafficking of
chemicals, xenobiotics or xenometals [96-98] to the brain may increase
the risk of neuronal apoptosis with the promotion of neuroendocrine
disease and the increased risk for PD in these individuals [96,97-99].
Association between xenobiotics and insulin resistance adds support to
the affects of xenobiotics on their receptors CYP 450 in liver and brain
cells of obese and diabetic individuals [100-104].
Figure 3: Nuclear receptors control xenobiotic metabolism with effects on
DNA modification and neuron apoptosis.
In experimental animals high fat diets were closely associated
with disturbances in the suprachiasmatic nucleus and appetite control
with the abnormal involvement of Sirt1 in the central control of
circadian rhythms [105-111]. Sirt 1’s abnormal involvement in food
intake and appetite regulation has been associated with the risk for
obesity [107,110,111]. The clearance, metabolism and elimination
of xenobiotics are controlled by nuclear receptors (Sirt1/PXR) and
the circadian regulation of CYP450 enzymes that are involved in
xenobiotic and nutrient metabolism [49,112-114]. High calorie diets
with lifestyle alterations after relocation to urban areas possibly delays
the metabolism of xenobiotics with induction of cardiovascular disease
[115-121] metabolic diseases such as obesity and diabetes [11,122] and
relevance to drug induced Parkinsonian and neurodegeneration in
these countries [123-125].
Accelerated neurodegeneration such as in PD and AD is connected
to the diabetic global epidemic with insulin resistance and abnormal
peripheral glucose and lipid metabolism. Excess xenobiotics (CNS
drugs, CAD drugs, anti-cancer drugs, antimicrobial, antiviral,
compounds) are possibly involved in the molecular mechanisms of
neuroendocrine disease that is linked to diabetes, PD and AD. Organic
pollutants in the environment are higher in developing countries and
the half life of xenobiotics by poor hepatic metabolism is decreased with
the increase in NAFLD (20%) and diabetes associated with these under
developed countries (Figure 3). Loss of hepatic cholesterol metabolism
as associated with NAFLD is closely connected to poor liver Aβ
homeostasis with consequences to severe neurodegeneration such as
PD and AD. In 60% of individuals in global populations (developed
and developing countries) the peripheral sink Aβ hypothesis is absent
since NAFLD has increased to nearly half of the world population and
ill affects of poor xenobiotic and hepatic Aβ metabolism correlated
with toxic affects to various tissues such as the heart and brain [61,62].
Interests in xenobiotic metabolism have escalated recently since
xenobiotics are involved in the generation of reactive intermediates
that corrupt DNA repair and promote DNA modifications [126-128].
Xenobiotics release reactive electrophiles that are possibly connected to
nuclear aggregation and endoplasmic reticulum (ER) stress  with
protein deposits in cells (Figure 4). The damage to DNA occurring in
neuronal cells with xenobiotics is with the formation of DNA adducts, DNA strand breakage and altered DNA function [127,130]. Sirt 1 is
closely involved in with chromatin modification and protection of
neurons from genotoxic stress with the involvement of DNA repair
enzymes and repair of double strand breaks in damaged chromatin
structure [131,132]. In liver and brain cells with low Sirt 1 activity
electrophiles from xenobiotic metabolism react with micro ribonucleic
acid (RNA) [133-135] or by covalent binding to nucleophillic centres
in cellular protein and DNA [136-139]. Adduct formation disrupts
DNA or protein structure with damage to the nucleus and various
subcellular organelles [128,130,140] such as the ER and mitochondria
with metabolic alterations. Diets that disrupt Sirt 1’s protection of
ER stress are also implicated in mitochondrial dysfunction with
the essential role of Sirt 1 and nuclear receptors in the maintenance
of the mitochondria and their biogenesis [140-143]. Xenobiotics
promote oxidative stress with the release of radicals that cause chain
reactions with the attack on DNA, lipids, proteins and carbohydrates.
Xenobiotics generate electrophilic intermediates that involve abnormal
protein folding as assessed by quality control mechanisms such as the
unfolded protein response and the deposition of unfolded proteins
in the ER. As nutrient levels rise Sirt 1 activity falls and xenobiotic
oxidative processes rise with protein misfolding connected with insulin
resistance in neurodegenerative diseases such as PD and AD.
Figure 4: The effects of xenobiotics on nuclear apoptosis and ER stress in
obesity and diabetes.
Unhealthy Diet, Drugs and Lifestyle Induce Chronic
Disease and Neurodegeneration
Populations that consume alcohol and tobacco such as that in
developing countries may inhibit hepatic nuclear receptors with
alterations in metabolic regulation of cholesterol, fatty acids, glucose
and toxic chemicals. Alcohol is a Sirt1 inhibitor [144-147] and its
consumption may promote hepatic dysfunction such as alcoholic
fatty liver with the ill affects on hepatic xenobiotic metabolism that are
now released to various organs in the periphery and brain. Activators
of hepatic Sirt 1 are important to prevent chronic diseases with the
maintenance of liver nuclear receptors and regulation of nutrient and
xenobiotic metabolism [61,62] Foods that contain toxic xenobiotics
 induce genotoxic stress with chromatin modifications that leads
to hepatic DNA damage and NAFLD that threaten the survival of
various obese and diabetic individuals [148,149].
Interest in fat consumption (low or high) may require further
evaluation and may contain lipophillic xenobiotics. Lipophillic
xenobiotics [150,151] such as aldrin and dieldrin may rapidly transport
across membranes to various cells and tissues may not be processed by
the liver. Gene-environment interactions that lead to changes in diet
and appetite affect peripheral gene expression with the development of
the metabolic syndrome and possibly involve the excess consumption
of lipophillic xenobiotics found in fat (milk) that are toxic to the
neurons in the central nervous system. Rapid xenobiotic metabolism
is triggered by low calorie diets and poor nutrition leads to abnormal
xenobiotic metabolism with significant affects on DNA strand breakage
with cell apoptosis. Compounds such as reservatrol (Sirt1 activator)
are essential to maintain the DNA repair [152-154] and are involved
in inhibition of CYP450 enzymes required for xenobiotic metabolism
In developing countries higher environmental organic pollutants
can enter the water supply and foods such as vegetables, rice, fruits,
meat and dairy products. Consumption of water and food may
release xenobiotics that may alter cellular DNA and RNA related to
the epigenetic changes in metabolic diseases and neurodegeneration
(Figure 5). Food monitoring for xenobiotics and xenometals has become of central interest to prevent chronic diseases and acceleration of aging
with the prevention of ingestion of toxic chemicals, xenobiotics and
organic pollutants (88-90). In Western communities nutritional diets
are of importance to prevent NAFLD and improve hepatic xenobiotic
metabolism in these communities. Xenobiotics and its connections
with various chronic diseases may involve abnormal xenobiotic
biotransformation and their reactions such as oxidation, conjugation
and reduction are important to its rapid metabolism and excretion
in bile and urine. Chronic diseases such as gall bladder disease and
hypothyroidism has increased with the metabolic syndrome and gall
bladder removal now closely related to NAFLD [157,158]. The slow
metabolism of xenobiotics in individuals with insulin resistance 
may lead to dysfunction of the thyroid and hypothyroidism is now
involved with the progression to obesity and diabetes [160-162].
Figure 5: Nutritional diets and active lifestyle improve xenobiotic metabolism
and reduce chronic diseases such as obesity, diabetes and neurodegenration
in developing countries.
Anti-obese drug therapy in obese individuals may be more useful
and successful with consumption of selected foods that are very low
in xenobiotics, chemicals or xenometals that allowing the the liver to
rapidly clear these toxic compounds from the periphery before entering
the brain (Figure 5). Anti-steatotic diets and drug treatment may
accelerate clearance of liver xenobiotics by improving insulin resistance
and expression of CYP450 expression [102-104] in obese or diabetic
individuals. Other behavioural factors such as stress and anxiety that
affect the circadian rhythm that regulates xenobiotic metabolism have
become important to various communities. Nutritional diets (plant
versus meat) are designed to maintain the toxicological processing of
xenobiotics with the critical role of liver xenobiotic enzymes (CYP450)
in their metabolism. Micronutrients, minerals and vitamins such
as nicotinamide, riboflavain, niacin, folic acid, vitamin E, vitamin
A are essential for xenobiotic metabolism . Diets that contain
appropriate protein quality, carbohydrate and lipid (polyunsaturated)
content are essential for xenobiotic metabolism and nutritional
deficiency has been closely related to poor xenobiotic metabolism.
In various regions in developed and underdeveloped countries the
incidence of overweight and obesity has been closely connected to the
diabetic epidemic. Urbanization in developing countries may possibly
provide an explanation for the global diabetic epidemic. The obesity
and diabetic epidemic in developing countries require urgent attention
to maintain cellular DNA and RNA and reverse epigenetic changes
induced by diet and xenobiotics that accelerate insulin resistance,
cardiovascular disease and neurodegeneration. Severity of the world
wide diabetic epidemic may be controlled by consumption of low calorie nutritional diets that are designed to maintain liver glucose, lipid and
xenobiotic metabolism and prevent genotoxic stress that is associated
with the increase in the diabetic epidemic and neurodegeneration in
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