boron

Boron

In by Raphikammer

boron is essential for all higher plants in

phylogenetic kingdom Viridiplantae

 

(1) and at least some organisms in the phylogenetic kingdoms Eubacteria (2),

Stramenopila (3), and Animalia (4,5). Specific species in

the kingdom Fungi have a demonstrated physiological

response to boron, an important finding because Fungi

species are thought to share a common ancestor with animals

exclusive of plants (6). Physiologic concentrations of

the element are needed to support metabolic processes in

several species in Animalia. For example, embryological

development in fish and frogs does not proceed normally

in the absence of boron. There is evidence that higher vertebrates,

that is, chicks, rats, and pigs require physiological

amounts of boron to assist normal biologic processes including

immune function, bone development, and insulin

regulation. In humans, boron is under apparent homeostatic

control and is beneficial for immune function and

calcium and steroid metabolism.

 

COMMON CHEMICAL FORMS

Boron is the fifth element in the periodic table with a

molecular weight of 10.81 and is the only nonmetal in

Group III. Organoboron compounds are those organic

compounds that contain B–O bonds, and they also include

B–N compounds, because B–N is isoelectronic with

C–C (7). Organoboron compounds are apparently important

in biological systems and are the result of interaction

with OH or amine groups. Organoboron complexes occur

in plants and are produced in vitro with biomolecules

isolated from animal tissues (8).

 

BORON SPECIATION

Environmental Forms

Boron does not naturally occur free nor bind directly to

any element other than oxygen except for trivial exceptions,

for example, NaBF4 (ferrucite) and (K,Cs)BF4 (avogadrite)

(7). Its average concentration in the oceans is

4.6mg/Land is the 10th most abundant element in oceanic

salts (9). Weathering of clay-rich sedimentary rock is the

major source of total boron mobilized into the aquatic environment

(10). Undissociated boric acid (orthoboric acid)

is the predominant species of boron in most natural freshwater

systems (10) where most concentrations are below

0.4 mg/L and not lowered by typical treatments for drinking

water. The most common commercial compounds

of boron are anhydrous, pentahydrate, and decahydrate

(common name: tincal) forms of disodium tetraborate

(borax, Na2B4O7), colemanite (2CaO°§3B2O3°§5H2O), ulexite

(Na2O°§2CaO°§5B2O3°§16H2O), boric acid (H3BO3), and

monohydrate and tetrahydrate forms of sodium perborate

(NaBO3) (11).

Inorganic boron, within the concentration range

expected for human blood (2–61 M B; 22–659 ng

B/g wet blood) (12), is essentially present only as the

monomeric species orthoboric acid (common name: boric

acid) B(OH)3 and borate, that is, B(OH)4

(13). Boric acid

is an exclusively monobasic acid and is not a proton donor,

but rather accepts a hydroxyl ion (a Lewis acid) and leaves

an excess of protons to form the tetrahedral anion B(OH)4

(14):

B (OH)3

+ 2H2O ⇔ H3O+ + B (OH)

4 pKa = 9.25(25C)

Within the normal pH range of the gut and kidney,

B(OH)3 would prevail as the dominant species (pH 1:

∼100% B(OH)3; pH 9.3: 50%; pH 11: ∼0%) (15).

 

Biochemical Forms

Many biomolecules contain one or more hydroxy groups

and those with suitable molecular structures can react with

boron oxo compounds to form boosters, an important

class of biologically relevant boron species. Several types

of boron esters exist. Boric acid reacts with suitable dihydroxy

compounds to form corresponding boric acid monoesters

(“partial” esterification) (Fig. 1) that retain the

trigonal-planar configuration and no charge.

In turn, a boric acid monoester can form a complex

with a ligand containing a suitable hydroxyl to create

a borate monoester (“partial” esterification; monocyclic)

(Fig. 2), but with a tetrahedral configuration and a negative

charge. A compound of similar configuration and

charge is also formed when borate forms a complex

with a suitable dihydroxy compound. The two types

of boro monoesters can react with another suitable dihydroxy

compound to give a corresponding spirocyclic

borodiester (“complete” esterification) that is a chelate

Figure 1 Boric acid may complex with a suitable dihydroxy ligand to form

a boric acid monoester (“partial” esterification) that retains a trigonal-planar

configuration and no charge.  Borate may complex with a suitable dihydroxy ligand to form

a borate monoester (“partial” esterification; monocyclic) with a tetrahedral

configuration and a negative charge.

complex with a tetrahedral configuration and negative

charge (16)

Boric acid and boric acid–like structures, instead of

borate, are most likely the reactive species with biological

ligands, because it is probably easier for a diol to substitute

for a relatively loosely bound water molecule associated

with boric acid or a boric acid-like structure than it is for

the diol to substitute for a charged hydroxyl ion in borate

or a borate-like structure (16).

Procaryotes

Boron is an integral component of several biomolecules

in which it is thermodynamically stabilized in a covalent

bond (17–20) or by forming a boroester (21). Its presence in

these molecules is essential; in its absence, they no longer

perform their normal physiologic functions. Of great interest

is a boron-containing biomolecule produced by a bacterium

that is not an antibiotic but rather a cell-to-cell communication

signal (20). Communication between bacteria

is accomplished through the exchange of extracellular signaling

molecules called autoinducers (AIs). This process,

termed “quorum sensing,” allows bacterial populations

to coordinate gene expression for community cooperative

processes such as antibiotic production and virulence factor

expression. AI-2 is produced by a large number of bacterial

species and contains one boron atom per molecule.

Not surprisingly, it is derived from the ribose moiety of

biomolecule, (S)-adenosylmethionine (SAM). The gliding

bioluminescent marine bacterium, Vibrio harveyi (phylum

Proteobacteria), produces and also binds AI-2. In V. harveyi,

the primary receptor and sensor for AI-2 is the protein

LuxP, which consists of two similar domains connected by

a three-stranded hinge. The AI-2 ligand binds in the deep

cleft between the two domains to form a furanosyl borate

diester complex (Fig. 4) (20).

Boron is a structural component of certain antibiotics

produced by certain myxobacteria, a distinct and unusual

group of bacteria. For example, tartrolon B (Fig. 5)

is characterized by a single boron atom in the center of the

Figure 3 Boric acid monoesters or borate monoesters can combine with a

suitable dihydroxy compound to form a corresponding spirocyclic borodiester

[“complete” (add the close parenthesis) esterification] that is a chelate

complex with a tetrahedral configuration and negative charge.

Figure 4 The autoinducer, AI-2, with its integral boron atom is stabilized

by a hydrogen network in the binding site of the receptor. The O–O or O–N

distances for potential hydrogen bonds are shown in angstroms. Source: From

Ref. 20.

molecule (18). Another related antibiotic, boromycin, was

discovered to be potent against human immunodeficiency

virus (HIV) (22). It strongly inhibits the replication

of the clinically isolated HIV-1 strain and apparently, by

unknown mechanisms, blocks release of infectious HIV

particles from cells chronically infected with HIV-1.

Animal and Human Tissues

Only meager information is available on the speciation of

boron in animal or human tissues. However, animal and

human biocompounds with vicinal cis-diol moieties bind

Figure 5 Tartrolon B, an example of certain antibiotics produced by certain

myxobacteria that require the presence of a single atom of boron for

functionality.

Experimental data indicate that biochemical species with vicinal cis-diols bind strongly to boron: (S)-adenosylmethionine (SAM) ≡ diadenosine

hexophosphate (Ap6A) ≡ Ap5A > Ap4A > Ap3A ≡ NAD+ > Ap2A > NADH ≡ 5ATP > 5ADP > 5AMP > adenosine (ADS). Species without these moieties

do not bind boron well: 3AMP ≡ 2AMP ≡ cAMP ≡ adenine (ADN).

boron; those without these moieties typically do not. Of

these animal or human biocompounds examined, SAM

has the highest known affinity for boron (8). It is the predominant

methyl donor in biological methylations and is

therefore a versatile cofactor in various physiologic processes.

NAD+, an essential cofactor for five sub-subclasses

of oxidoreductase enzymes, also has a strong affinity

for boron (23). The di-adenosine-phosphates (ApnA) are

structurally similar to NAD+. Boron binding by Ap4A,

Ap5A, and Ap6A is greatly enhanced compared with

NAD+ but is still less than that of SAM (8). The ApnA

molecules are present in all cells with active protein synthesis

and reportedly regulate cell proliferation, stress response,

and DNA repair (24). At physiologic pH, the adenine

moieties ofApnAare driven together by hydrophobic

forces and stack interfacially (25). Stacking of the terminal

adenine moieties brings their adjacent ribose moieties

into close proximity, a phenomenon that apparently potentiates

cooperative boron binding between the opposing

riboses.

Plant-Based Foods

All higher plants require boron and contain organoboron

complexes. There may have been considerable evolutionary

pressure exerted to select for carbohydrate energy

sources that do not interact with boron. Sugars often form

intramolecular hemiacetals: those with five-membered

rings are called furanoses and those with six-membered

rings are called pyranoses. In cases where either five- or

six-membered rings are possible, the six-membered ring

usually predominates for unknown reasons (26). In general,

compounds in a configuration in which there are

cis-diols on a furanoid ring (e.g., ribose, apiose, and erythritan)

form stronger complexes with boron than do those

configured to have cis-diols predominately on a pyranoid

ring (e.g., the pyranoid form of –D-glucose). D-Glucose

reacts with boric acid (27) but the near absence (<0.5%)

of an -furanose form of D-glucose in aqueous solutions

(26) suggests that glucose was selected as the aldose for

general energy metabolism because of its lower reactivity

with boric acid. On the other hand, ribose may have

been selected as part of the chemistry of nucleic acid and

nucleotide function and apiose for, rather than against, its

extraordinary borate-complexing capability.

Recent evidence suggests that the predominant

place of boron function in plants is in the primary cell

walls where it cross-links rhamnogalacturonan II (RG-II)

(Fig. 7), a small, structurally complex polysaccharide of the

pectic fraction. RG-IIs have an atom of boron that crosslinks

two RG-II dimers at the site of the apiose residues

to form a borodiester (28). However, this function is not

adequate to explain all boron deficiency signs in plants.

Twenty-six boron-binding membrane-associated proteins

were identified recently in the higher plant, Arabidopsis

thaliana (29), and boron oxo compounds also form stable

ionic complexes with the polyol ligands mannitol, sorbitol,

and fructose in liquid samples of celery phloem sap

and vascular exudate and phloem-fed nectaries of peach

(30).

Dietary Supplements

Boron speciation in dietary supplements varies widely

(31) as does the relevant information provided by various

dietary supplement manufacturers. It is sometimes listed

only in a general manner (e.g., “borates” or “boron”),

and occasionally in a more specific manner (e.g., “sodium

Boron

Schematic representation of two monomers of the pectic polysaccharide

rhamnogalacturonan-II cross-linked by an atom of boron at the site

of the apiose residues to form a borodiester. Multiple cross-links form a

supramolecular network. Source: From Ref. 75.

borate” or “sodium tetraborate decahydrate”). Several

commercially available forms (e.g., “boron amino acid

chelate,” “boron ascorbate,” “boron aspartate,” “boron

chelate,” “boron citrate,” “boron gluconate,” “boron glycerborate,”

boron glycinate,” “boron picolinate,” “boron

proteinate,” “boron bonded with niacin,” and “calcium

fructoborate”) are not well characterized in the scientific

literature. Most often, dietary boron supplements are provided

in conjunction with other nutrient supplements.

 

BIOAVAILABILITY, EXCRETION, AND HOMEOSTASIS

If plant and animal boron absorption mechanisms are

analogous, the organic forms of the element per se are

probably unavailable (32). However, the strong association

between boron and polyhydroxyl ligands (described

later) is easily and rapidly reversed by dialysis, change in

pH, heat, or the excess addition of another low-molecular

polyhydroxyl ligand (27). Thus, within the intestinal tract,

most ingested boron is probably converted to orthoboric

acid (common name: boric acid), B(OH)3, the normal end

product of hydrolysis of most boron compounds (7). Gastrointestinal

absorption of inorganic boron and subsequent

urinary excretion (33) is near 100%.

Several lines of evidence suggest regulation of boron

in humans. For example, lack of boron accumulation and

relatively small changes in blood boron values during a

substantial increase in dietary boron support the concept

of boron homeostasis (33). Boron contents in human milks

0

10

20

30

40

50

60

Weeks After Birth

Mean Concentration and Model

of Boron (ug/kg milk)

B FT Means

B FT Model

B PRT Means

B PRT Model

1 2 3 4 5 6 7 8 9 10 11 12

Figure 8 Model and mean (°æSE) concentrations of boron in breast milk

from mothers of full-term (FT) and premature (PRT) infants; n = 9 per group

over 12 weeks after birth. During the first 12 weeks of lactation, prematurity

affected the rate of change in concentrations (P = 0.01).

were similar and stable throughout lactation of full-term

infants in two cohorts of women living in either Houston,

TX (34), or St. John’s, Newfoundland (Fig. 8) (35), have

been interpreted as suggestive of regulatory mechanisms

for the elements, which remain undefined. Evidence for

the homeostatic control of boron is enhanced further by a

report (36) of a specific borate transporter, NaBC1, in mammalian

cell lines, a finding that has yet to be confirmed by

another laboratory.

 

DIETARY BORON SOURCES AND INTAKES

Dietary Recommendations

The tolerable upper intake level (UIL) for boron varies by

life stage (Table 1) (37).No Estimated average requirement,

recommended dietary allowance, or adequate intake has

been established for boron for any age–sex group.

Dietary Supplements

For adults, the amount of boron commonly provided in

a single dietary boron supplement is 0.15 mg (31). However,

the reported amount of boron available per serving

varies considerably among commercially available products

as indicated in the relevant information provided by

Table 1 Upper Limits for Boron Set by the 2001 Food and Nutrition

Board of the National Academy of Sciences (37)

Life stage Age (yr) Upper limit (mg/day)

Children 1–3 3

4–8 6

9–13 11

Adolescents 14–18 17

Adults 19–70 20

70 20

Pregnancy ≤18 17

19–50 20

Lactation ≤18 17

19–50 20

86 Hunt

various dietary supplement manufacturers. Some manufacturers

publish reported values of 6.0mgboron per serving

of dietary supplement (38). The mean of usual intake

of boron (mg/day) from dietary supplements for children

(1–8 years), adolescents (9–15 years), males (19+ years),

females (19+ years), and pregnant/lactating women is

0.269, 0.160, 0.174, 0.178, and 0.148, respectively. The median

boron intake from supplements in the U.S. population

is approximately 0.135 mg/day (37).

Nonfood Personal Care Products

Boron is a notable contaminant or ingredient of many

nonfood personal care products. For example, an antacid

was reported to have a high concentration of boron

(34.7 g/g) (39) such that the maximum recommended

daily dose would provide 2.0 mg B/day, two times the

estimated daily boron consumption for the overall adult

U.S. population.

Dietary Sources and Intakes

Ten representative foods with the highest boron concentrations

are distributed among several food categories

(40): raw avocado (14.3 g/g), creamy peanut butter,

(5.87 g/g); salted dry roasted peanuts (5.83 g/g),

dry roasted pecans (2.64 g/g), bottled prune juice

(5.64 g/g), canned grape juice (3.42 g/g), sweetened

chocolate powder (4.29 g/g), table wine (12.2% alcohol)

(3.64 g/g), prunes with tapioca (3.59 g/g), and granola

with raisins (3.55 g/g). Several fruit, bean, pea, and nut

products contained more than 2 g B/g. Foods derived

from meat, poultry, or fish have relatively low concentrations

of boron.

Infant foods supply 47% of boron (B) intake to infants.

For toddlers, consumption from fruits and fruit

juices, combined, is twice that from milk/cheese (38% vs.

19%). For adolescents, milk/cheese foods are the single

largest source of boron (18–20%), and for adults and senior

citizens, it is beverages (mainly represented by instant regular

coffee) (21–26%). For all groups (except infants), 7%

to 21% of boron intake is contributed by each of the vegetable,

fruit, and fruit drink products. Infants, toddlers,

adolescent girls and boys, adult women and men, and

senior women and men are estimated to consume the following

amounts of boron: 0.55, 0.54, 0.59, 0.85, 0.70, 0.91,

0.73, and 0.86 mg/day, respectively.

 

INDICATIONS AND USAGE

Boron and Calcium Metabolism and Bone Structure

There are several lines of evidence that dietary boron is

important for normal bone growth and function. Boron

deprivation induced abnormal limb development in frogs

(41) and retarded maturation of the growth plate in chicks

(42). Dietary boron deprivation decreases bone strength

in pigs (43) and rats (44). The trabecular microarchitecture

of vertebral bone was impaired in rats deprived of the

element (44). Similarly, in mice, modeling and remodeling

of alveolar bone (45), as well as alveolar bone healing

after experimental tooth extraction (46), was impaired by

dietary boron deprivation.

Findings from human studies suggest that boron

influences calcium metabolism. For example, in postmenopausal

women, boron supplementation (3 mg/day)

of a low-boron diet (0.36 mg B/day) resulted in a 5%

increase in urinary calcium excretion (33). A similar

phenomenon occurred in either free-living sedentary or

athletic premenopausal women consuming self-selected

typical Western diets: boron supplementation increased

urinary calcium loss (47). These findings may reflect an

increase in intestinal calcium absorption because increase

in dietary calcium often result in increased urinary calcium

excretion.

Dietary boron also alleviates the signs of marginal

vitamin D deficiency relevant to bone structure and function.

Marginal vitamin D deficiency impairs bone structure,

elevates plasma alkaline phosphatase concentrations,

and reduces body weight. In the growing rachitic

chick, dietary boron substantially alleviated the perturbed

histomorphometric indices of bone growth cartilage

(42,48), reduced elevated serum concentrations of

alkaline phosphatase (49,50), and improved body weight

(50,51).

Boron and Insulin and Energy Substrate Metabolism

Circulating insulin concentrations respond to dietary

boron in a manner that suggests the element may function

to reduce the amount of insulin needed to maintain

glucose levels. For example, in the rat model (with

overnight fasting), boron deprivation increased plasma

insulin with no concurrent change in glucose concentrations

(52). In the chick model, boron deprivation increased

in situ peak pancreatic insulin release (52). In

older volunteers (men and women) fed a low-magnesium,

marginal copper diet, dietary boron deprivation induced

a modest but significant increase in fasting serum glucose

concentrations (53).

Findings from several studies indicate that dietary

boron may attenuate the deleterious effects of marginal

vitamin D deficiency on insulin and energy substrate

metabolism. In vitamin D–deprived rats, hyperinsulinemia

was decreased by dietary boron (54). It has been

demonstrated repeatedly in the chick model that physiological

amounts of dietary boron can attenuate the rise

in plasma glucose concentration induced by vitamin D

deficiency (42,48,55). In addition, boron decreases the abnormally

elevated plasma concentrations of pyruvate, ßhydroxybutyrate,

and triglycerides that are typically associated

with this inadequacy (42). It is not understood how

boron deprivation perturbs energy substrate metabolism

in humans and animal models, particularly when other

nutrients are provided in suboptimal amounts.

Boron and Immune Function

Dietary boron may have a role in control of the normal

inflammatory response, especially as it relates to production

of various cytokines. Cytokines, including interferongamma

(IFN-), tumor necrosis factor- (TNF-), and

interleukin-6 (IL-6), are produced and secreted by immune

cells that regulate immune responses. Production of IFN-

and TNF- was increased in peripheral blood monocytes

cultured in the presence of lipopolysaccharide (an inflammatory

agent) after isolation from pigs fed supplemental

dietary boron. In the same animals, boron caused a reduction

in localized inflammation following a challenge with

Boron

the antigen phytohemagglutinin (PHA) (56). In cell culture

studies with human fibroblasts (57) and chick embryo cartilage

(58), the addition of boric acid also increased TNF-

release by the respective cells. Certain boron-containing

RG-II s from Panax ginseng leaves enhanced the expression

of IL-6–producing activity of mouse macrophages (59).

Finally, perimenopausal women who excreted <1.0 mg

B/day during the placebo period exhibited an increased

percentage of polymorphonuclear leukocytes during the

boron (as sodium borate) supplementation period (60). Dietary

boron may serve as a signal suppressor that downregulates

specific enzymatic activities typically elevated

during inflammation at the inflammation site. Suppression,

but not elimination, of these enzyme activities by

boron is hypothesized to reduce the incidence and severity

of inflammatory disease.

Boron and Steroid Metabolism

There is a clear evidence that dietary boron affects steroid

metabolism. In particular, circulating concentrations of

vitamin D metabolites are sensitive to boron nutriture.

Findings from animal models indicate that dietary boron

enhances the efficacy of vitamin D but cannot substitute

for the vitamin. In volunteers (men, and women

on or not on estrogen therapy), boron supplementation

after consumption of a low-boron diet increased serum

25-hydroxycholecalciferol concentrations (62.4 °æ 7.5 vs.

44.9 °æ 2.5 mmol/L; mean °æ SEM) (61,62), an effect that

may be especially important during the winter months

when these concentrations normally range between

35 and 105 mmol/L (63).

The circulating concentrations of 17-estradiol also

respond to boron nutriture. Perimenopausal women who

excreted <1.0 mg B/day during the placebo period exhibited

increased serum concentrations of estradiol after

boron supplementation (2.5 mg B/day) of self-selected diets

(60). In a separate study, postmenopausal women on

estrogen therapy, but neither men nor postmenopausal

women not ingesting estrogen, also exhibited increased

serum concentrations of estradiol after boron supplementation

(3 mg B/day) of a low-boron diet (0.25 mg B/2000

kcal) (62). However, plasma estradiol, but not testosterone,

concentrations increased in young male volunteers when

their self-selected diets were supplemented with ample

amounts of boron (10 mg/day) (64).

 

Boron and Cancer

Indirect evidence from several epidemiological and cell

culture studies indicate that dietary boron intake may affect

cancer risk. For example, observations from epidemiologic

human studies suggest that increased intakes of

boron are associated with decreased risk of prostate (65)

and lung (66) cancers and abnormal cervical cytopathology

(67). In cultures of human prostatic epithelial cells

(not tested for proliferative activity), physiological levels

of boron reduced Ca2+ release from ryanodine receptor sensitive

stores in a dose-dependent manner, without affecting

cytoplasmic Ca2+ concentrations (68). In immunocompromised

mice fed physiological amounts of dietary

boron, the element reduced the growth of transplanted

human prostate adenocarcinoma tumors (69).

 

OVERDOSAGE

As with all other elements, boron produces toxicity in

all tested biological organisms when excessive amounts

are absorbed. The toxicity signs associated with boric acid

when used as an antiseptic in lieu of antibiotics on abraded

epithelium (i.e., surgical wounds and diaper rash) were

overlooked for many years even though signs of poisoning

were reported soon after its introduction into clinical use.

Boron is more bacteriostatic than does bactericidal and,

thus, may suppress bacterial growth.

Deaths can occur at doses between 5 and 20 g of boric

acid for adults and below 5 g total for infants (70,71). Potential

lethal doses are usually cited as 3 to 6 g total for infants

and 15 to 20 g total for adults. However, an independent

examination of 784 cases of boric acid ingestion found

minimal or no toxicity at these intake levels or higher (72).

Signs of acute boron toxicity, regardless of route of administration,

include nausea, vomiting, headache, diarrhea,

erythema, hypothermia, restlessness, weariness, desquamation,

renal injury, and death from circulatory collapse

and shock. Autopsy may reveal congestion and edema of

brain, myocardium, lungs, and other organs, with fatty

infiltration of the liver. Chronic heavy borax dust occupational

exposure (average air concentration: 4.1 mg/m3;

range: 1.2–8.5 mg/m3) may manifest as eye irritation,

nosebleeds, chest tightness, sore throat, dry mouth, and

productive cough (71). Chronic boron toxicity symptoms

include poor appetite; nausea; weight loss; decreased sexual

activity, seminal volume, sperm count, and motility

and increased seminal fructose. At present, death from

boron poisoning is exceptionally rare probably because of

the emphasis placed on maintaining electrolytic balance

and supporting kidney function during the worst part of

the illness. Depending upon boron blood levels, treatment

ranges from observation to gastric lavage to dialysis.

 

CONCLUSIONS

Boron is ubiquitous in the environment and daily dietary

boron intakes of adult American males, for example, are

slightly less than 1.0 mg. The evidence to date suggests

that higher animals (43,73) and humans (33,62,74) probably

require boron to support normal biological functions.

Despite the progress made in studies of boron essentiality

for plants, animals, and man, the biochemical mechanisms

responsible for the beneficial physiologic effects of boron

across the phylogenetic spectrum are poorly understood.

However, the unique nature of boron biochemistry suggests

specific lines of investigation. In particular, further

characterization of the various cell signaling molecules

that form complexes with boron under physiological conditions

should provide insights into the specific biochemical

function(s) of boron in humans.

 

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