Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Medical Biochemistry and Pathophysiology > Week 2A: Signal transduction pathways, gluconeogenesis, oxidative phosphorylation 1+2 > Flashcards

Week 2A: Signal transduction pathways, gluconeogenesis, oxidative phosphorylation 1+2 Flashcards

HC07-10

You may prefer our related Brainscape-certified flashcards:
USMLE® Step 1 flashcards
1
Q

Signal transduction principles

A

-Primary signals like hormones which bind receptor
-Second messengers: signal transduction intracellular
-Activation of effectors like enzymes
-Termination of the signal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Receptor for epinephrine

A

beta-adrenergic receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Reaction EGF to EGF receptor

A

Expression of growth promoting genes > wound healing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Between which steps in signal transduction is amplification performedn

A

Between reception and transduction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Chemical signaling types

A

-Autocrine
-Across gap junctions
-Paracrine
-Endocrine (through blood)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Which cells respond directly to increased glucose levels?

A

Pancreatic islet cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Adrenaline/ epinephrine response

A

Epinephrine + beta-adrenergic receptor (7TM) > fight or flight response: energy store mobilization

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Release insulin effect on glucagon

A

Beta cells contain ready to go granules of insulin before the signal (secretion upon glucose influx)
> insulin binds to pancreatic alpha cells to inhibit glucagon secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Beta cell insulin secretion pathway

A
  • Carbohydrate rich meal > rise blood glucose > release insulin beta cells
    1. Glucose uptake by GLUT2
    2. Glycolysis (glucokinase for phosphorylation glucose), TCA cycle and oxidative phosphorylation > increasing ATP and ATP/ADP ratio
    3. Block ATP sensitive K+ (potassium, more inside cell) channel
    a. More positives stay inside > depolarisation > -30 mV from -80 mV.
    b. Na+ influx coupled to glucose uptake.
    4. Membrane depolarization
    5. Open Ca2+ channel (reaction on the depolarisation) > influx
    a. A second messenger > induces transport of the insulin vesicles to the plasma membrane and excretion (fusion with membrane).
    b. Cleavage to monomer form on insulin which is active.
    6. Insulin release
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

The liver cannot sense increased glucose levels in blood, while pancreatic beta cells do. How is glycogen storage induced in hepatocytes?

A

Insulin receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

When stress, secretion of …

A

adrenaline by the adrenal gland

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Most primary messenger cannot pass the PM, so binding

A

To cell surface receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Types of plasma-membrane receptors

A

-G-protein coupled receptor (GPCR) / 7TM receptor
> glucagon and epinephrine receptor
-Protein tyrosine kinase (PTK)
> insulin receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Name GPCRs and their general pathway

A

-Receptor activation by binding ligand (conformational change)
-Activation of the bound G-protein (GDP exchanged for GTP)
-Protein protein interactions for activation of transducing proteins and targets
> glucagon receptor, beta adrenergic receptors, chemokine receptors, taste and smell etc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

K+-Na+-ATPase (pump)

A

Costs 1 ATP
2 sodium influx for 3 potassium efflux
> retain negative charge inside cytosol for voltage of -90mV over PM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Name a drug which can block the potassium channel to generate Ca2+ influx by depolarization and induce insulin release

A

Sulfonylurea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Pathway glucagon receptor and beta-adrenergic receptor

A

-Binding ligand
-Activation receptor
-Exchange GDP for GTP in G-alpha subunit of trimeric G protein
-Ga dissociates from G-delta,gamma and both are active (new G protein can bind active receptor: amplification)
-Gas activates adenylate cyclase by binding
-Adenylate cyclase catalyzes ATP to cAMP
-Second messenger cAMP activates proteins like Protein Kinase A (PKA) by binding and releasing regulatory subunits.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Structure PKA

A

Tetrameric when inactive (C2R2, catalytic/regulatory)
> cAMP binds the R-subunits and conformational change releases them and activates PKA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Amplification in glucagon and adrenaline pathways

A

-Activated receptor can bind and activate multiple trimeric G-proteins
-Activated G-protein can bind and activate multiple targets like adenylate cyclases
-Adenylate cyclase converts multiple ATP to cAMP.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Which receptor and pathway for the hormones angiotensin II and noradrenaline

A

Alpha-adrenergic receptor
> GPCR activated and G-protein activated (exchange) through Gaq
- Gaq activates Phospholipase C (PLC)
-PLC cleaves PIP2 to IP3 (free) and DAG (membrane bound)
-IP3 binds and opens IP3-sensitive Ca2+ channels on the ER membrane
-Ca2+ influx
-Ca2+ facilitates binding of DAG as activator to Protein kinase C (PKC)
-Activation PKC by releasing regulatory subunits

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Ca2+, IP3 and DAG are…

A

second messengers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Cytosolic Ca2+ as second messenger

A

-Interaction with negatively charged oxygen atoms in bining proteins
-Able to cross link protein domains > conformational change (calmodulin, CaM)
- Subsequent binding and activation of other enzymes: CaM kinase bound and activation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Rise in cytosolic Ca2+ essential for:

A

Glycogen metabolism (liver and muscle) and exocytosis (secretory cells)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Receptor tyrosine kinase function

A

-Binding ligand
-Dimerization intracellular domains upon binding
-Conformational change: kinase domains come nearby > trans-autophosphorylation of tyrosine residues by the tyrosine kinases
-Tyrosine kinases become fully active by this phosphorylation
-phosphorylate substrates, recruitment adaptors
> activatin of the target (PKB)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Which amino acids can be phosphorylated?

A

Serine, Threonine, Tyrosine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Insulin pathway

A
  1. Insulin induces conformational change in structure
  2. Trans-auto-phosphorylation of tyrosines > docking sites for insulin receptor substrates (IRS)
  3. Docking of PI3-K (kinase) to IRS-1
  4. PIP2 > PIP3
  5. Translocation of PDK1 to PM (PIP3-dependent protein kinase, serine/threonine kinase)
  6. Phosphorylation and activation of PKB (Akt)
  7. Akt targets are (in)activated by PKB/Akt
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Muscle and adipose response to insulin

A

GLUT4 surface expression, insulin-dependent glucose transport
> GLUT4 vesicles with GLUT4 in the cell, exocytosis when activated by insulin.
> fasted state, no insulin, endocytosis
> PKB and PKC promote translocation of GLUT4 vesicles to PM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Slow vs fast response to extracellular signal

A

Fast: altered protein function, slow: altered gene expression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Termination of signals in GPCRs

A

-Dissociation ligand-receptor
-Internalization receptor-ligand complex by endocytosis
-Phosphorylation receptor-ligand complex by GRK2 > binding beta-arrestin to block signal
(remember, phosphorylations cost ATP)
-GTPase activity by G protein: hydrolysis GTP to GDP, inactive G-protein and inactivation adenylate cyclase
-cAMP degraded by cAMP-phosphodiesterase (cAMP-PDE) to AMP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Name a well known PDE inhibitor

A

Sildenafil (viagra), inhibits PDE 5 which converts cGMP to GMP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Epidermal growth factor (EGF) signaling

A

-EGF receptor binds EGF
-Dimerization and trans-autophosphorylation
-Binding adaptor Grb2 which binds adaptor Sos
-Sos binds Ras in GDP form and induces exchange for GTP.
> Ras signals for cell division and growth
> Ras is a small GTP binding protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Response in signalling after activation of the

A

effector(s)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

HC08: How long do glucose stores last?

A

One day

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Glycogen levels during day

A

Fluctuate: peaks after dinner and after breakfast

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Healthy blood glucose

A

5 mM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Glucose homeostasis in times after fasting

A

-Short term: exogenous glucose
-Up to 12 hrs: glycogenolysis
-long term: gluconeogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Why is blood glucose maintenance so important

A

Vital functions like the brain and erythrocytes depend on it

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

In which organs gluconeogenesis?

A

Liver and kidney

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Gluconeogenesis is largely the reversal of glycolysis, except which steps?

A

The regulation steps

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Regulation steps of gluconeogenesis

A

-Pyruvate carboxylase
-Phosphofructokinase-2 complex
-Glucose-6-phasphatase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

In which tissues is glucose-6-phosphatase expressed?

A

Liver and kidney

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

The direction for enzymes that catalyze reaction both ways depends on ..

A

the concentration of the substrates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

What energy is needed for gluconeogenesis

A

NADH and ATP (6 ATP)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Why are some steps irreversible

A

Huge change in Gibbs free energy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

For which conversion from the reverse route of glycolysis in gluconeogenesis is a sideroute needed

A

Pyruvate to phosphoenolpyruvate (PEP)
(animal PK cannot phosphorylate pyruvate)
> detour through mitochondrion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Conversion pyruvate to PEP in gluconeogenesis

A

Pyruvate > Oxaloacetate > PEP
From pyruvate (C3) to oxaloacetate (C4)
> pyruvate carboxylase

47
Q

Substrates pyruvate carboxylase

A

Pyruvate, CO2 in the form of HCO3- (bicarbonate, hydrogen carbonate), ATP

48
Q

Where is pyruvate carboxylate located

A

Mitochondrial matrix

49
Q

How is oxaloacetate transported from mitochondial matrix to cytosol

A

Malate shuttle
> oxaloacetate to malate using 1 NADH, transport to cytosol, make oxaloacetate and yield the NADH back

50
Q

Conversion oxaloacetate to PEP/phosphoenolpyruvate in cytosol

A

Oxaloacetate + GTP > PEP + GDP + CO2 (by PEP carboxykinase in cytosol)

51
Q

Regulation pyruvate carboxylase

A

-Activation by acetyl-CoA
-Inhibition by ADP

52
Q

Regulation PEP carboxykinase

A

Inhibition by ADP

53
Q

Reciprocal regulation of glycolysis and gluconeogenesis

A

By Fructose-2,6-bisphosphate
> activation PFK-1
> inhibition F-1,6-BPase (gluconeogenesis: F-1,6-P > F-6-P)

54
Q

Regulation Fructose-1,6-bisphosphatase

A

Inhibition by F-2,6-BP and AMP
Activation by citrate

55
Q

How is PFK-2 inactivated and FBPase2 activated simultaneously?

A

PKA phosphorylates the PFK-2 domain of the bifunctional enzyme which activates FBPase2
> Insulin promotes phosphoprotein phosphatase and therefore PFK-2 by dephosphorylating it.
> F-6-P promotes the phosphatase as well
> Glucagon (or adrenaline) stimulates PKA and therefore FBPase2
> PFK-2 promotes formation F-2,6-BP which promotes glycolysis while inhibiting gluconeogenesis.
> FBPase2 prevents formation of F-2,6-BP (phosphatase)

56
Q

Function Glucose-6-phosphatase

A

Convert G6P to glucose to export it to blood, increase blood glucose levels
> only in liver and kidney

57
Q

Where G6Pase activity?

A

ER luminal side of ER membrane
> T1 imports G6P
> G6Pase converts to glucose and Pi
> Pi export out of ER using T2
> glucose exports with T3

58
Q

Substrate and precursors for gluconeogenesis

A

Substrate: pyruvate (2)
Precursors: lactate, some amino acids, glycerol
> lactate (oxidation, yield NADH) and alanine and other C3 amino acids converted to pyruvate
> C4 and C5 amino acids anaplerosis and through conversion to oxaloacetate entering
> Glycerol converted (C3) to Glycerol-3-P which can be oxidized (yield NADH) to triose-P

59
Q

Cori cycle

A

Lactate from anaerobic glycolysis transported to liver via blood and gluconeogenesis and glucose back to muscle for anaerobic glycolysis

60
Q

Glycerol can be used for gluconeogensis. Can FAs be as well?

A

No (often not)

61
Q

Prosthetic group of pyruvate carboxylase

A

Biotin (vitamin B7)
> biotin is the carrier of activated CO2 (HCO3-)

62
Q

Which molecule is essential for pyruvate carboxylase to work

A

Acetyl-CoA > allosteric activator

63
Q

Fatty acids are required for gluconeogenesis but cannot be converted. explain

A

Generate energy (ATP, GTP) for gluconeogenesis and to activate pyruvate carboxylase through acetyl-CoA

64
Q

Acetyl-CoA (breakdown product FA oxidation) cannot be used to make glucose, explain

A

Acetyl-CoA (C2) cannot be converted to pyruvate (PDH step is irreversible)
> goes into TCA cycle, broken down into CO2

65
Q

Futile cycle glycolysis and gluconeogenesis costs

A

Waste of energy: is avoided through reciprocal regulation
> 2 ATP + 2 GTP + 4 H2O > 2 ADP + 2 GDP + 4 Pi
> gluconeogenesis costs 2 NADH as well, but same yield in glycolysi

66
Q

Gluconeogenesis from 2 pyruvate to 1 glucose costs

A

6 NTPs > 4 ATP and 2 GTP

67
Q

distribution gluconeogenesis

A

90% in liver and 10% in kidney

68
Q

HC09: energy release from ATP hydrolyses reactions

A

-ATP + H2O > ADP + Pi: dG: -30.5 kJ/mole
-ADP + H2O > AMP + Pi. dG: -30.5 kJ/mole
-ATP + H2O > AMP + PPi: dG: -40.6 kJ/mole
-PPi + H2O > 2 Pi: dG -31.8 kJ/mole
-AMP + H2O > A + Pi (-12.6 kJ/mole)

69
Q

ATP has how many energy rich … bonds

A

2 phosphoanhydride bonds
> unstable, negative charges

70
Q

Energy rich bond in acetyl-CoA

A

Thioester bond

71
Q

Metabolic roads to acetyl-CoA predominantly in the …

A

mitochondria

72
Q

The mitochondrial inner membrane folds into …

A

Cristae

73
Q

Dynamism of mitochondria

A

Fusion and fission, also mitophagy (then recycling) by autophagy or apoptosis induction by release cytochrome c

74
Q

Which chain of enzymes is found in inner mitochondrial membrane?

A

Electron transport chain (respiratory chain)

75
Q

Proton motive force

A

delta p = chemical gradient (delta pH based on concentrations) + charge gradient (d w)
> electrochemical gradient

76
Q

Highly regulated transport over mitochondrial membranes?

A

Outer membrane: no special transport needed, porous, free entry
Inner membrane: selective, transporters needed.

77
Q

ATP is produced in a process called …

A

intermediate metabolism
> glucose is oxidized in controlled way, to release its energy in the form of ATP
> glycolysis, PDH oxidative decarboxylation, mitochondrion, oxidative phosphorylation

78
Q

Where PDH oxidative decarboxylation?

A

In mitochondrial matrix

79
Q

TCA cycle generates …

A

3 NADH + H+
1 FADH2
1 GTP

80
Q

NADH carries … high energy electrons

A

2 (hydride ion)
dE0= 61.2 kJ/mole

81
Q

Electron transport chain + ATP synthase numbered

A

Complex I: NADH dehydrogenase
Complex II: succinate dehydrogenase (no protons pumped for proton gradient)
Complex III: cytochrome b-c1
Complex IV: cytochrome oxidase
Complex V: ATP synthase

82
Q

Complex II is an … of the TCA cycle

A

Enzyme > succinate dehydrogenase converts succinate into fumarate, reducing its prosthetic (tightly bound) group FADH2.
> contains Fe-S cluster (iron sulfur) to transport electrons.
> donates electrons to Coenzyme Q to deliver it to complex III
> skips complex I: less ATP yield because less protons pumped through FADH2

83
Q

Complex I gives energy rich electrons after pumping … protons to the intermembrane space to ..

A

4 protons pumped, electrons give to Coenzyme Q

84
Q

How many protons do complex III and IV pump

A

2 (III) and 4 (IV) respectively

85
Q

What is the electron acceptor at complex III?

A

Cytochrome c

86
Q

Is FADH2 generated in tca a regulator of many enzymes except complex II?

A

No, FADH2 is stuck in the enzyme (it is a protein, prosthetic group)

87
Q

What happens to leftover low energy electron at complex IV

A

Molecular oxygen will happily receive them as acceptor > reduction to water.

88
Q

What happens to the generated proton gradient

A

Proton motive force used to generate ATP through transport through ATP synthase back to matrix
> proton gradient has a maximim like a battery: electron transport chain is stopped because the extra protons cannot be used anymore: and TCA cycle stops because too much NADH and no NAD+

89
Q

Coenzyme Q and cytochrome c are … of the electron transport chain

A

Electron shuttles

90
Q

Which of the electron transport chain molecules contain iron sulfur clusters?

A

Complex I, II, III

91
Q

What is CoQ as molecule

A

A lipid
> 10 isoprene units and quinone head group

92
Q

Reduction CoQ

A

CoQ ubiquinone Q (oxidized form)
> one electron transfer + H+
- Semiquinone, free radical, Q*-
> one electron transfer + H+
-Ubiquinol CoQH2 (QH2, reduced form)

93
Q

NADH has allosteric influence, why not FADH2 as regulator of other enzymes

A

It is tightly bound by enzymes as prosthetic group so cannot move freely (flavoprotein)

94
Q

Which enzyme in cellular respiration besides succinate dehydrogenase has FAD as prosthetic group?

A

E3 of the PDH complex

95
Q

HC10: FADH2 has … energy conserved than NADH

A

less

96
Q

FADH2 is a flavoprotein, is it soluble?

A

No

97
Q

How many NADH + H+ needed to reduce one molecular oxygen O2?

A

2 NADH + 2 H+
> four protons needed and Electrons needed

98
Q

Reaction in cytochrome c oxidase (Complex IV)

A

Four substrate protons and four translocated protons:
4 cyt c-red + 8 H+ (matrix) + O2 > 4 cyt c-ox + 2 H2O + 4 H+ (intermembrane space)

99
Q

Reducing oxygen at complex IV is an .. reaction (endo/exo)

A

Exergenic reaction

100
Q

The catalytic mechsnism of cytochrome c oxidase represents a

A

cycle
> the electron transfers is coupled to proton translocation across the inner mitochondrial membrane.

101
Q

What happens at high ATP?

A

ATP synthase stops
> proton gradient builds up to maximum and oxidative phosphorylation comes to complete stop
> No respiratory control, no TCA cycle (coupled systems), too much NADH and no NAD+ to keep TCA cycle running

102
Q

ATP synthase structure

A

-c subunits of the F0 (integrated in inner membrane) > each bind one proton and rotate
-Alpha and beta subunits of the F1 headpiece (hangs into matrix) remain static
-Central gamma subunit of F1 rotates, changing the conformation of the beta subunits

103
Q

Conformations of beta subunits ATP synthase

A

-From loose: binding ADP and Pi
-Via tense (after rotation): squash ADP and Pi together to make ATP
-To open: releasing ATP
> three beta subunits in headpiece which changes constantly in this order (loose, tense, open)
> ATP release with each conformational change

104
Q

Price of ATP generation when respiratory chain completely reduced

A

Respiratory chain completely reduced and oxygen present > ROS
-electron stolen from the process by oxygen
-Three ROS
>Superoxide (O2-), hydrogen peroxide (H2O2), Hydroxyl radical (OH) (+ hydroxide OH-, no ROS)
> through one electron reduction reactions from O2 to 2 H2O as intermediates

105
Q

ROS come mostly from complexes …

A

I and III
NADH dehydrogenase and cytochome b-c1 complex

106
Q

When superoxide production by complex I

A

Reperfusion injury
> reverse electron transport
> equilibrium reactions: reverse possible
> chance of making superoxygen reactants.

107
Q

Supercomplex increase … and reduce …

A

increase efficiently and reduce ROS formation
> cristae reconfiguration> bring complexes together to respiratory supercomplex

108
Q

Which enzyme nutralizes superoxide (O2*-)

A

Superoxide dismutase (SOD)
> O2- + O2- + 2H+ > H2O2 (hydrogen peroxide)
- electron transfer attracts protons to neutralize
-GPX converts H2O2 to H2O

109
Q

Can the hydroxyl radical be neutralized

A

No, you are screwed.

110
Q

ROS signaling

A

ROS because of exercise or hypoxia etc activates TFs, and leads to gene transcription of antioxidant enzymes, phase I and II detoxifying enzymes, UCP1
> increases health and lifespan

111
Q

Mitohormesis

A

reduced amount of mitochondrial stress is beneficial for health because of ROS signaling, but too much is dangerous and deadly

112
Q

Uncoupling

A

If energy is not caught as ATP, it is lost as heat

113
Q

Chemical uncoupling agent

A

Dinitophenol (DNP), used to ‘burn fat’
> high H+ concentrations causes outside protons to bind to DNP molecules
> transfer DNP across inner mitohondrial membrane
> low H+ in matrix causes dissociation of DNP molecules
> generation heat
> energy and thus fat when fasting used for energy, but no ATP generation thus the respiratory chain and TCA cycle and burning of fat continues
> patients may die to hyperthermia and too low ATP when overdose

114
Q

Uncoupling in brown fat

A

Uncoupling protein (UCP-1, thermogenin) in babies and adults
> proton motive force used for movement into matrix without coupling to ATP synthase but rather through UCP-1 transporter which releases the energy as heat
> protons shake while brought back to matrix which gives heat

Medical Biochemistry and Pathophysiology (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions