JANUARY 2023 ARTICLE QUESTIONS

1- What is meant by “neurodegenerative disorders”?

- A neurodegenerative disease is caused by the progressive loss of
structure or function of neurones, e.g. multiple sclerosis, Parkinson’s
disease and Alzheimer’s disease

Normal brain on left contrasted with structural changes shown in brain on right of person with Alzheimer's disease,
the most common neurodegenerative disease
Comparison of brain tissue between healthy individual and Alzheimer's disease patient, demonstrating
extent of neuronal death

Alzheimer's disease
Alzheimer's disease (AD) is a chronic neurodegenerative disease that results in
the loss of neurons and synapses in the cerebral cortex and certain subcortical
structures, resulting in gross atrophy of the temporal lobe, parietal lobe, and
parts of the frontal cortex and cingulate gyrus. The cingulate cortex is a part of
the brain in the middle of the cerebral cortex. The two parts of the cingulate
cortex are the cingulate gyrus and the cingulate sulcus. The cingulate cortex is
above the corpus callosum. It is the most common neurodegenerative
disease. No effective treatments have been found. However, clinical trials
have developed certain compounds that could potentially change the future of
Alzheimer's disease treatments. Alzheimer's has a 20% misdiagnosis rate. AD
pathology is primarily characterized by the presence of amyloid
plaques and neurofibrillary tangles. Plaques are made up of small peptides,
typically 39–43 amino acids in length, called amyloid beta (also written as A-
beta or Aβ). Amyloid beta is a fragment from a larger protein called amyloid
precursor protein (APP), a transmembrane protein that penetrates through the
neuron's membrane. APP appears to play roles in normal neuron growth,
survival and post-injury repair. APP is cleaved into smaller fragments
by enzymes such as gamma secretase and beta secretase. One of these
fragments gives rise to fibrils of amyloid beta which can self-assemble into the
dense extracellular amyloid plaques.
Parkinson's disease
Parkinson's disease (PD) is the second most common neurodegenerative
disorder. It typically manifests as bradykinesia (slow movement), rigidity,
resting tremor and posture instability.
PD is primarily characterized by death of dopaminergic neurons in
the substantia nigra, a region of the midbrain. The cause of this selective cell
death is unknown. Notably, (alpha-synuclein-ubiquitin) complexes and
aggregates are observed to accumulate in Lewy bodies within affected
neurons. It is thought that defects in protein transport machinery and
regulation, may play a role in this disease mechanism. Impaired axonal
transport of alpha-synuclein may also lead to its accumulation in Lewy bodies.
Experiments have revealed reduced transport rates of both wild-type and two
familial Parkinson's disease-associated mutant alpha-synucleins through axons
of cultured neurons. Membrane damage by alpha-synuclein could be another
Parkinson's disease mechanism.
Lewy body is a substance that stains eosin, and commonly found in Parkinson’s
disease. The main disease associated with the presence of Lewy bodies
is Parkinson's disease. Lewy bodies are also present in neurons in dementia
with Lewy bodies and the Lewy body variant of Alzheimer's disease.

The main known risk factor is age. Mutations in genes such as α-synuclein
(SNCA), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA),
and tau protein (MAPT) can also cause hereditary PD or increase PD risk. While
PD is the second most common neurodegenerative disorder, problems with
diagnoses still persist.
Multiple sclerosis
Multiple sclerosis (MS) is a chronic debilitating demyelinating disease of
the central nervous system, caused by an autoimmune attack resulting in the
progressive loss of myelin sheath on neuronal axons. The resultant decrease in
the speed of signal transduction leads to a loss of functionality that includes
both cognitive and motor impairment depending on the location of the
lesion. The progression of MS occurs due to episodes of increasing
inflammation, which is proposed to be due to the release of antigens such as
myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid
protein, causing an autoimmune response. This sets off a cascade of signaling
molecules that result in T cells, B cells, and Macrophages to cross the blood-
brain barrier and attack myelin on neuronal axons leading to
inflammation. Further release of antigens drives subsequent degeneration
causing increased inflammation. Multiple sclerosis presents itself as a
spectrum based on the degree of inflammation, a majority of patients
experience early relapsing and remitting episodes of neuronal deterioration
following a period of recovery. Some of these individuals may transition to a
more linear progression of the disease, while about 15% of others begin with a
progressive course on the onset of Multiple sclerosis. The inflammatory
response contributes to the loss of the grey matter, and as a result current
literature devotes itself to combatting the auto-inflammatory aspect of the
disease. While there are several proposed causal links between some alleles to
the onset of MS – they may contribute to the degree of autoimmune attack
and the resultant inflammation – they do not determine the onset of MS.
Creutzfeldt–Jakob disease
Creutzfeldt–Jakob disease (CJD) is a prion disease that is characterized by
rapidly progressive dementia. Abnormal proteins called prions aggregate in
brain tissue leading to nerve cell death. Prions are misfolded proteins. They
are also infectious. Variant Creutzfeldt–Jakob disease (vCJD) is the infectious
form that comes from the meat of a cow that was infected with bovine
spongiform encephalopathy, also called mad cow disease.
Prions are misfolded proteins that have the ability to transmit their
misfolded shape onto normal variants of the same protein. They characterize
several fatal and transmissible neurodegenerative diseases in humans and
many other animals. It is not known what causes a normal protein to misfold,
but the resulting abnormal three-dimensional structure confers infectious
properties by collapsing nearby protein molecules into the same shape.
The word prion is derived from the term, "proteinaceous infectious particle". In
comparison to all other known infectious agents such
as viruses, bacteria, fungi, and parasites, all of which contain nucleic
acids (DNA, RNA, or both), the hypothesised role of a protein as an infectious
agent stands in contrast.

Risk factor Aging brain

Mitochondrial DNA mutations as well as oxidative stress both contribute to
aging. Many of these diseases are late-onset, meaning there is some factor
that changes as a person ages for each disease. One constant factor is that in
each disease, neurons gradually lose function as the disease progresses with
age. It has been proposed that DNA damage accumulation provides the
underlying causative link between aging and neurodegenerative disease. About
20–40% of healthy people between 60 and 78 years old experience discernable
decrements in cognitive performance in several domains including working,
spatial, and episodic memory, and processing speed.
Protein misfolding Stress granule
Several neurodegenerative diseases are classified as proteopathies as they are
associated with the aggregation of misfolded proteins. Protein toxicity is one of
the key mechanisms of many neurodegenerative diseases.

 alpha-synuclein: can aggregate to form insoluble fibrils in pathological

conditions characterised by Lewy bodies, such as Parkinson's
disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-
synuclein is the primary structural component of Lewy body fibrils. In
addition, an alpha-synuclein fragment, is found in amyloid
plaques in Alzheimer's disease.
 tau: hyperphosphorylated tau protein is the main component
of neurofibrillary tangles in Alzheimer's disease; tau fibrils are the main
component of Pick bodies found in behavioral variant frontotemporal
dementia.
 amyloid beta: the major component of amyloid plaques in Alzheimer's
disease.
 prion: main component of prion diseases and transmissible spongiform
encephalopathy.

2- Describe and explain the process of glycolysis

3- What is meant by synaptic plasticity? (paragraph 4)
 - Synaptic plasticity is the ability of synapses to strengthen or weaken
over time in response to increases or decreases in their activity.
- Since memories are postulated to be represented by vastly
interconnected neural circuits in the brain, synaptic plasticity is one of
the important neurochemical foundations of learning and memory.
- Plastic change often results from the alteration of the number of
neurotransmitter receptors located on a synapse. There are several
underlying mechanisms that cooperate to achieve synaptic plasticity,
including changes in the quantity of neurotransmitters released into
a synapse and changes in how effectively cells respond to those
neurotransmitters. Synaptic plasticity in both excitatory and inhibitory
synapses has been found to be dependent upon postsynaptic calcium
release.
4- Explain the process of inflammation
-Inflammation is involved in the non-specific response of the body to
infection and injury.
-The four characteristics of inflammation are swelling, pain/aches,
redness, warmth and loss of function.
- Pain alerts the person that there is an injury
-Warmth speeds up chemical reactions, phagocytosis and defence
mechanism
-Swelling and redness result in more platelets, white blood cells and
phagocytes to the wound
5- Describe the different anatomical regions of the brain and their
functions
6- Compare and contrast the 3 types of neurones; sensory, motor and relay
neurone
7- How is resting potential maintained?
8- How is an action potential propagated in an axon?
9- Explain the mechanisms for an action potential to be transmitted
between neurones
10- What are the disadvantages of fatty acid oxidation (Paragraph 6 )
11- How to measure the RQ of different respiratory substrates?
12- What is a proteome? (paragraph 7)
- The proteome is the entire set of proteins that is, or can be, expressed
by a genome, cell, tissue, or organism at a given time under defined
conditions. Proteomics is the study of the proteome.
13- How different genes are expressed?
14- Explain the three epigenetic systems used to switch genes or
chromosomes on or off
15- What brain imaging techniques are used to diagnose
Neurodegenerative diseases like Alzheimer’s or Parkinson’s disease?
16- Explain the compartmentalisation of neurones
17- What is the importance of synaptic mitochondria? (paragraph 9)
18- What are the specific properties mitochondria have?
(paragraphs 10 & 12)
19- What is autophagy and how does it happen in case of aged or
damaged mitochondria (mitophagy)?
- Autophagy is a form of intracellular phagocytosis in which a cell
actively consumes damaged organelles or misfolded proteins by
encapsulating them into an autophagosome, which fuses with a
lysosome to form a phagolysosome to destroy the contents of the
autophagosome. Because many neurodegenerative diseases show
unusual protein aggregates, it is hypothesised that defects in
autophagy could be a common mechanism of neurodegeneration.
20- Explain the structure of the mitochondrial membrane and relate
this to its function?
21- What is the structure of the cell membrane?
22- What is meant by fluid mosaic property of the plasma membrane?
23- What is apoptosis? How does it take place?
- Apoptosis is a form of programmed cell death in multicellular
organisms. It is one of the main types of programmed cell death
(PCD) and involves a series of biochemical events leading to a
characteristic cell morphology and death.
- Extrinsic apoptotic pathways: Occur when factors outside the cell
activate cell surface death receptors
- Intrinsic apoptotic pathways: Result from mitochondrial release of
cytochrome c or endoplasmic reticulum malfunctions.
The nucleus and Golgi apparatus are other organelles that have
damage sensors, which can lead the cells down apoptotic pathways.
24- What are the distinct mitochondrial populations? ( paragraph 13)
25- Multiple sclerosis is an autoimmune disease. Explain what an
autoimmune disease means.
 - T cells produce receptors that bind strongly to MHC self-antigen and
are not destroyed or inactivated in the thymus gland; B cells and
Macrophages are activated. They attack the body cells, so the body’s
immune system attacks its own cells. The function of the immune
system is to recognise and reject foreign bodies like bacteria.
Sometimes the system goes wrong, and the body itself gets damaged
by its immune system.
26- Explain what is meant by “Bioenergetics”?
- Bioenergetics is a field in biochemistry and cell biology that
concerns energy flow through living systems. It includes the study of the
transformation of energy in living organisms, making and breaking of
chemical bonds in the molecules found in biological organisms, and the
study of different cellular processes such as cellular respiration and the
many other metabolic and enzymatic processes that lead to production
and utilisation of energy in forms such as adenosine triphosphate (ATP)
molecules. It is the study of energy relationships and energy
transformations and transductions in living organisms.
Growth, development, anabolism and catabolism are some of the
central processes in the study of biological organisms, because the role
of energy is fundamental to such biological processes.
-Adenosine triphosphate (ATP) is the main "energy currency" for
organisms; the goal of metabolic and catabolic processes are to
synthesize ATP from available starting materials (from the environment),
and to break- down ATP (into adenosine diphosphate (ADP) and
inorganic phosphate) by utilising it in biological processes. In a cell, the
ratio of ATP to ADP concentrations is known as the "energy charge" of
the cell. A cell can use this energy charge to relay information about
cellular needs; if there is more ATP than ADP available (has a high energy
charge), the cell can use ATP to do work, but if there is more ADP than
ATP available, the cell must synthesise ATP via oxidative
phosphorylation.
-Living organisms produce ATP from energy sources via oxidative
phosphorylation. The terminal phosphate bonds of ATP are relatively
weak compared with the stronger bonds formed when ATP
is hydrolysed (broken down by water) to adenosine diphosphate and
inorganic phosphate. Here it is the thermodynamically favorable free
energy of hydrolysis that results in energy release.
 Examples of major bioenergetic processes
- Glycolysis is the process of breaking down glucose into pyruvate
- Gluconeogenesis is the opposite of glycolysis, when the cell’s energy
charge is low (the concentration of ADP is higher than that of ATP),
the cell must synthesise glucose from carbon-containing
biomolecules such as proteins, amino acids, fats, pyruvate.
- For example, proteins can be broken down into amino acids, and
these simpler carbon skeletons are used to build/ synthesise glucose.
- The citric acid cycle is a process of cellular respiration in which acetyl
coenzyme A, synthesised from pyruvate dehydrogenase, is first
reacted with oxaloacetate to yield citrate.
- The remaining eight reactions produce other carbon-containing
metabolites. These metabolites are successively oxidised, and the
free energy of oxidation is conserved in the form of the reduced
coenzymes FADH2 and NADH. These reduced electron carriers can
then be re-oxidized when they transfer electrons to the electron
transport chain.
- Oxidative phosphorylation and the electron transport chain is the
process where reducing equivalents such as FADH2 and NADH can be
used to donate electrons to a series of redox reactions that take
place in electron transport chain complexes. These redox reactions
take place in enzyme complexes situated within the mitochondrial
membrane. These redox reactions transfer electrons "down" the
electron transport chain. This difference in proton concentration
between the mitochondrial matrix and inner membrane space is used
to drive ATP synthesis via ATP synthase.

27- What are the respiratory complexes?

- Respiratory complex I, (also known as mitochondrial complex I) is
the first large protein complex of the respiratory chains of many
organisms from bacteria to humans. It catalyses the transfer
of electrons from NADH to coenzyme Q10 (CoQ10) and translocates
protons across the inner mitochondrial membrane in eukaryotes or
the plasma membrane of bacteria.
- This enzyme is essential for the normal functioning of cells, and
mutations in its subunits lead to a wide range of inherited
 neuromuscular and metabolic disorders such as ischemia damage
(stroke and cardiac infarction), Parkinson's disease and others.
- Complex I is the first enzyme of the mitochondrial electron transport
chain. There are three energy-transducing enzymes in the electron
transport chain - NADH:ubiquinone oxidoreductase (complex
I), Coenzyme Q – cytochrome c reductase (complex III),
and cytochrome c oxidase (complex IV). Complex I is the largest and
most complicated enzyme of the electron transport chain.
- The reaction catalyzed by complex I is:
- (NADH + H+ + CoQ + 4H+in→ NAD+ + CoQH2 + 4H+out)
- In this process, the complex translocates four protons across the
inner membrane per molecule of oxidized NADH, helping to build
the electrochemical potential difference used to produce ATP.
- Complex I may have a role in triggering apoptosis. In fact, there has
been shown to be a correlation between mitochondrial activities
and programmed cell death (PCD) during somatic embryo
development.
- As a result of a two NADH molecule being oxidized to NAD+, three
molecules of ATP can be produced by Complex V (ATP synthase)
downstream in the respiratory chain.
GOOD LUCK
3 Mitochondria are organelles specialised for the production of ATP.
(a) One part of the process involved in ATP production is the electron transport chain.

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(i) State the location of the electron transport chain in mitochondria.
(1)

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(ii) The diagram below shows the arrangement of six electron carriers in the
electron transport chain.
Complete the diagram by filling in each of the boxes appropriately.
(3)

Cyt C

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I II III IV
CoQ

ADP + Pi

. . ...................... ...........................
ATP
. . . . . . . . . . . . .................

........................
...........................

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 (b) Explain how ATP is formed by the process of oxidative phosphorylation in the
mitochondria.
(5)
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(Total for Question 3 = 9 marks)

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Question Answer Additional Guidance Mark
Number
3(a)(i)
inner membrane; ACCEPT crista / cristae / inside
membrane (1)
IGNORE membrane or
intermembrane space

Question Answer Additional Guidance Mark

Number
3(a)(ii) 1. first box: { reduced NAD / NADH / NADH2 } and
second box : { NAD+ / NAD } ;
2. middle box: {H+ / hydrogen ion / proton} ; 2. IGNORE hydrogen / H2 / H

3. fourth box: { oxygen / ½ O2 / O} and fifth box: { water /

H2O }; (3)
Question Answer Additional Guidance Mark
Number
3(b) 1. reference to chemiosmosis;

2. {use / release} energy from electrons; 2. ACCEPT reference to transfer of

electrons along ETC
3. protons moved {through the inner membrane / into
the intermembrane space} ;

4. reference to {ATP synthase / stalked particles}; 4. ACCEPT ATP synthetase / ATP-ase

5. formation of phosphate bond between phosphate in 5. IGNORE phosphorylation makes ATP

ADP and inorganic phosphate / eq; ACCEPT ADP + Pi -> ATP

6. by the movement of protons (from intermembrane

space) into matrix ; (5)

*(b) Inherited mitochondrial diseases affect muscle function.
The diagram shows the electron transport chain in a mitochondrion.

reduced oxidised
TMPD TMPD

cytochrome
C

complex CoQ complex complex

I III IV
complex
II

reduced
NAD oxidised water
oxygen
oxidised FAD
reduced
NAD
FAD

In an investigation, samples of muscle tissue from healthy individuals and from

four individuals with mitochondrial disease were collected.
The function of mitochondria, when these samples were treated with different
substrates, was investigated.
Treating muscle tissue from healthy individuals with:
 pyruvate and malate increases the production of reduced NAD
 succinate increases the production of reduced FAD
 reduced TMPD increases the reduction of cytochrome c.
The oxygen consumption of the muscle tissue samples from healthy individuals
and from four individuals with mitochondrial disease were recorded.
The results are shown in the table.

Oxygen consumption in the presence of each treatment

/ pmol O2 min–1 mg–1 of muscle tissue
Sample taken from
pyruvate and
succinate reduced TMPD
malate
Individual 1       3.0       3.5 13.0
Individual 2 18.0 10.0 60.0
Individual 3       6.5 14.0 51.0
Individual 4       7.5       6.0 40.0
Healthy individuals 21.0 ± 5.0 13.5 ± 4.5  63.0 ± 20.0

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The results of this investigation can be used to identify the defects in the electron
transport chain of individuals with mitochondrial disease.
Comment on the defects in the electron transport chain in the individuals with
mitochondrial disease.
(6)

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............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

............................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................................................................................................................................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(Total for Question 4 = 10 marks)

15
*P67793A01532* Turn over
Question Answer Mark
number
4(b) Answers will be credited according to candidate's deployment of knowledge and understanding of the material in
relation to the qualities and skills outlined in the generic mark scheme.

The indicative content below is not prescriptive and candidates are not required to include all the material indicated
as relevant. Additional content included in the response must be scientific and relevant.

Indicative content

Descriptive points
- individual 1 no treatment stimulated normal oxygen consumption
- individual 2 pyruvate all three treatments stimulated normal oxygen consumption
- individual 3 succinate and reduced TMPD stimulated normal oxygen consumption
- individual 4 only reduced TMPD stimulated normal oxygen consumption

Linking treatments to activation of different points in etc

- pyruvate and malate (produce reduced NAD) acts on (complex) I
- succinate acts on (complex) II
- reduced TMPD acts on cytochrome c

Links to etc defect

- idea that defects in different parts of etc
- individual 1 defect is in or after cytochrome c
- individual 2 defect is in before (complex) I / etc is intact
- individual 3 defect is in (complex) I
- individual 4 defect is in (complex) I, coQ or III (Ignore complex II)
(6)
Level Marks Descriptor

0 No awardable content.

1 1-2 An explanation may be attempted but with limited interpretation or analysis of the scientific information and with a
focus on mainly just one piece of scientific information.

The explanation will contain basic information, with some attempt made to link knowledge and understanding to the
given context.

2 3-4 An explanation will be given, with occasional evidence of analysis, interpretation and/or evaluation of both pieces of
scientific information.

The explanation shows some linkages and lines of scientific reasoning with some structure.
3 5-6 An explanation is made that is supported throughout by sustained application of relevant evidence of analysis,
interpretation and/or evaluation of both pieces of scientific information.

The explanation shows a well-developed and sustained line of scientific reasoning, which is clear and logically
structured.