Chemicals can cause cellular dysfunction through several mechanisms, ultimately leading to cell death via necrosis or apoptosis. Necrosis is unprogrammed cell death caused by external factors like toxins that damage cells and rupture the membrane. Apoptosis is programmed cell death where cells activate intracellular pathways to die in a controlled way. Toxins may induce apoptosis by damaging DNA or proteins, causing oxidative stress, or interfering with specific protein targets in cellular processes like respiration. This disrupts cellular homeostasis and can trigger either necrosis or apoptosis.
this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.
Basic definition and types of toxicology (general, mechanistic, regulatory and descriptive), Regulatory guidelines for conducting toxicity studies OECD, ICH, EPA and Schedule Y OECD principles of Good laboratory practice (GLP)
Mechanism of cell injury
Types of cell injury
Reversible and irreversible cell injury
Etiology of cell injury
Apoptosis, it's types and mechanism
Necrosis, it's types and mechanism
Hi! I am Komal Sankaran, M.Sc. Biotechnology (Pune University Gold Medalist, 2013), CSIR-NET SPM fellow (Jun- 2014, 4th rank), CSIR-NET- LS (Dec 2013, 2nd rank), DBT JRF category- I. Please contact if anyone is interested in Life Sciences CSIR-NET coaching in Pune (Khadki area).
Email- komalsan91@gmail.com
this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.
Basic definition and types of toxicology (general, mechanistic, regulatory and descriptive), Regulatory guidelines for conducting toxicity studies OECD, ICH, EPA and Schedule Y OECD principles of Good laboratory practice (GLP)
Mechanism of cell injury
Types of cell injury
Reversible and irreversible cell injury
Etiology of cell injury
Apoptosis, it's types and mechanism
Necrosis, it's types and mechanism
Hi! I am Komal Sankaran, M.Sc. Biotechnology (Pune University Gold Medalist, 2013), CSIR-NET SPM fellow (Jun- 2014, 4th rank), CSIR-NET- LS (Dec 2013, 2nd rank), DBT JRF category- I. Please contact if anyone is interested in Life Sciences CSIR-NET coaching in Pune (Khadki area).
Email- komalsan91@gmail.com
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
3. Mechanisms of Toxicity
1. Delivery: Site of Exposure to
the Target
2. Reaction of the Ultimate
Toxicant with the Target
Molecule
3. Cellular Dysfunction and
Resultant Toxicity
4. Repair or Dysrepair
4. Chemical Factors that Cause Cellular
Dysfunction
• Chemicals that cause DNA adducts can lead to
DNA mutations which can activate cell death
pathways; if mutations activate oncogenes or
inactivate tumor suppressors, it can lead to
uncontrolled cell proliferation and cancer (e.g.
benzopyrene)
5. • Chemicals that cause protein adducts can lead
to protein dysfunction which can activate cell
death pathways; protein adducts can also lead to
autoimmunity; if protein adducts activate
oncogenes or inactivate tumor suppressors, it can
lead to uncontrolled cell proliferation and cancer
(e.g. diclofenac glucuronidation metabolite)
• Chemicals that cause oxidative stress can
oxidize DNA or proteins leading to DNA mutations
or protein dysfunction and all of the above. (e.g.
benzene, CCl4)
6. Chemicals that specifically interact with
protein targets
chemicals that activate or inactivate ion
channels can cause widespread cellular
dysfunction and cause cell death and many
physiological symptoms—Na+, Ca2+, K+ levels
are extremely important in neurotransmission,
muscle contraction, and nearly every cellular
function (e.g. tetrodotoxin closes voltage-
gated Na+ channels)
Chemicals that inhibit cellular respiration—
inhibitors of proteins or enzymes involved in
oxygen consumption, fuel utilization, and ATP
production will cause energy depletion and cell
death (e.g. cyanide inhibits cytochrome c
oxidase)
7. Chemicals that inhibit the production of
cellular building blocks, e.g. nucleotides,
lipids, amino acids (e.g. amanitin from
Deathcap mushrooms)
Chemicals that inhibit enzymatic processes of
bioactive metabolites that alter ion channels
and metabolism (e.g. sarin inhibits
acetylcholinesterase and elevates
acetylcholine levels to active signaling
pathways and ion channels)
All of the above can also cause inflammation
which can lead to cellular dysfunction
9. Two Forms of Cell Death
1. Necrosis: unprogrammed cell death (dangerous)
A. Passive form of cell death induced by
accidental damage of tissue and does not
involve activation of any specific cellular
program.
B. Early loss of plasma membrane integrity
and swelling of the cell body followed by
bursting of cell.
10. C. Mitochondria and various cellular processes
contain substances that can be damaging to
surrounding cells and are released upon
bursting and cause inflammation.
D. Cells necrotize in response to tissue
damage [injury by chemicals and viruses,
infection, cancer, inflammation, ischemia
(death due to blockage of blood to tissue)].
11. 2. Apoptosis: one of the main forms of programmed
cell death (not as dangerous to organism as
necrosis).
A. Active form of cell death enabling individual
cells to commit suicide.
B. Caspase-dependent
12. C. Dying cells shrink and condense and then
fragment, releasing small membrane-bound
apoptotic bodies, which are phagocytosed by
immune cells (i.e. macrophages).
D. Intracellular constituents are not released
where they might have deleterious effects on
neighboring cells.
13.
14. Mechanisms of Apoptosis
Apoptosis is a cell mechanism used to eliminate
cells that contain mutations, are unnecessary, or
dangerous to the body
It is critical to normal embryonic development
and to cancer prevention
15. Mechanisms of Apoptosis
Phenotypes of apoptosis:
1. Overall shrinkage in volume of the cell and its
nucleus
2. Loss of adhesion to neighboring cells
3. Formation of blebs on the cell surface
4. DNA fragmentation: dissection of the chromatin
into small fragments
5. Rapid engulfment of the dying cell by
phagocytosis
16. Factors that induce apoptosis:
1. Internal stimuli: abnormalities in DNA
2. External stimuli: removal of growth factors,
addition of cytokines (tumor necrosis factor—
TNF)
Signal transduction pathways leading to apoptosis:
Two major pathways:
1. Intrinsic pathway (mitochondria-dependent)
2. Extrinsic pathway (mitochondria-independent)
17. Extrinsic Apoptosis
• The death receptor pathway I activated by
external cytokines and is mitochondria-
independent
• The ligands of the death receptors are
members of the tumor necrosis factor (TNF)
family of proteins, including TNF-alpha, Fas
ligand (FasL), TRAIL/Apo2L, Apo3L
• Binding of ligand to the death receptors
results in homotrimerization of the receptors
• Death receptors contain a death domain in the
cytoplasmic region that is required for
apoptosis signaling
20. Intrinsic Apoptosis
Intrinsic apoptosis is mitochondria-dependent
and is induced by DNA damage, binding of
nuclear receptors by glucocorticoids, heat,
radiation, nutrient deprivation, viral infection,
hypoxia, and increased intracellular calcium
concentration
Process of Intrinsic apoptosis:
1. Bax forms homo-dimers in the presence of
apoptotic signals, opening a channel that
translocates cytochrome c from the
intermembrane space to the cytoplasm
2. Bcl2 interferes with Bax function by forming
a heterodimer with Bax, closing the channel
and inhibiting cytochrome c translocation
3. In the cytosol, cytochrome c binds to Apaf-1
to form apoptosome
4. Apoptosome recruits procaspase 9 and
activates it to caspase 9
5. Caspase 9 activates executioner caspases 3,
6, and 7
22. Mechanisms of Necrosis
• Cells must synthesize endogenous molecules,
assemble macromolecular complexes,
membranes, and cell organelles, maintain
intracellular environment, and produce energy
for operation.
• Agents that disrupt these functions
(especially energy-producing function of the
mitochondria and protein synthesis) will cause
cell death.
23. Three Primary Metabolic Disorders
Jeopardizing Cell Survival:
I. ATP depletion
II. Sustained rise in intracellular Ca2+
III. Overproduction of ROS, RNS
24. I. ATP Depletion
ATP plays a central role in cellular maintenance
both as a chemical for biosynthesis and as the
major source of energy.
1. ATP drives ion transporters such as Na+/K+-
ATPase (plasma membrane), Ca2+ -ATPase
(endoplasmic reticulum and plasma membrane)
to maintain cellular ion gradients. (most
important for necrosis!)
2. Used in biosynthetic reactions (phosphorylation
and adenylation)
3. Used for signal transduction regulation (e.g.
phosphorylation of receptor tyrosine kinase and
kinase pathways)
25. 4. Incorporated into DNA
5. Muscle contraction (actin/myosin interaction)
and neurotransmission
6. Polymerization of cytoskeleton (actin and
tubule polymerization)
7. Cell division
8. Maintenance of cell morphology
27. Direct Consequences of ATP Depletion
ATP Depletion
compromised
ion pumps (eg Na/K ATPase and Ca2+-ATPases)
loss of ionic and volume
regulatory controls
cell swelling
(water influx)
(rise in intracellular Na+)
cell lysis
necrosis
Ca2+/Na+ levels rise intracellularly
and leads to opening of voltage-gated channels
that depolarize membranes leading to further
Ca2+ and Na+ influx into the cell
28. Agents That Impair ATP Synthesis
1. Inhibitors of electron transport
a) Cyanide inhibits cytochrome oxidase
b) Rotenone inhibits complex I—insecticide that may be an
environmental cause of Parkinson’s Disease
c) Paraquat inhibits complex I—herbicide, but also causes
lung hemorrhaging in humans
2. Inhibitors of oxygen delivery
a) Ischemic agents such as ergot alkaloids, cocaine
b) Carbon monoxide—displaces oxygen from hemoglobin
3. Inhibitors of ADP phosphorylation – DDT
4. Chemicals causing mitochondrial DNA damage - antivirals,
chronic ethanol
29. II. Sustained Rise of Intracellular Ca2+
Ca2+ is involved in :
1. signal transduction regulation (i.e. PKC
activation by DAG and Ca2+) and exocytosis
2. muscle contraction (actin/myosin interaction)
3. cytoskeletal polymerization (i.e. Ca2+
inhibition of actin)
4. neurotransmission (via glutamate receptor Ca2+
channel and voltage-gated Ca2+ channels) and
synaptic plasticity
5.enzyme induction (i.e. citrate and -
ketoglutarate dehydrogenases from the TCA
cycle)
6. Transporters (Ca2+/ATPase, Na/Ca2+ exchanger,
etc.)
32. Reactive Oxygen and Nitrogen
Species Generation
A. Direct generation of ROS/RNS
a. Xenobiotic bioactivation (i.e. carbon tetrachloride,
benzene)
b. Redox cycling (paraquat, MPP+)
c. Transition metals (Fe2+, Cu2+)
d. Inhibition of mitochondrial electron transport (many
phytochemicals)
34. B. Indirect generation of ROS/RNS
a. Increased Ca2+ can cause ROS/RNS
i. Activates dehydrogenases in citric acid cycle and
increases electron output (NADH and FADH2)leads
to an increase in O2
- (superoxide) by the e- transport
chain.
ii. Ca2+ -activated proteases proteolytically convert
xanthine dehydrogenase to xanthine oxidase, the
by-products of which are O2
-. and H2O2.
iii. Neurons and endothelial cells constitutively express
NOS that is activated by Ca2+ increase .NO
production which reacts with O2
.- to produce highly
reactive ONOO- (peroxynitrite).
b. Induction of CYPs (i.e. TCDD binding AhR)
35. Consequences of ROS/RNS
1. ROS can directly oxidize and affect protein
function and can mutate DNA leading to cellular
dysfunction
2. ROS/RNS oxidatively inactivate Ca2+ /ATPases
and elevate Ca2+
3. ROS and RNS also drain ATP reserves:
a. NO. is a reversible inhibitor of cytochrome
oxidase
b. ROS can disrupt mitochondrial membranes
and dissipate the electrochemical gradient
needed for ATP synthase.
4. Lipid peroxidation, cell swelling, and cell rupture
36. decreased ATP
decreased Ca2/ATPase
decreased mitochondrial
potential
increased mitochondrial e-
transport
induction of NOS, XO
decreased ATP synthase
increased e- transport
(increased NADH)
decreased
Ca2+/ATPase
inactivation of e-
transport complexes
DNA injury
decreased NADPH/
NADH
increased ROS
increased RNS
increased Ca2+
lipid peroxidation
membrane destruction
and/or cell swelling
cell lysis
microfilamental dissociation
membrane blebbing
cell destruction
Cell osmolarity disruption
(transporter disruption)
cell swelling
cell destruction