Genetic variations in G protein-coupled receptors (GPCRs) can alter receptor function and cause diseases. Single nucleotide polymorphisms and other mutations have been linked to impaired or enhanced receptor signaling. For example, a mutation in the vasopressin V2 receptor causes nephrogenic diabetes insipidus by decreasing ligand binding and receptor expression. Similarly, mutations in chemokine receptors CCR5 and CCR2 impact HIV infection by altering receptor function or interaction with other coreceptors. Overall, GPCR polymorphisms are associated with diseases by changing ligand binding, receptor activation, trafficking, and coupling to downstream signaling pathways.
Assignment on Preclinical Screening of ImmunomodulatorsDeepak Kumar
Assignment on Preclinical screening of new substances for the pharmacological activity using in vivo, in vitro, and other possible animal alternative models
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
Extrapolation of in vitro data to preclinical.
the topic is included in m.pharmacy 1st sem syllabus. which is essential for the study and that include the details about how you deal with the preclinical data that will help to decide the NOEAL and LOEAL, the humane dose of the drug can be calculated and further formation is also done.
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
Non adrenergic non cholinergic transmission(nanc)Merlin Binu
Neurotransmitters other than Acetyl choline and NorAdrenaline of parasympathetic and sympathetic nervous system play important role in synaptic junction transmission. That neurotransmitters are called NANC.
Preclinical Screening of Antiasthmatic DrugsShubham Kolge
Bronchial asthma is characterized by both bronchoconstriction and airway inflammation which leads to bronchial hyperresponsiveness to various stimuli. Different mediators are implicated in asthma. As the precise etiology is not known and multiple biochemical processes are triggered by different causative factors, it is difficult to have a single drug which can effectively and simultaneously act upon different mediators. This led to an intense search for potent and safe antiasthmatic drugs. This presentation intends to compile different screening methods for the evaluation of new candidate drugs with potential for the treatment of asthma. These include in vitro, in vivo, receptor binding and enzymatic methods.
Assignment on Preclinical Screening of ImmunomodulatorsDeepak Kumar
Assignment on Preclinical screening of new substances for the pharmacological activity using in vivo, in vitro, and other possible animal alternative models
Extrapolation of in vitro data to preclinical and.pptxARSHIKHANAM4
Extrapolation of in vitro data to preclinical.
the topic is included in m.pharmacy 1st sem syllabus. which is essential for the study and that include the details about how you deal with the preclinical data that will help to decide the NOEAL and LOEAL, the humane dose of the drug can be calculated and further formation is also done.
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
Non adrenergic non cholinergic transmission(nanc)Merlin Binu
Neurotransmitters other than Acetyl choline and NorAdrenaline of parasympathetic and sympathetic nervous system play important role in synaptic junction transmission. That neurotransmitters are called NANC.
Preclinical Screening of Antiasthmatic DrugsShubham Kolge
Bronchial asthma is characterized by both bronchoconstriction and airway inflammation which leads to bronchial hyperresponsiveness to various stimuli. Different mediators are implicated in asthma. As the precise etiology is not known and multiple biochemical processes are triggered by different causative factors, it is difficult to have a single drug which can effectively and simultaneously act upon different mediators. This led to an intense search for potent and safe antiasthmatic drugs. This presentation intends to compile different screening methods for the evaluation of new candidate drugs with potential for the treatment of asthma. These include in vitro, in vivo, receptor binding and enzymatic methods.
GPCRs are the most dynamic and most abundant all the receptors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. GPCRs are responsible for every aspect of human biology from vision, taste, sense of smell, sympathetic and parasympathetic nervous functions, metabolism, and immune regulation to reproduction. GPCRs interact with a number of ligands ranging from photons, ions, amino acids, odorants, pheromones, eicosanoids, neurotransmitters, peptides, proteins, and hormones.
Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
This presentation is about the functioning of G-Protein coupled receptors. It also gives necessary information about the G-protein and it functions. It ends by explaining some of the faults associated with GPCR (G-PROTEIN COUPLED RECEPTORS).
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
2. What is G-protein??
• also known as guanine nucleotide-binding proteins.
• family of protein that act as a molecular switches inside the
cell.
• Activity regulated by factors that controls their ability to bind
to and hydrolyze GTP into GDP.
• When they are bound to GTP, they are 'on', and, when they
are bound to GDP, they are 'off'. G proteins belong to the
larger group of enzymes called GTPase.
• There are two classes of G proteins:
a. monomeric small GTPase
b. heterotrimeric G protein complexes (alpha (α), beta (β)
and gamma (γ) subunit)
3. G-Protein Coupled Receptor
7 trans membrane helices connected by alternating cytosolic and
extra cellular loop
C terminal: inside the cell
N terminal : extra cellular region
Extra cellular portion has unique messenger binding site
Cytosolic loop allow receptor to interact with G protein.
The eventual effect of agonist -induced activation is a change in the
relative orientations of the TM helices (likened to a twisting motion)
leading to a wider intracellular surface and "revelation" of residues
of the intracellular helices and TM domains crucial to signal
transduction function (i.e., G-protein coupling).
Inverse agonists and antagonists may also bind to a number of
different sites, but the eventual effect must be prevention of this TM
helix reorientation
4.
5. Genetic variations may be due to
1.Sequence variations of the human genome
• Introduces variability in genetic make-up
• Suspected to play a main role in diseases &
variable response in drug therapy
• Polymorphism- refers to sequence variation
leading to occurrence of two or more clearly
different forms.
• Single nucleotide polymorphism accounts for
approx. 80% of all sequence variations.
6. 2. Structure & function of GPCRs
• Comprises a large class of membrane proteins –
encoded by approx. 600 human genes.
• Molecular architecture might permit the
prediction of functionally relevant domains
where sequence variations are more likely to
alter receptor function.
• Normally, TM domains are highly conserved, the
loops are variable in sequence & length, &the C-
and N-terminals tails represents the most
diverse elements.
7. 3. GPCR coupling to G proteins and other signaling
pathways
• GPCR thought to be couple to heterotrimeric G
proteins composed of α, β and γ subunits. It display
considerable heterogenecity, with a predicted
number of 27 different α, 5 β and 13 γ subunits.
• Main sites of contact between receptor and G
proteins include the third intracellular loop, but i1, i2
and the C- terminus have also been reported to
contribute G protein coupling
• Proteins like protein kinases, arrestin &
phosphatases modulates receptor functions at
distinct domains that are possible targets for
polymorphic effects.
8. 4. GPCR binding pockets
• Ca++, acetyl choline, glutamate, bradykinin,
prostaglandins, & the large polypeptide FSH bind
to the same site.
• Distinct binding sites appear to exist, either
embedded within the pocket formed by the 7-
TMD bundle within the membrane, at pockets
formed by the extracellular loops, or in the N-
terminus.
• The thrombin receptor family represents a
special case whereas the protease activity of the
ligand thrombin cleaves a portion of the N-
terminus. The newly generated N-terminus then
serves as a tethered ligand.
9. • GPCRs appear to be activated by ligand binding to many
different sites of the protein . At the opioid receptors, peptide
endorphins bind primarily to the extracellular loops, whereas
opioid alkaloids dock deep into the 7-TMD core.
Human μ opioid receptor
10. • Sequence variation in the receptor protein can affect ligand
binding or the structural integrity of the receptor , indirectly
changing ligand binding .
5. Spontaneous GPCR signalling
• Exchange of single amino acid residues can lead
to constitutive receptor activation.
• Considerable number of human polymorphisms
enhance signalling (gain of function) or even
activate the receptor constitutively, causing
serious genetic disorders.
11. 6. Multiple receptor conformations with distinct
functions
• GPCRs are flexible structures and may
accommodate ligands in various ways. It exists in
multiple conformations. Discrete signalling
pathways are triggered by discrete
conformational states of GPCR
13. Impaired or enhanced agonist
signalling efficacy
Several inactivating sequence variants of peptide
receptors have been associated with congenital
disorders. For example,
1. A point mutation causing truncation of
thyrotropin stimulating hormone receptor leads to
leydig’s cell hyperplasia.(activating mutation)
Truncated TM5, D578G, T398M
14. 2. Inactivating mutations of the ACTH receptor are
associated with familial glucocorticoid deficiency .
The mutation occurs in the large N-terminus , the
binding site for glycoprotein hormone receptor,
leading to toxic multinodular goiter.
S120R, R201Stop, S74I, V254C
15. V2 vasopressin recptors
• A number of mutations in the gene encoding the
V2 vasopressin receptor leads to functionally
inactive receptor protein and are causative for
nephrogenic diabetes insipidus.(missense
mutations)
• This a clear indication that receptor activity
depends on intact signalling pathways.
(multiple SNPs; decreased ligand binding;
R113W; R137H)
16.
17. Thromboxane A2 Receptor
• This receptor performs an essential role in
haemostasis by inducing platelet aggregation. An
R60L amino acid substitution in the first
cytoplasmic loop of TBXA2 receptor causes a
dominantly inherited bleeding disorder
characterised by defective platelet response to
TBXA2. This leads to decreased agonist-induced
second messenger formation.
18.
19. P2Y 12ADP Receptor
• This receptor sub-type is shown to be the target
for anti-thrombotic drugs such as ticlodipine &
clopidogrel. 2-nucleotide deletion in a region
mapping to the end of TMD6, associated with a
rare bleeding disorder.
20. Chemokine reeptors
• Fusin and CKR5 have been identified as a co-
receptors for the cellular entry of HIV. Similarly ,
certain chemokines were found to block HIV
entry into cells.
• Natural resistance can be either by high
endogenous levels of chemokines or by
mutations of the receptors.
• A 32 bp deletion in CKR5 leading to a frame shift
and a non functional protein appeared to protect
homozygous carriers against HIV infection &
blocking its entry.
21. • Val 64 substitution with Ile was shown to result
in heterodimerisation of CCR2 with CCR5 or
CXCR4, thereby promoting resistance to AIDS.
22. Biogenic amine receptors
• The R16G substitution in the β2 adrenoreceptors
has been associated with nocturnal asthma
whereas W64R in the β3 receptor expressed in
adipocytes are involved in energy metabolism –
is linked with obesity.
24. receptors Variant/Allele Disease/ Phenotype
cellular mechanism/ Event
Β1 adrenergic receptor R16G Nocturnal asthma;
Enhanced agonist promoted
down regulation of receptor
Β3 adrenergic receptors W64R Obesity
Luteinising hormone Truncated TM5
D578G
Leydig’s cell hyperplasia;
Precocious puberty in male
children
FSH A189V Ovarian dysgenesis;
Altered protein folding;
inactivation of receptor
Thyrotropin (TSH) S120R, R201Stop, S74I,
V254C
Glucocorticoid deficiency;
altered/ loss of receptor
function/ reduced
expression
ACTH D727E Altered receptor
function/conformation;
Toxic multinodular goiter
Vasopressin V2 receptor Multiple SNPs Nephrogenic diabetes
insipidus;
25. Decreased ligand binding;
reduced expression of
receptor
Chemokine receptors CCR2
CCR3
CCR5
V64I
R275Q,L351P
CCR5P1 alleles
Delayed progression of AIDS
Unknown functional change
or influence on disease
Increased progression of
AIDS
Thromboxane A2 R60L Bleeding disorder
ADP receptor P2Y12 Del of 2 nt (TTCATT) in
coding region (end of
TMD6)
Bleeding disorder