Heat shock proteins (HSPs) help other proteins properly fold and function. HSP90 and HSP70 are molecular chaperones that work sequentially to fold proteins in the cytoplasm. Misfolded proteins can cause disease. HSP90 helps buffer hidden genetic variations but under stress these variations are expressed and can lead to morphological changes. HSP90 is highly conserved across species and plays a role in evolution by allowing traits to change in response to stress. Current research studies HSP90 to better understand protein misfolding diseases.
HEAT SHOCK PROTEIN AND DISEASE CONTROL IN AQUEOUS ORGANISM ppt.pptxArkedMuse
Hsps (Heat Shock Proteins) also known as "molecular chaperones." are highly conserved across species and known for its key roles in cellular activities such as protein translocation, folding, and assembly.
Major Hsp families consists of Hsp60, Hsp70, Hsp90, Hsp100, Hsp110 and small Hsps or sHsps (mol wt. < 40kDa)
Hsp70 release into extracellular compartments has noticeable impacts on APCs for peptides absorption by MHCs. They often take up the role of “danger signals”
Hsp synthesis, both constitutively expressed [heat shock cognates (Hscs)] and more usually not, upon protein denaturation stimulation.
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
RESPONSE OF AQUATIC ORGANISMS TO DISEASE THROUGH HSP SYNTHESIS ALTERATION
Penaeus monodon (Black tiger shrimp) upon challenge with V. harveyi (heat-killed ) in gills results in synthesis of Hsp90, Hsp70, Hsp21
Encounter of nodavirus by Epinephelus coioides ( orange-spotted grouper); involving virus-induced Hsp synthesis in fish, leads to an increase in Hsp90
Disease Management Approach In Aquatic Organisms By Increasing Hsps
Heat shock- Hsp70
Hsp synthesis by exposure to chemical inducers- PRO-TEX
Exogenous Hsps Administration
Extracellular Hsps facilitated cell surface synthesis of peptides, support in distressed cells identification by the immune system “Danger signals” such as monocytes, dendrites, neutrophils, and macrophages are transmitted to immune cells by Hsp70 via TLR2 and TLR4 activation
Stimulates inflammatory cytokines, nitric oxide (NO) synthase, NO, tumor necrosis factor-alpha (TNF-, Interleukin1-beta (IL-1, and IL-6) production
Hsps may play a key role during adaptive immunity during Ag presentation by arranging MHC-peptide complexes into an assembly along with T lymphocytes activation for destroying or coordinating pathogen death and infections as well as cells that are not functional anymore
Exploitation of pathogen derived Hsps that takes the role of prominent antigen.
Heat stress as well as other stresses can trigger some mechanisms of defense such as the obvious gene expression that was not expressed under “normal” conditions.
The sudden changes in genotypic expression resulting in an increase in the synthesis of protein groups. These groups are called “heat-shock proteins” (Hsps), “Stress-induced proteins” or “Stress proteins”
HSP90 client proteins include steroid hormone receptors, receptor tyrosine kinases, cytosolic signaling proteins, and cell cycle regulators, some of which are involved in apoptosis and cell cycle regulation. Many Hsp90-dependent client proteins (e.g. ErbB2, B-Raf, Akt, steroid hormone receptors, mutant p53, HIF-1, survivin, telomerase, etc.) are associated with the six hallmarks of cancer. Therefore, oncogenic client protein degradation via Hsp90 inhibition represents a promising approach toward anticancer drug development.
This talk I gave at the Biocuration 2012 conference. It describes our method STOP (Statistical tracking of ontological phrases), a web tool for gene set enrichment analysis using multiple ontologies.
HEAT SHOCK PROTEIN AND DISEASE CONTROL IN AQUEOUS ORGANISM ppt.pptxArkedMuse
Hsps (Heat Shock Proteins) also known as "molecular chaperones." are highly conserved across species and known for its key roles in cellular activities such as protein translocation, folding, and assembly.
Major Hsp families consists of Hsp60, Hsp70, Hsp90, Hsp100, Hsp110 and small Hsps or sHsps (mol wt. < 40kDa)
Hsp70 release into extracellular compartments has noticeable impacts on APCs for peptides absorption by MHCs. They often take up the role of “danger signals”
Hsp synthesis, both constitutively expressed [heat shock cognates (Hscs)] and more usually not, upon protein denaturation stimulation.
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
Hsp families establish an intracellular networks consisting of chaperones, co-chaperones, and accessory proteins for hsp to act together.
For eg- Hsp90
Dimeric protein; an amino-terminal domain of individual monomeric protein for ATP hydrolysis co-chaperons interaction with
-COO (carboxylic) domains.
substrate binding by a middle domain
RESPONSE OF AQUATIC ORGANISMS TO DISEASE THROUGH HSP SYNTHESIS ALTERATION
Penaeus monodon (Black tiger shrimp) upon challenge with V. harveyi (heat-killed ) in gills results in synthesis of Hsp90, Hsp70, Hsp21
Encounter of nodavirus by Epinephelus coioides ( orange-spotted grouper); involving virus-induced Hsp synthesis in fish, leads to an increase in Hsp90
Disease Management Approach In Aquatic Organisms By Increasing Hsps
Heat shock- Hsp70
Hsp synthesis by exposure to chemical inducers- PRO-TEX
Exogenous Hsps Administration
Extracellular Hsps facilitated cell surface synthesis of peptides, support in distressed cells identification by the immune system “Danger signals” such as monocytes, dendrites, neutrophils, and macrophages are transmitted to immune cells by Hsp70 via TLR2 and TLR4 activation
Stimulates inflammatory cytokines, nitric oxide (NO) synthase, NO, tumor necrosis factor-alpha (TNF-, Interleukin1-beta (IL-1, and IL-6) production
Hsps may play a key role during adaptive immunity during Ag presentation by arranging MHC-peptide complexes into an assembly along with T lymphocytes activation for destroying or coordinating pathogen death and infections as well as cells that are not functional anymore
Exploitation of pathogen derived Hsps that takes the role of prominent antigen.
Heat stress as well as other stresses can trigger some mechanisms of defense such as the obvious gene expression that was not expressed under “normal” conditions.
The sudden changes in genotypic expression resulting in an increase in the synthesis of protein groups. These groups are called “heat-shock proteins” (Hsps), “Stress-induced proteins” or “Stress proteins”
HSP90 client proteins include steroid hormone receptors, receptor tyrosine kinases, cytosolic signaling proteins, and cell cycle regulators, some of which are involved in apoptosis and cell cycle regulation. Many Hsp90-dependent client proteins (e.g. ErbB2, B-Raf, Akt, steroid hormone receptors, mutant p53, HIF-1, survivin, telomerase, etc.) are associated with the six hallmarks of cancer. Therefore, oncogenic client protein degradation via Hsp90 inhibition represents a promising approach toward anticancer drug development.
This talk I gave at the Biocuration 2012 conference. It describes our method STOP (Statistical tracking of ontological phrases), a web tool for gene set enrichment analysis using multiple ontologies.
Antibiotic Stewardship by Anushri Srivastava.pptxAnushriSrivastav
Stewardship is the act of taking good care of something.
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
WHO launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS) in 2015 to fill knowledge gaps and inform strategies at all levels.
ACCORDING TO apic.org,
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
ACCORDING TO pewtrusts.org,
Antibiotic stewardship refers to efforts in doctors’ offices, hospitals, long term care facilities, and other health care settings to ensure that antibiotics are used only when necessary and appropriate
According to WHO,
Antimicrobial stewardship is a systematic approach to educate and support health care professionals to follow evidence-based guidelines for prescribing and administering antimicrobials
In 1996, John McGowan and Dale Gerding first applied the term antimicrobial stewardship, where they suggested a causal association between antimicrobial agent use and resistance. They also focused on the urgency of large-scale controlled trials of antimicrobial-use regulation employing sophisticated epidemiologic methods, molecular typing, and precise resistance mechanism analysis.
Antimicrobial Stewardship(AMS) refers to the optimal selection, dosing, and duration of antimicrobial treatment resulting in the best clinical outcome with minimal side effects to the patients and minimal impact on subsequent resistance.
According to the 2019 report, in the US, more than 2.8 million antibiotic-resistant infections occur each year, and more than 35000 people die. In addition to this, it also mentioned that 223,900 cases of Clostridoides difficile occurred in 2017, of which 12800 people died. The report did not include viruses or parasites
VISION
Being proactive
Supporting optimal animal and human health
Exploring ways to reduce overall use of antimicrobials
Using the drugs that prevent and treat disease by killing microscopic organisms in a responsible way
GOAL
to prevent the generation and spread of antimicrobial resistance (AMR). Doing so will preserve the effectiveness of these drugs in animals and humans for years to come.
being to preserve human and animal health and the effectiveness of antimicrobial medications.
to implement a multidisciplinary approach in assembling a stewardship team to include an infectious disease physician, a clinical pharmacist with infectious diseases training, infection preventionist, and a close collaboration with the staff in the clinical microbiology laboratory
to prevent antimicrobial overuse, misuse and abuse.
to minimize the developme
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Alongside the 77th World Health Assembly in Geneva on 28 May 2024, we launched the second version of our Index, allowing us to track progress and give new insights into what needs to be done to keep populations healthier for longer.
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Dr Hans Groth, Chairman of the Board, World Demographic & Ageing Forum
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M Capital Group (“MCG”) predicts that with, against, despite, and even without the global pandemic, the medical technology (MedTech) industry shows signs of continuous healthy growth, driven by smaller, faster, and cheaper devices, growing demand for home-based applications, technological innovation, strategic acquisitions, investments, and SPAC listings. MCG predicts that this should reflects itself in annual growth of over 6%, well beyond 2028.
According to Chris Mouchabhani, Managing Partner at M Capital Group, “Despite all economic scenarios that one may consider, beyond overall economic shocks, medical technology should remain one of the most promising and robust sectors over the short to medium term and well beyond 2028.”
There is a movement towards home-based care for the elderly, next generation scanning and MRI devices, wearable technology, artificial intelligence incorporation, and online connectivity. Experts also see a focus on predictive, preventive, personalized, participatory, and precision medicine, with rising levels of integration of home care and technological innovation.
The average cost of treatment has been rising across the board, creating additional financial burdens to governments, healthcare providers and insurance companies. According to MCG, cost-per-inpatient-stay in the United States alone rose on average annually by over 13% between 2014 to 2021, leading MedTech to focus research efforts on optimized medical equipment at lower price points, whilst emphasizing portability and ease of use. Namely, 46% of the 1,008 medical technology companies in the 2021 MedTech Innovator (“MTI”) database are focusing on prevention, wellness, detection, or diagnosis, signaling a clear push for preventive care to also tackle costs.
In addition, there has also been a lasting impact on consumer and medical demand for home care, supported by the pandemic. Lockdowns, closure of care facilities, and healthcare systems subjected to capacity pressure, accelerated demand away from traditional inpatient care. Now, outpatient care solutions are driving industry production, with nearly 70% of recent diagnostics start-up companies producing products in areas such as ambulatory clinics, at-home care, and self-administered diagnostics.
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Leading the Way in Nephrology: Dr. David Greene's Work with Stem Cells for Ki...Dr. David Greene Arizona
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Leading the Way in Nephrology: Dr. David Greene's Work with Stem Cells for Ki...
HSPs.ppt
1. Heat shock Proteins (HSPs)
Heat shock proteins (HSP) are expressed in
response to various biological stresses,
including heat, high pressures, and toxic
compounds. It is also one of the most
abundant cellular proteins found under non-
stress conditions
Hsp90 is part of a family of proteins known
as "chaperones," which are solely dedicated
to helping other proteins fold and assume
their proper functions.
The chaperones Hsp70 and Hsp90 together
with co-chaperones function to fold proteins in
the cytoplasm. Sometimes Hsp70 and Hsp90
function sequentially to fold the same protein
Cells are vigilant about getting these folds
right because misfolded proteins can change
the normal life of the cell. In some cases
change is good, in others deadly.
When HSP90 is compromised the number of
morphological changes increases, which lead
to formation of inactive or abnormally active
polypeptides.
Domain structure of HSP90.
2. Mad Cows, People & yeast
What do "mad cows," people with
neurodegenerative diseases and an
unusual type of yeast have in common?
They are all experiencing the effects of
misfolded proteins, according to HHMI
investigator Susan Lindquist of the
University of Chicago.
Her research identified a role for HSP90 in
the process of evolution.
They have reported that fruit flies that
make too little of the Hsp90 protein
develop dramatic deformities, such as an
extra antenna, additional bristles, notched
wings or malformed eyes.
The defects result from multiple hidden
variations in the genome.
When affected flies are interbred, these
factors are enriched and subsequent
generations have the same deformities,
even though they have normal levels of
Hsp90.
Susan Lindquist
University of Chicago
"My view is that
molecular chaperones
are a way of changing
the traits of an
organism that arose
very early in evolution.
They might be as old as
RNA and DNA."
Source:http://www.hhmi.org/annual98/research/madcow.html
3. HSPs in protein folding
The diagram shows the role of heat-
shock proteins and a chaperonin in
protein folding. As the ribosome moves
along the molecule of messenger RNA, a
chain of amino acids is built up to form a
new protein molecule. The chain is
protected against unwanted interactions
with other cytoplasmic molecules by
heat-shock proteins and a chaperonin
molecule until it has successfully
completed its folding.
Source: (http://www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/HSP/FUNCTION.HTML)
4. HSP90-alpha protein sequence
HSP90alpha 732 aa HSP90beta 724 aa
>HSP90alpha
MPEETQTQDQPMEEEEVETFAFQAEIAQLMSLIINTFYSNKEIFLRELISNSSDALDKIRYESLTDPSKLDSGKELHINLIPNKQDRTLTIVDTGIGMTKADLINNLGTIAKSGTKAFMEALQAGADISMI
GQFGVGFYSAYLVAEKVTVITKHNDDEQYAWESSAGGSFTVRTDTGEPMGRGTKVILHLKEDQTEYLEERRIKEIVKKHSQFIGYPITLFVEKERDKEVSDDEAEEKEDKEEEKEKEEKESEDKPEIED
VGSDEEEEKKDGDKKKKKKIKEKYIDQEELNKTKPIWTRNPDDITNEEYGEFYKSLTNDWEDHLAVKHFSVEGQLEFRALLFVPRRAPFDLFENRKKKNNIKLYVRRVFIMDNCEELIPEYLNFIRGVVD
SEDLPLNISREMLQQSKILKVIRKNLVKKCLELFTELAEDKENYKKFYEQFSKNIKLGIHEDSQNRKKLSELLRYYTSASGDEMVSLKDYCTRMKENQKHIYYITGETKDQVANSAFVERLRKHGLEVIY
MIEPIDEYCVQQLKEFEGKTLVSVTKEGLELPEDEEEKKKQEEKKTKFENLCKIMKDILEKKVEKVVVSNRLVTSPCCIVTSTYGWTANMERIMKAQALRDNSTMGYMAAKKHLEINPDHSIIETLRQK
AEADKNDKSVKDLVILLYETALLSSGFSLEDPQTHANRIYRMIKLGLGIDEDDPTADDTSAAVTEEMPPLEGDDDTSRMEEVD
Green bases = Geldanamycin-Binding Domain
Brown bases = Transmembrane segments as
predicted by Tmap.
Hydrophobic: A,C, I,L, M, F, V,P, Y,W
Hydrophilic: R,N, H,D, E,Q, K, S,T Either G
GREASE output
TMAP output
5. BLASTp
With the HSP90 sequence in hand we used Blastp to find homologous sequences
We were surprised to find a lot of homologous sequences across many species like Humans,
Chicken,Pig, Mouse,Horse,Fish, Coral,fruit fly, mosquito, nematode,& even crops like rice,
maize & tobacco.
The first 100 matches had e-values ranging from 0 to e-153, so they were *very* strong
matches indicating a high degree of conservation of the protein through evolution.
ID Name Score Evalue
304882 heat shock 90kDa protein 1, alpha [Homo sapiens] N... 1247 0.0
352285 heat shock protein 1, alpha [Mus musculus] NP_0346... 825 0.0
761972 heat shock protein 86 [Rattus norvegicus] NP_78693... 825 0.0
341493 heat shock protein 90A [Cricetulus griseus] AAA369... 817 0.0
609431 heat shock protein 90 - chicken 816 0.0
609432 heat shock protein 84 - mouse 745 0.0
449511 (Q9W6K6) Heat shock protein hsp90 beta [Salmo sala... 731 0.0
459017 heat shock protein hsp90 [Oncorhynchus tshawytscha... 730 0.0
446434 heat shock protein hsp90beta [Danio rerio] AAC2156... 729 0.0
361999 heat shock protein 90 [Rattus sp.] AAB23369.1 [S45... 724 0.0
460597 heat shock protein 90 [Pleurodeles waltl] AAA92343... 719 0.0
738604 90-kDa heat shock protein [Bombyx mori] BAB41209.1... 712 0.0
146263 Heat shock protein 83 CG1242-PA [Drosophila melano... 669 0.0
755572 heat shock protein 90 [Dendronephthya klunzingeri]... 662 0.0
226533 (P33126) Heat shock protein 82 [Oryza sativa (Rice)] 612 e-174
1888761 heat shock protein 82 - common tobacco (fragment) 612 e-174
252633 heat shock protein [Arabidopsis thaliana] CAA72513... 600 e-170
236351 (Q9XGF1) HSP80-2 [Triticum aestivum (Wheat)] 598 e-169
283559 (Q08277) Heat shock protein 82 [Zea mays (Maize)] 593 e-168
152674 heat shock protein 86 [Plasmodium falciparum] AAA6... 591 e-167
1899880 (Q8LLI6) Heat shock protein Hsp90 [Achlya ambisex... 579 e-164
245912 heat shock protein 90 [Lycopersicon esculentum] AA... 544 e-153
6. Multiple sequence alignment
Multiple
sequence
alignments
were done
using ClustalW
using different
species & the
following
unrooted
phylogenetic
tree was
generated.
8. Structure analysis
Comparison between Open & Closed conformations of human
HSP90 alpha
Transmembrane segments in yellow
We found ‘open’ and
‘closed’ conformations for
the Geldanamycin-
Binding Domain of the
Human Hsp90 protein &
decided to study their
differences. The parts in
yellow are the selected
residues which are also
the transmembrane
segments. The residues
‘gtia’ in the sequence
viewer show where the
structures differ. The
same region is depicted
as the little grey segment
at one end of the
transmembrane
segments
9. Comparison of HSP90 structures in Yeast & Human
We compared the HSP90 structures in yeast & human & found that the protein structures were very similar. The picture
below shows the 2 structures superimposed with the highlighted portion showing an additional residue in the yeast
sequence.
Structures compared:
1YES Human Hsp90 Geldanamycin-Binding Domain, "open" Conformation [mmdbId:7483]
1AMW : Atp Binding Site In The Hsp90 Molecular Chaperone,Saccharomyces cerevisiae (yeast) [mmdbId:7950]
Red : identical residues
Blue : similar residues
Yellow: selected residues
10. Microarray Data
We found microarray data on the Cancer Genome Anatomy Project web site
http://cgap.nci.nih.gov/Genes/GeneFinder
HSP90-alpha
This screen shot
shows the
microarray data for
HSP90 alpha
expression in
various types of
cancers.
12. Current Studies on HSP90
Changes in protein conformation are involved in some of the most devastating and
intractable diseases.
“Studies in yeast may help us decipher the fundamental nature of these disorders,
including Creutzfeldt-Jakob, Alzheimer’s, Huntington’s, and Parkinson’s
disease in humans and mad cow disease in cattle. Several of the protein culprits
are being imported into yeast, which allows for the manipulation & study of their
folding transitions & testing of therapeutic strategies.
(http://www.wi.mit.edu/nap/pdfs/Directors_Report/dir_lindquist02.pdf)
Conclusion:
HSP90 is a powerful evolutionary mechanism that ensures apparent genetic stability at
physiological conditions and at the same time allows the mutations that could rapidly
become manifest under stress.
References:
http://www.stanford.edu/class/gene211/hsp90_search
http://www.chemie.tu-muenchen.de/biotech/en/hsp90-e.html
http://www.hhmi.org/annual98/research/madcow.html
www.ashland.edu/~kstine/Research/Stress%20proteins.pdf
