Regulation of KDM5 by multiple cofactors regulates cancer and stem cellsChristopher Wynder
Presentation of data regarding proteins that regulate the activity of KDM5b.
The studies use multiple disciplines including in vitro enzymology, ES cell studies of differentiation, Mass spectrometry to detect protein protein interactions.
These studies resulted in a comprehensive view of KDM5b function. It required development of at least three novel assays that are focused on moving epigenetic research from yeast and HeLa cell types to primary, clinically relevant cell types.
The techniques have been successfully used in Embryonic stem cells (human and mouse), Neural stem cells (mouse and patient derived as well as iPSCs.
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Targeted T-cell receptor beta immune repertoire sequencing in several FFPE ti...Thermo Fisher Scientific
T-cell receptor beta (TCRβ) immune repertoire analysis by next-generation sequencing is a valuable tool for studies of the tumor microenvironment and potential immune responses to cancer immunotherapy. Here we describe a TCRβ sequencing assay that leverages the low sample input requirements of AmpliSeq library preparation technology to extend the capability of targeted immune repertoire sequencing to include FFPE samples which can often be degraded and in short supply
Regulation of KDM5 by multiple cofactors regulates cancer and stem cellsChristopher Wynder
Presentation of data regarding proteins that regulate the activity of KDM5b.
The studies use multiple disciplines including in vitro enzymology, ES cell studies of differentiation, Mass spectrometry to detect protein protein interactions.
These studies resulted in a comprehensive view of KDM5b function. It required development of at least three novel assays that are focused on moving epigenetic research from yeast and HeLa cell types to primary, clinically relevant cell types.
The techniques have been successfully used in Embryonic stem cells (human and mouse), Neural stem cells (mouse and patient derived as well as iPSCs.
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Targeted T-cell receptor beta immune repertoire sequencing in several FFPE ti...Thermo Fisher Scientific
T-cell receptor beta (TCRβ) immune repertoire analysis by next-generation sequencing is a valuable tool for studies of the tumor microenvironment and potential immune responses to cancer immunotherapy. Here we describe a TCRβ sequencing assay that leverages the low sample input requirements of AmpliSeq library preparation technology to extend the capability of targeted immune repertoire sequencing to include FFPE samples which can often be degraded and in short supply
Epigenetics and it's relevance in crop improvementShamlyGupta
Epigenetics means ‘above’ or ‘on top of genetics’
A study of the changes in gene expression that are mitotically and/or meiotically heritable and do not involve a change in the DNA sequence
Gene-regulatory information that is not expressed in DNA sequences but transmitted from one generation (of cells or organisms) to the next
Coined by embryologist C. H. Waddington in 1942.
Presentation made by Dr. Simon Alberti on October 30, 2015 at the Alzforum-hosted live webinar titled "Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?"
More information and the recording of the session available at http://www.alzforum.org/webinars/fluid-business-could-liquid-protein-herald-neurodegeneration
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.
Epigenetics and it's relevance in crop improvementShamlyGupta
Epigenetics means ‘above’ or ‘on top of genetics’
A study of the changes in gene expression that are mitotically and/or meiotically heritable and do not involve a change in the DNA sequence
Gene-regulatory information that is not expressed in DNA sequences but transmitted from one generation (of cells or organisms) to the next
Coined by embryologist C. H. Waddington in 1942.
Presentation made by Dr. Simon Alberti on October 30, 2015 at the Alzforum-hosted live webinar titled "Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?"
More information and the recording of the session available at http://www.alzforum.org/webinars/fluid-business-could-liquid-protein-herald-neurodegeneration
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a type of
cancer that starts in the blood-forming cells of the bone marrow and invades the blood.
Each human cell contains 23 pairs of chromosomes. Most cases of CML start when a "swapping"
of chromosomal material (DNA) occurs between chromosomes 9 and 22 during cell division due
to attack of DNA by radiation or other damage. Part of chromosome 9 goes to 22 and part of 22
goes to 9. This is known as a translocation and gives rise to a chromosome 22 that is shorter than
normal. This new abnormal chromosome is known as the Philadelphia chromosome.
Recent publication showing an interesting approach to identify potential cancer cells and related cell signalling inhibitors in development of anticancer drugs.
Tumor suppression and inflammation: controlling the senescence associated se...adamfreund
This is the powerpoint presentation from a talk I gave at a conference in October, 2009. It will be hard to follow without the spoken part, but it will hopefully give anyone who is interested a brief introduction to my thesis research.
GraphRAG is All You need? LLM & Knowledge GraphGuy Korland
Guy Korland, CEO and Co-founder of FalkorDB, will review two articles on the integration of language models with knowledge graphs.
1. Unifying Large Language Models and Knowledge Graphs: A Roadmap.
https://arxiv.org/abs/2306.08302
2. Microsoft Research's GraphRAG paper and a review paper on various uses of knowledge graphs:
https://www.microsoft.com/en-us/research/blog/graphrag-unlocking-llm-discovery-on-narrative-private-data/
Le nuove frontiere dell'AI nell'RPA con UiPath Autopilot™UiPathCommunity
In questo evento online gratuito, organizzato dalla Community Italiana di UiPath, potrai esplorare le nuove funzionalità di Autopilot, il tool che integra l'Intelligenza Artificiale nei processi di sviluppo e utilizzo delle Automazioni.
📕 Vedremo insieme alcuni esempi dell'utilizzo di Autopilot in diversi tool della Suite UiPath:
Autopilot per Studio Web
Autopilot per Studio
Autopilot per Apps
Clipboard AI
GenAI applicata alla Document Understanding
👨🏫👨💻 Speakers:
Stefano Negro, UiPath MVPx3, RPA Tech Lead @ BSP Consultant
Flavio Martinelli, UiPath MVP 2023, Technical Account Manager @UiPath
Andrei Tasca, RPA Solutions Team Lead @NTT Data
Generative AI Deep Dive: Advancing from Proof of Concept to ProductionAggregage
Join Maher Hanafi, VP of Engineering at Betterworks, in this new session where he'll share a practical framework to transform Gen AI prototypes into impactful products! He'll delve into the complexities of data collection and management, model selection and optimization, and ensuring security, scalability, and responsible use.
Key Trends Shaping the Future of Infrastructure.pdfCheryl Hung
Keynote at DIGIT West Expo, Glasgow on 29 May 2024.
Cheryl Hung, ochery.com
Sr Director, Infrastructure Ecosystem, Arm.
The key trends across hardware, cloud and open-source; exploring how these areas are likely to mature and develop over the short and long-term, and then considering how organisations can position themselves to adapt and thrive.
Smart TV Buyer Insights Survey 2024 by 91mobiles.pdf91mobiles
91mobiles recently conducted a Smart TV Buyer Insights Survey in which we asked over 3,000 respondents about the TV they own, aspects they look at on a new TV, and their TV buying preferences.
A tale of scale & speed: How the US Navy is enabling software delivery from l...sonjaschweigert1
Rapid and secure feature delivery is a goal across every application team and every branch of the DoD. The Navy’s DevSecOps platform, Party Barge, has achieved:
- Reduction in onboarding time from 5 weeks to 1 day
- Improved developer experience and productivity through actionable findings and reduction of false positives
- Maintenance of superior security standards and inherent policy enforcement with Authorization to Operate (ATO)
Development teams can ship efficiently and ensure applications are cyber ready for Navy Authorizing Officials (AOs). In this webinar, Sigma Defense and Anchore will give attendees a look behind the scenes and demo secure pipeline automation and security artifacts that speed up application ATO and time to production.
We will cover:
- How to remove silos in DevSecOps
- How to build efficient development pipeline roles and component templates
- How to deliver security artifacts that matter for ATO’s (SBOMs, vulnerability reports, and policy evidence)
- How to streamline operations with automated policy checks on container images
The Art of the Pitch: WordPress Relationships and SalesLaura Byrne
Clients don’t know what they don’t know. What web solutions are right for them? How does WordPress come into the picture? How do you make sure you understand scope and timeline? What do you do if sometime changes?
All these questions and more will be explored as we talk about matching clients’ needs with what your agency offers without pulling teeth or pulling your hair out. Practical tips, and strategies for successful relationship building that leads to closing the deal.
Observability Concepts EVERY Developer Should Know -- DeveloperWeek Europe.pdfPaige Cruz
Monitoring and observability aren’t traditionally found in software curriculums and many of us cobble this knowledge together from whatever vendor or ecosystem we were first introduced to and whatever is a part of your current company’s observability stack.
While the dev and ops silo continues to crumble….many organizations still relegate monitoring & observability as the purview of ops, infra and SRE teams. This is a mistake - achieving a highly observable system requires collaboration up and down the stack.
I, a former op, would like to extend an invitation to all application developers to join the observability party will share these foundational concepts to build on:
Elevating Tactical DDD Patterns Through Object CalisthenicsDorra BARTAGUIZ
After immersing yourself in the blue book and its red counterpart, attending DDD-focused conferences, and applying tactical patterns, you're left with a crucial question: How do I ensure my design is effective? Tactical patterns within Domain-Driven Design (DDD) serve as guiding principles for creating clear and manageable domain models. However, achieving success with these patterns requires additional guidance. Interestingly, we've observed that a set of constraints initially designed for training purposes remarkably aligns with effective pattern implementation, offering a more ‘mechanical’ approach. Let's explore together how Object Calisthenics can elevate the design of your tactical DDD patterns, offering concrete help for those venturing into DDD for the first time!
FIDO Alliance Osaka Seminar: The WebAuthn API and Discoverable Credentials.pdf
Noble, Marc
1. M. Chemiakin Redox status and progenitor cell function in development, degeneration and neoplasia Mark Noble University of Rochester Stem Cell and Regenerative Medicine Institute
2. The optimal cell for promoting neuronal survival and axonal regeneration … may not be progenitors or stem cells! O-2A progenitors Type-2 astrocytes Type-1 astrocytes GRP cells Type-2 astrocytes + BMP + BMP + CNTF
4. How do you control precursor cell function? Survival Death
5. Critical point: Small changes in redox state have big effects. The extent of redox change in this experiment is only ~15%. Mayer and Noble (1994) PNAS 91:7496-7500 Response to signaling molecules is dependent on intracellular redox state
6. Precursor cells that are reduced when isolated from the animal undergo more self-renewal in vitro. Smith et al (2000) PNAS 97:10032-10037 Oxidized Reduced Oxidized + NAC
9. Cell-extrinsic signaling molecules alter intracellular redox state in a predictable manner. Oxidized Reduced Differentiation Self-Renewal
10. Redox state modulation is a necessary component of the action of signaling molecules that alter the balance between self-renewal and differentiation
12. The challenge of toxicology World Health Organization estimates 30-40% of the burden of childhood disease is due to environmental factors There are 80-150 thousand registered chemicals for which we have no information - which means they are unregulated (an assumption of safety) We each have hundreds of these chemicals in our bodies - and we know nothing about combined activities
13. Developmental maladies are diseases of precursor cells • generation of specific precursor cell populations • generation of differentiated cell types • generation of sufficient numbers of cells
15. MeHg toxicity for precursor cells and oligodendrocytes is an order of magnitude lower than reported in the literature for other cells. Astrocyte LD50=500nM O-2A progenitor cell LD50 = 25nM
17. Low levels of environmental toxicants enhance vulnerability to multiple physiological stressors
18. ERK1/2 Akt SRE PDGF receptor-α NF-kB PDGF P P P P ERK1/2 Akt SRE NF-kB P P ERK1/2 Akt SRE TrkC NF-kB NT-3 P P P P ERK1/2 Akt SRE TrkC NF-kB NT-3 P P P P PDGF receptor-α PDGF Toxicants cause loss of PDGRα but not TrkC
23. c-Cbl targets PDGFR EGFR c-Met c-Kit IGF-IR etc The redox/Fyn/c-Cbl pathway: Oxidative status converges on c-Cbl-mediated degradation of specific RTKs Li et al. (2007) PLoS Biology 5:e35 ERK1/2 Akt SRE NF-kB Fyn c-Cbl B P P P P P P ERK1/2 Akt SRE c-Cbl targeted RTK NF-kB A Receptor ligand P P P P ERK1/2 Akt SRE NF-kB Fyn c-Cbl Increased oxidative status C Ub Ub P P P P P P ERK1/2 Akt SRE NF-kB Fyn c-Cbl D P P Increased oxidative status Ub Ub Increased oxidative status Increased oxidative status
31. Increased oxidative status is seen in many diseases Alzheimer’s disease Parkinson’s disease Amyotrophic lateral sclerosis Ataxia telangiectasia Autism Multiple leukodystrophies Traumatic injuries Inflammation Chemotherapy AIDS etc, etc, etc
32. Rat neural cells Survival after BCNU treatment 0 20 40 60 80 100 120 meningioma UT-12 glioma NSC astrocytes UT-4 glioma GRP human GRP human NSC NRP O-2A/OPC Oligodendrocytes % survival Survival after cisplatin treatment 0 20 40 60 80 100 SW480 UT-12 glioma NSC UT-4 glioma meningioma human NSC astrocytes human GRP GRP NRP Oligodendrocytes O-2A/OPC % survival Human neural cells Cancer cells Normal CNS progenitor cells and oligodendrocytes are more vulnerable than cancer cells to chemotherapy Dietrich et al. (2006) J. Biology 5:22
34. Activation of c-Cbl and degradation of EGFR is blocked in GBM cells Ctrl BCNU 100 uM EGFR levels Ctrl BCNU 50 uM BCNU/ 0.5 uM PP1 Fyn kinase activity
36. The optimal cell for promoting neuronal survival and axonal regeneration … may not be progenitors or stem cells! O-2A progenitors Type-2 astrocytes Type-1 astrocytes GRP cells Type-2 astrocytes + BMP + BMP + CNTF
37. Optimizing SCI repair by pre-differentiation of specific progenitor cells into specific populations of astrocytes J. Davies et al., 2008 Journal of Biology GDA gp130 GDA BMP Lesion Control
40. Joerg Dietrich Ruolan Han Ornella Santoni Yin Miranda Yang Ana Nunes Zaibo Li Wanchang Cui Brett Stevens Hsing-Yu (Warner) Chen Christopher Folts Addie Bardin Chris Farnsworth Jun Wang Xing Qiu Erin Mahoney
42. Funding sources for work discussed NYSTEM NIH Komen Foundation for the Cure Autism Speaks Hunters Hope Department of Defense The Carlson Stem Cell Fund Ludwig Institute for Cancer Research Huntsman Cancer Institute
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
This is one approach - extrending the reach of grwoth factgor combinations
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Want to emphasize that these are very small changes in redox state/glutathioen content that have these large effects. This suggested right away that we were dealing with a critical cellular mechanism, if it is senstiive to 15% changes
Not all precursors are the same - Look at how different these precursos are, depstie being isolated from the same animals. The cortical cells are also resistant ot inducers of differentiation and the oligodendrocytes they genearete are resistent to cell death. This work is providing us with important clues as to why different rgions of the nervous system have differnetiatl senstiityv to the same types of damage. Back to right cell for the right job - which ones do we want to transplant?
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
These receptor changes, and also reductions in cell divison, are seen in SJL mice - but not in CBA mice. To understand why this might be, we isolated O-2A progenitor cells from SJL and CBA mice and compared their vulnerability to different toxicants (with thimerosal shown here as an example). As you can see, cells from SJL mice are more vulnerable. That leads us to be interested in whether these cells are also more oxidized - and it turns out that they are. We believe that the vulnerability of SJL mice, and their cells, lies in their being intrinsically more oxidized. I will return to thimerosal in my discussion, but want to show you one more piece of data first.
Comment on programmed cell death during development
Comment on programmed cell death during development
I want to first focus on the critical impediment to the development of cancer treatments
Not all precursors are the same - Look at how different these precursos are, depstie being isolated from the same animals. The cortical cells are also resistant ot inducers of differentiation and the oligodendrocytes they genearete are resistent to cell death. This work is providing us with important clues as to why different rgions of the nervous system have differnetiatl senstiityv to the same types of damage. Back to right cell for the right job - which ones do we want to transplant?
These receptor changes, and also reductions in cell divison, are seen in SJL mice - but not in CBA mice. To understand why this might be, we isolated O-2A progenitor cells from SJL and CBA mice and compared their vulnerability to different toxicants (with thimerosal shown here as an example). As you can see, cells from SJL mice are more vulnerable. That leads us to be interested in whether these cells are also more oxidized - and it turns out that they are. We believe that the vulnerability of SJL mice, and their cells, lies in their being intrinsically more oxidized. I will return to thimerosal in my discussion, but want to show you one more piece of data first.
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Tissue engineering without biomaterials - how common a principle is this, now that we know to look for it?
This is one approach - extrending the reach of grwoth factgor combinations
Tissue engineering without biomaterials - how common a principle is this, now that we know to look for it?
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Let me quickly summarize this with a demosntration We’re scientists – our tools – the tools of reason are the antidote to superstition and dishonesty we can do better, and we can help teach others how to do it better – we don’t do it enough, and we, and our whole society, is paying the price As Thomas Paine, the man most responsible for conceiving the what this country might be, wrote: The most formidable weapon against errors of every kind is reason. I have never used any other, and I trust I never shall. [Thomas Paine, "Age of Reason"]
This is one approach - extrending the reach of grwoth factgor combinations
We also decided to go for something more broad-reaching it is consequences, which was to address metabolic control of cell function in genearl, and precursor cell function in particular. This is appraoched from both an empirical perspective and an evolutionary perspective
