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Archive for the ‘Innovation in Immunology Diagnostics’ Category

AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class X: +300 Audio Podcasts Library: Interviews with Scientific Leaders

AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class X: +300 Audio Podcasts Library: Interviews with Scientific Leaders

Curator: Aviva Lev-Ari, PhD, RN

We had researched the topic of AI Initiatives in Big Pharma in the following article:

  • Authentic Relevance of LPBI Group’s Portfolio of IP as Proprietary Training Data Corpus for AI Initiatives at Big Pharma

https://pharmaceuticalintelligence.com/2025/11/15/authentic-relevance-of-lpbi-groups-portfolio-of-ip-as-proprietary-training-data-corpus-for-ai-initiatives-at-big-pharma/

 

We are publishing a Series of Five articles that demonstrate the Authentic Relevance of Five of the Ten Digital IP Asset Classes in LPBI Group’s Portfolio of IP for AI Initiatives at Big Pharma.

  • For the Ten IP Asset Classes in LPBI Group’s Portfolio, See

https://pharmaceuticalintelligence.com/portfolio-of-ip-assets/

The following Five Digital IP Asset classes are positioned as Proprietary Training Data and Inference for Foundation Models in Health care.
This Corpus comprises of Live Repository of Domain Knowledge Expert-Written Clinical Interpretations of Scientific Findings codified in the following five Digital IP ASSETS CLASSES:
 IP Asset Class I: Journal: PharmaceuticalIntelligence.com
6,250 scientific articles (70% curations, creative expert opinions.  30% scientific reports).
2.4MM Views, equivalent of $50MM if downloading an article is paid market rate of $30.

https://pharmaceuticalintelligence.com/vision/pharmaceuticalintelligence-com-journal-projecting-the-annual-rate-of-article-views/

 

 

• IP Asset Class II: 48 e-Books: English Edition & Spanish Edition.
152,000 pages downloaded under pay-per-view. The largest number of downloads for one e-Publisher (LPBI)
• IP Asset Class III: 100 e-Proceedings and 50 Tweet Collections of Top Biotech and Medical Global Conferences, 2013-2025

• IP Asset Class V: 7,500 Biological Images in our Digital Art Media Gallery, as prior art. The Media Gallery resides in WordPress.com Cloud of LPBI Group’s Web site

• IP Asset Class X: +300 Audio Podcasts: Interviews with Scientific Leaders
BECAUSE THE ABOVE ASSETS ARE DIGITAL ASSETS they are ready for use as Proprietary TRAINING DATA and INFERENCE for AI Foundation Models in HealthCare.
Expert‑curated healthcare corpus mapped to a living ontology, already packaged for immediate model ingestion and suitable for safe pre-training, evals, fine‑tuning and inference. If healthcare domain data is on your roadmap, this is a rare, defensible asset.
The article TITLE of each of the five Digital IP Asset Classes matched to AI Initiatives in Big Pharma, an article per IP Asset Class are:
  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class I: PharmaceuticalIntelligence.com Journal, 2.5MM Views, 6,250 Scientific articles and Live Ontology

https://pharmaceuticalintelligence.com/2025/11/22/ai-initiatives-in-big-pharma-grog-prompt-proprietary-data-training-and-inference-by-lpbi-groups-ip-asset-class-i-pharmaceuticalintelligence-com-journal-2-5mm-views-6250-scientific-article/

 

  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class II: 48 e-Books: English Edition & Spanish Edition. 152,000 pages downloaded under pay-per-view

https://pharmaceuticalintelligence.com/2025/11/22/ai-initiatives-in-big-pharma-grog-prompt-proprietary-training-data-and-inference-by-lpbi-groups-ip-asset-class-ii-48-e-books-english-edition-spanish-edition-152000/

 

  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class III: 100 e-Proceedings and 50 Tweet Collections of Top Biotech and Medical Global Conferences, 2013-2025

https://pharmaceuticalintelligence.com/2025/11/22/ai-initiatives-in-big-pharma-grog-prompt-proprietary-training-data-and-inference-by-lpbi-groups-ip-asset-class-iii-100-e-proceedings-and-50-tweet-collections-of-top-biotech/

 

  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class V: 7,500 Biological Images in LPBI Group’s Digital Art Media Gallery, as prior art

https://pharmaceuticalintelligence.com/2025/11/22/ai-initiatives-in-big-pharma-grog-prompt-proprietary-training-data-and-inference-by-lpbi-groups-ip-asset-class-v-7500-biological-images-in-lpbi-groups-digital-art/

 

  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class X: +300 Audio Podcasts Library: Interviews with Scientific Leaders

https://pharmaceuticalintelligence.com/2025/11/22/ai-initiatives-in-big-pharma-grog-prompt-proprietary-training-data-and-inference-by-lpbi-groups-ip-asset-class-x-300-audio-podcasts-library-interviews-with-scientific-leaders/

Conclusions by @Grok
Conclusions and Implications
LPBI Group’s IP Asset Class X: A Library of Podcasts are a “live repository” primed for Big Pharma AI, fueling from R&D reviews to global equity. Technical Implications: Enables auditory-multimodal models for diagnostics/education. Business Implications: Accelerates $500M ROI; licensing for partnerships. Unique Insight: As unscripted leader interviews, they provide a “verbal moat” in AI—completing series’ holistic pharma data ecosystem.Promotional with links to podcast library/IP portfolio. Synthesizes series by emphasizing auditory human-AI synergy.

In the series of five articles, as above, we are presenting the key AI Initiatives in Big Pharma as it was created by our prompt to @Grok on 11/18/2025:

  • What are PFIZER’s AI INITIATIVES?

@Grok Response:

x.com/i/grok/share/0ol5VOJsEYs11baXq4xkzNb0h

Generative AI tools that save scientists up to 16,000 hours annually in literature searches and data analysis.
Drug Discovery and Development Acceleration Pfizer uses AI, supercomputing, and ML to streamline R&D timelines
Clinical Trials and Regulatory Efficiency AI:

-Predictive Regulatory Tools

-Decentralize Trials

-inventory management

Disease Detection and Diagnostics:

–       ATTR-CM Initiative

–       Rare diseases

Generative AI and Operational Tools:

–       Charlie Platform

–       Scientific Data Cloud AWS powered ML on centralized data

–       Amazon’s SageMaker /Bedrock for Manufacturing efficiency

–       Global Health Grants:

Pfizer Foundation’s AI Learning Lab for equitable access to care and tools for community care

Partnerships and Education

–       Collaborations: IMI Big Picture for 3M – sample disease database

–       AI in Pharma AIPM Symposium: Drug discovery and Precision Medicine

–       Webinars of AI for biomedical data integration

–       Webinar on AI in Manufacturing

Strategic Focus:

–       $500M R&D reinvestment by 2026 targets AI for Productivity

–       Part of $7.7B cost savings

–       Ethical AI, diverse DBs

–       Global biotech advances: China’s AI in CRISPR

 

  • AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class X: +300 Audio Podcasts Library: Interviews with Scientific Leaders

The Left Column was written @Grok

The Right Column was written by Aviva Lev-Ari, PhD, RN

 

AI Initiative at Big Pharma

i.e., Pfizer

Library of Audio and Video Podcasts

N = +300

Generative AI tools that save scientists up to 16,000 hours annually in literature searches and data analysis.
Drug Discovery and Development Acceleration Pfizer uses AI, supercomputing, and ML to streamline R&D timelines Review ALL SCIENTIFIC BREAKTHROUGHS
Clinical Trials and Regulatory Efficiency AI:

-Predictive Regulatory Tools

-Decentralize Trials

-inventory management

Disease Detection and Diagnostics:

–       ATTR-CM Initiative

–       Rare diseases

Generative AI and Operational Tools:

–       Charlie Platform

–       Scientific Data Cloud AWS powered ML on centralized data

–       Amazon’s SageMaker/Bedrock for Manufacturing efficiency

–       Global Health Grants:

Pfizer Foundation’s AI Learning Lab for equitable  access to care and tools for community care

Ingest to Charlie Platform all +300 Podcasts
Partnerships and Education

–       Collaborations: IMI Big Picture for 3M – sample disease database

–       AI in Pharma AIPM Symposium: Drug discovery and Precision Medicine

–       Webinars of AI for biomedical data integration

–       Webinard on Ai in Manufacturing

Use Podcast for Education

Use Podcast as Hybrid: Start presentation with a Podcast continue with a life interview

Strategic Focus:

–       $500M R&D reinvestment by 2026 targets AI for Productivity

–       Part of $7.7B cost savings

–       Ethical AI, diverse DBs

–       Global biotech advances: China’s AI in CRISPR

 

CONCLUSIONS: The Voice of Dr. Stephen J. Williams PhD

PENDING

Article Summary by @Grok of the ArticleTitle:

AI Initiatives in Big Pharma @Grok prompt & Proprietary Training Data and Inference by LPBI Group’s IP Asset Class X: +300 Audio Podcasts Library: Interviews with Scientific Leaders

Publication Date: November 22, 2025

Author/Curator: Aviva Lev-Ari, PhD, RN
(Curator; Posted by 2012pharmaceutical)
@Grok SOURCE:

Overview: Final (fifth) in LPBI Group’s five-article series on AI-ready digital IP assets for pharma. This installment highlights IP Asset Class X—+300 audio podcasts of interviews with scientific leaders—as a proprietary, expert-curated auditory corpus for training and inference in healthcare AI models. Using a November 18, 2025, Grok prompt on Pfizer’s AI efforts, it maps the library to pharma applications, emphasizing audio ingestion for breakthroughs review, education, and platform integration. Unlike visual/text prior classes, this focuses on verbal expert insights for multimodal/hybrid AI, positioning them as a “rare, defensible” resource for ethical, diverse foundation models.
Main Thesis and Key Arguments

  • Core Idea: LPBI’s +300 podcasts capture unscripted scientific discourse from leaders, forming a live repository of domain knowledge ideal for AI ingestion—enhancing Big Pharma’s shift from generic to human-curated models for R&D acceleration and equitable care.
  • Value Proposition: Part of ten IP classes (five AI-ready: I, II, III, V, X); podcasts equivalent to $50MM value in series benchmarks, with living ontology for semantic mapping. Unique for hybrid uses (e.g., education starters) and safe pre-training/fine-tuning, contrasting open-source data with proprietary, ethical inputs.
  • Broader Context: Caps series by adding auditory depth to text/visual assets; supports Pfizer’s $500M AI reinvestment via productivity gains (e.g., 16,000 hours saved).

AI Initiatives in Big Pharma (Focus on Pfizer) Reuses Grok prompt highlights, presented in an integrated mapping table (verbatim):

AI Initiative at Big Pharma i.e., Pfizer
Description
Generative AI tools
Save scientists up to 16,000 hours annually in literature searches and data analysis.
Drug Discovery and Development Acceleration
Pfizer uses AI, supercomputing, and ML to streamline R&D timelines.
Clinical Trials and Regulatory Efficiency AI
Predictive Regulatory Tools; Decentralize Trials; Inventory management.
Disease Detection and Diagnostics
ATTR-CM Initiative; Rare diseases.
Generative AI and Operational Tools
Charlie Platform; Scientific Data Cloud AWS powered ML on centralized data; Amazon’s SageMaker/Bedrock for Manufacturing efficiency; Global Health Grants: Pfizer Foundation’s AI Learning Lab for equitable access to care and tools for community care.
Partnerships and Education
Collaborations: IMI Big Picture for 3M-sample disease database; AI in Pharma AIPM Symposium: Drug discovery and Precision Medicine; Webinars of AI for biomedical data integration; Webinar on AI in Manufacturing.
Strategic Focus
$500M R&D reinvestment by 2026 targets AI for Productivity; Part of $7.7B cost savings; Ethical AI, diverse DBs; Global biotech advances: China’s AI in CRISPR.
Mapping to LPBI’s Proprietary DataCore alignment table (verbatim extraction, linking Pfizer initiatives to Class X podcasts):
AI Initiative at Big Pharma i.e., Pfizer
Library of Audio and Video Podcasts N = +300
Generative AI tools (16,000 hours saved)
(No specific mapping provided.)
Drug Discovery and Development Acceleration
Review ALL SCIENTIFIC BREAKTHROUGHS.
Clinical Trials and Regulatory Efficiency
(No specific mapping provided.)
Disease Detection and Diagnostics (ATTR-CM, rare diseases)
(No specific mapping provided.)
Generative AI and Operational Tools (Charlie, AWS, etc.)
Ingest to Charlie Platform all +300 Podcasts.
Partnerships and Education (IMI, AIPM, webinars)
Use Podcast for Education; Use Podcast as Hybrid: Start presentation with a Podcast continue with a life interview.
Strategic Focus ($500M reinvestment, ethics)
(No specific mapping provided.)

Methodologies and Frameworks

  • AI Training Pipeline: Ingest audio into Charlie/AWS for pre-training (expert discourse corpus), fine-tuning (e.g., breakthrough reviews), and inference (e.g., educational hybrids). Use ontology for thematic mapping; Grok prompt for sourcing initiatives.
  • Productivity Model: Boosts Pfizer’s $7.7B savings via auditory data for diverse, ethical AI (e.g., Learning Lab grants); hybrid formats for webinars/symposia.
  • Insights: Quote from Dr. Stephen J. Williams, PhD: Assets as “codified digital treasures” for safe healthcare AI. Predicts revolution in verbal inference for precision medicine.

Conclusions and Implications

LPBI Group’s IP Asset Class X:
A Library of Podcasts are a “live repository” primed for Big Pharma AI, fueling from R&D reviews to global equity. Technical Implications: Enables auditory-multimodal models for diagnostics/education. Business Implications: Accelerates $500M ROI; licensing for partnerships. Unique Insight: As unscripted leader interviews, they provide a “verbal moat” in AI—completing series’ holistic pharma data ecosystem.Promotional with links to podcast library/IP portfolio. Synthesizes series by emphasizing auditory human-AI synergy.
@Grok was prompted to summarize the Table of Contents of the e-Book that present the Library of Podcast INDEX.

Overview of IP Asset Class X: +300 Audio Podcasts – Interviews with Scientific LeadersThe BioMed Audio Podcast Library from LPBI Group is a valuable intellectual property asset in the biomedical field, featuring over 301 audio podcasts created from interviews, curations, and discussions with prominent scientific leaders. This collection highlights breakthroughs in areas like genomics, cancer research, immunology, precision medicine, and public health policy. Curated by experts such as Aviva Lev-Ari, PhD, RN (197 podcasts), Larry H. Bernstein, MD, FCAP (48 podcasts), and Stephen J. Williams, PhD (38 podcasts), the library is organized into 21 thematic chapters for easy navigation.Key features include:

  • Search and Accessibility: Filter by chapter, curator, subject, or podcast ID. Each entry includes text-to-speech conversion and NLP-generated WordClouds for topic visualization.
  • Content Focus: Emphasizes Nobel laureates, key opinion leaders, and innovators discussing technologies like CRISPR-Cas9, mRNA vaccines, immunotherapy, and biotechnology ventures.
  • Format and Updates: Derived from articles on real-time events (e.g., COVID-19 impacts, award announcements). The library continues to expand, with no direct audio embeds—access via linked articles for full transcripts and playback.
  • Themes Covered: Public health policy, cardiovascular science, neuroscience, academic institutions, and more, with a strong emphasis on translational research and personalized medicine.

This asset represents a rich repository for researchers, students, and professionals seeking insights from leaders like Francis Collins, Jennifer Doudna, and Siddhartha Mukherjee.Selected Highlights by ChapterBelow are curated examples from key chapters, showcasing interviews with scientific leaders. For the full library (301+ entries), visit the source page.

Chapter 1: Public Health
Podcast ID
Curator
Title
Scientific Leader(s)
Brief Description
Link
17
Aviva Lev-Ari
LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2
Leaders in genome sequencing
Explores genetic mutations’ role in personalized cancer therapies.
161
Aviva Lev-Ari
FDA Commissioner, Dr. Margaret A. Hamburg on HealthCare for 310Million Americans and the Role of Personalized Medicine
Dr. Margaret A. Hamburg
Discusses personalized medicine’s impact on U.S. healthcare policy.
273
Aviva Lev-Ari
Live Notes and Conference Coverage in Real Time. COVID19 And The Impact on Cancer Patients Town Hall with Leading Oncologists; April 4, 2020
Leading oncologists
Real-time analysis of COVID-19’s effects on cancer care.
Chapter: Genomics & Genome Biology
Podcast ID
Curator
Title
Scientific Leader(s)
Brief Description
Link
23
Aviva Lev-Ari
2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.
Francis Collins, Craig Venter, Eric Lander
Reflections on post-human genome sequencing advancements.
226
Aviva Lev-Ari

Dr. Jennifer Doudna (UC Berkeley): PMWC 2017 Luminary Award, January 22, 2017

@PMWC

2017

Jennifer Doudna (CRISPR pioneer)
Award speech on CRISPR’s applications in biomedicine.
288
Aviva Lev-Ari
Allon Klein, Harvard Medical School, and Aviv Regev, Genentech, Recipients of National Academy of Sciences James Prize…
Allon Klein, Aviv Regev
Integration of science and technology in genomics research.
Chapter: Precision Medicine & Cancer (35+ Entries)
Podcast ID
Curator
Title
Scientific Leader(s)
Brief Description
Link
15
Aviva Lev-Ari
Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders
Cancer scientific leaders
Expert opinions on preventing and curing cancer via personalization.
12
Aviva Lev-Ari
The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953
James Watson (Nobel laureate)
Critique of cancer research institutions by DNA co-discoverer.
132
Aviva Lev-Ari
Practicing Oncology: Medscape Editor-in-Chief Eric J. Topol, MD interviews Siddhartha Mukherjee, MD, PhD
Siddhartha Mukherjee (interviewed by Eric J. Topol)
Insights into oncology practices and patient care.
102
Aviva Lev-Ari
Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer
Reuben Shaw, Ph.D.
How metabolism drives cancer progression.
209
Aviva Lev-Ari
Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells…
Immunotherapy pioneers
Advances in CAR-T and immune-based cancer therapies.
This selection captures the library’s depth, blending historical perspectives (e.g., Watson) with cutting-edge topics (e.g., CRISPR, immunotherapy). For deeper dives, use the site’s search tools to explore chapters like Cardiovascular Science (36 podcasts) or Immunology.

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Immuno-Timebombs: The Hidden Drivers of Age-Related Illness

Curator: Dr. Sudipta Saha, Ph. D.

 

There are two converging biological processes that drive most age-related diseases: immunosenescence and inflammaging. Together, they explain how a deteriorating immune system and chronic low-grade inflammation contribute to neurodegenerative diseases, cancer, cardiovascular disorders, and frailty.

Immunosenescence refers to the waning competence of both innate and adaptive immune systems. With age, T and B cells become less effective, and macrophage function declines. This makes older individuals more susceptible to infections and less efficient at clearing dysfunctional cells.

Inflammaging, on the other hand, is the persistent presence of inflammation without infection. Factors like gut microbiome alterations, senescent cell accumulation, and epigenetic drift contribute to this condition. Over time, this “silent fire” damages tissues and lays the groundwork for disease.

These drivers don’t just correlate with disease—they often precede it. This positions inflammaging and immunosenescence as targets for prevention, not just treatment. Interventions like exercise, caloric modulation, and anti-inflammatory diets may attenuate their effects. Emerging therapies such as senolytics and immune rejuvenation approaches (e.g., thymic regeneration) are showing promise.

This article also calls for a paradigm shift in medical science—from reactive disease management to proactive longevity interventions. As we unravel the biological clocks of aging, strategies targeting immune recalibration may delay or prevent multiple diseases simultaneously.

The future of healthy aging may well depend on how early we can intervene in this immuno-inflammatory loop—before pathology sets in.

References:

https://erictopol.substack.com/p/the-drivers-of-age-related-diseases

https://www.nature.com/articles/s41591-019-0661-0

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761661

https://www.cell.com/fulltext/S0092-8674(19)30184-4

https://www.frontiersin.org/articles/10.3389/fimmu.2020.579220/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649506

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Sleeping Threats: Immune System’s Watch on Dormant Cancer

Curator: Dr. Sudipta Saha, Ph. D.

 

The immune system’s role in regulating dormant cancer cells has been increasingly elucidated, revealing a complex interplay that influences metastasis and cancer recurrence. Dormant cells, which enter a non-proliferative state, can evade immune detection and remain quiescent for prolonged periods.


Mechanisms of immune evasion include down-regulation of antigen presentation and residence within immune-privileged niches such as bone marrow. Both innate and adaptive immunity, particularly CD8+ T cells and natural killer cells, are involved in maintaining dormancy and preventing metastatic outgrowth.


Micro-environmental factors that modulate immune surveillance and dormancy status have been identified. Changes in cytokine profiles and inflammation can disrupt dormancy, leading to cancer cell reactivation and metastasis.


Therapeutic approaches to sustain dormancy or eliminate dormant cells are under development. These include immune checkpoint inhibitors, cancer vaccines, and cytokine modulators aimed at enhancing immune recognition and clearance.


By targeting dormant cancer cells through immune modulation, it is anticipated that metastasis can be delayed or prevented, significantly improving long-term patient outcomes and reducing cancer mortality.

References:

https://www.cancer.gov/news-events/cancer-currents-blog/2025/metastasis-dormant-cancer-cells-immune-system

https://www.nature.com/articles/nrc2256

https://pubmed.ncbi.nlm.nih.gov/33681821/

https://pubmed.ncbi.nlm.nih.gov/33811127/

https://www.nature.com/articles/nrc3910

https://pubmed.ncbi.nlm.nih.gov/27015306

 

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SNU-BioTalk 2025: Symphony of Cellular Signals in Metabolism and Immune Response – International Conference at Sister Nivedita University, Kolkata, India on 16 & 17 January 2025

SNU-BioTalk 2025: Symphony of Cellular Signals in Metabolism and Immune Response – International Conference at Sister Nivedita University, Kolkata, India on 16 & 17 January 2025

Joint Convenor: Dr. Sudipta Saha (Member of LPBI since 2012)

About the Conference:

The International Conference on ‘Symphony of Cellular Signals in Metabolism and Immune Response’ focuses on the complex signalling pathways governing cellular functions in health and disease. It will explore the cellular mechanisms that regulate metabolism, immune responses, and survival, highlighting advances in medical science and biotechnology. Bringing together leading experts and emerging researchers, the conference will feature keynote lectures, panel discussions, research presentations, and interactive sessions, all designed to foster collaboration and innovation. By promoting an exchange of ideas, the event aims to drive transformative insights and solutions that impact human health and sustainable healthcare practices.

The conference will also be livestreamed on YouTube and Facebook

This programme will also host I-STEM: Indian Science, Technology and Engineering facilities Map (I-STEM) is a dynamic and interactive national portal for research cooperation.

Thrust areas:

  • Intracellular signalling processes of cellular metabolism
  • Signalling pathways in physiological and pathological processes
  • Signalling in innate and adaptive immunity

Conference Webpage: https://www.snuniv.ac.in/snu-biotalk-2025/

NU-BioTalk 2025 Abstract Submission Form: https://forms.gle/ygdGqtuBGa7DEhDFA

SNU-BioTalk 2025 Registration Form: https://forms.gle/unasPpByLmYwrRBM6

Programme Schedule:

YouTube Links of Live Telecast:

Day 1:

Day 2:

Media:

Newspaper:

The Telegraph – Click to View

 

Abstract Book

Scan to Download:

Click: 

Abstract Book

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Regulatory T cells (Tregs) are important for sperm tolerance and male fertility

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Regulatory T cells (Tregs) are specialized immune cells that modulate tissue homeostasis. They are a specialized subset of T lymphocytes that function as suppressive immune cells and inhibit various elements of immune response in vitro and in vivo. While there are constraints on the number or function of Tregs which can be exploited to evoke an effective anti-tumor response, sufficient expansion of Tregs is essential for successful organ transplantation and for promoting tolerance of self and foreign antigens. Current studies have provided evidence that a defect in the number or function of Tregs contributes to the etiology of several reproductive diseases.

In the male reproductive tract, prevention of autoimmune responses against antigenic spermatozoa, while ensuring protection against stressors, is a key determinant of fertility. Using an autoimmunity-induced model, it was uncovered that the role of Tregs in maintaining the tolerogenic state of the testis and epididymis. The loss of tolerance induced an exacerbated immune cell infiltration and the development of anti-sperm antibodies, which caused severe male subfertility. By identifying immunoregulatory mechanisms in the testis and epididymis.

Tregs modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, it was reported that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature. It was found that Treg depletion induces severe autoimmune orchitis and epididymitis, manifested by an exacerbated immune cell infiltration [CD4 T cells, monocytes, and mononuclear phagocytes (MPs)] and the development of anti-sperm antibodies (ASA).

In Treg-depleted mice, MPs increased projections toward the epididymal lumen as well as invading the lumen. ASA-bound sperm enhance sperm agglutination and might facilitate sperm phagocytosis. Tolerance breakdown impaired epididymal epithelial function and altered extracellular vesicle cargo, both of which play crucial roles in the acquisition of sperm fertilizing ability and subsequent embryo development. The affected mice had reduced sperm number and motility and severe fertility defects.

Deciphering these immunoregulatory mechanisms may lead to the development of therapies for infertility and identifying potential targets for immuno-contraception. Ultimately, such knowledge fills gaps related to reproductive mucosa, which is an understudied facet of human male health.

References:

https://www.pnas.org/doi/10.1073/pnas.2306797120

https://pubmed.ncbi.nlm.nih.gov/24048122/

https://pubmed.ncbi.nlm.nih.gov/34845322/

https://pubmed.ncbi.nlm.nih.gov/34845322/

https://pubmed.ncbi.nlm.nih.gov/29648649/

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Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Curators:

 

THE VOICE of Aviva Lev-Ari, PhD, RN

In this curation we wish to present two breaking through goals:

Goal 1:

Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer

Goal 2:

Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.

According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.

These eight subcellular pathologies can’t be measured at present time.

In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.

Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases

  1. Glycation
  2. Oxidative Stress
  3. Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
  4. Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
  5. Membrane instability
  6. Inflammation in the gut [mucin layer and tight junctions]
  7. Epigenetics/Methylation
  8. Autophagy [AMPKbeta1 improvement in health span]

Diseases that are not Diseases: no drugs for them, only diet modification will help

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

Exercise will not undo Unhealthy Diet

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:

  1. Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
  2. IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL

In the Bioelecronics domain we are inspired by the work of the following three research sources:

  1. Biological and Biomedical Electrical Engineering (B2E2) at Cornell University, School of Engineering https://www.engineering.cornell.edu/bio-electrical-engineering-0
  2. Bioelectronics Group at MIT https://bioelectronics.mit.edu/
  3. The work of Michael Levin @Tufts, The Levin Lab
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
Born: 1969 (age 54 years), Moscow, Russia
Education: Harvard University (1992–1996), Tufts University (1988–1992)
Affiliation: University of Cape Town
Research interests: Allergy, Immunology, Cross Cultural Communication
Awards: Cozzarelli prize (2020)
Doctoral advisor: Clifford Tabin
Most recent 20 Publications by Michael Levin, PhD
SOURCE
SCHOLARLY ARTICLE
The nonlinearity of regulation in biological networks
1 Dec 2023npj Systems Biology and Applications9(1)
Co-authorsManicka S, Johnson K, Levin M
SCHOLARLY ARTICLE
Toward an ethics of autopoietic technology: Stress, care, and intelligence
1 Sep 2023BioSystems231
Co-authorsWitkowski O, Doctor T, Solomonova E
SCHOLARLY ARTICLE
Closing the Loop on Morphogenesis: A Mathematical Model of Morphogenesis by Closed-Loop Reaction-Diffusion
14 Aug 2023Frontiers in Cell and Developmental Biology11:1087650
Co-authorsGrodstein J, McMillen P, Levin M
SCHOLARLY ARTICLE
30 Jul 2023Biochim Biophys Acta Gen Subj1867(10):130440
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
Regulative development as a model for origin of life and artificial life studies
1 Jul 2023BioSystems229
Co-authorsFields C, Levin M
SCHOLARLY ARTICLE
The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left–Right Functional Differences
1 Jul 2023International Journal of Molecular Sciences24(13)
Co-authorsMasuelli S, Real S, McMillen P
SCHOLARLY ARTICLE
Bioelectricidad en agregados multicelulares de células no excitables- modelos biofísicos
Jun 2023Revista Española de Física32(2)
Co-authorsCervera J, Levin M, Mafé S
SCHOLARLY ARTICLE
Bioelectricity: A Multifaceted Discipline, and a Multifaceted Issue!
1 Jun 2023Bioelectricity5(2):75
Co-authorsDjamgoz MBA, Levin M
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part I: Classical and Quantum Formulations of Active Inference
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):235-245
Co-authorsFields C, Fabrocini F, Friston K
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part II: Tensor Networks as General Models of Control Flow
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):246-256
Co-authorsFields C, Fabrocini F, Friston K
SCHOLARLY ARTICLE
Darwin’s agential materials: evolutionary implications of multiscale competency in developmental biology
1 Jun 2023Cellular and Molecular Life Sciences80(6)
Co-authorsLevin M
SCHOLARLY ARTICLE
Morphoceuticals: Perspectives for discovery of drugs targeting anatomical control mechanisms in regenerative medicine, cancer and aging
1 Jun 2023Drug Discovery Today28(6)
Co-authorsPio-Lopez L, Levin M
SCHOLARLY ARTICLE
Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine
12 May 2023Patterns4(5)
Co-authorsMathews J, Chang A, Devlin L
SCHOLARLY ARTICLE
Making and breaking symmetries in mind and life
14 Apr 2023Interface Focus13(3)
Co-authorsSafron A, Sakthivadivel DAR, Sheikhbahaee Z
SCHOLARLY ARTICLE
The scaling of goals from cellular to anatomical homeostasis: an evolutionary simulation, experiment and analysis
14 Apr 2023Interface Focus13(3)
Co-authorsPio-Lopez L, Bischof J, LaPalme JV
SCHOLARLY ARTICLE
The collective intelligence of evolution and development
Apr 2023Collective Intelligence2(2):263391372311683SAGE Publications
Co-authorsWatson R, Levin M
SCHOLARLY ARTICLE
Bioelectricity of non-excitable cells and multicellular pattern memories: Biophysical modeling
13 Mar 2023Physics Reports1004:1-31
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
There’s Plenty of Room Right Here: Biological Systems as Evolved, Overloaded, Multi-Scale Machines
1 Mar 2023Biomimetics8(1)
Co-authorsBongard J, Levin M
SCHOLARLY ARTICLE
Transplantation of fragments from different planaria: A bioelectrical model for head regeneration
7 Feb 2023Journal of Theoretical Biology558
Co-authorsCervera J, Manzanares JA, Levin M
SCHOLARLY ARTICLE
Bioelectric networks: the cognitive glue enabling evolutionary scaling from physiology to mind
1 Jan 2023Animal Cognition
Co-authorsLevin M
SCHOLARLY ARTICLE
Biological Robots: Perspectives on an Emerging Interdisciplinary Field
1 Jan 2023Soft Robotics
Co-authorsBlackiston D, Kriegman S, Bongard J
SCHOLARLY ARTICLE
Cellular Competency during Development Alters Evolutionary Dynamics in an Artificial Embryogeny Model
1 Jan 2023Entropy25(1)
Co-authorsShreesha L, Levin M
5

5 total citations on Dimensions.

Article has an altmetric score of 16
SCHOLARLY ARTICLE
1 Jan 2023BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY138(1):141
Co-authorsClawson WP, Levin M
SCHOLARLY ARTICLE
Future medicine: from molecular pathways to the collective intelligence of the body
1 Jan 2023Trends in Molecular Medicine
Co-authorsLagasse E, Levin M

THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC

PENDING

THE VOICE of  Stephen J. Williams, PhD

Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes

 

  1. 25% of US children have fatty liver
  2. Type II diabetes can be manifested from fatty live with 151 million  people worldwide affected moving up to 568 million in 7 years
  3. A common myth is diabetes due to overweight condition driving the metabolic disease
  4. There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
  5. Thirty percent of ‘obese’ people just have high subcutaneous fat.  the visceral fat is more problematic
  6. there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects.  Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
  7. At any BMI some patients are insulin sensitive while some resistant
  8. Visceral fat accumulation may be more due to chronic stress condition
  9. Fructose can decrease liver mitochondrial function
  10. A methionine and choline deficient diet can lead to rapid NASH development

 

Read Full Post »

Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

 

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as 

  • melanoma,
  • lung,
  • colon, and
  • liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)

 

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of 

  • CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
  • genetic inactivation of KLRB1 or
  • antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

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Read Full Post »

RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response

Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face

 

UPDATED on 9/8/2020

What bats can teach us about developing immunity to Covid-19 | Free to read

Clive Cookson, Anna Gross and Ian Bott, London

https://www.ft.com/content/743ce7a0-60eb-482d-b1f4-d4de11182fa9?utm_source=Nature+Briefing&utm_campaign=af64422080-briefing-dy-20200908&utm_medium=email&utm_term=0_c9dfd39373-af64422080-43323101

 

UPDATED on 6/29/2020

Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC

on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT

How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST

Mike Yoffe, MD, PhD 

In COVID-19 patients: two life threatening conditions are seen in ICUs:

  • Blood Clotting – Hypercoagulability or Thrombophilia
  • Cytokine Storm – immuno-inflammatory response
  • The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.

Mike Yoffe’s related domain of expertise:

Signaling pathways and networks that control cytokine responses and inflammation

Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models.  We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.

SOURCE

https://www.bidmc.org/research/research-by-department/surgery/acute-care-surgery-trauma-and-surgical-critical-care/michael-b-yaffe

 

See

The Genome Structure of CORONAVIRUS, SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Open Access Published:May 15, 2020DOI:https://doi.org/10.1016/j.cell.2020.04.026

Highlights

  • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
  • Strong chemokine expression is consistent across in vitroex vivo, and in vivo models
  • Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19

Summary

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

Graphical Abstract

Keywords

Results

Defining the Transcriptional Response to SARS-CoV-2 Relative to Other Respiratory Viruses

To compare the transcriptional response of SARS-CoV-2 with other respiratory viruses, including MERS-CoV, SARS-CoV-1, human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and IAV, we first chose to focus on infection in a variety of respiratory cell lines (Figure 1). To this end, we collected poly(A) RNA from infected cells and performed RNA sequencing (RNA-seq) to estimate viral load. These data show that virus infection levels ranged from 0.1% to more than 50% of total RNA reads (Figure 1A).

Discussion

In the present study, we focus on defining the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. In general, our data show that the overall transcriptional footprint of SARS-CoV-2 infection was distinct in comparison with other highly pathogenic coronaviruses and common respiratory viruses such as IAV, HPIV3, and RSV. It is noteworthy that, despite a reduced IFN-I and -III response to SARS-CoV-2, we observed a consistent chemokine signature. One exception to this observation is the response to high-MOI infection in A549-ACE2 and Calu-3 cells, where replication was robust and an IFN-I and -III signature could be observed. In both of these examples, cells were infected at a rate to theoretically deliver two functional virions per cell in addition to any defective interfering particles within the virus stock that were not accounted for by plaque assays. Under these conditions, the threshold for PAMP may be achieved prior to the ability of the virus to evade detection through production of a viral antagonist. Alternatively, addition of multiple genomes to a single cell may disrupt the stoichiometry of viral components, which, in turn, may itself generate PAMPs that would not form otherwise. These ideas are supported by the fact that, at a low-MOI infection in A549-ACE2 cells, high levels of replication could also be achieved, but in the absence of IFN-I and -III induction. Taken together, these data suggest that, at low MOIs, the virus is not a strong inducer of the IFN-I and -III system, as opposed to conditions where the MOI is high.
Taken together, the data presented here suggest that the response to SARS-CoV-2 is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation. Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties.

SOURCE

https://www.cell.com/cell/fulltext/S0092-8674(20)30489-X

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

Yoriyuki KonnoIzumi KimuraKeiya UriuMasaya FukushiTakashi IrieYoshio KoyanagiSo NakagawaKei Sato

Abstract

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasi-species with extended ORF3b that may exacerbate COVID-19 symptoms.

Highlights

  • ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist

  • SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog

  • The anti-IFN activity of ORF3b depends on the length of its C-terminus

  • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

Competing Interest Statement

The authors have declared no competing interest.

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

 

SOURCE

https://www.biorxiv.org/content/10.1101/2020.05.11.088179v1

 

 

A deep dive into how the new coronavirus infects cells has found that it orchestrates a hostile takeover of their genes unlike any other known viruses do, producing what one leading scientist calls “unique” and “aberrant” changes.Recent studies show that in seizing control of genes in the human cells it invades, the virus changes how segments of DNA are read, doing so in a way that might explain why the elderly are more likely to die of Covid-19 and why antiviral drugs might not only save sick patients’ lives but also prevent severe disease if taken before infection.“It’s something I have never seen in my 20 years of” studying viruses, said virologist Benjamin tenOever of the Icahn School of Medicine at Mount Sinai, referring to how SARS-CoV-2, the virus that causes Covid-19, hijacks cells’ genomes.The “something” he and his colleagues saw is how SARS-CoV-2 blocks one virus-fighting set of genes but allows another set to launch, a pattern never seen with other viruses. Influenza and the original SARS virus (in the early 2000s), for instance, interfere with both arms of the body’s immune response — what tenOever dubs “call to arms” genes and “call for reinforcement” genes.The first group of genes produces interferons. These proteins, which infected cells release, are biological semaphores, signaling to neighboring cells to activate some 500 of their own genes that will slow down the virus’ ability to make millions of copies of itself if it invades them. This lasts seven to 10 days, tenOever said, controlling virus replication and thereby buying time for the second group of genes to act.This second set of genes produce their own secreted proteins, called chemokines, that emit a biochemical “come here!” alarm. When far-flung antibody-making B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal professional killers to arrive and start eradicating viruses.

“Most other viruses interfere with some aspect of both the call to arms and the call for reinforcements,” tenOever said. “If they didn’t, no one would ever get a viral illness”: The one-two punch would pummel any incipient infection into submission.

SARS-CoV-2, however, uniquely blocks one cellular defense but activates the other, he and his colleagues reported in a study published last week in Cell. They studied healthy human lung cells growing in lab dishes, ferrets (which the virus infects easily), and lung cells from Covid-19 patients. In all three, they found that within three days of infection, the virus induces cells’ call-for-reinforcement genes to produce cytokines. But it blocks their call-to-arms genes — the interferons that dampen the virus’ replication.

The result is essentially no brakes on the virus’s replication, but a storm of inflammatory molecules in the lungs, which is what tenOever calls an “unique” and “aberrant” consequence of how SARS-CoV-2 manipulates the genome of its target.

In another new study, scientists in Japan last week identified how SARS-CoV-2 accomplishes that genetic manipulation. Its ORF3b gene produces a protein called a transcription factor that has “strong anti-interferon activity,” Kei Sato of the University of Tokyo and colleagues found — stronger than the original SARS virus or influenza viruses. The protein basically blocks the cell from recognizing that a virus is present, in a way that prevents interferon genes from being expressed.

In fact, the Icahn School team found no interferons in the lung cells of Covid-19 patients. Without interferons, tenOever said, “there is nothing to stop the virus from replicating and festering in the lungs forever.”

That causes lung cells to emit even more “call-for-reinforcement” genes, summoning more and more immune cells. Now the lungs have macrophages and neutrophils and other immune cells “everywhere,” tenOever said, causing such runaway inflammation “that you start having inflammation that induces more inflammation.”

At the same time, unchecked viral replication kills lung cells involved in oxygen exchange. “And suddenly you’re in the hospital in severe respiratory distress,” he said.

In elderly people, as well as those with diabetes, heart disease, and other underlying conditions, the call-to-arms part of the immune system is weaker than in younger, healthier people, even before the coronavirus arrives. That reduces even further the cells’ ability to knock down virus replication with interferons, and imbalances the immune system toward the dangerous inflammatory response.

The discovery that SARS-CoV-2 strongly suppresses infected cells’ production of interferons has raised an intriguing possibility: that taking interferons might prevent severe Covid-19 or even prevent it in the first place, said Vineet Menachery of the University of Texas Medical Branch.

In a study of human cells growing in lab dishes, described in a preprint (not peer-reviewed or published in a journal yet), he and his colleagues also found that SARS-CoV-2 “prevents the vast amount” of interferon genes from turning on. But when cells growing in lab dishes received the interferon IFN-1 before exposure to the coronavirus, “the virus has a difficult time replicating.”

After a few days, the amount of virus in infected but interferon-treated cells was 1,000- to 10,000-fold lower than in infected cells not pre-treated with interferon. (The original SARS virus, in contrast, is insensitive to interferon.)

Ending the pandemic and preventing its return is assumed to require an effective vaccine to prevent infectionand antiviral drugs such as remdesivir to treat the very sick, but the genetic studies suggest a third strategy: preventive drugs.

It’s possible that treatment with so-called type-1 interferon “could stop the virus before it could get established,” Menachery said.

Giving drugs to healthy people is always a dicey proposition, since all drugs have side effects — something considered less acceptable than when a drug is used to treat an illness. “Interferon treatment is rife with complications,” Menachery warned. The various interferons, which are prescribed for hepatitis, cancers, and many other diseases, can cause flu-like symptoms.

But the risk-benefit equation might shift, both for individuals and for society, if interferons or antivirals or other medications are shown to reduce the risk of developing serious Covid-19 or even make any infection nearly asymptomatic.

Interferon “would be warning the cells the virus is coming,” Menachery said, so such pretreatment might “allow treated cells to fend off the virus better and limit its spread.” Determining that will of course require clinical trials, which are underway.

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Pharmaceutical Companies Racing Together to Find a Cure for COVID-19

Reporter: Irina Robu, PhD

The global outbreak has put pressure on companies and the Food and Drug Administration (FDA) to act quickly to make medications available to patients. Several companies are working together to find solutions to treat those infected by the virus and prevent it from spreading.

AstraZeneca is responding to the COVID-19 (novel coronavirus) outbreak to accelerate the development of its di diagnostic testing capabilities to scale-up screening and is also working in partnership with governments on existing screening programs to supplement testing. In addition, AstraZeneca is working to identify monoclonal antibodies to progress towards clinical trial evaluation as a treatment to prevent COVID-19.

Bayer, German multinational pharmaceutical and life sciences company is donating malaria drug, Resochin to the US government for possible use to treat COVID-19. Resochin, made of chloroquine phosphate is a current approve treatment for malaria. China is evaluating it for potential use of COVID-19 and presented decent effects against the first SARS virus in 2003. Doctors consider it a promising treatment for seriously ill coronavirus patients.

AbbVie is research-driven biopharmaceutical company dedicated to developing innovative advanced therapies for four primary therapeutic areas: immunology, oncology, virology and neuroscience. The company declared plans to evaluate HIV medicine as COVID-19 treatment and go into partnerships with health authorities in various countries to explore the efficacy and antiviral activity of the medication.

Boehringer Ingelheim, research driven company  is collaborating with the German Center for Infectious Research to develop therapies and diagnostic tools for COVID-19. Their research teams are screening their entire molecule library with more than one million compounds to identify novel small molecules with activity against the virus.

EMD Serono is the biopharmaceutical business of Merck KGaA, Germany donated interferon beta-1a to French Institute of National Health and Medical Research to use for a clinical trial. Interferon beta-1a is presently in use to treat multiple sclerosis and is under investigation as potential treatment for people with COVID-19 coronavirus disease caused by the SARS-nCoV-2 virus. When confronted with the virus, each cell shoots an emergency flare of interferon to tell the immune system to strengthen its defenses. The interferon beta1a cytokine activates macrophages that engulf antigens and natural killer cells, which are integral to innate immune system. The trial is subsidized by INSERM and its start has been announced by the French Health authorities on March 11. To date, Merck interferon beta-1a is not approved by any regulatory authority for the treatment of COVID-19 or for use as an antiviral agent.

GLAXOSMITHKLINE (GSK) has been working to make vaccine using its established pandemic vaccine adjuvant platform technology available. Sanofi and GSK announced on April 14, 2020 they will collaborate to develop an adjuvanted vaccine for COVID-19, using innovative technology from both companies. Sanofi will donate its S-protein COVID-19 antigen, which is based on recombinant DNA technology. This technology gives an exact genetic match to proteins found on the surface of the virus and the DNA sequence encoding this antigen has been combined into the DNA of the baculovirus expression platform, the basis of Sanofi’s licensed recombinant influenza product in the US.GSK will contribute its proven pandemic adjuvant technology to the collaboration, since it may reduce the amount of vaccine protein required per dose, letting more vaccine doses to be produced and consequently contributing to protect more people.

JOHNSON & JOHNSON has started research into a vaccine, leveraging the same innovative technology used for  Ebola vaccine. Janssen, the pharmaceutical arm of J&J has donated medicines for use in laboratory-based investigations to support efforts in finding a resolution against COVID-19.

Eli Lilly entered into an agreement with AbCellera to co-develop antibody products for the treatment and prevention of COVID-19. The collaboration will leverage AbCellera’s rapid pandemic response platform, established under the DARPA Pandemic Prevention Platform Program, along with Lilly’s global capabilities for rapid development, manufacturing and distribution of therapeutic antibodies. Eli Lilly has also entered an agreement with NIH, NIAID to study baricitinib as an arm in NIAID’s Adaptive COVID-19 treatment trial. Baricitinib, an oral JAK1/JAK2 inhibitor is accepted in more than 65 countries as a treatment for adults with moderately to severely active rheumatoid arthritis. Because of the inflammatory cascade in COVID-19, baricitinib’s anti-inflammatory activity has been hypothesized to have a potential beneficial effect in COVID-19 and needs further study in patients with this infection. Eli Lilly is also using an investigational selective monoclonal antibody against Angiopoientin-2 to Phase 2 testing in pneumonia patients hospitalized with COVID-19 who are at higher risk of delveoping acute respiratory distress syndrome. The company will look whether inhibiting the effects of Angiopoientin-2 with monoclonal antibody which can reduce the progression of acute respiratory distress syndrome. The trial will start in April 2020.

Pfizer and BioNTech work together to develop a potential COVID-19 vaccine which aims to accelerate development of BioNTech’s potential first-in-class COVID-19 mRNA vaccine program, BNT162 . A clinical study is expected to start by the end of April 2020. The collaboration is a continuation of the original agreement in 2019 between the two companies to develop mRNA-based vaccines for prevention of influenza.

Roche, Canada has been designated as a participant in a Phase III clinical trial evaluating the safety and efficacy of one of Roche’s portfolio medicines in hospitalized adult patients with severe COVID-19 pneumonia. The company announced the future launch of its Elecsys Anti-SARS-CoV-2 serology test to detect antibodies in people who have been exposed to SARS-CoV-2 that causes the COVID-19 disease. Antibody testing is vital to help detect people who have been infected by the virus, particularly those who may have been infected but did not display symptoms. Furthermore, the test can support priority screening of high-risk groups who might by now have advanced a certain level of immunity and can continue serving and/or return to work.

Takeda Pharmaceutical Company is initiating the development of an anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) to treat high-risk individuals with COVID-19, although also investigating whether Takeda’s currently marketed products may be effective treatments for infected patients. Hyperimmune globulins are plasma derived-therapies that have been effective in the treatment of severe acute viral respiratory infections and could be a treatment option for COVID-19. Takeda has the research expertise to develop and manufacture a potential anti-SARS-CoV-2 polyclonal H-IG.

Takeda is presently in discussions  with multiple national health and regulatory agencies and health care partners in the US, Asia, and Europe to expeditiously move the research into anti-SARS-CoV-2 polyclonal H-IG forward. The research requires access to source plasma from people who have efficaciously recovered from COVID-19. The donors have developed antibodies to the virus that could possibly alleviate severity of illness in COVID-19 patients and perhaps prevent it. By transferring the antibodies to a new patient, it may help that person’s immune system respond to the infection and increase their chance of recovery. These efforts to find a vaccine are at an early stage nevertheless being given a high priority within the company.

SOURCE

https://www.marketwatch.com/story/these-nine-companies-are-working-on-coronavirus-treatments-or-vaccines-heres-where-things-stand-2020-03-06

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Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

Reporter: Aviva Lev-Ari, PhD, RN

 

Emergency room doctor, near death with coronavirus, saved with experimental treatment

Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.

He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.

Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.

Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.

It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”

The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.

Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.

Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.

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