Restoring the Wnt/β-catenin signaling rescues bone defects in Job syndrome

Dr. Prem Swaroop Yadav was born in the Chaubeypur village of Varanasi district of Uttar Pradesh, India. He finished his schooling from the Govt. Queens Inter College (GIC), Varanasi. After completing his Bachelor’s and Master’s degrees from the Udai Pratap Autonomous College in Varanasi, he joined the PhD program at the Biological Sciences and Bioengineering (BSBE) Department, IIT Kanpur, India in 2016. He pursued his PhD under the supervision of Prof. Amitabha Bandyopadhyay. For his post-doctoral research, he moved to Boston, USA and joined the laboratory of Prof. Yingzi Yang at the Harvard School of Dental Medicine (HSDM) where he studied the pathophysiology of skeleton-related genetic disorders. Recently, he has joined Prof. Marie B. Demay’s group as a Research Fellow in Medicine at the Massachusetts General Hospital (MGH) & Harvard Medical School (HMS), Boston, USA. In Demay’s lab, he is investigating the role of key signaling pathways involved in hypertrophic differentiation of chondrocytes (which are the cartilage forming cells) and their endocrine regulation during bone development.

How would you explain your paper’s key results to the non-scientific community?

Job syndrome is a rare genetic disorder caused by mutations in STAT3 gene, largely manifested at a young age. The disease is primarily characterized by immune dysfunction and comorbid skeleton developmental abnormalities, including osteopenia, recurrent fracture of long bones, and scoliosis. One of the key characteristics of this disease is an elevated level of Immunoglobulin-E in the serum; therefore, it is also referred as Hyper Immunoglobulin-E Syndrome (HIES). So far, there is no targeted cure for this disease, and only symptomatic treatments are available. To understand the cellular and molecular mechanisms underlying the skeleton defects observed in Job syndrome, we genetically deleted the Stat3 gene in osteoprogenitor cells (stem cells for cartilage & bone) in mice. Using different experimental approaches, we demonstrated that the Stat3 function is essential in osteoblast lineage cells for the proper development of osteoblasts, the bone-forming cell types. Stat3 was found to be required for maintaining Wnt/β-catenin signaling, a key signaling pathway necessary for normal bone development. We have shown that ablation of Stat3 impaired the normal bone formation due to reduced Wnt/β-catenin signaling with an increase in Sclerostin (Sost) protein, an inhibitor of Wnt/ β-catenin signaling. Our research provides a foundation for further investigation on the principles whereby Stat3 regulates the non-immune cells and governs bone formation and maintenance. Furthermore, we also demonstrated that restoration of Wnt/β-catenin signaling using BIO, a small molecule inhibitor of GSK3, or genetically using Lrp5 gain of function (GOF) allele, rescued the skeletal defects cause by Stat3 loss to a large extent. Overall, our results strongly suggest that enhancing Wnt/β-catenin signaling could be a potential therapeutic approach to reduce bone defects in Job syndrome patients.

Graphical summary

What are the possible consequences of these findings for your research area?

Studying the underlying cellular and molecular mechanisms of rare genetic diseases provides invaluable insights into human biology and the pathophysiology of rare genetic disorders. The results from our work provide a basic understanding of why patients with Job syndrome have skeletal abnormalities and what is the molecular mechanism behind these defects. Our study and future research would help us develop better therapeutics for treating Job syndrome patients.

What was the exciting moment (eureka moment) during your research?

We could not get skeletal tissues at the post-natal stages since Osx-Cre mediated Stat3 knockout in osteoprogenitor cells causes lethality in neonates. Interestingly, when pregnant females and later pups were treated with BIO, a small molecule inhibitor of GSK3b, the skeletal phenotypes of loss of Stat3 were rescued and it was indeed a eureka moment for us. We could see that Stat3 knockout mouse pups were able to survive postnatally. This enabled us to study the post-natal skeletal defects upon Stat3 loss of function.

What do you hope to do next?

My current research aims to elucidate the roles of the key signaling pathways involved in the hypertrophic differentiation of chondrocytes. Most of the long bones in our body are formed by a process known as endochondral ossification, involving a transient cartilage template to make future long bones. This transient cartilage later undergoes hypertrophic differentiation and eventually gets replaced by the bone. The hypertrophic differentiation of the chondrocytes is a highly coordinated and molecularly regulated process. Any perturbation in this regulation may lead to various skeleton anomalies such as rickets and osteomalacia. Rickets primarily affects children and are characterized by developing poor, soft, and weak bones, leading to bone deformities. In adults, a similar condition is known as osteomalacia or soft bones. Therefore, detailed insight into the molecular regulation of hypertrophic differentiation of chondrocytes is required to understand the pathophysiology of skeletal-related disorders and I would like to pursue this in future.

Where do you seek scientific inspiration?

It’s nearly impossible to live a single day in our life that does not require scientific interventions. Thus, science is everywhere, and it is changing the world on a day-to-day basis, starting from the internet, mobile, Google, genomics, climate change, stem cells, energy, carbon dioxide, water, etc. The scientific discoveries inspire me the most, for example, vaccine development for Covid-19. The first case of Covid-19 was reported in Wuhan, China, in December 2019, and just within a year, hundreds of COVID-19 vaccine candidates were developed using various unrelated approaches and some of them reached the stage of human trials. All of this could happen because of the long-term investment into basic research and our belief in science and technology, and eventually we could vaccinate many individuals to help us combat this deadly pandemic. I think science is interesting because it provides opportunities to learn, make relevant observations and then use it in addressing the relevant questions.

How do you intend to help Indian science improve?

A developing country like India requires more scientific innovations to solve the problems and meet the demands. Therefore, early exposure to Science, Technology, Engineering, and Mathematics (STEM) is necessary to ignite young minds. This would encourage more people to come forward and believe in scientific innovation. I also believe that including more multidisciplinary approaches that involve inputs from all the possible branches of science could certainly improve scientific research in our country. This would be my mantra whenever I have the opportunity to improve teaching and research in my country.

Reference

P. S. Yadav et al., Stat3 loss in mesenchymal progenitors causes Job syndrome-like skeletal defects by reducing Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A 118 (2021).

Edited by: Neha Varshney

Job opening in Syngene

#hiring#computeraideddesign#drugdiscovery

We are hiring for the below position at Biocon Bristol Myers Squibb, Syngene International Limited.

Education and Experience : PhD in computational chemistry or computer aided drug discovery with 3 to 4 Years of relevant experience.
Department : Computer aided drug design (CADD)
Location : Bangalore

Key Responsibilities: 

•   Provide comprehensive and impactful Computer aided drug design support to drug discovery programs.
•   Demonstrate an understanding of full spectrum of project SAR (in vitro biology, DMPK, structural and computational).
•   Work in close collaboration with medicinal chemists.
•   Present plans, progress and results at CADD, chemistry and project team meetings.
•   Identify and implement the best computational techniques to address specific problems.
•   Maintain a good awareness of the literature related to the project and the discipline
•   Maintain good records and provide data as required.

Technical/functional Skills: 

•   Proficiency in structure and ligand based computational approaches – theory: molecular mechanics and quantum mechanics; Methods: docking, pharmacophore modelling, molecular dynamics simulation, QM calculations.
•   Proficiency in statistical methods
•   Proficiency in physical organic chemistry
•   Proficiency in Python and/or Unix Shell scripting
•   Experience in working with interdisciplinary teams such as medicinal chemistry, biology and DMPK scientist
•   Experience in disease areas such as oncology, immunology, cardiovascular and fibrosis

If interested or know anyone who would be interested, Please share the profile on gunjan.shah1@syngeneintl.com

Job opening in Stabicon Life Sciences Pvt. Ltd

Hello All,

We are hiring for below positions, please let me know if you are looking for a job change and you have any references!

1) Designation: Research Associate/Sr Research Associate
Number of Positions : 3 Positions
Department : Analytical R & D
Requirements: Experience in Analytical Method development & Validation and handling of HPLC and GC knowledge will be added advantage.
Qualification: M.Sc or M.Pharm with 2 to 3 years of relevant experience
 Location: Bangalore

2) Designation: Chemist/Sr. Chemist
Number of Positions : 4 Positions
Department : Quality Control Laboratory
Requirements: Experience in QC laboratory and handling of HPLC and GC.
Qualification: M.Sc or M.Pharm with 2 to 3 years of relevant experience
 Location: Bangalore
 
 3) Designation: Executives QA/Sr Executive QA
 Department : Quality Assurance
 Number of Positions : 3 Positions
 Requirements: Experience in handling of laboratory QMS , analytical data review, compliance as per GMP practices.
 Qualification: M.Sc or M.Pharm with 2-3 years of relevant experience.
 Location: Bangalore
 
4) Designation: Technician /Sr. Technician 
   Department : Engineering
   Experience: 2 to 4 Years
   Location: Bangalore
  Number of Positions : 1 Positions
  Technical knowledge :Facility maintenance, Equipment maintenance handling.
 
5) Designation: Manager/Sr, Manager QA
   Department : Quality Assurance
   Number of Positions : 1 Positions
  Responsible for implementation, managing and monitoring of Quality Management system and compliance activities.
  Manage all laboratory investigations (Deviation, Change control, Laboratory error, OOS, OOT, CAPA) and timely closure of these records.
  Plan and manage Internal and external Audits, ensure the timely renewal of regulatory approvals.
  Qualification: Post Graduate with 7 to 10 Years of relevant experience

Preferred immediate joiners

Share your CV at hrd@stabicon.com

please mention the below mandatory details while sending your resume.
Role applied for
Current CTC:
Expected CTC:
Notice Period:
(3 Months’ notice period candidates are not eligible)

Share your CV now and grab this opportunity! if you are not looking for change then please like and share this post for better reach!

BIOFILM BAITHAK: AN INDIA SPECIFIC MEETUP

Adline Princy Solomon (Associate Dean of Research, SASTRA Deemed University and Head/Principle Investigator, Quorum Sensing Lab, SASTRA Deemed University), Arval Viji Elango (Project student, SASTRA Deemed University), Deepti Jain (Associate Professor, Regional Centre for Biotechnology), Karishma Kaushik (Assistant Professor, University of Pune), Karthi Shanmugham (PhD Student, SASTRA Deemed University), Mahima Lall (Professor, Armed Forces Medical College) Nijamuddin Shaikh (Junior Research Fellow, University of Pune), Parvathy Venkateswara (Project student, SASTRA Deemed University), Radhika Dhekane (Senior Research Fellow, University of Pune), Rohit Ruhal (Research Associate), Sahana Vasudevan (DST – INSPIRE fellow, SASTRA Deemed University) & Snehal Kadam (PhD Student, Hull York Medical School)

Introduction to Biofilms

Biofilms are resilient and organized communities of microbes embedded in a glue-like matrix of extracellular polymers. Bacteria and fungi form biofilms on biotic and abiotic surfaces, such as tooth enamel, skin, mucosa, catheters, prosthetic valves, as well as water pipelines and filtration units. In the human body, biofilms mediate a range of infections including chronic wound infections, pneumonia, endocarditis, and eye, ear and implant-associated infections, posing a significant challenge and burden to the healthcare industry. Food, dairy, and pharmaceutical industries are also impacted by microbial biofilms as they cause contamination, hinder manufacturing processes, and may lead to economic losses.

Overview of India Biofilms Society

India Biofilms Society (IBS) is a consortium of biofilm researchers spread across India, consisting of independent investigators, postdoctoral researchers and research associates, Ph.D. students, research assistants, Masters and undergraduate students. The society aims to foster biofilm-related research in the country, across academia, industry and the clinic, as well as forge international partnerships. In February 2021, IBS organized “Biofilm Baithak”, a virtual meet-up for biofilm researchers across the country. This article aims to present an account of the key takeaways from the meeting, and provide a collection of resources and materials that can be of value to biofilm researchers across India.

Scientific Sessions and Panel Discussions

Building A Biofilm Research Group in India: Dr. Adline Solomon (Associate Dean of Research, SASTRA Deemed University and Head/Principle Investigator, Quorum Sensing Lab, SASTRA Deemed University)

Dr. Adline shared the overall journey of her research group, ‘The Quorum Sensing Lab’, and focused on contributions her group has made towards organising international conferences and workshops and industrial collaborations. For this, her group has received extramural funding from ICMR, DST, DBT, DRDO, and CSIR. In her talk, Adline shared the importance of tie-ups and collaborations in the advancement of their research agenda. While she has regularly interfaced with various companies and research institutes, one of her key collaborative partnerships (with Dr. Prasanna Neelakantan from The University of Hong Kong) enabled MHRD-SPARC funding for 2 years and student exchange programs. More recently, a partnership with industry has led to the formation of a new start-up, AI (Anti-Infectives), which focuses on using AI-assisted development of anti-infective therapeutics.

Biofilm problems and solutions in CAUTI, an industrial perspective: Dr. Milind Choudhari (Founder & CEO, WeInnovate Biosolutions Pvt. Ltd)

The CEO of WeInnovate Biosolutions Pvt. Ltd, Dr. Milind Choudhari described the company’s recently developed product, silver-impregnated catheters to prevent Catheter Associated Urinary Tract Infections (CAUTI), a very common biofilm infection and complication of long-term hospital stay. WeInnovate Biosolutions has developed SilvoguardTM, a broad-spectrum antimicrobial catheter for preventing CAUTI. In doing so, the company serves as an excellent example of a biofilm-based start-up industry, focusing on an important and imminent consequence of hospital stays and hospital-acquired infections.

Biofilm-related scientific and health challenges in India: Dr. Deepti Jain (Associate Professor, Regional Centre for Biotechnology) and Lt. Col. Mahima Lall (Professor, Armed Forces Medical College)

In this discussion, Dr. Deepti Jain highlighted some key questions related to biofilm regulation currently being addressed in her laboratory, while Dr. Mahima Lall described her experiences with detecting and treating with biofilms in clinical settings. The important takeaway was that biofilm research is an emerging field in India and requires multidisciplinary approaches with individuals from various fields such as basic sciences, mathematical modelling, drug discovery and engineering. Further, given that biofilms are a leading cause of antibiotic resistance in clinics, this multipronged approach should endeavour to bridge the gap between clinicians and researchers. Notably, there is a need to focus these collaborations towards development of standard protocols and diagnostic methods, bacterial repositories, better model systems, and approaches to test combinatorial therapies and screen chemical libraries for anti-biofilm potential.

Challenges and solutions for biofilm research in India: Dr. Ashwini Chauhan (Assistant Professor, Tripura University)

Dr. Ashwini Chauhan opened his discussion acknowledging the limited awareness of biofilm research and its relevance in India, and the need to develop a synergistic model of networking, collaboration, and scientific exchange to fill this gap. Biofilm evangelism would entail a volunteer-driven model that organizes engaging events such as a biofilms hackathon, podcasts, journal clubs, laboratory troubleshooting, and trainings and internships. Biofilm stewardship on the other hand, would require multicentric support and funding towards building infrastructure, equipment, bio-repositories for biofilm-relevant research.

Building a biofilm society, National Biofilms Innovation Centre, U.K: Dr. Mark Richardson (CEO, National Biofilms Innovation Centre)

Discussing the NBIC working model, Dr. Mark Richardson stated that NBIC was established to focus on ‘the valley of death’, that exists between researchers and industry partners, and aims at striking dialogues between the two. For this, the centre procured a 5-year grant from UK’s national funding agency (UKRI) in two parts, the UK Innovate component funds companies and the Biotechnology and Biological Sciences Research Council (BBSRC) component funds academic researchers and laboratories. The society’s governance system consists of an international scientific advisory board, industrial advisory board, NBIC executive management team, and a non-executive board to monitor and deliver research and operational strategies. To conclude, Mark highlighted that NBIC-IBS engagements could provide a gateway to research and industry partnerships at both ends, and lead to long-term complementary connections.

Introduction to the Biofilm Journal: Dr. Tom Coenye (Senior Editor, Biofilm Journal)

Dr. Tom Coenye discussed the scope of the Biofilm journal and the different aspects of publishing in the journal. The Biofilm journal, started in 2019, focuses on publishing research on all aspects of biofilms. With four senior editors and 41 specialists across the globe, the diverse team at the journal spans different countries as well as different areas of research. The journal is indexed in PubMed, is open-access, and endeavours to offer waivers to authors with publication cost constraints. Apart from submitting their research work to the journal, biofilm researchers can volunteer to be reviewers by registering themselves in the editorial system.

Taking India Biofilms Society outside India: Dr. Joey Shepherd (Senior Lecturer, The University of Sheffield), Dr. Neha Jain (Assistant Professor, IIT Jodhpur) and Dr. Srinandan (Assistant Professor, SASTRA Deemed University)

This session focused and discussed ways to take IBS forward to engage with the international community. Dr. Shepherd shared her experience with initiating collaborative grants with Indian researchers, pointing out India-specific grants offered by international agencies such as Global Challenges Research Fund (GCRF), UK Research and Innovation (UKRI) , etc. Dr. Srinandan stated the opportunity for biofilm researchers in India to apply for national funding opportunities, seeking to build international partnerships (for example, DST supported international projects). Dr. Neha Jain shared her experience of procuring international grants as a new Principal Investigator, pointing out that some grants may have specific conditions, such as, an agreement with the host lab to match the amount granted by the funding agency. In the open discussion, Dr. Ashwini Chauhan suggested the possibility of exploring short-term mobility grants and small collaborations to produce preliminary results, which could strengthen larger funding applications in the future.

Lab technique troubleshooting: led by Sahana Vasudevan (DST–INSPIRE fellow, SASTRA Deemed University)

This open discussion was focused on the challenges and considerations of designing biofilm experiments. For this, Dr. Ashwini suggested starting with standard reference methods, following which, the experiment could be modified and optimized. Important considerations for assessment of biofilms include selection of biofilm media for mono- and poly-microbial biofilms, substrate or surface choice, pH optimization, quantifying the initial inoculum of infection, and use of different staining techniques. The discussion underscored the need for developing standard protocols, applicable across laboratories, with examples of relevant work in this direction such as this and this.

Why should biofilms have all the fun? led by Arval Viji Elango and Parvathy Venkateswaran (Project students, SASTRA Deemed University)

The final session focused on team building using an engaging, virtual set of biofilm games. In the first game ‘Connexions’, the participants had to figure out a biofilm-related connection among four clues given in the form of images, GIFs, or audios (one of the clues included a track of Taylor Swift’s song, Tolerance). The second round, ‘What comes next?’, was an extension of the first one. The participants were presented with a sequence of clues, for example, the stages of biofilm formation or the steps in the protocol to identify biofilms, and were asked to identify what would come next in the sequence. The final round, ‘Turn it over!’, comprised of 16 squares, each with a hidden clue. Every participant was given a chance to reveal a grid, identify another related clue in the grid and organize four clues in a group with a common theme, for example, the different components of biofilms, horizontal gene transfer, antimicrobial resistance, and anti-biofilm strategies.

Future of India Biofilms Society

India Biofilms Society aims to be India’s foremost organization for biofilm-related research, industry partnerships, and citizen engagement. Towards this, the meeting brought forth other suggestions such as building databases with information on biofilm researchers across India and availability of high-end instrumentation facilities relevant to biofilm research in India. As the immediate next steps, building the framework of the formal society and continued engagement along the lines of scientific sessions, international seminar series, and conducting student-focused workshops, are on the agenda.

Edited by: Anjali Mahilkar

Job opening in XBio

JOB ALERT: XBio is looking for a science writer!
Our partners at The Explorer’s Guide to Biology (XBio) are seeking a Science Writer to help communicate the stories of discoveries in biology to educators and their students. Successful candidates will have a Ph.D. in a relevant field (Biological Sciences, Science Education, Science Communication) and experience writing about biological topics, preferably for an educational audience. Check out the full job ad for more information.

https://lnkd.in/gQPSSfQV

Avoiding Antibiotic Abuse

Antibiotics can save lives but overuse poses a serious threat to the human body. Overuse of antibiotics is a leading cause of antimicrobial resistance. Continuing our commitment to the public education on social and health issues, Biopatrika team created infographic to educate public on how to avoid this antibiotic abuse. Lets join hands to overcome this abuse and teach our society how to stay healthy and avoid unnecessary use of antibiotics.

Credits

Reference

  1. https://elifesciences.org/articles/64116?utm_source=twitter&utm_medium=social&utm_campaign=pr2021
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753246/
  3. https://www.cdc.gov/drugresistance/biggest-threats.html
  4. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/battle-bugs-fighting-antibiotic-resistance
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604941/
  6. https://www.researchgate.net/figure/Infographic-depicting-a-timeline-of-antibiotic-resistance-when-antibiotics-were_fig1_327989715
  7. https://www.everydayhealth.com/ears-nose-throat-pictures/common-ears-nose-throat-complaints.aspx
  8. http://www.pulsehospitalpune.com/latest-update/throat-infection-/93
  9. https://www.onlinehomeocare.com/blog/how-to-cure-sore-throat-causes-symptoms-and-medication/
  10. https://www.infobloom.com/what-is-a-throat-infection.htm
  11. https://www.alamy.com/illustration-of-a-teenage-boy-with-open-mouth-and-showing-sore-throat-image267569360.html
  12. https://www.verywellhealth.com/throat-pain-4174240

Job opening in Dr. Reddys

We are Hiring PhD freshers or Phd with 01 to 2 yrs of relevant experience in Cell line development / Molecular Biology. Aspirants interested to start their career in corporate can apply across ”Nareshkumar.g@drreddys.com” with relevant subject line.
Job Location: Dr.Reddys, Biologics, Bachupally, Hyderabad, India.
#celllinedevelopment #molecularbiology #drreddys #productdevelopment