Medicine/Health

Identification of Novel Toxins Using Machine Learning

6 August, 2024

New study reveals how bacteria use a special system, like a tiny syringe, to inject toxins into other organisms. This is important because it helps us understand how bacteria interact with hosts and likely with each other. Using artificial intelligence, the researchers identified over 2,000 possible toxins, likely injected by the syringe, some of which could be potentially used as new antimicrobials. By combining AI and microbiology these findings could lead to new ways to treat infections and create new biotechnological tools.

Microscopic Syringes and AI: Scientists Uncover New Bacterial Weapons

In a novel study, featured on the cover of August 2024 volume of Molecular Systems Biology journal, researchers have unveiled new secrets about a fascinating bacterial weapon system that acts like a microscopic syringe. Led by Dr. Asaf Levy from the Hebrew University and collaborators from the Hebrew University and from the University of Illinois Urbana-Champaine, the team has made significant strides in understanding the extracellular contractile injection system (eCIS), a unique mechanism used by bacteria and archaea to inject toxins into other organisms.

Cracking the Bacterial Code with Artificial Intelligence

The eCIS is a 100-nanometer long weapon that evolved from viruses that previously attacked microbes (phages). During evolution these viruses lost their ability to infect microbes and turned into syringes that inject toxins into different organisms, such as insects. Previously, the Levy group identified eCIS as a weapon carried by more than 1,000 microbial species. Interestingly, these microbes rarely attack humans, and the eCIS role in Nature remains mostly unknown. (Geller et al. 2021). However, we know that it loads and injects protein toxins.

The specific proteins injected by eCIS and their functions have long remained a mystery. Before the study we knew about ~20 toxins that eCIS can load and inject. To solve this biological puzzle, the research team developed an innovative machine learning tool that combines genetic and biochemical data of different genes and proteins to accurately identify these elusive toxins. The project resulted in identification of over 2,000 potential toxin proteins.

"Our discovery not only sheds light on how microbes interact with their hosts and maybe with each other, but also demonstrates the power of machine learning in uncovering new gene functions," explains Dr. Levy. "This could open up new avenues for developing antimicrobial treatments or novel biotechnological tools."

New Toxins with Enzymatic Activities against Different Molecules

Using AI technology, the researchers analyzed 950 microbial genomes and identified an impressive 2,194 potential toxins. Among these, four new toxins (named EAT14-17) were experimentally validated by demonstrating that they can inhibit growth of bacteria or yeast cells. Remarkably, one of these toxins, EAT14, was found to inhibit cell signaling in human cells, showcasing its potential impact on human health. The group showed that the new toxins likely act as enzymes that damage the target cells by targeting proteins, DNA or a molecule that is critical to energy metabolism. Moreover, the group was able to decipher the protein sequence code that allow loading of toxins into the eCIS syringe. Recently, it was demonstrated that eCIS can be used as a programmable syringe that can be engineered for injection into various cell types, including brain cells (Krietz et al. 2023). The new findings from the current paper leverage this ability by providing thousands of toxins that are naturally injected by eCIS and the code that facilitates their loading into the eCIS syringe. The code can be transferred into other proteins of interest.

From Microscopic Battles to Medical Breakthroughs

The study's findings could have far-reaching applications in medicine, agriculture, and biotechnology. The newly identified toxins might be used to develop new antibiotics or pesticides, efficient enzyme for different industries, or to engineer microbes that can target specific pathogens. This research highlights the incredible potential of combining biology with artificial intelligence to solve complex problems that could ultimately benefit human health.

"We're essentially deciphering the weapons that bacteria evolved and keep evolving to compete over resources in Nature" adds Dr. Levy. “Microbes are creative inventors and it is fulfilling to be part of a group that discovers these amazing and surprising inventions”.

The study was led by two talented students: Aleks Danov and Inbal Pollin from the department of Plant Pathology and Microbiology, the Institute of Environmental Sciences, and was performed in collaboration with Prof. Tommy Kaplan (School of Computer Science and Engineering) and Dr. Philippos A Papathanos (Department of Entomology) from the Hebrew University of Jerusalem in collaboration with Prof. Brenda A Wilson from University of Illinois Urbana Champaign.

The research paper titled “Identification of novel toxins associated with the extracellular contractile injection system using machine learning” is now available in Molecular Systems Biology and can be accessed at https://www.embopress.org/doi/full/10.1038/s44320-024-00053-6

The cover of Molecular Systems Biology featuring eCIS injecting toxins that were predicted by AI. Artwork by Dr. Yitzhak Yadegari

Funding:

The study was funded by the Israeli Science Foundation, Israeli Ministry of Innovation, Science and Technology, Volkswagen Foundation, and a joint seed grant between the two universities.

Researchers:

Aleks Danov¹, Inbal Pollin¹, Eric Moon², Mengfei Ho², Brenda A Wilson², Philippos A Papathanos³, Tommy Kaplan^4,5 and Asaf Levy¹

Institutions:

Department of Plant Pathology and Microbiology, Institute of Environmental Sciences, The Robert H. Smith Faculty of Agriculture, Food & Environment, The Hebrew University of Jerusalem
Department of Microbiology, University of Illinois
Department of Entomology, Institute of Environmental Sciences, The Robert H. Smith Faculty of Agriculture, Food & Environment, The Hebrew University of Jerusalem
School of Computer Science and Engineering, The Hebrew University of Jerusalem
Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University of Jerusalem

The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 86th according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en

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Sex Bias in Pain Management at Emergency Rooms

6 August, 2024

New study reveals a significant sex bias in pain management at emergency rooms, showing that female patients are consistently less likely to receive pain medication prescriptions compared to male patients with similar complaints. This bias persists across different ages, pain levels, and physician sex, indicating a systemic issue. Female patients' pain scores are less frequently recorded, and they spend more time in the emergency room than male patients. The findings highlight the need for urgent policy interventions and training for healthcare professionals to address and counteract these biases, ensuring equal pain treatment for all patients.

A new study led by Prof. Shoham Choshen-Hillel and Mika Guzikevits from the Hebrew University, Dr. Alex Gileles-Hillel from Hebrew University- Hadassah Medical Center, Dr. Tom Gordon-Hecker from Ben-Gurion University, and an international team of researchers from Hebrew University, Hadassah Medical Center, the University of Missouri, and Marshall University has uncovered a concerning sex bias in pain management decisions at emergency rooms. The research, published in the journal PNAS, analyzed over 21,000 patient records across the United States and Israel and found that female patients are consistently less likely to receive pain medication prescriptions compared to male patients with similar complaints.

The study revealed that female patients are prescribed fewer pain relief medications than male patients, even after considering the levels of pain reported and other variables such as age, medical history, and the type of complaint. This suggests a systemic issue where women's pain may not be taken as seriously or treated as aggressively as men's pain.

By analyzing electronic health records from American and Israeli healthcare systems, the researchers present evidence that a female patient discharged from the emergency department is less likely to receive treatment for a pain complaint compared to a male patient. Specifically, datasets from emergency departments in the US and Israel, with a total sample size of 21,851 discharge notes, revealed that female patients are less likely to receive a prescription for any type of analgesic medication, both opioids and non-opioids, compared to male patients.

Female patients with pain complaints are less likely to receive analgesics for every pain score and at every age group and receive less analgesics from both male and female physicians. In addition, female patients stay an additional 30 minutes at the emergency department, and their pain score is 10% less likely to be recorded by triage nurses. In a controlled experiment involving 109 nurses, pain was rated as less intense if the patient was said to be female rather than male, suggesting that the bias is driven by gender stereotypes. According to the authors, the under-treatment of females’ pain bears immediate implications for the healthcare system and broad implications for society’s attitude toward female pain.

Interestingly, the study found that this disparity in prescribing pain medication exists regardless of whether the treating physician is male or female. Both male and female doctors are less likely to prescribe pain medication to women, indicating that the bias is pervasive and not limited to one sex of healthcare providers.

The research also highlighted that nurses are 10% less likely to record pain scores for female patients compared to male patients. This lack of documentation can contribute to underestimating the severity of women's pain and result in inadequate treatment. Additionally, the study found that female patients spend an average of 30 minutes longer in the emergency department than male patients. This delay could be due to a variety of factors, including potentially being taken less seriously when they report pain or symptoms.

In a controlled experiment, nurses judged female patients' pain as less intense than male patients' pain when presented with identical clinical scenarios. This suggests that there may be a subconscious bias in how healthcare professionals perceive and assess pain based on the patient's sex..

"Our research reveals a troubling bias in how women's pain is perceived and treated in emergency care settings," said Prof. Choshen-Hillel. "This under-treatment of female patients' pain could have serious implications for women's health outcomes, potentially leading to longer recovery times, complications, or chronic pain conditions."

Recommendations: The study argues that these findings reflect a systemic under-treatment of women's pain in medical settings. The researchers call for urgent policy interventions to address this bias and ensure equal pain treatment regardless of sex. They recommend training programs for healthcare professionals to recognize and counteract sex biases and suggest that pain management protocols should be revisited and standardized to ensure fair and adequate treatment for all patients.

This research highlights the critical need to address unconscious biases in healthcare to provide fair and effective treatment for all patients. The full study, "Sex Bias in Pain

Management Decisions," is published in PNAS and can be accessed at: 10.1073/pnas.2401331121

Illustration Credit: Avi Blyer

Discrimination Against Women in Pain Management in Emergency Rooms

Researchers

Mika Guzikevits^MA^1,2^*, Tom Gordon- Hecker^PhD³^*, David Rekhtman^MD⁴, Shaden Salameh^MD⁴, Salomon Israel^{PhD 5}, Moses Shayo^{PhD 2,6}, David Gozal^MD^7,8, Anat Perry ^{PhD 5}, Alex Gileles-Hillel^{MD 9,10}^**, Shoham Choshen-Hillel^{PhD 1,2}^**

Affiliations:

¹Hebrew University Business School, Hebrew University of Jerusalem; Jerusalem, Israel.

²Federmann Center for the Study of Rationality, Hebrew University of Jerusalem; Jerusalem, Israel.

³Department of Business Administration, Ben-Gurion University of the Negev; Be’er-Sheva, Israel.

⁴The Department of Emergency Medicine, Hadassah Medical Center, Jerusalem, Israel.

⁵Psychology department, Hebrew University of Jerusalem; Jerusalem, Israel.

⁶Economics department, Hebrew University of Jerusalem; Jerusalem, Israel.

⁷The University of Missouri School of Medicine, Columbia, MO, USA

⁸ Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

⁹ Pediatric Pulmonology Unit, Department of Pediatrics, Hadassah, Medical Center

¹⁰The Faculty of Medicine, Hebrew University of Jerusalem; Jerusalem, Israel.

*Equal first authorship

**Co-senior authorship

Funding

Israel Science Foundation grant 2824/22 (AGH)

Israel Science Foundation grant 354/21 (AP, SCH)

Recanati Fund at the Hebrew University Business School at the Hebrew University (SCH)

Azrieli Fellowship of the Azrieli Foundation (AP)

National Institutes of Health grant AG061824 (DG)

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Proteins Revolutionize Organ Preservation

17 June, 2024

A new study has revealed that specialized proteins can dramatically delay ice crystal evolvement, even in extreme cold down to minus 80 degrees Celsius. This breakthrough could revolutionize freezing methods, offering new possibilities for the long-term preservation of tissues and organs. Such advancements might pave the way for organ transplants that were once considered impossible, transforming medical practices and saving countless lives.

Cryogenic damage has long presented a significant barrier to effective organ preservation, posing challenges to advancements in transplantation and medical treatments. The formation of ice crystals during freezing can compromise cellular structures, leading to irreversible damage and organ failure. However, a new study led by Prof. Ido Braslavsky, Dr. Vera Sirotinskaya, and Dr. Liat Bahari from the Faculty of Agriculture, Food and Environment at the Hebrew University, in collaboration with Dr. Victor Yashunsky from Ben Gurion University of the Negev and Dr. Maya Bar Dolev from the Technion, has unveiled a promising solution.

Cryogenic damage significantly impacts the potential success of organ preservation, affecting thousands of people worldwide who are in need of organ transplants. Each year, millions of individuals are diagnosed with conditions that could be treated with organ transplants, yet the shortage of viable, preserved organs leaves many on long waiting lists. The inability to effectively preserve organs for extended periods means that a substantial number of organs are discarded due to damage from ice crystal formation and other cryogenic effects. This not only limits the number of transplants that can be performed but also exacerbates the shortage, ultimately impacting the health and survival of countless patients who depend on these life-saving procedures.

Building on the foundation of previous research into ice-binding proteins (IBPs), this groundbreaking study demonstrates how the strategic use of antifreeze proteins (AFPs) can mitigate cryogenic damage and revolutionize organ freezing techniques. Through the strategic deployment of different types of antifreeze proteins, such as AFPIII from fish and TmAFP from larvae of flour beetles, the research team successfully delayed crystallization and influence devitrification even at temperatures below -80 degrees Celsius.

Utilizing a state-of-the-art microscope stage capable of precise temperature control and rapid cooling at a rate of 100 degrees Celsius per second, the study compared samples containing antifreeze proteins with those without. These samples were not frozen to an astonishing -180 degrees Celsius but when thawed gradually some were frozen while other did not. The samples were analysed under a microscope.

"The findings of our research mark a significant step forward in organ preservation technology," explained Dr. Maya Bar Dolev. "By inhibiting crystallization and crystal growth, antifreeze proteins hold immense promise for extending the viability of frozen organs and enabling previously impossible transplants."

Prof. Ido Braslavsky further emphasized the potential impact of this breakthrough: "This advancement opens doors to a new era in tissue preservation and organ transplantation. With further development, we envision longer preservation periods, enhanced quality during transport, and innovative transplant procedures, including complex organ combinations like heart-lung transplants and uterine tissue transplants."

The implications of this research are profound, offering hope for improved organ availability, extended preservation windows, and ultimately, saving countless lives. As the field of tissue preservation embraces the potential of antifreeze proteins, the future of organ transplantation shines brighter than ever before.

The research paper titled “Extended Temperature Range of the Ice-Binding Protein Activity” is now available in Langmuir and can be accessed at https://doi.org/10.1021/acs.langmuir.3c03710.

Researchers:

Vera Sirotinskaya¹, Maya Bar Dolev^1,2, Victor Yashunsky^1,3, Liat Bahari¹, and Ido Braslavsky¹

Institutions:

1) Institute of Biochemistry, Food Science, and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem

2) Faculty of Biotechnology and Food Engineering, Technion

3) The Swiss Institute for Dryland Environmental and Energy Research, Ben Gurion University

The Hebrew University of Jerusalem is Israel's premier academic and research institution. Serving over 23,000 students from 80 countries, the University produces nearly 40% of Israel’s civilian scientific research and has received over 11,000 patents. Faculty and alumni of the Hebrew University have won eight Nobel Prizes and a Fields Medal. For more information about the Hebrew University, please visit http://new.huji.ac.il/en.

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Unveiling Type 1 Diabetes - Secrets of Aging Beta Cells and their Ability to Secrete Insulin

4 June, 2024

A new study reveals that aging human pancreatic beta cells display features of senescence while maintaining elevated levels of genes crucial for their function. Despite their aging status, these cells therefore exhibit an ability to release insulin in response to glucose, aiding in blood sugar regulation. Additionally, these aged cells show increased activity of genes that can stimulate the immune system. This sheds light on the potential role of aging beta cells in immune regulation and their relevance to autoimmune reactions in type 1 diabetes.

A new study led by Dr. Milan Patra along with Professors Ittai Ben-Porath and Yuval Dor from the Faculty of Medicine of the Hebrew University has revealed that senescent human pancreatic beta cells, which play a crucial role in insulin production, exhibit enhanced functional maturation through chromatin reorganization. Additionally, the study finds that these cells show increased activity of the interferon pathway which stimulates the immune system. This finding may offer a potential new avenue for tackling type I diabetes.

Background: The Diabetes Challenge

Diabetes, characterized by insulin deficiency or resistance, hinges on dysfunctional pancreatic beta cells, which are responsible for secreting insulin to remove glucose from the blood. Enhancing or preserving the function of these cells is pivotal for developing diabetes treatments. Globally, an estimated 463 million adults, or roughly 1 in 11, grapple with this condition, a figure expected to balloon due to aging populations, urbanization, poor diets, and sedentary lifestyles. Projections indicate that by 2045, over 700 million could be afflicted, posing daunting challenges to healthcare, economies, and public health efforts. Urgent action is imperative to stem this tide, necessitating effective prevention strategies, better access to care, and innovative treatments.

Key Findings: Functionality and Immune Response

The study, published in Nucleic Acids Research, demonstrates that a significant portion of adult human pancreatic beta cells activate a gene called p16, which indicates that they are in an aging-like state, termed cellular senescence. Interestingly, these senescent cells, rather than showing signs of dysfunctionality, show elevated levels of genes that are important for their function. Thus, these cells appear to possess a higher level of functionality and maturity compared to their non-senescent neighbors. This is surprising, as previously identified senescent cells in other tissues are generally thought to be dysfunctional and have harmful effects.

By analyzing the gene organization of senescent beta cells, the researchers discovered that they change the packaging of the genes – the chromatin, generating a reprogrammed organization that allows activation of functionality. Because of this, it appears that the aging beta cells have the ability to release insulin in response to glucose in even larger amounts, which helps regulate blood sugar levels effectively.

This study also found that senescent beta cells have elevated levels of genes that communicate with the immune system. This response, termed the “interferon response” normally acts to indicate a viral infection to immune cells, recruiting their attack. However, the senescence beta cells activate this pathway in the absence of such infection: it is molecular changes in the cells themselves simulate this response. The potential consequence is increased stimulation of immune cells to attack beta cells, the fundamental process that drives type I diabetes. This means that aging beta cells might help regulate immune responses and could be important for understanding autoimmune reactions in type 1 diabetes. Potentially, blocking this response, or the process of senescence, could be used to prevent the progression of type I diabetes in its early stages.

Implications for Diabetes Treatment

The discovery that aging pancreatic beta cells can retain high functionality and respond to immune signals challenges the traditional view that senescent cells are purely detrimental. This new understanding opens the door to potential therapies aimed at preserving or enhancing the insulin-secreting function of beta cells in diabetic patients.

"These findings are pivotal because they suggest that senescent beta cells are not a liability, but may act, in a pre-designed manner, to improve insulin production as we age, countering other detrimental effects," said Professor Ittai Ben Porath. “Furthermore, if it will be further established that senescence of beta cells is a prominent feature of the early stages of type I diabetes, targeting of these cells through drug treatment could represent a novel approach for preventing autoimmune attack of beta cells."

Future Research Directions

Future research plans include delving deeper into the mechanisms driving the increased activity of functional-maturation programs in aging beta cells, influenced by chromatin dynamics. A comprehensive understanding of these processes holds promise for the development of targeted therapies aimed at enhancing beta-cell functionality and lifespan, thereby improving the quality of life for individuals grappling with diabetes. Understanding how the process of senescence affects the interaction of immune cells with beta cells, and whether this is indeed associated with diabetes, may open the door for new treatment approaches.

The research paper titled “Senescence of human pancreatic beta cells enhances functional maturation through chromatin reorganization and promotes interferon responsiveness” is now available in Nucleic Acids Research and can be accessed at https://pubmed.ncbi.nlm.nih.gov/38682582/

DOI: 10.1093/nar/gkae313

Researchers:

Milan Patra¹, Agnes Klochendler¹, Reba Condiotti¹, Binyamin Kaffe², Sharona Elgavish³, Zeina Drawshy¹, Dana Avrahami¹, Masashi Narita⁴, Matan Hofree^{5 6}, Yotam Drier⁵, Eran Meshorer², Yuval Dor¹, Ittai Ben-Porath¹

Institutions:

1. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem

2. Department of Genetics, the Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem

3. Info-CORE, Bioinformatics Unit of the I-CORE at the Hebrew University of Jerusalem

4. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge

5. The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem

6. School of Computer Science and Engineering, The Hebrew University of Jerusalem

Pictures

Title: Adult pancreatic islets marking senescent beta cells

Description: Beta cells (marked in green) in the pancreas are organized in structures termed islets. In most adults, it was found that a subset become senescent and display the marker p16, shown here in red. The image shows a typical islet in an adult pancreas. Scale bar = 50 μm.

Credit: Nucleic Acids Research

Title: Senescent beta cells show high levels of proteins that display antigens to the immune system.

Description: Pancreatic islets from adult human subject stained for Insulin (INS) marking beta cells, for p16, and for HLA-I – the system by which cells display antigens to attract immune attack. Blue (DAPI) marks DNA. Arrows indicate p16high cells. Scale bar = 10 μm.

Credit: Nucleic Acids Research

Funding

Stichting Onderzoek Nederland (Y. Dor and I.B.-P.); Israel Science Foundation Legacy Heritage Program [1245/16 to I.B.-P.]; British Council BIRAX Program [65BX18MNIB to M.N. and I.B.-P.];Juvenile Diabetes Research Fund [3-SRA-2024-1479-S-B to Y. Dor and I.B.-P.]; Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science, Technology and Space (MOST) [0004062 to I.B.-P.]; Human Islet Research Network [HIRN, U01 DK135001] and NIDDK [R01 DK133442 to Y. Dor]; Human Islet Research Network [HIRN, U01 DK134995 to D.A.]; Cancer Research UK Cambridge Institute Core Grant [C9545/A29580 to M.N.]; I.B.-P. holds the Woll Sisters and Brothers Chair in Cardiovascular Diseases; Y. Dor holds the Walter and Greta Stiel Chair and Research Grant in Heart studies. Funding for open access charge: Woll Sisters and Brothers Chair in Cardiovascular Diseases.

The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 25,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes and a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 86^th according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en

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Muscle Disorder Caused by Key Protein Mutations Uncovered in New Study

4 June, 2024

A recent study has found that the SMCHD1 protein plays a key role in controlling how genes are processed, which affects the progression of Facioscapulohumeral Muscular Dystrophy (FSHD). This discovery about SMCHD1's function in gene regulation is important because it opens new possibilities for developing targeted therapeutic strategies to combat the disease. By understanding more about how SMCHD1 works, scientists can explore new ways to fight the disease.

A recent study by MD-PhD student Eden Engal under the guidance of Dr. Yotam Drier and Prof. Maayan Salton from the Faculty of Medicine at the Hebrew University has highlighted the crucial role of the SMCHD1 protein in the regulation of alternative splicing, shedding light on the disease development of Facioscapulohumeral Muscular Dystrophy (FSHD). This complex disorder, which leads to the progressive weakening and loss of muscle function, is driven by genetic factors. The team's findings enhance our understanding of the genetic mechanisms that underlie this debilitating condition.

FSHD is one of the most common forms of muscular dystrophy, affecting approximately 1 in 20,000 people worldwide. It is caused by genetic mutations that lead to the inappropriate activation of the DUX4 gene in muscle cells and this activation disrupts normal muscle function and causes muscle cells to deteriorate over time. The severity of the disease can vary widely, with some individuals experiencing mild symptoms while others may lose significant muscle function and mobility. There is currently no cure for FSHD.

As DNA is transcribed into RNA, parts of the genes are removed from the RNA in a process known as splicing. Which parts are removed is regulated by multiple proteins and can lead to production of different proteins from the same DNA, a phenomenon therefore termed alternative splicing. The new study found that in addition to SMCHD1 known role in regulating chromosome structure, it is also strongly affecting alternative splicing. Mutations in the SMCHD1 gene were already known to lead to DUX4 expression and FSHD, but it was not clear how.

A detailed analysis of RNA sequencing data from muscle biopsies of FSHD patients and cells genetically modified to lack SMCHD1 revealed extensive splicing errors in numerous genes due to the absence of SMCHD1. A comprehensive screening of splicing factors identified the involvement of the splicing factor RBM5 in these anomalies, and further experiments confirmed that SMCHD1 is required for recruiting RBM5 to its target RNA sites. Amongst the genes whose splicing was disrupted, the researchers identified the DNMT3B gene. They have then demonstrated that the changes in DNMT3B splicing lead to reduced DNA methylation at specific sites near DUX4 which in turn cause harmful overexpression of the DUX4 gene, significantly contributing to FSHD development.

"Our findings underscore a vital link between SMCHD1 and the regulation of splicing mechanisms that, when disrupted, activate pathological processes in Facioscapulohumeral Muscular Dystrophy," stated Eden Engal. "This understanding opens new avenues for potential therapeutic strategies that target these splicing errors, offering hope for mitigating the disease's progression."

This research emphasizes the significant role of SMCHD1 in gene splicing regulation and its impact on the genetic foundations of FSHD, pointing to promising directions for therapeutic intervention.

The research paper titled “DNMT3B splicing dysregulation mediated by SMCHD1 loss contributes to DUX4 overexpression and FSHD pathogenesis” is now available in Science Advances and can be accessed at https://pubmed.ncbi.nlm.nih.gov/38809976/.

Researchers:

Eden Engal^1,2,3, Aveksha Sharma², Uria Aviel^1,4, Nadeen Taqatqa², Sarah Juster4,5, Shiri Jaffe-Herman2, Mercedes Bentata^1,2, Ophir Geminder^2,3, Adi Gershon², Reyut Lewis¹, Gillian Kay², Merav Hecht¹, Silvina Epsztejn-Litman⁴, Marc Gotkine^6,5, Vincent Mouly⁷, Rachel Eiges^4,5, Maayan Salton², Yotam Drier¹

Institutions:

The Lautenberg Center for Immunology and Cancer Research, The Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem
Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem
Department of Military Medicine and "Tzameret", Faculty of Medicine, The Hebrew University of Jerusalem
Stem Cell Research Laboratory, Shaare Zedek Medical Center
Faculty of Medicine, The Hebrew University of Jerusalem
Department of Neurology, Hadassah Medical Center
UPMC University Paris 06, Inserm UMRS974, CNRS FRE3617, Center for Research in Myology, Sorbonne University

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Revolutionizing Cancer Treatment: A New Predictive Tool. Breakthrough in Cancer Prediction with Nano Informatics and AI

29 May, 2024

A recent study has introduced a novel method combining nano informatics and machine learning to precisely predict cancer cell behaviors, enabling the identification of cell subpopulations with distinct characteristics like drug sensitivity and metastatic potential. This research could transform cancer diagnosis and treatment, enhancing personalized medicine by facilitating rapid and accurate testing of cancer cell behaviors from patient biopsies and potentially leading to the development of new clinical tests to monitor disease progression and treatment effectiveness.

In an important advance in the fight against cancer, a research team from The Hebrew University has developed a new method to predict the behavior of cancer cells with high accuracy. This innovative approach, combining nano informatics and machine learning, could revolutionize the diagnosis and treatment of cancer by allowing for the rapid identification of cancer cell subpopulations with varying biological behaviors.

In a novel study led by doctoral student Yoel Goldstein and Prof. Ofra Benny from the School of Pharmacy in the Faculty of Medicine, in collaboration with Prof. Tommy Kaplan, Head of the Department of Computational Biology at the School of Engineering and Computer Science at Hebrew University, The Hebrew University, an innovative method was developed to predict cancer cell behavior using nano informatics and machine learning. This discovery may lead to a significant breakthrough in cancer diagnosis and treatment, enabling the identification of cancer cell subpopulations with different characteristics through simple and quick tests.

The initial phase of the study involved exposing cancer cells to particles of various sizes, each identified by a unique color. Subsequently, the precise amount of particles consumed by each cell was quantified. Machine learning algorithms then analyzed these uptake patterns to predict critical cell behaviors, such as drug sensitivity and metastatic potential.

"Our method is novel in its ability to distinguish between cancer cells that appear identical but behave differently at a biological level," Yoel Goldstein elaborated and explained "This precision is achieved through algorithmic analysis of how micro and nanoparticles are absorbed by cells. Being capable to collect and analyze new types of data brings up new possibilities for the field, with the potential to revolutionize clinical treatment and diagnosis through the development of new tools."

The research has paved the way for new types of clinical tests that could significantly impact patient care. "This discovery allows us to potentially use cells from patient biopsies to quickly predict disease progression or chemotherapy resistance," stated Prof. Benny. "It could also lead to the development of innovative blood tests that assess the efficacy of targeted immunotherapy treatments as example."

Current tools for predicting and detecting cancer often lack accuracy and efficiency. Traditional methods like imaging scans and tissue biopsies can be invasive, costly, and time-consuming, leading to delays in treatment and potential misdiagnoses. These approaches may not capture the dynamic nature of cancer progression and can result in limited insights into the disease's behavior at a cellular level. Consequently, patients may experience delays in diagnosis, suboptimal treatment outcomes, and increased psychological distress. This highlights the urgent need for more effective and non-invasive diagnostic tools, like the recent breakthrough achieved by researchers at The Hebrew University, which represent a significant advancement in personalized medicine, providing hope for more effective and customized treatment strategies for cancer patients.

The research paper titled “Particle uptake in cancer cells can predict malignancy and drug resistance using machine learning” is now available in Science Advances and can be accessed at
10.1126/sciadv.adj4370.

Researchers:

Yoel Goldstein¹, Ora T. Cohen¹, Ori Wald², Danny Bavli³, Tommy Kaplan^4,5, Ofra Benny¹

Institutions:

Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem
Department of Cardiothoracic Surgery, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University
School of Computer Science and Engineering, The Hebrew University of Jerusalem
Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University of Jerusalem

Picture

Illustration. Credit: Made by Ofra Benny by OpenAI software DALL-E

Title: Yoel Goldstein and Ofra Benny in the Lab. Credit: Yoram Aschheim

Disclaimer: In these challenging times of war and crisis, Hebrew University of Jerusalem is resolute in its dedication to advancing research and education. We stand in full support of the brave individuals on the frontlines, safeguarding our nation and the well-being of all Israelis, and extend our deepest gratitude and unwavering solidarity to our community and fellow citizens. Together, we shall prevail against the challenges that confront us, and our shared commitment to the well-being of all Israelis and the pursuit of knowledge remains resolute.

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Personalized Phage Therapy Heals Resistant Wounds - Squeaks Makes Full Recovery

29 May, 2024

A new study demonstrates an advance in treating antibiotic-resistant infections in animals through personalized phage therapy. The treatment combined a specific anti-P. aeruginosa phage applied topically with ceftazidime administered intramuscularly, resulting in the complete healing of a persistent surgical wound after fourteen weeks. This highlights the potential of phage therapy as a practical and effective solution for antibiotic-resistant infections in veterinary practice, with implications for human medicine as well

A new study led by Prof. Ronen Hazan and his team, from the Faculty of Dental Medicine at the Hebrew University of Jerusalem, in collaboration with the team of Vet Holim, JVMV -Veterinary medical center in Kiryat -Anavim, Israel, has shown an advance in the treatment of antibiotic-resistant infections in animals. This research, focusing on a five-year-old Siamese cat Squeaks with a multidrug-resistant Pseudomonas aeruginosa infection post-arthrodesis surgery, marks the first published documented application of personalized phage therapy in veterinary medicine.

Squeaks, initially treated at the JVMV for injuries sustained from a high-rise fall, developed a severe infection in the right hind leg following multiple surgeries. This infection persisted despite various antibiotic treatments over four months. Facing a potential implant-replacement surgery, the team turned to the new treatment which involved a meticulously designed combination of a specific anti-P. aeruginosa phage, a virus that kills bacteria, applied topically to the surgical wound and ceftazidime administered intramuscularly. Moreover, the owners of the cat, after short demonstration, provides most of the treatment doses of phages and antibiotics at their home.

The integration of phage therapy with antibiotics was aimed at targeting the pathogen effectively and directly at the site of infection, leveraging the phage’s ability to be applied topically, which simplifies administration and maximizes its concentration at the infection site. This approach allowed the surgical wound, which had remained open for five months, to fully heal after to fourteen weeks of treatment.

The successful outcome of this case underscores the critical need for novel therapeutics like phage therapy to address the growing concern of antibiotic-resistant infections, which affect up to 8.5% of surgical sites following orthopedic surgeries in companion animals. These infections not only pose significant health risks to the animals but also increase the morbidity, mortality, and costs associated with these procedures.

Recent studies suggest that phage therapy, already showing high success rates in human medicine for treating orthopedic infections and chronically infected wounds, can offer a promising solution for similar issues in veterinary practice. Moreover, the successful treatment of this cat by its owners at home highlights the practicality and efficacy of personalized phage therapy, which could be extended to treat other pets facing similar antimicrobial resistance challenges.

Interestingly, opposite to common situations, this case was performed on an animal based on the team's insights from treating humans first.

The positive reception from veterinarians and pet owners regarding phage therapy points to a growing awareness and acceptance of this treatment option. As the new treatment continues to be explored in veterinary settings, it not only improves the health and well-being of pets but also offers valuable data that contribute to the broader application of phage therapy in both animals and humans. This bridging of data can enhance treatment protocols and outcomes across a variety of bacterial infections, potentially changing the landscape of infection treatment in both veterinary and human medicine.

The research paper titled “Successful phage-antibiotic therapy of P. aeruginosa implant-associated infection in a Siamese cat” is now available in Veterinary Quarterly and can be accessed at https://doi.org/10.1080/01652176.2024.2350661.

Researchers:

Ron Braunstein¹, Goran Hubanic², Ortal Yerushalmy¹, Sivan Oren-Alkalay¹, Amit Rimon^1,3, Shunit Coppenhagen-Glazer¹, Ofir Niv², Hilik Marom², Alin Barsheshet², Ronen Hazan¹

Institutions:

1) Institute of Biomedical and Oral research (IBOR), Faculty of Dental Medicine, Hebrew University of Jerusalem, Israel

2) Vet Holim, JVMV -Veterinary medical center, Kiryat-Anavim, Israel

3) Tzameret, The Military Track of Medicine, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

Picture: Squeaks, Relaxing after full recovery

Credit: Milat and Larry Berkley

Funding

This work was supported by the EveryCat Health Foundation, Wyckoff, New Jersey, under GRANT EC23—0000000060.

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Israeli public opinion is split regarding the appropriate response to the Iranian attack new survey finds

16 April, 2024

The Gaza War Omnibus–April 15, 2024

Description

The Gaza War Omnibus by Agam Labs at Hebrew University of Jerusalem is a series of surveys. Each survey represents a comprehensive exploration within a diverse cross-section of Israeli society. These successive studies meticulously capture the evolving sentiments and perspectives of the Israeli public, offering frequent snapshots of attitudes and feelings prevalent across various segments of the community. Rooted in a robust and inclusive sampling methodology, these findings showcase the dynamic responses and viewpoints emerging amidst the ongoing conflict. The series of surveys intricately trace the fluid developments and shifting public sentiment throughout the duration of the 2023 Gaza War, providing a detailed and updated understanding of the ever-evolving landscape of attitudes within the Israeli public sphere.

This sample mirrors the demographic makeup of Israeli adult society, encompassing a diverse range of factors including gender, age, levels of religiosity, geographical location, political affiliations, and voter turnout in the recent elections for the 25th Knesset. Notably, all respondents actively participated in multiple prior assessments throughout the campaign's evolution, facilitating a comprehensive exploration of fundamental perspectives and changes within this cohort.

Highlights

Israeli public opinion is split regarding the appropriate response to the Iranian attack – 52% believe Israel shouldn’t respond, aiming to end the current round of the conflict, while 48% argue that Israel should respond even if it means extending the current round of the conflict.

28% support military action even if it leads to a larger overall war, 34% oppose it, and 38% don’t know.

Israel and its Allies (USA, UK and moderate Arab countries)

74% of Israelis oppose counter-attacking Iran if it undermines Israel’s security alliance with its allies. However, 26% think Israel should strike back at Iran even at the cost of harming coordination with its allies.

56% of Israelis believe that Israel should respond positively to political and military demands from its allies to ensure a sustainable defense system over time. 32% are undecided, and 12% disagree.

59% believe that American aid to Israel against the Iranian attack obligates Israel to coordinate security actions down the road with America. 26% are undecided, and 15% disagree.

44% of Israelis support military action in Rafah if at the cost of a crisis in Israel’s foreign relations and damage to its relations with the US, 31% are undecided and 25% disagree.

The day after – 43% of the public believes that Israel should rely on its allies in the future settlement of the issue of the day after in Gaza. 33% are undecided, and 24% oppose this.

Online Link: https://docsend.com/view/2h42u39p22x5b2bx

Researchers:
Nimrod Nir, Ido Seltzer and Nimrod Zeldin – Hebrew University of Jerusalem
Asa Shapira and Roy Schulman – Tel Aviv University

Methodology

The Gaza War Omnibus – April 15, 2024, was prepared by Agam Labs at the Hebrew University of Jerusalem. The survey was conducted via the internet and by telephone between April 14-15, 2024 with 1,466 men and women consisting of a nationally representative sample of the adult population in Israel aged 18 and over (Jews and Arabs). The margin of sampling error stands at +4.2%, affirming a confidence level of 99%. Field work was carried out by iPanel.

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