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Identifying genetic variants and the role they play in predisposing people to Alzheimer’s disease can help researchers better understand how to treat the neurodegenerative condition for which there is currently no cure. A new study led by Boston University School of Public Health (BUSPH) and UTHealth Houston School of Public Health has identified several genetic variants that may influence Alzheimer’s disease risk, putting researchers one step closer to uncovering biological pathways to target for future treatment and prevention.

Published in the journal Alzheimer’s & Dementia, the study utilized whole genome sequencing and identified 17 significant variants associated with Alzheimer’s disease in five genomic regions. This data enables researchers to pinpoint rare and important genes and variants, building upon genome-wide association studies, which focus only on common variants and regions. The findings underscore the value of whole genome sequencing data in gaining long-sought insight into the ultimate causes and risk factors for Alzheimer’s disease, which is the fifth leading cause of death among people 65 and older in the United States. As the most common form of dementia, Alzheimer’s disease currently affects more than 6 million Americans and that number is expected to skyrocket to nearly 13 million by 2050.

“Prior genome-wide association studies using common variants have identified regions of the genome, and sometimes genes, that are associated with Alzheimer’s disease,” says study co-senior author Dr. Anita DeStefano, professor of biostatistics at BUSPH.

By Boston University 

Article can be accessed on: MedicalXpress

The liver is not only the largest internal organ but also vital for human life as a metabolic center. It also possesses remarkable self-healing powers: even when large portions are removed, such as during surgery, they quickly regenerate in healthy individuals. However, in cases of repeated or chronic injury to the liver tissue, as caused by excessive alcohol consumption or viral hepatitis, this regenerative capacity fails. Scarring occurs, known as fibrosis, where liver cells are replaced by fibrous tissue. The liver hardens and becomes increasingly unable to perform its function in the worst case, this leads to liver failure.

To better understand the scarring process, a research team led by Thomas Reiberger, Professor of Gastroenterology and Hepatology at MedUni Vienna and Adjunct Principal Investigator at CeMM, examined gene activity in two different mouse models exhibiting varying degrees of liver disease severity, also capturing certain phases of spontaneous regression of the disease.

At the same time, important indicators of disease severity, such as portal venous pressure, blood markers of liver injury, or the extent of liver fibrosis based on liver tissue samples, were recorded. The study, “Transcriptomic signatures of progressive and regressive liver fibrosis and portal hypertension,”was published in the journal iScience.

By CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Article can be accessed on: MedicalXpress

Numerous anti-cancer drugs function by targeting the DNA within cancerous cells, halting their proliferation. Yet, cancer cells occasionally develop mechanisms to repair the damage inflicted by these drugs, diminishing their effectiveness. Consequently, physicians are increasingly embracing a novel approach to cancer treatment known as precision medicine. This method involves selecting medications that precisely align with the unique attributes of an individual’s cancer. Precision medicine proves particularly beneficial in addressing cancers that have evolved to evade conventional treatments.

Trabectedin, a promising drug derived from the sea squirt Ecteinascidia turbinata, has shown potential in combating cancers resistant to conventional treatments. However, its precise mechanism of action has remained elusive until now. A collaborative effort led by Dr. Son Kook and Professor Orlando D. Schärer from the Center for Genomic Integrity within the Institute for Basic Science in South Korea, along with Dr. Vakil Takhaveev and Professor Shana Sturla from ETH Zurich, Switzerland, has illuminated the inner workings of this mysterious compound. Their research is published in the journal Nature Communications.

Using highly sensitive COMET chip assays to detect breaks formed in the genomes of cells, IBS researchers revealed trabectedin induces persistent breaks in the DNA of cancer cells. The researchers showed that these DNA breaks are only formed in cells with high levels of DNA repair, specifically those that operate a pathway called transcription-coupled nucleotide excision repair (TC-NER).

By Tom Leonhardt, Martin Luther University Halle-Wittenberg

Article can be accessed on: phys.org

Tomato plants emit a scent to resist bacterial attacks. This aroma or volatile compound is hexenyl butanoate (HB). A team from the Research Institute for Plant Molecular and Cellular Biology (IBMCP), a joint center of the Universitat Politècnica de Valencia (UPV) and the Spanish National Research Council (CSIC), has discovered that its mode of action is novel, as it works independently of the classic hormone involved in the process of stomatal closure (abscisic acid).

In this way, it is possible to protect plants from threats like drought or pathologies that could threaten crops. The work has been published in Horticulture Research.

“Given the importance of stomatal control in water stress, HB treatments alleviate the symptoms caused by drought and improve the productivity of crops such as tomato. Therefore, in the context of the severe drought we are currently experiencing in Spain, the development of this type of compound is a breakthrough to address this situation,” says Purificación Lisón, IBMCP researcher and professor in the Department of Biotechnology at the School of Agricultural Engineering and Environment (ETSIAMN) of the UPV.  Among other advantages, the UPV and CSIC team points out that the HB compound resists diseases that enter the stomata. In the case of tomatoes, its use protects against Pseudomonas syringae. This bacterium causes significant damage, particularly in cold and wet weather, making the fruit unsuitable for marketing.

By Universitat Politècnica de València

Article can be accessed on: phys.org

Gene editing is revolutionizing the understanding of health and disease, providing researchers with vast opportunities to advance the development of novel treatment approaches. Traditionally, researchers used various methods to introduce double strand breaks (DSBs) into the genome, including transactivator-like effectors, meganucleases, and zinc finger nucleases. While useful, these techniques are limited in that they are time and labor intensive, less efficient, and can have unintended effects. In contrast, the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9) system (CRISPR/Cas9) is among the most sensitive and efficient methods for creating DNA DSBs, making it the leading gene editing technology.

CRISPR/Cas9 is a naturally occurring immune protective process that bacteria use to destroy foreign genetic material. Researchers repurposed the CRISPR/Cas9 system for genetic engineering applications in mammalian cells, exploiting the molecular processes that introduce DSBs in specific sections of DNA, which are then repaired to turn certain genes on or off, or to correct genomic errors with extraordinary precision. This technology’s applications are far reaching, from cell culture and animal models to translational research that focuses on correcting genetic mutations in diseases such as cancer, hemophilia, and sickle cell disease. Researchers exploit plasmids, the small, closed circular DNA strands native to bacteria, as delivery vehicles in CRISPR/Cas9 gene editing protocols. Plasmids shuttle the CRISPR/Cas9 gene editing components to target cells and can be manipulated to control gene editing activity, including targeting multiple genes at a time. Plasmids can also deliver gene repair instructions and machinery. For example, poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that drives DNA repair and transcription.⁵ It is a critical aspect of CRISPR/Cas9 gene editing technology in part because it helps repair the DSBs created by the CRISPR/Cas9 system. PARP1 CRISPR plasmids can edit, knockout, or upregulate PARP1 gene expression depending on the specific instructions encoded in the plasmid.

By The Scientist and Santa Cruz Biotechnology, Inc.

Article can be accessed on: The Scientist

Most approved gene therapies today, including those involving CRISPR-Cas9, work their magic on cells removed from the body, after which the edited cells are returned to the patient.

This technique is ideal for targeting blood cells and is currently the method employed in newly approved CRISPR gene therapies for blood diseases like sickle cell anemia, in which edited blood cells are reinfused in patients after their bone marrow has been destroyed by chemotherapy. A new, precision-targeted delivery method for CRISPR-Cas9, published in the journal Nature Biotechnology, enables gene editing on very specific subsets of cells while still in the body a step toward a programmable delivery method that would eliminate the need to obliterate patients’ bone marrow and immune system before giving them edited blood cells.

The delivery method, developed in the University of California, Berkeley, laboratory of Jennifer Doudna, co-inventor of CRISPR-Cas9 genome editing, involves wrapping the Cas9 editing proteins and guide RNAs in a membrane bubble that has been decorated with pieces of monoclonal antibodies that home in on specific types of blood cells.

As a demonstration, Jennifer Hamilton, a CRISPR researcher in the Doudna laboratory at the Innovative Genomics Institute (IGI), targeted a cell of the immune system a T-cell which is the starting point for a revolutionary cancer treatment called chimeric antigen receptor (CAR) T-cell therapy.

By University of California – Berkeley

Article can be accessed on: phys.org

Individually tailored RNA or DNA-based molecules are able to reliably fight off viral infections in plants, according to a new study by the Martin Luther University Halle-Wittenberg (MLU) published in the International Journal of Molecular Sciences. The researchers were able to fend off a common virus using the new active substances in up to 90% of cases. They also developed a method for finding substances tailored specifically to the virus. The team has now patented the method.

During a viral infection, the plant’s cells are hijacked by the virus to multiply itself. Key products of this process are viral RNA molecules that serve as blueprints for the production of proteins. “A virus cannot reproduce without producing its proteins,” explains Professor Sven-Erik Behrens from the Institute of Biochemistry and Biotechnology at MLU. For years, his team has been working on ways to disrupt this process and degrade the viral RNA molecules inside the cells.

In the new study, the researchers describe how this can be achieved using the so-called “antisense” method. It relies on short, synthetically produced DNA molecules known as antisense oligonucleotides (ASOs). In the plant cells, the ASOs direct cellular enzymes acting as scissors towards the foreign RNA so they can degrade it.  For this process to work, it is crucial to identify a suitable target structure in the viral RNA which the enzyme scissors can attach to,” explains Behrens.

By Tom Leonhardt, Martin Luther University Halle-Wittenberg

Article can be accessed on: phys.org

Successful immunotherapy for cancer involves activating a person’s own T cells to identify telltale proteins called antigens on the surface of a tumor and attack it. But some tumors have a trick: They hide themselves from the immune system by preventing their antigens from being displayed. A team led by Harvard Medical School researchers at Boston Children’s Hospital has now found a way around this defense in mice.

The findings suggest a strategy for developing add-on treatments that make cancer immunotherapies more effective. The key lies in a protein called prosaposin, the team reported in Science. Tumor tissue contains a large percentage of dying cells that shed little capsules, or vesicles, containing the tumor antigens. Immune cells called dendritic cells absorb these vesicles, process the antigens, and sprout pieces of the antigens on their surface, which teaches T cells to recognize and attack the antigens. The researchers found that without prosaposin, dendritic cells can’t break down the vesicles and present the tumor antigens to the immune system as a teaching tool. Specifically, the dendritic cells need proteins called saposins that form from prosaposin, the team discovered.

“We found that saposins are needed to digest these vesicles and free the tumor antigen for display to the immune system,” explained senior author Florian Winau, HMS associate professor of pediatrics in the Program in Cellular and Molecular Medicine at Boston Children’s.

By Nancy Fliesler, Harvard Medical School

Article can be accessed on: MedicalXpress

Columbia researchers have found that a rare type of lipid is a key driver of ferroptosis, a form of cell death discovered by Columbia professor Brent Stockwell. The findings, appearing in Cell, provide new detail on how cells die during ferroptosis and could improve understanding of how to stop ferroptosis in contexts where it is harmfully occurring in neurodegenerative diseases, for example or induce it in contexts where it could be useful, such as using it to kill dangerous cancer cells.

The new research found that a rare type of lipid with two polyunsaturated fatty acyl tails, called a diPUFA phospholipid, was present in a range of contexts where ferroptosis was occurring, including in aging brains and Huntington disease-affected brain tissue. The finding indicates that the lipid is efficient at promoting ferroptosis.

The research was conducted by professors in Columbia’s Department of Biological Sciences, Department of Chemistry, and the Columbia University Irving Medical Center.

Stockwell first discovered ferroptosis in 2012, when he found that certain cells were dying because their lipid layers were collapsing an unusual form of cell death that differs from the most common kind, which begins with the cell forming blisters on its outer surface. Since that discovery, researchers in Stockwell’s lab and elsewhere have continued to investigate ferroptosis, discovering that it can occur naturally in aging cells, in pathological contexts, and can be induced to treat disease.

By Columbia University

Article can be accessed on: phys.org

A team at NDORMS has developed a new approach to significantly improve the accuracy of RNA sequencing. They have pinpointed the primary source of inaccurate quantification in both short and long-read RNA sequencing, and have introduced the concept of “majority vote” error correction leading to a substantial improvement in RNA molecular counting. Accurate sequencing of genetic material is crucial in modern biology, particularly for comprehending and addressing diseases linked to genetic anomalies. However, current methodologies encounter substantial constraints.

In a landmark study, an international consortium of researchers, led by Adam Cribbs, Associate Prof. in Computational Biology, and Jianfeng Sun, Postdoctoral Research Associate at the Botnar Institute, University of Oxford, have developed an innovative method to correct errors in PCR amplification a widely used technique used in high-throughput sequencing. By pinpointing PCR artifacts as the primary source of inaccurate quantification, the researchers, address a long-standing challenge in generating accurate absolute counts of RNA molecules, which is crucial for various applications in genomics research. The study is published in the journal Nature Methods.

The researchers focused on Unique Molecular Identifiers (UMIs), which are random oligonucleotide sequences used to remove biases introduced during PCR amplification. While UMIs have been widely adopted in sequencing methods, the study reveals that PCR errors can undermine the accuracy of molecular quantification, particularly across different sequencing platforms.

By Adam Cribbs, University of Oxford

Article can be accessed on: phys.org