Many IVF embryos fail to develop

In humans, a fertilized egg is no guarantee of reproductive success. Most embryos stop developing and perish within days of fertilization, usually because they have an abnormal number of chromosomes. Now, researchers at Columbia University Vagelos College of Physicians and Surgeons have found that most of these mistakes are due to spontaneous errors in DNA replication in the earliest phase of cell division. The findings provide new insights into the basic biology of human reproduction and in the long term could lead to improvements in the success rate of in vitro fertilization (IVF). Approximately 24 hours after a human egg is fertilized, the process of cell division begins. During cell division, the entire genome containing more than 3 billion base pairs of DNA must be faithfully duplicated. The duplicate sets of chromosomes must then be separated so that each daughter cell receives a complete set. In many human embryos created for IVF, something goes wrong and some cells within the embryo have too few or too many chromosomes. Researchers have theorized that errors occur during the final phase of cell division, when the duplicate sets of chromosomes separate into two identical daughter cells. Most of these failures were attributed to issues with the microtubule spindle, the apparatus that pulls the two sets of chromosomes apart. But studies found that chromosomal abnormalities stem from errors that occur much earlier in the process of cell division when the genome's DNA is duplicated. If the DNA is not copied precisely, the spindle malfunctions and places the wrong number of chromosomes into each daughter cell. When DNA duplication is abnormal, the spindle does not function normally. Though the studies were conducted with embryos created in a petri dish including from individuals undergoing IVF and egg donors who were not seeking fertility treatment the same problems may contribute to the failure of embryos created in natural human reproduction. The source of DNA copying errors in embryos appears to spring from obstacles within the DNA's double helix. Though the precise reason for these obstacles is not yet known, they cause duplication of the DNA to pause, or even stop, which results in DNA breakage and an abnormal number of chromosomes. Spontaneous DNA errors can occur as early as the first cycle of cell division in human embryos, the researchers found, as well as in subsequent cell divisions. If too many cells in the early embryo are affected by chromosomal abnormalities, the embryo cannot develop further. Most human embryos created for IVF stop developing within days after fertilization. This inefficiency of human development is an obstacle to successful fertility treatments. Many women undergoing fertility treatment require multiple IVF cycles in order to get pregnant, and some never get pregnant at all. Not only is this enormously expensive, it's emotionally taxing. The researchers are planning additional studies looking at DNA damage during replication in the hope of understanding normal and disease causing variations in the human germ line. In the long term, these studies may lead to methods to reduce the risk of genetic abnormalities and embryo attrition for patients undergoing IVF.

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SARS-CoV-2 hijacks nanotubes between neurons to infect them

COVID-19 often leads to neurological symptoms, such as a loss of taste or smell, or cognitive impairments, both during the acute phase of the disease and over the long term with "long COVID" syndrome. But the way in which the infection reaches the brain was previously unknown. Scientists from Institute Pasteur and CNRS laboratories have used state-of-the-art electron microscopy approaches to demonstrate that SARS-CoV-2 hijacks nanotubes, tiny bridges that link infected cells with neurons. The virus is therefore able to penetrate neurons despite the fact that they are lacking the ACE2 receptor that the virus usually binds to when infecting cells. A study published recently in Science Advances shows that the virus uses nanotubes that form between infected cells and neurons to gain access to neurons. These transient dynamic structures are a result of membrane fusion in distant cells. They enable the exchange of cellular material without the need for membrane receptors, the normal means of entering and exiting the cytoplasm. The Membrane Traffic and Pathogenesis Unit has already found that nanotubes play a role in degenerative diseases such as Alzheimer's and Parkinson's by facilitating the transport of proteins responsible for these diseases. Although the human cell receptor ACE2 serves as a gateway for SARS-CoV-2 to enter lung cells the main target of the virus and cells in the olfactory epithelium, it is not expressed by neurons. But viral genetic material has been found in the brains of some patients, which explains the neurological symptoms that characterize acute or long COVID. The olfactory mucosa has previously been suggested as a route to the central nervous system, but that does not explain how the virus is able to enter neuronal cells themselves. According to this new study, SARS-CoV-2 is also thought to be capable of inducing the formation of nanotubes between infected cells and neurons, as well as among neurons, which would explain how the brain is infected from the epithelium. The research team revealed multiple viral particles located both inside and on the surface of nanotubes. Since the virus spreads more rapidly and directly from within nanotubes than by exiting one cell to move to the next via a receptor, this mode of transmission therefore contributes to the infectious capacity of SARS-CoV-2 and its spread to neuronal cells. But the virus also moves on the external surface of nanotubes, where it can be guided more quickly to cells that express compatible receptors. This publication combines research on in vitro cultures, showing that healthy neuronal cells are infected if they come into contact with infected cells, with the use of state-of-the-art microscopy tools. This study is an example of how basic interdisciplinary research, involving cellular biologists, virologists and state-of-the-art imaging techniques, can lead to new discoveries. It paves the way for further research on the role of cell-to-cell communication in the spread of SARS-CoV-2.

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A common mechanism for cancer metastasis and atherosclerosis

A key molecule for cancer metastasis has been identified as a molecule already known for its involvement in cardiovascular disease, suggesting a possible treatment approach for both diseases simultaneously. Cancer is the uncontrolled growth of body cells leading to the formation of tumors, triggered by the accumulation of mutations in a cell's genome. In order to become malignant, metastasizing cancer, tumor cells go through a series of transformations involving interactions between the body's immune system and the tumor. However, many mechanistic details in this process are still unclear, making the prevention and treatment of cancer notoriously difficult. However, there is growing evidence that in tumor progression to metastasis, inflammation of endothelial cells is a key process. Concerned with the molecular mechanism behind this process in cancer malignancy, a team of researchers have discovered that, in malignant tumors, endothelial cells accumulate low-density lipoprotein  (LDL) and attract neutrophils. Neutrophils are immune suppressor cells which are known to contribute to tumor progression. Previous work by the team had revealed that blood vessels in malignant tumors expressed a high level of proteoglycans, and it is known that cancerous tissue is inflamed. These features are similar to what is seen in atherosclerosis, and the team wished to investigate if the similarities went deeper. The research team showed that metastasizing tumors, in contrast to non-metastasizing ones, accumulate proteoglycan molecules. These, in turn, attach to and accumulate LDL to the walls of blood vessels. The bound LDL becomes oxidized. There are also high levels of its receptor, called "LOX-1," in the blood vessel lining endothelial cells of metastasizing tumors. This, they found, causes these cells to produce inflammation signals that attract neutrophils. They then proved that in mice, the suppression of LOX-1 can significantly reduce tumor malignancy, and also that LOX-1 overexpression caused an increase in signaling molecules attracting neutrophils. As the team hypothesized, this sequence of interactions observed in malignant tumors occurs in atherosclerosis. Even though some questions remain open, especially on the mechanism of how neutrophils contribute to cancer malignancy, this study is the first to explicitly prove the mechanistic commonalities between cardiovascular disease and cancer progression and trace the mechanism involving LDL accumulation and LOX-1 expression in in vivo tumor tissue. Their present study focused on the importance of LOX-1 in endothelial cells as a common factor between cancer and atherosclerosis. The study also points to a promising approach for treating and preventing malignant cancer and cardiovascular disease by targeting neutrophil recruitment to endothelial cells. The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidized LDL axis might be a promising strategy for the treatment of the two diseases concomitantly.

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