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Gut Microbe Movements Regulate Host Circadian Rhythms

Even gut microbes have a routine. Like clockwork, they start their day in one part of the intestinal lining, move a few micrometers to the left, maybe the right, and then return to their original position. New research in mice now reveals that the regular timing of these small movements can influence a host animal's circadian rhythms by exposing gut tissue to different microbes and their metabolites as the day goes by. Disruption of this dance can affect the host. The study was published online on December 1, 2016 in Cell. The article is titled: “Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations." "This research highlights how interconnected the behavior is between prokaryotes and eukaryotes, between mammalian organisms and the microbes that live inside them," says Eran Elinav, Ph.D., an immunologist at the Weizmann Institute of Science, who led the work with co-senior author Eran Segal, Ph.D., a computational biologist, also at the Weizmann. "These groups interact with and are affected by each other in a way that can't be separated." The new study had three major findings: 1. The microbiome on the surface layer of the gut undergoes rhythmical changes in its "biogeographical" localization throughout the day and night; thus, the surface cells are exposed to different numbers and different species of bacteria over the course of a day. "This tango between the two partners adds mechanistic insight into this relationship," Dr. Elinav says. 2. The circadian changes of the gut microbiome have profound effects on host physiology, and unexpectedly, they affect tissue that is far away from the gut, such as the liver, whose gene expression changes in tandem with the gut microbiome rhythmicity. "As such," adds Dr.

CRISPR/Cas9 Editing of HAT Enzyme Gene in Pancreatic Beta Cells Reduces Cell Death & Increases Insulin Secretion

With the help of the CRISPR/Cas9 gene scissors, researchers at the Lund University Diabetes Centre in Sweden have managed to "turn off" an enzyme that proved to play a key role in the regulation of a diabetes-associated gene. The results are decreased cell death and increased insulin production in the genetically modified pancreatic beta cells. In the study, researchers conducted an investigation on a group of enzymes, histone acetyltransferases (HATs), that play a crucial role in the regulation of the TXNIP gene that, in cases of high blood sugar levels, leads to beta cell death and reduced insulin production. The researchers compared donated insulin -producing pancreatic islets from type 2 diabetes patients with those from healthy people and discovered that the gene activity of HAT enzymes is twice times higher in diabetic cells than in the healthy cells. Following this discovery, the goal was to remove the genetic function of the enzyme to study its effect on diabetes. And this effort proved to be successful. Using CRISPR/Cas9, the researchers were able to remove a sequence in the genetic code that controls the function of the HAT enzyme in insulin-producing cells from rats. This resulted in reduced TXNIP gene activity, and thereby reduced cell death and increased insulin production. "Our research shows that HAT enzymes play a key role in the regulation of TXNIP gene and that by targeting at this mechanism, we improved insulin secretion and prevent cell death,” says researcher Dr. Yang De Marinis who led the study. She adds: "CRISPR/Cas9 is one of the most important discoveries in molecular genetics made in recent years, and we are very happy to have managed to establish this cutting-edge technology in our research team. It opens up new possibilities to study the function of an endless number of genes related to diabetes.

Results from Three Ground-Breaking Cancer Studies Show Early Benefit To Patients

The "revolution in the understanding of cancer at the molecular level" has led to dramatic responses in cancer patients to new therapies that are targeted precisely at their particular type of tumours, according to an expert. Dr. Kapil Dhingra, a member of the executive committee for the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics that is taking place in Munich, Germany, told the meeting on December 1, 2016: "We are seeing an important shift in oncology as we move from a one-treatment-fits-all approach to an era of personalized medicine for cancer. In this new era, it is essential to discover novel, targeted drugs and to identify the patients most likely to benefit from them. This is highlighted at this meeting by several new drugs that show dramatic efficacy in patients with very advanced disease who have failed standard therapies. These drugs can be developed rapidly, based on trials involving relatively small numbers of patients. At the same time, advances in liquid biopsy technologies, in which blood is taken and analyzed to detect genetic mutations, allow clinicians and researchers to obtain a real time portrait of the patients' cancers and their responses to treatment in a non-invasive way, thereby ushering in a new era of cancer therapeutics." Dr. Dhingra, who is managing member of KAPital Consulting LLC (USA), highlighted several meeting presentations that show how new drugs can be very effective when targeted at cancers with the right molecular profile, and how liquid biopsies can accurately identify mechanisms of resistance in patients receiving targeted therapies. The highlighted presentations include the following:

Sleep Apnea Promotes Release of Circulating Exosomes That Can Increase Tumor Growth

A team of researchers from the University of Chicago and the University of Barcelona has found that intermittent hypoxia, or an irregular lack of air experienced by people with sleep apnea, can increase tumor growth by promoting the release of circulating exosomes. Their results were published in the November 2016 issue of the journal CHEST. The article is titled “Tumor Cell Malignant Properties Are Enhanced by Circulating Exosomes in Sleep Apnea.” Obstructive sleep apnea has been associated with increased incidence of cancer and mortality. In order to better understand the connection between the two, investigators took a detailed look at lung cancer tumor cell growth in mice. Half of the mice experienced regular breathing patterns, while the other half were exposed to intermittent hypoxia (IH) to simulate sleep apnea. The team found that exosomes released in the mice exposed to IH enhanced the malignant properties of the lung cancer cells. Exosomes are microscopic spheres that transport proteins, lipids, mRNAs, and miRNAs between cells, similar to courier messengers delivering packages. They play a central role in cell-to-cell communication and are involved in promoting cancer cell growth and metastasis. "Exosomes are currently under intense investigation since they have been implicated in the modulation of a wide range of malignant processes," explained lead investigator David Gozal, M.D., M.B.A., Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois. "Hypoxia can increase exosomal release and selectively modify exosome contents such as to enhance tumor proliferation and angiogenesis.

EphA2 Identified As Elusive Functional Signaling Receptor for Progranulin; Finding May Aid Advances in Cancer & Neurodegenerative Disease Studies

Progranulin is produced and secreted by most cells in the body. From skin to immune cells, brain to bone marrow cells, progranulin plays a key role in maintaining normal cellular function. In cancer, too much progranulin makes tumors (particularly prostate carcinomas) more aggressive and metastatic, whereas, in neurodegenerative diseases, too little progranulin is associated with disease onset and progression. Until now, studying progranulin has been tricky as the progranulin receptor that communicates biological information to the cell's signaling machinery has remained elusive for decades. Now, researchers at Thomas Jefferson University's Sidney Kimmel Cancer Center have discovered a cell-surface receptor highly expressed by cancerous and brain cells that directly and tightly binds progranulin. Importantly, the researchers also showed that this binding activates a cellular program that makes cancer cells more aggressive. The results were published online on November 30, 2016 in The Journal of Cell Biology. The article is titled “EphA2 Is a Functional Receptor for the Growth Factor Progranulin." "Identifying the functional signaling receptor for progranulin will help us understand how this molecule functions in cancer and whether pharmacologically targeting it will slow the progression of a number of cancers," says Renato V. Iozzo, M.D., Ph.D., Gonzalo E. Aponte Professor and Deputy Chair of the Department of Pathology, Anatomy & Cell Biology at Thomas Jefferson University and researcher at the Sidney Kimmel Cancer Center at Jefferson.

Study Reveals Key Role of mRNA's “Fifth Nucleotide” in Sex Determination in Fruit Flies

A team of scientists led by researchers at the University of Birmingham has shown how a common mRNA modification, N6-methyladenosine (m6A), regulates gene expression to determine the sex of fruit flies. The function of m6A, an mRNA modification known as the “fifth nucleotide,” has long been a mystery. But a new study, published online on November 30, 2016 in Nature, has revealed that m6A plays a key role in the regulation of the Sex-lethal (Sxl) gene, which controls sex determination of the fruit fly Drosophila. The Nature article is titled “m6A Potentiates Sxl Alternative pre-mRNA Splicing for Robust Drosophila Sex Determination.” Sxl is a “switch gene,” meaning that Drosophila sex is determined by whether or not Sxl protein is made. The Sxl gene is transcribed into mRNA in both males and females, but through a process called “alternative splicing” only the female mRNA can be made into a functional protein. Alternative splicing is a widespread mechanism of gene expression and occurs in almost all human genes, allowing the synthesis of many more proteins than would be expected from the 20,000 protein-coding genes in our genome. The new study shows that m6A mediates this process for Sxl in Drosophila, ultimately determining whether a fly develops as male or female. The new findings offer an important insight into a classic textbook example of an essential and widely studied process. “Despite sex determination being so fundamental, nature has found many ways of determining sex,” says Dr. Matthias Soller from the School of Biosciences at the University of Birmingham and lead author on the paper. “Our study suggests that m6A-mediated adjustment of gene expression might be an ancient yet unexplored mechanism for the development of this diversity.” The collaboration began after co-author Dr.

Each Animal Species Hosts Unique Microbial Community and Benefits from It, Study Suggests

Each animal species hosts its own, unique community of microbes that can significantly improve its health and fitness. That is the implication of a laboratory study that investigated four different animal groups and their associated microbiota. The research found that each species within the group has a distinctive microbial community. Additional experiments with two of the groups - one mammal and one insect - demonstrated that individuals possessing their natural microbiota digested food more efficiently and had greater survival than those that were implanted with the microbial communities of closely related species. "Previous research has tended to concentrate on the negative effects of microbes. In this case, we are showing that whole communities of microbes have positive effects as well," said Vanderbilt graduate student Andrew Brooks, co-first author of the study. The paper describing the study's results is titled "Phylosymbiosis: Relationships and Functional Effects of Microbial Communities across Host Evolutionary History" and it was published online on November 18, 2016 in PLOS Biology. "We coined the term phylosymbiosis a couple of years ago to denote the fact that evolution can act on host species and change their microbial communities," said Seth Bordenstein, Ph.D., Associate Professor of Biological Sciences and Pathology, Microbiology, and Immunology at Vanderbilt University, who directed the study. Postdoctoral researcher Dr. Kevin Kohl and Robert Brucker at Harvard University were other co-first authors, and another participant, Edward Van Opstal, is a graduate student at Vanderbilt. All animals teem with thousands of different species of microbes collectively called the microbiome.

Fiber Optic pH Probe May Aid Breast Cancer Surgery

University of Adelaide researchers have developed an optical fiber probe that distinguishes breast cancer tissue from normal tissue - potentially allowing surgeons to be much more precise when removing breast cancer. The device could help prevent follow-up surgery, currently needed for 15-20% of breast cancer surgery patients where all the cancer is not removed. In an article published online on November 30, 2016 in the journal Cancer Research, researchers at the University of Adelaide in the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), the Institute for Photonics and Advanced Sensing, and the Schools of Physical Sciences and Medicine, describe how the optical probe works by detecting the difference in pH between the two types of tissue. The article is titled “Cancer Detection in Human Tissue Samples Using a Fiber-Tip pH Probe.” The research was carried out in collaboration with the Breast, Endocrine and Surgical Oncology Unit at the Royal Adelaide Hospital. "We have designed and tested a fiber-tip pH probe that has very high sensitivity for differentiating between healthy and cancerous tissue with an extremely simple - so far experimental - setup that is fully portable," says project leader Dr. Erik Schartner, postdoctoral researcher at the CNBP at the University of Adelaide. "Because it is cost-effective to do measurements in this manner compared to many other medical technologies, we see a clear scope for this technology in operating theaters." Current surgical techniques to remove cancer lack a reliable method to identify the tissue type during surgery, relying on the experience and judgement of the surgeon to decide on how much tissue to remove. Because of this, surgeons often perform “cavity shaving,” which can result in the removal of excessive healthy tissue.

Nanotechnology “Green” Approach May Have Impact on Liver Cancer; Photothermic Therapy Using Gold Nanoparticles Coated with Gum Arabic Shows Promise

According to the American Cancer Society, more than 700,000 new cases of liver cancer are diagnosed worldwide each year. Currently, the only cure for the disease is to surgically remove the cancerous part of the liver or to transplant the entire organ. However, an international study led by University of Missouri (MU) School of Medicine researchers has proven that a new, minimally invasive approach targets and destroys precancerous tumor cells in the livers of mice and in vitro human cells. "The limitations when treating most forms of cancer involve collateral damage to healthy cells near tumor sites," said Kattesh Katti (photo), Ph.D., Curators' Professor of Radiology and Physics at the MU School of Medicine and lead author of the study. "For more than a decade we have studied the use of nanotechnology to test whether targeted treatments would reduce or eliminate damage to nearby healthy cells. Of particular interest has been the use of green nanotechnology approaches pioneered here at MU that use natural chemical compounds from plants." The study was conducted in the United States and Egypt, and it involved the use of gold nanoparticles encapsulated by a protective stabilizer called gum Arabic. The nanoparticles were introduced to the livers of mice intravenously and were heated with a laser through a process known as photothermal therapy. "Gum Arabic is a natural gum made of the hardened sap from acacia trees," said Dr. Katti, who also serves as director of the MU Institute of Green Nanotechnology and is the Margaret Proctor Mulligan Distinguished Professor of Medical Research at the MU School of Medicine. "It is FDA-approved for human consumption and is primarily used in the food industry as an additive.

Platypus Venom May Hold Clues to Fighting Type 2 Diabetes

Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation's most iconic native animal species - the platypus and the echidna - which could pave the way for new treatments for type 2 diabetes in humans. The findings, published online on November 29, 2016 in the Nature journal Scientific Reports, reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in its venom. The research is led by Professor Frank Grutzner at the University of Adelaide and Associate Professor Briony Forbes at Flinders University. The open-access article is titled “Monotreme Glucagon-Like Peptide 1 in Venom Gut—One Gene, Two Vdery Different Functions.” The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose. But GLP-1 typically degrades within minutes. In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn't sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer-lasting form of the hormone is needed to help provide an extended release of insulin. "Our research team has discovered that monotremes - our iconic platypus and echidna - have evolved changes in the hormone GLP-1 that make it resistant to the rapid degradation normally seen in humans," says co-lead author Professor Frank Grutzner, from the University of Adelaide's School of Biological Sciences and the Robinson Research Institute. "We've found that GLP-1 is degraded in monotremes by a completely different mechanism.

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