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Extraordinary Anglerfish Trade Adaptive Immunity for Reproductive Success; Much-Enhanced Innate Immunity Predicted; Male Fuses Its Body to Female in Rare Example of Sexual Parasitism in These Deep-Sea Fish

Deep-sea anglerfishes employ an incredible reproductive strategy. Tiny dwarfed males become permanently attached to relatively gigantic females, fuse their tissues, and then establish a common blood circulation. In this way, the male becomes entirely dependent on the female for nutrient supply, like a developing fetus in the womb of her mother or a donor organ in a transplant patient. In anglerfishes, this unusual phenomenon is referred to as sexual parasitism and contributes to the reproductive success for these animals living in the vast space of the deep sea, where females and males otherwise rarely meet. The permanent attachment of males to females represents a form of anatomical joining, which is otherwise unknown in nature except for the rare occurrence in genetically identical twins. The immune system represents an extraordinary obstacle here. It attacks foreign tissue as it would destroy cells infected by pathogens. Just witness the difficulties surrounding organ transplantation in humans, which requires the careful cross-matching of donor and recipient tissue characters, together with immunosuppressive drugs, to ensure the long-term survival of the organ graft. But how is it possible then that, in case of anglerfishes, that individuals of the same species accept each other so readily when tissue-rejection is the usual and expected result of any such union? The phenomenon of sexual parasitism has posed an enigma that has existed for 100 years, ever since the first attached couple was discovered by an Icelandic fisheries biologist in 1920. Now, scientists from Germany and the USA have solved this century-old conundrum and report their findings online on July 30, 2020 in Science.

Inhibition of BBOX1 Enzyme Might Be Effective Therapeutic Approach in Triple-Negative Breast Cancer

One member of a larger family of oxygen-sensing enzymes could offer a viable target for triple-negative breast cancer (TNBC) therapy, researchers from the University of Texas Southwestern (UTSW) report in a new study. The findings, published online on July 20, 2020 in Cancer Discovery, might offer hope to this subset of patients who have few effective treatment options and often face a poor prognosis. The article is titled “Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer.” TNBC – so called because it lacks estrogen receptors, progesterone receptors, and overexpression of the growth-promoting protein HER2 – makes up only 15 to 20 percent of all breast cancers. However, explains Qing Zhang, PhD, Associate Professor in the Department of Pathology at UTSW and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, it’s the deadliest of all breast cancers, with a five-year survival rate of 77 percent compared with 93 percent for other types. Unlike other cancers which are hormone receptor or HER2 positive, TNBC has no targeted treatments, so patients must rely only on surgery, chemotherapy, and radiation, which are less effective than targeted treatments and can harm healthy tissue. Dr. Zhang’s lab studies how cancers can thrive in low-oxygen environments. Looking for viable drug targets for TNBC, Dr. Zhang and his colleagues zeroed in on 2-oxoglutarate (2OG)-dependent enzymes, a family of 70 enzymes including some that function as oxygen sensors in cells. To determine their role in TNBC, the researchers used a library of short interfering RNAs (siRNAs)--snippets of genetic material that can shut off the expression of specific genes--to individually turn off each member of the 2-OG-dependent family in different TNBC and healthy breast cell lines.

Tumor-Derived Exosomes Containing GTPase Rab11a Can Drive Cancer Growth and Treatment Resistance, New Results from University of Oxford Suggest

Collaborative Cancer Research UK-funded studies from University of Oxford researchers have revealed a new mechanism by which cancer cells adapt to the stresses they encounter as they grow and respond to therapies. This mechanism involves cells releasing small vesicles, known as exosomes. These exosomes can contain complex mixtures of proteins, RNAs, and other molecules, which can reprogram surrounding cells. Exosomes are thought to be released by all cells in the body and play important roles in many processes in healthy individuals, such as immunity and reproduction. But, in cancer, they can sometimes drive pathological changes such as tumor growth and metastasis. Up until now, research has suggested that exosomes are made in compartments in cells, known as late endosomes, which are also used to keep cells healthy by clearing out damaged proteins and cell structures. By combining complementary analysis in fruit flies and human cancer cells, the collaborative teams have shown that exosomes are also made in the cell’s recycling system, which diverts reusable proteins away from the waste disposal system. They are called Rab11a-exosomes and carry a different set of cargos that may help cancers to grow and survive current treatments. As a tumor grows larger, the cells within it are starved of key nutrients such as amino acids, and these stressed cells produce Rab11a-exosomes loaded with molecules made by the cancer cells. According to Associate Professor Deborah Goberdhan (photo), who led the research, “These ‘bad exosomes’ can then give other cells around them a growth-promoting boost and can potentially lead to selection of more aggressive cell types and a worse outcome.

Dermal Exosomes Containing MicroRNA-218-5p Promote Hair Regeneration

Researchers from North Carolina State University (NC State) have identified a microRNA (miRNA) that could promote hair regeneration. This miRNA (miR-218-5p) plays an important role in regulating the pathway involved in follicle regeneration, and could be a candidate for future drug development. Hair growth depends on the health of dermal papillae (DP) cells, which regulate the hair follicle growth cycle. Current treatments for hair loss can be costly and ineffective, ranging from invasive surgery to chemical treatments that do not produce the desired result. Recent hair loss research indicates that hair follicles don’t disappear where balding occurs, they just shrink. If DP cells could be replenished at those sites, the thinking goes, then the follicles might recover. A research team led by Ke Cheng, PhD, the Randall B. Terry, Jr. Distinguished Professor in Regenerative Medicine at NC State’s College of Veterinary Medicine and Professor in the NC State/UNC Joint Department of Biomedical Engineering, cultured DP cells both alone (2D) and in a 3D spheroid environment. A spheroid is a three-dimensional cellular structure that effectively recreates a cell’s natural microenvironment. In a mouse model of hair regeneration, Dr. Cheng looked at how quickly hair regrew on mice treated with 2D cultured DP cells, 3D spheroid-cultured DP cells in a keratin scaffolding, and the commercial hair loss treatment Minoxidil. In a 20-day trial, mice treated with the 3D DP cells had regained 90% of hair coverage at 15 days. “The 3D cells in a keratin scaffold performed best, as the spheroid mimics the hair microenvironment and the keratin scaffold acts as an anchor to keep them at the site where they are needed,” Dr. Cheng says.

Clues to Why Burkholderia cepacia Only Infects Teenage and Adult Cystic Fibrosis Patients, While Pseudomonas auriginosa Infects Infants or Young Children with CF and Persists for Life; Type VI Secretion Systems (T6SS) Likely Play Key Role

Several different kinds of bacteria can cause lung infections in people with cystic fibrosis (CF). Pseudomonas aeruginosa, which can cause pneumonia, typically infects infants or young children and persists for life, while Burkholderia cepacia complex species only infect teenagers and adults. Although Burkholderia infections are rare, when they do take hold, they are deadly. Now, UNC School of Medicine scientists led by Peggy Cotter, PhD, Professor in the UNC Department of Microbiology and Immunology, have discovered a reason for this pathogen's apparent age discrimination. This research, published online on August 4, 2020, in Cell Host & Microbe, shows that both Pseudomonas and Burkholderia use toxic weaponry, called Type VI Secretion Systems (T6SS), to compete with and establish dominance over each other. It's possible that scientists could target, or mimic, this weaponry to defeat the bacteria before they cause irreparable harm to lungs of patients. The article is titled “Host Adaptation Predisposes Pseudomonas aeruginosa to Type VI Secretion System-Mediated Predation by the Burkholderia cepacia Complex.” Scientists have wondered for a long time why Burkholderia does not infect infants and young children. First author and former Cotter Lab graduate student Andrew Perault, MPH, PhD, designed and conducted experiments to show that Pseudomonas bacteria isolated from infants and young children use their harpoon-like T6SS to fire toxins at, and kill, competing bacteria, including Burkholderia. "This may be one of the reasons Burkholderia does not take root in young patients," Dr. Cotter said.

Capricor Reports Second Quarter 2020 Financial Results and Provides Corporate Update; Exosome Platform for COVID-19 Vaccine Containing mRNA for Four COVID-19 Proteins Among Highlights

On August 6, 2020, Capricor Therapeutics (NASDAQ: CAPR), a clinical-stage biotechnology company focused on the development of first-in-class cell and exosome-based therapeutics for the treatment and prevention of diseases, announced its financial results for the second quarter ending June 30, 2020 and provided a corporate update. “We had a very successful first half of 2020, marked by continued achievements in our expanding cell and exosome programs. We are now well underway in animal studies and have seen promising results showing the mRNA vaccine is capable of generating an antibody response to multiple antigens expressed by COVID-19. Two distinct vaccines are now in development, one using the exosomes as virus-like particles and the other using exosomes loaded with viral protein mRNAs. We are moving forward as quickly as possible with the goal of bringing a vaccine into the clinic. Additionally, we have submitted a new investigational new drug application (IND) to the FDA for a randomized, placebo-controlled, double-blind, Phase II clinical trial to treat up to 60 patients in severe or critical condition with COVID-19 with CAP-1002. Furthermore, we continue to discuss next steps in our DMD (Duchenne muscular dystrophy) program with the FDA” said Linda Marbán (photo), PhD, Capricor’s President and Chief Executive Officer. Dr. Marbán continued, “We are enthusiastic and encouraged to be engaged in the development of the next generation of potential vaccines using our proprietary exosome platform. Exosomes are intercellular communicators and are uniquely suited and have the potential to change how we treat, immunomodulate, and mediate serious life-threatening illnesses, correct genetic disorders, engineer vaccines to prevent diseases, and modify enzymes.

Tasmanian Devil Research Offers New Insights for Tackling Cancer in Humans; Gene Mutation in Devils Leads to Regression of Deadly Tumor; Similar Gene Has Been Implicated in Human Prostate & Colon Cancers

A rare, transmissible tumor has brought the iconic Tasmanian devil to the brink of extinction, but new research by scientists at Washington State University and the Fred Hutchinson Cancer Research Center in Seattle indicates hope for the animals’ survival and possibly new treatment for human cancers. The study, published online in Genetics on August 1, 2020 in Genetics (https://www.genetics.org/content/215/4/1143), found a single genetic mutation (activation of RASL11A) that leads to reduced growth of a transmissible cancer in Tasmanian devils in the wild. The article is titled "Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation." “This gene is implicated in human prostate and colon cancers,” said Andrew Storfer, PhD, Professor of Biological Sciences at WSU. “While the findings hold the most immediate promise to help save the world’s few remaining Tasmanian devils, these results could also someday translate to human health.” The research team, led by Dr. Storfer and and Mark Margres, PhD, now a postdoctoral fellow at Harvard University, studied the genomes of cases of devil facial tumor disease, or DFTD, that regressed spontaneously — that is, the cancer began disappearing on its own. They were surprised to find the mutation contributing to tumor regression doesn’t change the gene function but instead, turns on a gene that slows cell growth in the tumor. At least, it behaves that way in the lab. Current human cancer therapies focus on removing every trace of a tumor, often through toxic or debilitating treatments, said David Hockenbery, MD, a cancer biologist and Professor at Fred Hutch who contributed to the study. “If there were ways that tumors could be tricked into regressing without having to administer cytotoxic drugs or deforming surgeries, it would be a major advance,” he said.

Curious Genome of the Tuatara; Rare & Ancient New Zealand Reptile Can Live Over 100 Years; Preliminary Analysis Reveals More Anti-Aging Genes Than Found In Any Other Vertebrate

A global team of researchers has partnered up with the Māori tribe Ngātiwai to sequence the genome of the tuatara, a rare reptile endemic to New Zealand. Their work, published online on August 5, 2020 in Nature, lays the foundation for understanding the evolution of this ancient species, and can inform conservation efforts to protect it. The open-access article is titled "The Tuatara Genome Reveals Ancient Features of Amniote Evolution." The study included collaborators at the University of Otago (New Zealand) and at European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI). With its small, scaly body, pointy tail, and clawed feet, the tuatara seems to tick all the boxes to be a lizard--yet it isn't. This ancient reptile is the sole survivor of its own evolutionary branch on the tree of life, the Sphenodontia. Until now, biologists had not reached consensus on the evolutionary history of tuatara--whether they are more closely related to birds, crocodiles, and turtles, or if they stemmed from an ancestor shared with lizards and snakes. "Our research confirms that tuatara have diverged from the ancestor of lizards and snakes about 250 million years ago," says Matthieu Muffato, PhD, the Analysis Lead from Ensembl Comparative Genomics at EMBL-EBI. "This long period of independent evolution explains why we found the tuatara genome to be so unlike those of other vertebrates." "The tuatara genome is considerably bigger than the human genome, and it has a unique constitution. It contains a lot of repetitive DNA segments that are unique to the species and have no known function," explains Fergal Martin, PhD, Vertebrate Annotation Coordinator at EMBL-EBI. The sequence of the tuatara genome revealed a number of aspects of this reptile's lifestyle.

Factorial Diagnostics & IncellDx Sign Exclusive License for Novel in Situ Library Prep for Subsequent Next-Generation DNA Sequencing

On August 6, 2020, Factorial Diagnostics (https://www.factorialdx.com/) and IncellDx (https://incelldx.com/) announced that they have agreed to terms on an exclusive license and supply agreement for technology that will enable the development of their multi-omic, cancer diagnostic workflow. The San Carlos based start-up Factorial Diagnostics, is utilizing IncellDX's new reagent, IncellMax-Seq™, to perform in situ library preparation for Next-Generation Sequencing (NGS) applications. The collaboration will enable simultaneous immunophenotyping capabilities, along with unequivocal cell pre-identification. Factorial's proprietary front-end technology will be compatible with a number of cell isolation strategies, including fluorescence-activated and microfluidic cell sorting. John Wells, CEO and Co-Founder of Factorial Diagnostics, commented, "Current bulk, NGS-based cancer diagnostic tests are losing valuable phenotypic information during library prep. With this collaboration, Factorial aims to preserve that critical phenotypic information in order to increase clinical sensitivity and enable more precise therapeutic approaches." Bruce Patterson MD, CEO and Founder of IncellDx, added, "IncellDx is continuing to advance intracellular molecular biology with its unique IncellMAX-Seq™ reagent which allows access to the inside of the cell, while allowing simultaneous, unequivocal identification of the cell. IncellDx is excited to enter the sequencing space with a technology that will greatly complement our current portfolio of clinical cancer assays. Factorial Diagnostics and IncellDX have agreed to terms, but no specific terms of the agreement were disclosed. Factorial Diagnostics is a seed-stage molecular diagnostics company focused on developing high-resolution, multi-omic cancer diagnostic workflows.

SARS-CoV-2 RNA May Move Through Tiny Pore in Peculiar Intracellular Double-Membraned Replication Vesicles into Cytosol for Packaging into Complete, Infectious Virus; Pore in Double-Membraned Vesicle Revealed by Electron Tomography

By visualizing coronavirus replication in an infected host cell, researchers may have answered a long-standing question about how newly synthesized coronavirus components are able to be incorporated into fully infectious viruses. The scientists’ work uncovers a coronavirus-specific structure in cells that may be a target for much-needed antiviral strategies against this family of viruses. Coronaviruses replicate their large genomes in the host cell's cytoplasm. They do this by transforming host cell membranes into peculiar double-membrane vesicles (DMVs). Newly made viral RNA needs to be exported from these DMVs to the cytosol to be packaged into complete, infectious forms of the virus. To date, however, no openings to the cytosol have been detected in the DMV replication compartments. Here, seeking to understand how viral RNA is exported from sealed DMVs, Georg Wolff (photo), PhD Candidate, Department of Cell and Chemical Biology, Section Electron Microscopy, Leiden University Medical Center, Leiden, The Netherlands, and colleagues used electron tomography to visualize the middle stage of infection of a cell by mouse hepatitis coronavirus, used instead of SARS-CoV-2 due to biosafety constraints for in situ cryo-electron microscopy studies. They identified a coronavirus-specific crown-shaped structure--a molecular pore spanning the two DMV membranes--that likely plays a role during RNA release from the compartment. In further work using pre-fixed samples of SARS-CoV-2-infected cells, the researchers showed that the structure is also present in SARS-CoV-2-induced DMVs. The authors "surmise" that this structure may be a generic complex with a pivotal role in the coronavirus replication cycle, facilitating the export of newly synthesized viral RNA from the DMVs to the cytosol.

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