Culture

The neurotransmitter brain-derived neurotrophic factor (BDNF) acts in the muscle, so that during strength training endurance muscle fiber number is decreased. Researchers at the University of Basel's Biozentrum have more closely investigated this factor, from the group of myokines, and demonstrated that it is produced by the muscle and acts on both muscles and synapses. The results published in PNAS also provide new insights into age-related muscle atrophy.

Fitness clubs are booming: New gyms are springing up like mushrooms. More and more people are striving to build up and strengthen their muscles. But what exactly happens in the muscle during training? In their recent work, Prof. Christoph Handschin's research group at the Biozentrum, University of Basel, has more closely studied strength muscles and the myokine brain-derived neurotrophic factor (BDNF), which plays an important role in the formation of strength muscle fibers.

Handschin's team has demonstrated that this factor is produced by the muscle itself and remodels the neuromuscular synapses, the neuronal junctions between the motor neurons and muscle. BDNF not only causes the strength muscles to develop, but at the same time leads to endurance muscle fiber number decline.

BDNF acts on muscles and synapses

Generally, it is differentiated between two types of muscle, depending on the type of fibers they are made of: There are the slow-twitch fibers for endurance muscles, which are formed mainly during endurance sports. Marathon runners primarily exercise this type of muscle. A great deal less well studied is the second form of muscle consisting of fast-twitch fibers. These strength muscles gain in volume during strength training and provide particularly great muscular power.

Christoph Handschin's team has now studied the hormone-like neurotransmitter from the myokine family in the mouse model. Myokines are released by the muscle during contraction. "It is interesting that BDNF is produced by the muscle itself and not only exerts an influence on the muscle. At the same time, it affects the neuromuscular synapses, which are the junctions between the motor neurons and muscle," explains Handschin.

BDNF converts endurance muscles into strength muscles

This remodeling of the neuromuscular synapses during strength training results in the body developing more strength muscle fibers. "However, strength muscle growth occurs at the expense of the endurance fibers. More precisely, through the release of BDNF, the endurance muscles are transformed into strength muscles", clarifies Handschin. This makes BDNF a factor proven to be produced by the muscle itself and to influence the type of muscle fibers formed.

Relevance to muscle training and age-related muscle atrophy

The new knowledge gained about the myokine BDNF also provides a possible explanation for the decrease in endurance musculature seen as a result of strength training. This correlation is already being taken into account in the training plan for high performance sports. Particularly in sporting disciplines such as rowing, which are geared towards strength and endurance, the muscle remodeling must be considered.

Moreover, in a follow-up study, the research group showed that in muscle lacking BDNF the age-related decline in muscle mass and function is reduced. "We didn't expect this result", says Handschin. "It also makes the findings interesting for treatment approaches for muscle atrophy in the elderly."

The spread of pathogens like the human immunodeficiency virus (HIV) is often studied in a test tube, i.e. in two-dimensional cell cultures, even though it hardly reflects the much more complex conditions in the human body. Using innovative cell culture systems, quantitative image analysis, and computer simulations, an interdisciplinary team of scientists from Heidelberg University has now explored how HIV spreads in three-dimensional tissue-like environments. The researchers' results show that the tissue structure forces the virus to spread through direct cell-to-cell contact.

Despite over 30 years of research, many key aspects of how HIV, the causative agent of the acquired immune deficiency syndrome (AIDS) spreads are still not understood. One of these unresolved questions concerns the interactions between the virus with the environment in the human body. Traditionally it has been assumed that infected cells release viral particles which then diffuse and eventually infect other cells. But it is also possible that viral particles are directly transferred from one infected cell to the next through close contact. Until now it was unknown which of these modes of transmission prevailed in tissue. "Studies on HIV replication in the lab are mostly conducted in simple cell culture experiments in plastic dishes that do not reflect the complex architecture and heterogeneity of tissue", explains study director Prof. Dr Oliver Fackler of the Center for Integrative Infectious Disease Research (CIID) at Heidelberg University Hospital.

In their approach, the Heidelberg researchers took into account that the so-called CD4 T helper cells, the preferred cell type infected by HIV, are highly motile in their physiological environment. They used a novel cell culture system, in which a three-dimensional scaffold was generated with the help of collagen. This allowed for maintaining the cells' mobility and monitoring primary CD4 T cells infected with HIV-1 in a tissue-like environment over the course of several weeks. Using this innovative approach, the researchers measured a number of factors that characterise cell motility, virus replication, and the gradual loss of CD4 T helper cells. "This yielded a very complex set of data that was impossible to interpret without the help from scientists of other disciplines", explains Dr Andrea Imle, who worked on the project during her PhD at the CIID.

In analysing the data, the scientists who conducted the experiments collaborated with colleagues from the fields of image processing, theoretical biophysics and mathematical modelling. Together they were able to characterise the complex behaviour of cells and viruses and simulate it on the computer. This made it possible to make important predictions on the key processes that determine HIV-1 spread in these 3D cultures, which were confirmed by subsequent experimentation. "Our interdisciplinary study is a good example of how iterative cycles of experimentation and simulation can help to quantitatively analyse a complex biological process", states Prof. Dr Ulrich Schwarz of the Institute for Theoretical Physics at Heidelberg University.

The data analysis revealed that the 3D environment of the cell culture system suppresses infection with a cell-free virus while simultaneously promoting direct virus transmission from cell to cell. "Our models allowed us to integrate short single-cell microscopy films with long-term cell population measurements and thereby to estimate the minimal time span required for cell-to-cell contacts to transmit infection", explains Dr Frederik Graw of the BioQuant Centre of Heidelberg University. The researchers hope that these findings will eventually lead to new therapeutic approaches in the treatment of HIV.

The Zika virus has affected over 60 million people, mostly in South America. It has potentially devastating consequences for pregnant women and their unborn children, many of whom are born with severe microcephaly and other developmental and neurological abnormalities. There is currently no vaccine or specific treatment for the virus.

A new Tel Aviv University study uses a genetic screen to identify genes that protect cells from Zika viral infection. The research, led by Dr. Ella H. Sklan of TAU's Sackler School of Medicine, was published in the Journal of Virology on May 29. It may one day lead to the development of a treatment for the Zika virus and other infections.

The study was based on a modification of the CRISPR-Cas9 gene-editing technique. CRISPR-Cas9 is a naturally occurring bacterial genome editing system that has been adapted to gene editing in mammalian cells. The system is based on the bacterial enzyme Cas9, which can locate and modify specific locations along the human genome. A modification of this system, known as CRISPR activation, is accomplished by genetically changing Cas9 in a way that enables the expression of specific genes in their original DNA locations.

"CRISPR activation can be used to identify genes protecting against viral infection," Dr. Sklan says. "We used this adapted system to activate every gene in the genome in cultured cells. We then infected the cells with the Zika virus. While most cells die following the infection, some survived due to the over-expression of some protective genes. We then used next-generation sequencing and bioinformatic analysis to identify a number of genes that enabled survival, focusing on one of these genes called IFI6. A previous screen conducted by another research group had identified this gene with respect to its role vis-à-vis other viruses.

"IFI6 showed high levels of protection against the Zika virus both by protecting cells from infection and by preventing cell death," Dr. Sklan continues. "If its yet unknown mode of action can be mimicked, it may one day serve as the basis for the development of a novel antiviral therapy to fight the Zika virus or related infections."

Together with Dr. Nabila Jabrane-Ferrat of The French National Center for Scientific Research, Dr. Sklan moved the study of the identified genes into Zika-infected human placenta tissues, which serve as a gateway for viral transmission to the fetus. These genes were induced following infection, indicating they might play a protective role in this tissue as well.

"Our results provide a better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets," concludes Dr. Sklan. Moving forward, the researchers hope to discover the mechanism by which the IFI6 gene inhibits infection.

WEST LAFAYETTE, Ind. - Moore's law - which says the number of components that could be etched onto the surface of a silicon wafer would double every two years - has been the subject of recent debate. The quicker pace of computing advancements in the past decade have led some experts to say Moore's law, the brainchild of Intel co-founder Gordon Moore in the 1960s, no longer applies. Particularly of concern, next-generation computing devices require features smaller than 10 nanometers - driving unsustainable increases in fabrication costs.

Biology creates features at sub-10nm scales routinely, but they are often structured in ways that are not useful for applications like computing. A Purdue University group has found ways of transforming structures that occur naturally in cell membranes to create other architectures, like parallel 1nm-wide line segments, more applicable to computing.

Inspired by biological cell membranes, Purdue researchers in the Claridge Research Group have developed surfaces that act as molecular-scale blueprints for unpacking and aligning nanoscale components for next-generation computers. The secret ingredient? Water, in tiny amounts.

"Biology has an amazing tool kit for embedding chemical information in a surface," said Shelley Claridge, a recently tenured faculty member in chemistry and biomedical engineering at Purdue, who leads a group of nanomaterials researchers. "What we're finding is that these instructions can become even more powerful in nonbiological settings, where water is scarce."

In work just published in Chem, sister journal to Cell, the group has found that stripes of lipids can unpack and order flexible gold nanowires with diameters of just 2 nm, over areas corresponding to many millions of molecules in the template surface.

"The real surprise was the importance of water," Claridge said. "Your body is mostly water, so the molecules in your cell membranes depend on it to function. Even after we transform the membrane structure in a way that's very nonbiological and dry it out, these molecules can pull enough water out of dry winter air to do their job."

Their work aligns with Purdue's Giant Leaps celebration, celebrating the global advancements in sustainability as part of Purdue's 150th anniversary. Sustainability is one of the four themes of the yearlong celebration's Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.

The research team is working with the Purdue Research Foundation Office of Technology Commercialization to patent their work. They are looking for partners for continued research and to take the technology to market.

Researchers have long known that dozens of inherited diseases, called toxic proteinopathies, are caused by the build-up of specific misfolded proteins in cells. But, the molecular mechanisms responsible for this accumulation have remained a mystery -- hampering efforts to develop therapies.

Now, researchers at the Broad Institute of MIT and Harvard and Brigham and Women's Hospital (BWH), writing in the journal Cell, have discovered that some of these toxic proteinopathies may arise from a single, previously unrecognized cause: a jam at a specific step in a cellular shipping network called the secretory pathway, which delivers proteins either to the cell surface or one of the cell's protein-disposal systems.

The discovery came in a study of a rare disorder called MUC1 kidney disease (MKD), which the researchers showed stems from the harmful build-up of a misfolded version of a protein called MUC1 in kidney cells. Moreover, the researchers found that the cell's failure to remove the misfolded protein could be traced to a specific molecular step in the secretory pathway -- and, remarkably, that a compound called BRD4780 could clear the traffic jam. The compound worked in human kidney cells and kidney organoids (miniature kidneys-in-a-dish engineered from patient cells), and in an animal model of MKD. BRD4780 could be a starting point for developing new medicines for MKD and several other toxic proteinopathies, for which no treatments are currently available.

"What blew my mind is that, in the process of studying the mechanism behind MKD, we have uncovered fascinating new biology about how cells handle misfolded proteins, and these key insights may help us address several devastating diseases," said study senior author Anna Greka, an institute member and director of the Broad's Kidney Disease Initiative (KDI), an associate professor at Harvard Medical School, and a kidney specialist at BWH. "Our team is working around the clock to translate these discoveries into a new therapy we can bring to patients as quickly as possible."

TRANSPORTATION BREAKDOWN

MKD is a rare, inherited disease that leads to kidney failure. In 2013, a team led by Broad president and founding director Eric Lander and institute member and Program in Medical and Population Genetics co-director Mark Daly tracked down the genetic root of MKD (previously called medullary cystic kidney disease, or MCKD): the addition of a single letter in the gene mucin 1 (MUC1).

The mutation results in the production of a truncated, misfolded protein dubbed MUC1-fs that collects in patients' kidney cells. As MUC1-fs accumulates, kidney cells die, eventually leading to kidney failure.

To find drug-like compounds that might help clear MUC1-fs from cells, first author and postdoctoral fellow Moran Dvela-Levitt of the KDI, Greka and their colleagues turned to the Broad Drug Repurposing Hub -- a collection of more than 3,700 compounds at different stages of the drug development process, maintained by the institute's Center for the Development of Therapeutics. Their search turned up BRD4780, a compound that never made it to the clinic, cast aside when it proved to be unsuccessful as a blood pressure drug. Greka, Dvela-Levitt, and their colleagues found that BRD4780 eliminated MUC1-fs, left normal MUC1 untouched, and prevented kidney cells with the MKD mutation from dying.

When the researchers looked closely, they were surprised to find that BRD4780 does not bind to MUC1-fs. Rather, it latches onto TMED9, a so-called 'cargo receptor' that carries protein cargo along the secretory pathway.

Experiments in human kidney cells, an MKD mouse model, and patient-derived kidney organoids showed that the cargo receptor traps MUC1-fs. This keeps the misfolded protein from reaching the lysosome (an organelle whose job is to chew up unwanted proteins), causing MUC1-fs to rise to dangerous levels in kidney cells.

The researchers noted that when BRD4780 bound to TMED9, the cargo receptor released its hold on MUC1-fs, allowing the cell to degrade the misfolded protein. Knocking out the gene for TMED9 using CRISPR had the same effect.

"This is completely new biology," Greka said. "We did not know that a cargo receptor like TMED9 could block and ultimately interfere with the destruction of a misfolded protein. And the question became, is the same biology at work in other conditions caused by a build-up of misfolded proteins?"

BEYOND THE KIDNEY

More than 50 diseases are considered toxic proteinopathies, including retinitis pigmentosa (RP, an inherited form of blindness where the retina degenerates) and UMOD-associated kidney disease (UKD, another rare genetic kidney disorder). Greka and her colleagues reasoned that similar problems with the secretory pathway might be to blame in at least a few of these diseases.

In in vitro experiments, the researchers saw that BRD4780 could reduce misfolded protein levels and increase cell survival in RP and UKD cells. Greka and her colleagues estimate that drugs similar to BRD4780 might reverse roughly 20 diseases where misfolded proteins become trapped early in the secretory pathway.

"Many of these disorders may tie back to the same mechanism," Greka said. "Our next step is to develop a deeper understanding of cargo receptors, why they stop misfolded proteins from being eliminated as they should, and figure out exactly how to develop drugs to counter them."

(PHILADELPHIA) - For the past 20 years, researchers have been trying to perfect the construction of human artificial chromosomes, or HACs for short. In a paper published today in Cell, Penn researchers describe a new way to form an essential part of the artificial chromosome, called the centromere, by bypassing the biological requirements needed to form a natural one. Simply put, they biochemically delivered a protein called CENP-A directly to HAC DNA to simplify the building of a HAC in the lab.

"Our developments streamline the construction and characterization of HACs to aid in efforts to make synthetic whole human chromosomes," said Ben Black, PhD, a professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania, who has dedicated decades to understanding the process.

HACs essentially function as new mini-chromosomes carrying engineered sets of genes that are inherited alongside a cell's natural set of chromosomes. Bioengineers envision HACs performing all sorts of jobs, including delivering large proteins for gene therapy or transporting suicide genes to fight cancer.

"Think of the HACs we build now as model-sized chromosomes," said first author Glennis Logsdon, PhD, a doctoral student in Black's lab at the time of the study and now a postdoctoral fellow at the University of Washington. "By being able to build a centromere on a HAC in a more straightforward way, we are closer to scaling up to full-size chromosomes."

Inheritance of HACs from mother to daughter cells during division is key, and this speaks to the importance of the centromere--the cinched area of duplicated chromosomes responsible for holding together pairs of "sister" chromosomes created when cells divide. Without it, whole chromosomes can be lost during cell division.

For cell replication to occur, human centromeres are not simply coded by a DNA sequence, unlike baker's yeast long used synthetic chromosome research. For example, mammals depend on the CENP-A protein to specify centromere location on chromosomes for precise cell division.

Prior attempts to form HAC centromeres in test tubes only happened rarely when they "encountered" CENP-A, and this unlikely event only occurred at highly repetitive DNA sequences on the HAC genome. "Highly repetitive DNA, however, is the scourge of molecular biologists because it is the most difficult to work with using the approaches we have now, which are designed for non-repetitive DNA," Black said.

Black's team bypassed the repetitive DNA altogether by delivering CENP-A directly to the HAC DNA. Their work-around involves "forcing" CENP-A to associate with non-repetitive DNA sequences to form a new centromere for the HAC.

"We've taken our centromere bypass method to make a fully functional HAC without the cloning nightmares that repetitive centromere DNA has presented to mammalian chromosome engineers through the last two decades," Black said. "Building on our success, we and others in the synthetic chromosome field will now have a real chance to attain what has only been achieved so far in yeast cells."

One of the next steps for this area of synthetic biology will be to link the Black lab's centromere to sets of genes that others have designed. This step-by-step construction project is the goal of the Human Genome Project-Write, a collaboration to build that life-size synthetic chromosome. The Penn team's contribution will help speed creating useful research and clinical tools based on synthetic chromosomes.

Bottom Line: This research letter reports on the association of BRCA2 gene mutations and potential risk for pediatric or adolescent lymphoma. The study used whole-genome sequencing data for 1,380 survivors of pediatric or adolescent lymphoma (815 survivors of Hodgkin lymphoma and 565 survivors of non-Hodgkin lymphoma), of which 13 survivors had BRCA2 mutations (five survivors of Hodgkin lymphoma and eight survivors of non-Hodgkin lymphoma). Compared with individuals without cancer, there was a statistically significant association between BRCA2 mutations and risk of non-Hodgkin lymphoma but not Hodgkin lymphoma. The findings support including childhood non-Hodgkin lymphoma in the spectrum of cancers associated with BRCA2 mutations.

Authors: Zhaoming Wang, Ph.D., St. Jude Children's Research Hospital, Memphis, Tennessee, and coauthors

(doi:10.1001/jamaoncol.2019.2203)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Researchers led by Pierre Vanderhaeghen and Jérôme Bonnefont (VIB-KU Leuven and ULB) have unraveled a new mechanism controlling the switch between growth and differentiation of neural stem cells during brain development. They discovered a specific factor that makes stem cells 'deaf' to proliferative signals, which in turn causes them to differentiate into neurons and shape the marvelous complexity of our brain. The findings, published in this week's edition of Neuron, shed new light on our understanding of brain developmental processes and have important implications for stem cell biology.

The brain is an incredibly complex organ consisting of billions of cells with a diverse range of functions. The mechanisms that orchestrate the formation of this intricate network during development have kept neuroscientists awake for decades.

One such neuroscientist is Prof. Pierre Vanderhaeghen (VIB-KU Leuven) whose team studies the development of the brain cortex, the outer layer of neuronal tissue that contributes in an essential way to who we are, as a species and as individuals.

"During neural development, a complex cocktail of signals determines the fate of neuronal progenitor cells," explains Vanderhaeghen. "These stem cells receive many different 'proliferative' signals that instruct them to keep on dividing, generating more and more cells for the growing brain, but at some point they also need to stop doing this and differentiate. In other words, they need to specialize to become a specific type of brain cell."

Turning deaf at the right time to mature into a nerve cell

Vanderhaeghen's team set out to understand how this switch between growth and differentiation is regulated and identified a molecular factor, called Bcl6, that essentially makes progenitor cells "deaf" for the proliferative signals that tell them to keep on dividing, thereby ensuring that differentiation occurs efficiently.

Jérôme Bonnefont, a postdoctoral researcher in Vanderhaeghen's lab, explains: "We used an extensive set of genomic and cellular tools and found that a protein called Bcl6 acts as a global repressor of a repertoire of signaling components and pathways that are known to promote self-renewal. Since Bcl6 is expressed only in specific subsets of progenitors and neurons during brain development, it allows for the precise fine-tuning of brain developmental processes."

Fate transition, stem cells, and cancer

Vanderhaeghen is enthusiastic about the findings: "These results provide important insight into the molecular logic of so-called neurogenic conversion. Thanks to this ingenious switch, differentiation can occur in a robust way despite the presence of many, and sometimes even contradictory, extrinsic cues."

"We made this discovery focusing on neural stem cells, but I would predict that similar factors act in many stem cells in the embryo and even in adults to ensure proper differentiation," he continues. "This may be also important in the context of cancer biology, since stem cells and cancer cells usually respond to the same proliferative cues that are precisely inhibited by Bcl6."

Future work should determine whether and how other repressors in other parts of the nervous system and body can modulate responsiveness to extrinsic cues in a similar way. This will teach us more about differentiation, not only during development, but also beyond in the adult brain and in cancer cells.

What The Study Did: This observational study examined at what point an increasing number of operations to remove the thyroid performed annually by a surgeon is associated with a lower rate of complications among patients.

Authors: Charles Meltzer, M.D., of the Permanente Medical Group in Santa Rosa, California, is the corresponding author.

(doi:10.1001/jamaoto.2019.1752)

Editor's Note:  Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

A report from St. Jude Children's Research Hospital links inherited mutations in the BRCA2 gene with an increased risk of developing non-Hodgkin lymphoma in children and adolescents. The work appears as an advance online publication today in JAMA Oncology.

"The BRCA family of genes are known to be linked to risk for breast and ovarian cancer as well as several other types of adult onset cancers, but our study shows a relationship between BRCA2 and non-Hodgkin lymphoma diagnosed in childhood," said corresponding author Zhaoming Wang, Ph.D., associate member of the St. Jude Departments of Epidemiology and Cancer Control and Computational Biology. "This is the second time an inherited BRCA2 mutation has been associated with an increased risk of any primary pediatric or adolescent cancer. BRCA2 recently emerged as an important predisposition gene for childhood-onset medulloblastoma."

This investigation draws on whole genome sequencing data gathered through the St. Jude Lifetime Cohort (SJLIFE) study and the Childhood Cancer Survivors Study. The purpose of these efforts is to learn about the health of adult survivors of childhood cancer and to reduce the late effects of childhood cancer treatments. Wang and his colleagues investigated 1,380 lymphoma survivors, which included individuals with both Hodgkin and non-Hodgkin lymphoma subtypes. The link between inherited BRCA2 mutations was found predominantly with the non-Hodgkin lymphoma subtype.

Survivorship studies have indicated that childhood cancer survivors have a greater risk of secondary cancers later in life than the general public. Additionally, research has shown that when mutations to genes in the BRCA family are inherited this can put those individuals carrying the mutations at a greater risk of certain cancers. By linking inherited BRCA2 mutations and childhood cancer, this study expands what is known about inherited cancer risk for a new patient population.

"The more we know about the biology that drives a particular cancer, the more a patient's care can be precisely tailored," said co-senior author Leslie Robison, Ph.D., chair of the St. Jude Department of Epidemiology and Cancer Control. "This includes cancer prevention and cancer screening, where an understanding of inherited mutations can help us put in place strategies to care for that patient and family long-term."

The researchers also observed that members of the cohort who had inherited BRCA2 mutations and were survivors of childhood non-Hodgkin lymphoma were all men. Further research is needed to understand the finding.

"Understanding inherited risk helps childhood cancer survivors and it enables conversations among relatives who can then make decisions about their own health management strategies," said co-senior author Kim Nichols, M.D., director of the St. Jude Cancer Predisposition Division.

LEXINGTON, Ky (July 25, 2019) -- A team of scientists have designed and tested in mice a novel and promising therapeutic strategy for treating Lafora Disease (LD), a fatal form of childhood epilepsy. This new type of drug - called an antibody-enzyme fusion or AEF -- is a first-in-class therapy for LD and an example of precision medicine that has potential for treating other types of aggregate-based neurological diseases.

LD is an inherited epilepsy and neurodegenerative disorder caused by intracellular carbohydrate aggregates in the brain. LD patients develop normally until the teen years when seizures begin. Epileptic episodes become increasingly severe and more frequent, followed by rapid cognitive decline and a vegetative state. LD patients typically die within 10 years of diagnosis.

"LD is devastating for patients and their families, and currently there are no effective treatments," said Dr. Matthew Gentry of the University of Kentucky College of Medicine and a lead scientist on the study. "We've been working to define exactly what causes the disease and to develop effective therapies."

It is now understood that LD is caused by toxic carbohydrate aggregates called Lafora bodies. Structurally, the aggregates resemble plant starch, the major source of carbohydrates in the human diet.

"Amylase is an enzyme that our bodies naturally secrete in saliva and in the gut to break down the starch in our food," Gentry said. "A study from the 1970s suggested that amylase could also degrade Lafora bodies. However, we needed a way to get the amylase into brain cells, where the Lafora bodies are found."

The Gentry laboratory collaborated with Valerion Therapeutics, a clinical-stage biotechnology company with a novel antibody-based delivery platform capable of carrying active biotherapeutics into cells.

"We fused human amylase to our proprietary antibody fragment for intracellular delivery of enzyme into cells of mice genetically engineered to develop LD," said Dr. Dustin Armstrong, Valerion's Chief Scientific Officer.

This antibody-amylase fusion, called VAL-0417, virtually eliminated the Lafora bodies in LD mouse brains and other tissues.

"A seven-day continuous infusion of VAL-0417 directly into the brain restored normal brain metabolism in the LD mice, suggesting VAL-0417 could reverse the disease in humans," said Gentry. "I've been working to define the basic mechanisms of LD for nearly 15 years and it's truly amazing to see this science translated into a potential therapeutic."

Epilepsy is a heterogeneous condition with multiple genetic, environmental, and sporadic causes that affects 50 million people worldwide. One-third of these patients have drug-resistant seizures, demonstrating an urgent need for personalized therapeutic strategies.

Dr. Kathryn Brewer, also of the UK College of Medicine and co-investigator on the study, noted that the study results have potential treatment applications beyond this ultra-rare disease.

"Lafora Disease belongs to a family of human diseases called glycogen storage disease," she said. "GSDs are caused by mutations in genes that result in glycogen mis-regulation and cause pathogenic consequences in various tissues, and the Valerion technology is a promising drug platform to treat a range of GSDs."

The study was published in the July 25th edition of Cell Metabolism.

A research team led by experts at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center reports favorable five-year survival rates from the first multidose clinical trial of the immunotherapy drug nivolumab (anti-PD-1) as a treatment for patients whose previous therapies failed to stem their advanced melanoma, renal cell carcinoma (RCC) or non-small-cell lung cancer (NSCLC). The study, which followed 270 adult men and women, reports survival rates substantially higher than what was expected from cancer therapies available in 2008 at the start of the clinical trial, including chemotherapies, kinase inhibitors, biologic therapies, antiangiogenic therapies, biologic therapies and other clinical trials.

With conventional systemic treatments given for patients with stage IV cancers, three-year survival for advanced melanoma was approximately 5%, and the five-year survival rate for NSCLC was 6% at the time the current trial commenced.

By comparison, the results with nivolumab, reported July 25 in JAMA Oncology, show higher than expected rates of five-year survival: 34.2% for melanoma, 27.7% for RCC and 15.6% for NSCLC. Furthermore, in this study, which provides the longest available follow-up on patients with several types of cancer receiving a PD-1 pathway inhibitor, responses were durable.

The new study provides much-needed data on long-term clinical outcomes associated with nivolumab, a drug that blocks the activity of a molecule called PD-1, removing restraints on cancer-killing T cells, says Suzanne Topalian, M.D., professor of surgery, associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy and the lead author of the study report.

Topalian says the research team has also identified some clinical and laboratory features in these patients associated with five-year outcomes.

PD-1 on immune cells interacts with the molecule PD-L1 expressed by tumor cells. Cancer cells use this inhibitory interaction to essentially "hide" from the body's immune attack. Nivolumab (anti-PD-1) and other drugs in its class make the tumor cells visible again, restoring the immune system's ability to recognize and kill cancer cells. Much of the science behind anti-PD-1 drugs such as nivolumab (marketed as Opdivo) and pembrolizumab (marketed as Keytruda) was developed by Bloomberg~Kimmel Institute researchers, Topalian notes. The Food and Drug Administration approves both drugs to treat multiple cancer types, sometimes in combination with other therapies or after other therapies fail.

The five-year survival study included 270 patients with advanced melanoma, renal cell carcinoma or non-small-cell lung cancer enrolled at 13 U.S. medical centers, including the Johns Hopkins Kimmel Cancer Center, beginning in 2008 in a phase 1 clinical trial of nivolumab. Patients received different doses of the drug (between 0.1 to 10.0 mg/kg) intravenously in the outpatient clinic every two weeks in eight-week cycles for up to two years.

The patients were previously treated for their advanced cancers--meaning cancers that had spread beyond the reach of surgery and persisted--with 40.4% entering the nivolumab trial having undergone three or more prior systemic therapies. "While all patients had been treated previously, the number of prior treatments did not make a statistical difference in terms of five-year survival in this study," says Topalian.

The study found that patients with larger tumor burdens, or cancers that had spread to the bone or liver, were significantly less likely to survive for five years after starting nivolumab treatment. Furthermore, patients with low immune cell (lymphocyte) counts in their blood at the time nivolumab treatment began were significantly less likely to benefit--certain chemotherapies that patients might have received before entering the trial could have lowered their lymphocyte counts.

However, "patients who entered the trial without any cancer-related symptoms were significantly more likely to survive for five years, compared to those who were experiencing symptoms," Topalian says.

"These findings should help guide patients and their doctors as they consider nivolumab therapy," says lung cancer expert Julie Brahmer, M.D., professor of oncology and co-director of the upper aerodigestive program at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the clinical trial's principal investigator. Since the drug's safety was established, she says, it has moved from treating patients who have already received multiple lines of therapy to patients who had only one prior therapy, or even patients who could receive this as first-line systemic therapy for metastatic disease.

In addition, Topalian, Brahmer and colleagues reported in 2018 in The New England Journal of Medicine favorable responses when nivolumab was given before a first surgery for high-risk NSCLC, an approach known as neoadjuvant therapy. "I think we will see an accelerating pace of this kind of research, pushing the earlier use of these drugs," says Topalian.

A notable feature uncovered in the five-year survival study, Topalian says, is that overall survival time was significantly longer among patients who experienced sided effects related to nivolumab, compared to those who experienced no side effects. The midpoint duration of survival was 19.8 months for those with any adverse events and 20.3 months for those with severe adverse events, compared to 5.8 months for those who did not experience any adverse events.

About 10% to 20% of patients experience serious adverse events after taking nivolumab, including inflammatory reactions in the lung or intestines. The most common side effects of nivolumab are fatigue and rash. In most cases, side effects from immunotherapy can be clinically managed to prevent them from becoming life threatening.

Topalian says her team of investigators, and other teams, continue to explore the specific reasons why adverse events appear to be markers of long-term survival in patients taking nivolumab.

"Nivolumab activates immune responses. Although we would like those responses to be directed only at cancer cells, in some cases there is a spillover effect and we encounter immune responses against normal tissues," she says. "Based on the findings in this study, we can reassure our patients that if they develop these side effects, it may very well put them in a better response and long-term effect category. The real issue is whether we can devise treatments to manage these side effects that will not interfere at all with the anti-tumor immune response."

The large, error-correcting quantum computers envisioned today could be decades away, yet experts are vigorously trying to come up with ways to use existing and near-term quantum processors to solve useful problems despite limitations due to errors or "noise."

A key envisioned use is simulating molecular properties. In the long run, this can lead to advances in materials improvement and drug discovery. But not with noisy calculations confusing the results.

Now, a team of Virginia Tech chemistry and physics researchers have advanced quantum simulation by devising an algorithm that can more efficiently calculate the properties of molecules on a noisy quantum computer. Virginia Tech College of Science faculty members Ed Barnes, Sophia Economou, and Nick Mayhall recently published a paper in Nature Communications detailing the advancement.

Quantum computers are expected to be able to carry out certain kinds of calculations far more efficiently than the "classical" computers in use today. They are similar to classical computers, however, in that they run algorithms by applying sequences of logic gates -- in this case, "quantum gates," which together form quantum circuits -- to bits of information. For today's noisy quantum computers, the problem has been that so much noise would accumulate within a circuit that the computation would degrade and render any subsequent calculations inaccurate. Scientists have had difficulty designing circuits that are both shorter and more accurate.

The Virginia Tech team addressed this issue by developing a method that grows the circuit in an iterative way. "We start with a minimal circuit, then grow it as we add on logic gate after logic gate in short circuits until the computer finds the solution," said Mayhall, an assistant professor in the Department of Chemistry.

A second major benefit of the algorithm is that Barnes, Economou, and Mayhall designed it to adapt itself based upon the molecular system being simulated. Different molecules will dictate their own circuits, uniquely tailored to them.

The interdisciplinary collaboration between Virginia Tech's departments of Chemistry and Physics -- Barnes, Economou, and Mayhall and a team of graduate students and postdocs from both departments -- have received grants from the National Science Foundation and the U.S. Department of Energy totaling more than $2.8 million.

Virginia Tech and IBM recently established a partnership that gives the researchers access to IBM's quantum computing hardware. "Our team at Virginia Tech is really excited for the next steps in our work," said Economou, an associate professor in the Department of Physics, "which include implementing our algorithm on IBM's processors."

A mutant worm with a change in one mitochondrial gene produces more reactive oxygen species (ROS), which can be harmful to cells by causing oxidative stress. However, this mutant worm is able to live twice as long as the wild type. Professor Dr. Aleksandra Trifunovic and her team at the CECAD Cluster of Excellence in Aging Research at the University of Cologne showed for the first time that this longevity is driven by a detoxification pathway, directly regulated by the level of ROS. What makes these results more compelling is that this pathway, which is necessary for the cells to get rid of unwanted unnatural substances, is conserved throughout the animal kingdom and important, for example, in the liver for the drug metabolism. The study 'KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants' was now published in the journal Nature Communications.

Mitochondria are the powerhouses of the cells. They produce energy using oxygen during a process called respiration. The side effect of this process is the occurrence of reactive oxygen species or ROS, which are always a by-product of respiration. During aging, mitochondria go through wear and tear, reducing their capability to keep ROS production under control. Some scientists even believe that aging is a consequence of damage inflicted by ROS. Indeed, as we age, more ROS and other toxic metabolites are produced.

Detoxification pathways remove toxic metabolites in three steps. In the first phase, the metabolites are recognized and modified, so that they can be neutralized during the second phase, and eliminated from the cell during the third phase. The whole machinery to keep the degradation going is extremely energy-consuming and it is kept under tight transcriptional control. Usually it is only turned on when needed.

Dr Marija Herholz, the leading scientist of the recent study, showed that one transcription factor plays an important role: 'When we deleted KLF-1, the mutant lost its longevity and returned to a normal lifespan, while at the same time the detox pathway was shut off. This shows that KLF-1 keeps the pathway working and is important for the longevity of the organism.' But the longer life of the mutants has some downsides too: 'We could see that the mutants move slower and develop slower, since they make less energy and have to support the complex detox machinery running,' Herholz added.

So far, ROS were mostly seen as something bad, disturbing the cells. Newer research shows that ROS plays an important role as a signalling molecule. Within the study the researchers could show that higher levels of antioxidants given to the worms lead to a decreased lifespan by removing ROS and therefore blocking the signalling pathway. 'The public perception of ROS in a solely negative way is therefore not backed by scientific findings,' said Marija Herholz. 'Indeed, if the levels of antioxidants are too high, this might be harmful, as our study shows.'

In following studies, the researchers want to have a closer look at what exactly happens on the molecular level before and after activation of the signalling pathway.

Future wireless data networks will have to reach higher transmission rates and shorter delays, while supplying an increasing number of end devices. For this purpose, network structures consisting of many small radio cells will be required. To connect these cells, high-performance transmission lines at high frequencies up to the terahertz range will be needed. Moreover, seamless connection to glass fiber networks must be ensured, if possible. Researchers of Karlsruhe Institute of Technology (KIT) use ultra-rapid electro-optical modulators to convert terahertz data signals into optical signals. This is reported in Nature Photonics (DOI: 10.1038/s41566-019-0475-6).

While the new 5G cellular network technology is still tested, researchers are already working on technologies for the next generation of wireless data transmission. "6G" is to reach far higher transmission rates, shorter delays, and an increased device density, with artificial intelligence being integrated. On the way towards the sixth generation cellular network, many challenges have to be mastered regarding both individual components and their interaction. Future wireless networks will consist of a number of small radio cells to quickly and efficiently transmit large data volumes. These cells will be connected by transmission lines, which can handle tens or even hundreds of gigabits per second per link. The necessary frequencies are in the terahertz range, i.e. between microwaves and infrared radiation in the electromagnetic spectrum. In addition, wireless transmission paths have to be seamlessly connected to glass fiber networks. In this way, the advantages of both technologies, i.e. high capacity and reliability as well as mobility and flexibility, will be combined.

Scientists of the KIT Institutes of Photonics and Quantum Electronics (IPQ), Microstructure Technology (IMT), and Radio Frequency Engineering and Electronics (IHE) and the Fraunhofer Institute for Applied Solid State Physics IAF, Freiburg, have now developed a promising approach to converting data streams between the terahertz and optical domains. As reported in Nature Photonics, they use ultra-rapid electro-optical modulators to directly convert a terahertz data signal into an optical signal and to directly couple the receiver antenna to a glass fiber. In their experiment, the scientists selected a carrier frequency of about 0.29 THz and reached a transmission rate of 50 Gbit/s. "The modulator is based on a plasmonic nanostructure and has a bandwidth of more than 0.36 THz," says Professor Christian Koos, Head of IPQ and Member of the Board of Directors of IMT. "Our results reveal the great potential of nanophotonic components for ultra-rapid signal processing." The concept demonstrated by the researchers will considerably reduce technical complexity of future radio base stations and enable terahertz connections with very high data rates - several hundred gigabits per second are feasible.

Figure:

Seamless integration of wireless links into fiber-optical networks is the key to high-performance data networks: future cellular networks will consist of many small radio cells that can be connected flexibly by high-performance THz transmission links. At the receiver, THz signals can be converted directly into optical signals with the help of ultra-rapid plasmonic modulators and transmitted via glass fiber networks.