A Spicy Finding

Extracts of the plant turmeric — the spice that gives Indian curries a yellow color — have been used as an anti-inflammatory treatment in traditional Asian medicine for centuries. Clinical trials of curcumin (the active chemical compound in turmeric), however, have produced mixed results. A molecular understanding of curcumin’s biological effects is needed.

Claus Schneider, PhD, and colleagues have now discovered that curcumin is a “pro-drug” that is converted into reactive metabolites with anti-inflammatory activities. The metabolites of curcumin, produced by oxidation reactions, covalently bind to and inhibit proteins in the inflammatory NF-kappa-B signaling pathway.

The researchers found that curcumin undergoes oxidation reactions readily in vitro. They suggest that insufficient bioactivation in vivo may explain the mixed results in human studies of curcumin activity.

The findings, reported in the Journal of Biological Chemistry, suggest that metabolic bioactivation should be considered in clinical trials of curcumin and other dietary polyphenols of medicinal interest, such as resveratrol (red wine), quercetin (onions) and epigallocatechin gallate (green tea).

This research was supported in part by the National Institutes of Health (grant AT006896) and in part by pilot awards from the Vanderbilt Institute of Chemical Biology and the National Cancer Institute SPORE in GI Cancer (grant CA095103).

Source : Vanderbilt University

UNIST Researchers Introduce Novel Catalyst for Rechargeable Metal-Air Batteries

Research in lithium-ion batteries has opened up a plethora of possibilities in the development of next-generation batteries. In particular, the metal-air batteries with significantly greater energy density close to that of gasoline per kilogram, has recently been acknowledged and invested by world’s leading companies, like IBM.

A recent study, affiliated with UNIST has presented novel catalyst to accelerate the commercialization of metal-air batteries. This breakthrough has been jointly led by Professor Guntae Kim and Professor Jaephil Cho in the School of Energy and Chemical Engineering at UNIST in collaboration with Professor Yunfei Bu from Nanjing University of Science and Technology, Nanjing, China. Their new catalyst possesses the structure of nanofiber-based perovskite materials and exhibits excellent electrochemical performance, close that of today’s precious metal catalysts, yet still inexpensive.

metal air battery
Mesoporous nanofiber of cation ordered perovskite was prepared via electrospinning process, which exhibited notable cell performance and exceptionally high stability for Zn-air battery.

A metal-air battery is a type of fuel cell or battery that uses the oxidation of a metal with oxygen from atmospheric air to produce electricity. It is equipped with an anode made up of pure metals—like lithium or zinc—and an air cathode that is connected to an inexhaustible source of air. The catalysts in the air cathode aids the electrochemical reaction of the cell with oxygen gas. Metal-air batteries have attracted significant research attention as the new generation of high-performance batteries as they the advantages of (1) simple structure, (2) extremely high energy density, and (3) a relatively inexpensive production.

The currently existing metal-air batteries use rare and expensive metal catalysts for their air electrodes, such as platinum (Pt) and iridium oxide (IrO₂). This has hindered its further commercialization into the marketplace.

In the study, Professor Kim and his research team have developed a new catalyst, using the cation ordered double perovskite with high electrical conductivity and catalyic performance. They prepared a series of PrBa0.5Sr0.5Co2-xUS”>FexUS”>O5+δ (x = 0, 0.5, 1, 1.5, and 2, PBSCF) and determined the optimum cobalt (Co) and iron (Fe) contents through electrochemical evaluation.

metal air battery
OER activities of PBSCF-NF, PBSCF-P, BSCF and IrO2.

“The structure of mesoporous PrBa0.5Sr0.5Co2-xFexO5+δ nanofiber (PBSCF-NF) has high surface areas, result from uniform pore diameters,” says Ohhun Gwon in the Combined M.S/Ph.D. of Energy and Chemical Engineering, the first author of the study. “This nanofiber has also brought significant improvements in the performance of the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER).”

According to the research team, this nanofiber has improved the bi-functionality of ORR/OER. Particularly, the OER performance was about 9 times higher than that of state-of-the-art precious metal oxide IrO2 at overpotential of 0.3 V. Furthermore, it also demonstrated notable charge-discharge stability even at high current density in Zn-air batteries.

“We envision that the high electrochemical and catalytic performance of this material will play a major role in the commercialization of metal-air batteries,” says Professor Kim. “Metal-air battery technology is still in its infancy and extensive additional research efforts appear to be required before a viable commercial implementation is developed.”

He adds, “However, as many global corporates, such as IBM, Toyota, and Samsung Electronics are already working on the development of metal-air batteries, the technical challenges could soon be cleared out in a much faster pace than anticipated.”

The findings of the research have been published online in the October issue of the prestigious journal ACS Nano. This study has been supported by the Mid-Career Researcher Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning and 2017 Research Fund of UNIST.

Source : UNIST

U-M Startup Marks Milestone in Drug Therapy for Boys with Duchenne Muscular Dystrophy

Two boys under treatment outside the United States for Duchenne muscular dystrophy—an X-linked disease that affects only boys and young men—met key milestones while on Carmeseal-MD, a drug developed by a University of Michigan startup.

Phrixus Pharmaceuticals Inc. is working with Ethicor Pharma Ltd., its licensor, to commercialize the drug outside the U.S. with plans to begin the first trial of Carmeseal-MD at Cincinnati Children‘s Hospital in the first quarter 2018.

The drug’s active ingredient, P-188 NF, was developed by Joseph Metzger while a professor of molecular and integrative physiology at U-M. Metzger, now chair of the Department of Integrative Biology and Physiology at the University of Minnesota, has shown that P-188 NF could boost the blood-pumping capacity of damaged hearts by binding to the damaged regions of cell membranes.

When P-188 NF, which Metzger and his colleagues called a “molecular band-aid,” is infused into the bloodstream, it finds and attaches to microscopic instabilities and tears in the heart muscle. This can prevent the damaging pathological leakage of calcium into the heart cells and improve the heart’s ability to provide sufficient oxygen to the vital organs.

The drug is being prescribed to boys and young men outside the U.S. who have both respiratory and cardiac disease. The longest treatment so far has been for 15 months without apparent adverse events, but with significant reductions in biomarkers of damage to skeletal and heart muscle.

“It’s a progressive and lethal disease,” said Thomas A. Collet, president and CEO of Phrixus. “This is one of the most prevalent of the rare diseases and no treatment is fully approved for the numerous negative consequences of the disease.”

Duchenne muscular dystrophy affects roughly 15,000 to 20,000 boys in the U.S. and Europe each year. The disease becomes apparent from age 2 to 7. It first affects muscles in the arms and legs before progressing to the diaphragm, the main muscle that controls breathing, and then the heart.

“By the time they are 12 to 14, they become non-ambulatory and often die by their mid-20s,” Collet said. “These parents are told that not much can be done.”

Unlike many other drugs that focus on extending the time that the boys can walk, Carmeseal-MD works to delay damage to the diaphragm and heart muscles.

“This is the only drug that has the potential to treat both cardiac and respiratory dysfunction, the two leading causes of death,” Collet said.

If the treatment shows promise, Phrixus plans to make it widely available as an unlicensed special in Europe while pursuing FDA approval in the U.S.

Source : University of Michigan

Inflammation Required for “Smell” Tissue Regeneration

In a mouse study designed to understand how chronic inflammation in sinusitis damages the sense of smell, scientists at Johns Hopkins say they were surprised to learn that the regeneration of olfactory tissue requires some of the same inflammatory processes and chemicals that create injury and loss of smell in the first place.

In a report on their findings, published in the August 8 issue of Proceedings of the National Academy of Sciences, the researchers say their work adds to scientific understanding of the way olfactory tissue recovers from damage triggered by viruses, toxic chemicals and gases, or allergens.

“The kind of inflammation associated with immune system reactions to fight infection or injury appears to be part of a single system linked to tissue regeneration, so that normal healing of the olfactory system can’t happen without it,” says Andrew Lane, M.D., professor of otolaryngology–head and neck surgery at the Johns Hopkins University School of Medicine. “But more isn’t always better, and continued inflammation will eventually have the opposite effect of killing olfactory neurons and inhibiting their regeneration, resulting in the loss of smell.”

Lane frequently sees patients with chronic sinusitis who’ve lost their sense of smell over time, and this has long been presumed to be due to the permanent destruction of olfactory tissue by inflammation and replacement with scar tissue. However, treating patients with oral steroids that suppress the immune system can bring back the sense of smell temporarily, suggesting that the olfactory tissue is still present in the nose, but that chronic inflammation plays a role in repressing its function. The researchers say that how this might occur has been a mystery.

In the process of testing inflammation’s role in damaging olfactory tissue, researchers gave a chemical, methimazole, to mice that directly damages their olfactory tissue, waited a day, then treated them with a steroid injection. They then biopsied the tissue to measure how many new olfactory basal stem cells were growing and dividing (healing), using BrdU as a marker of replicating DNA. Compared to mice not given the steroids, mice given steroids had 45 percent fewer stem cells proliferating to replace the damaged ones in the tissue, suggesting that suppressing inflammation slowed olfactory stem cell regeneration.

Intrigued by this finding, the researchers then looked at levels of genes likely responsible for inflammation’s effects on the olfactory stem cells of the mice given steroids versus those not treated. In mice not treated with steroids, they found double the gene product levels of the inflammatory molecules TNF-a and IL-1?. In the mice given steroids, they also detected the inflammatory messenger NF-kB in olfactory stem cells.

“Not only is the presence of NF-kB in olfactory stem cells unexpected,” says Lane, “but the fact it gets turned on by inflammation shows communication occurring between the immune system and the olfactory system to initiate healing.”

Since steroids can have other effects on tissue other than repressing inflammation, the researchers decided to use specifically bred mice that lacked inflammatory molecules. They used mice bred without the receptor that detects TNF-a, and they used mice that didn’t have the gene for NF-kB in the olfactory stem cells. In both sets of mice, they damaged the olfactory tissue and observed the number of newly dividing stem cells in the tissue after two or three days. In both types of mice, the researchers measured greater than 50 percent fewer newly regenerating cells than normal mice with damaged olfactory tissue. The researchers say this demonstrates on a molecular level how the immune system can talk to olfactory stem cells to begin the healing process after injury.

“The sense of smell is often underappreciated,” says Lane. “People without a sense of smell have a greatly reduced quality of life, which may be accompanied by depression. They can’t enjoy food because the sense of smell is necessary to appreciate flavors, and they can’t sense dangerous or offensive odors.”

Lane wants to figure out how to better trigger healing in the olfactory tissue so that sinusitis patients can regain their sense of smell more permanently without needing to take steroid pills. He also has plans to investigate drugs that will block inflammation in the olfactory tissue that becomes overactive in sinusitis.

An estimated 29 million people in the U.S. have chronic sinusitis, according to the U.S. Centers for Disease Control and Prevention, and about two million people in the U.S. have lost their sense of smell.

Other authors include Mengfei Chen and Randall Reed of Johns Hopkins University.

The study was funded by grants from the National Institute on Deafness and Other Communication Disorders (R01 DC009026 and 5R56 DC008295) and the National Natural Science Foundation of China.

Source : The Johns Hopkins University

TowerJazz and UC San Diego Demonstrate Best in Class 5G Mobile Transmit-Receive Chips with Greater than 12 Gbps Data Rates

TowerJazz, the global specialty foundry leader, and the University of California San Diego, a recognized leader for microwave, millimeter-wave, mixed-signal RFICs, and phased arrays, demonstrate for the first time a greater than 12 Gbps, 5G phased-array chip set.  This chip set demonstrates that products can be fabricated today to meet the emerging 5G telecommunications standards for the next wave of worldwide mobile communications. The chipset operates at 28 to 31 GHz, a new communications band planned for release by the FCC. The chip set uses TowerJazz’s high volume SiGe BiCMOS technology, with record performance at 28 GHz, representing a more than tenfold improvement in data rate vs. 4G LTE, and today meets many other technical specification requirements of the emerging 5G standard.

The 5G transmit and receive chipsets achieved more than 12 Gbps data rates at 30 meters separation, and greater than 3 Gbps when separated by 300 meters, using two polarizations.  The UC San Diego chip utilizes 16-64-256 QAM (quadrature amplitude modulation) schemes to achieve these data rates.  The measured EVM (error vector magnitude), a figure of merit used to determine the quality of the data received, suggests both chip sets are already performing at 4G LTE levels.  The 64-QAM link reported today at 12 Gbps, has a less than 5 percent EVM at 30 meters.  The 16 QAM link at 3 Gbps has a less than 12 percent EVM at 300 meters and over all scan angles, and all with no FEC or equalization. The system operates in a dual-polarization mode.  In addition, the 4 x 8 (32-element) phased-arrays use SiGe core chips and are assembled on a multi-layer printed circuit board together with the antennas.  Record figures of merit such as NF (Noise Figure), EIRP (Equivalent Isotropically Radiated Power), and EVM have been demonstrated.

“The TowerJazz H3 platform is truly great, and allows for 13-20 dBm transmit power per element with high PAE (power-added efficiency) of 20 percent at 28 GHz. Also, it offers very low noise transistors resulting in an LNA NF (low noise amplifier noise figure) of 2.4 dB at 28 GHz, high-Q inductors and low-loss transmission-lines for on-chip power distribution,” said Gabriel Rebeiz, distinguished professor and wireless communications industry chair at the UC San Diego Jacobs School of Engineering, and member of the U.S. National Academy of Engineering..

By using TowerJazz’s SiGe BiCMOS technology, UC San Diego’s design team, led by graduate student Kerim Kibaroglu and postdoctoral fellow Mustafa Sayginer, and with the use of state-of-the-art Keysight equipment such as the 8195A Arbitrary Wave Generator, the DSOS804A Digital Scope and the Signal Studio suite with the VSA software, was able to achieve record links at 30 to 300 meters over all scan angles. “We thank TowerJazz for this wonderful process and look forward to continued collaboration,” Rebeiz said.

Today, peak wireless data rates for 4G LTE can be up to 1 Gbps, but are nominally lower around 100 to 300 Mbps.  Here, TowerJazz has demonstrated more than ten times those speeds using UC San Diego’s 5G next-generation mobile designs made with its high volume H3 technology.

”We continue to release additional technology nodes, for example our H5 and H6, which have even lower noise devices and higher speed capabilities.  These technologies will enable 5G designers to further increase data rates through higher QAM modulation schemes, or shrink chip sizes and increase the distance over which these 5G chips can perform,” said David Howard, Executive Director and TowerJazz Fellow.   “Also, as we add new features to ourSiGe Terabit Platform, we support easy evolution of customer technology. This allows our customers to grow with our technology roadmap as their products and the 5G standards evolve.”

5G Status and Recent Announcements

  • The FCC in July 2016 released plans to provide new frequency spectra to market ahead of agreed upon 5G (fifth generation) wireless standards. This included licensed spectra around 28, 37-40 GHz bands and an unlicensed 64-71 GHz band.
  • Recent reports (Jan 2017) have stated that 5G communications could foster a $12 trillion economy in 2035 (IHS Markit), and in the next 7 years $275 billion in spending on infrastructure could result from 5G implementation in the USA (CTIA/Accenture report).
  • Though 5G standards have not yet been fixed, several reports from the world’s leading network service providers suggest 5G data rates will be 1 to 10 Gbps, compared to the 4G standards which are 100 Mbps up to 1 Gbps.
  • 5G demos are beginning worldwide. Verizon has stated that it will begin pre-trials of 5G in the USA using the 28 GHz band, and will “achieve some level of commercialization” in 2017.
  • A new 5G marketing logo has been released by the 3rd Generation Partnership Project (3GPP), a telecommunications standards group.

Researchers Describe Novel Strategy for Combating Sepsis

In an article published in October in the journal Scientific Reports, Brazilian researchers describe a novel strategy to combat inflammation and reduce mortality among patients with sepsis based on inhibition of an enzyme called thioredoxin reductase-1 (TrxR-1).

Two drugs with this activity are commercially available but prescribed for different uses. Auranofin is currently used to treat rheumatoid arthritis, and lanthanum chloride is used to treat kidney failure. Tests in mice showed that these drugs improved survival in sepsis by 50%.

The investigation was conducted during Silvia Cellone Trevelin’s PhD research, with a scholarship from FAPESP and supervision from Fernando de Queiroz Cunha and Lucia Rossetti Lopes, researchers at the Center for Research on Inflammatory Diseases (CRID) and the Center for Research on Redox Processes in Biomedicine (Redoxoma), respectively. Both of these centers are funded by FAPESP under its Research, Innovation and Dissemination Centers (RIDCs) program.

“Our results show that the enzyme thioredoxin reductase may be a new therapeutic target for the treatment of sepsis,” Lopes toldAgência FAPESP. “However, the strategy must now be tested in human patients by means of a clinical trial designed to demonstrate its efficacy and explore any deleterious effects.”

According to Cunha, both research groups are engaged in talks with pharmaceutical companies to find ways of testing the strategy in patients with sepsis. “Data from in vitro experiments suggest the strategy could also be worth exploring in the treatment of chronic granulomatous disorder (CGD), a genetic defect that prevents the organism from producing free radicals of oxygen, which are important to combat infections,” he said.

Bacterial infection

Popularly known as “blood poisoning,” sepsis is a potentially life-threatening type of systemic inflammation and a leading cause of death in intensive care units worldwide.

The exacerbated inflammation associated with sepsis is usually triggered by bacterial infection and may remain active even after the pathogen has been eliminated, producing changes in body temperature, arterial blood pressure, heart rate, white blood cell count and breathing. The most severe form of sepsis, known as septic shock, can cause several organs to fail.

According to Cunha, these adverse effects are the result of tissue damage due to overproduction of inflammatory substances, especially the cytokine tumor necrosis factor alpha (TNF-α), by defense cells.

“The body’s defense cells contain a protein complex called nuclear factor kappa B, or NF-κB, which acts as a transcription factor for several inflammatory mediators. It’s normally located in the cytoplasm. When free radicals of oxygen are produced by cells after they come into contact with a pathogen, NF-κB is translocated into the nucleus, where it may bind to DNA and activate cytokine transcription,” said Cunha, who besides heading CRID is a professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRPUSP).

Initially, the researchers thought that eliminating the production of free radicals would be a good strategy to reduce inflammation because, in theory, NF-κB should no longer migrate to the cell nucleus. They tested this hypothesis in mice genetically modified not to express the enzymes that produce free radicals. To their surprise, all the animals died as a result of the inflammation, even when challenged with components of dead bacteria incapable of causing a genuine infection.

“In partnership with the team at Redoxoma, we discovered that inhibiting the production of oxygen radicals was a bad idea for two reasons: first, because they’re important to kill bacteria, and second, because they oxidize TrxR-1, preventing it from translocating to the nucleus and converting NF-κB into the form that induces the production of inflammatory mediators. So, while free radicals can cause damage, they also help balance inflammation during sepsis,” Cunha said.

Based on these findings, the researchers decided to test TrxR-1 inhibition as a therapeutic strategy. In a murine model, systemic inflammation was induced by cecal ligation and puncture (CLP), a procedure that involves puncturing the cecum, part of the large intestine, and allowing feces and intestinal bacteria to spill into the peritoneal cavity.

Half the mice were treated with antibiotics and displayed a survival rate of about 50%. The other half received TrxR-1-inhibiting drugs as well as antibiotics. The survival rate for this group rose to 80%.

Testing in leukocytes

Results of in vitro experiments suggest that the same approach can be used to treat CGD. According to Cunha, patients with this genetic disease do not express the enzymes required for the production of oxygen radicals and are therefore prone to recurring infections and chronic inflammation.

“The organism of a patient with CGD can’t kill pathogens, so it surrounds them with inflammatory cells to form cysts or granulomas. The aim is to keep the pathogen isolated and prevent it from circulating freely. However, recent research has shown that these granulomas often don’t contain bacteria, yet even so, there is inflammation,” he said.

Patients with CGD rarely reach adulthood, either because of recurrent infections or owing to excessive inflammation. “It occurred to us that by inhibiting TrxR-1, we could reduce inflammation and the damage it causes,” he added.

The hypothesis was tested in white blood cells from patients with CGD by stimulating the cells with bacterial components and then incubating them with lanthanum chloride. The TrxR-1-inhibiting drug considerably reduced the production of TNF-α, the key inflammatory mediator underlying the formation of granulomas.

The researchers stressed that this drug has been approved for human use in Brazil since 2013. In Europe and the US, it has been used by patients with kidney failure for about six years, without significant adverse side effects.

“The dose required to inhibit TrxR-1 is less than the dose used to treat kidney failure, so adverse side effects would be even less likely to occur. We therefore believe the conditions exist to commence clinical trials,” Cunha said.

NTU Develops Energy Saving Filters for Wastewater Treatment

Scientists at Nanyang Technological University (NTU Singapore) have invented a new type of nanofilter that could reduce the energy needed to treat wastewater by up to five times.

Typically, for the last steps of water purification in a wastewater treatment process, an ultrafiltration (UF) membrane filters out small particles before a reverse osmosis (RO) membrane is used.

In reverse osmosis, water is pushed through an extremely fine membrane at high pressure to separate water molecules from any remaining contaminants which are tiny – about a thousand times smaller than the width of a human hair, such as salt, heavy metals and toxic chemicals like benzene.

This high water pressure, typically 10 bars and above, means that the water pumps need a lot of energy.

However, NTU’s proprietary nanofiltration (NF) hollow fibre membrane does away with both ultrafiltration and reverse osmosis, combining the two processes.

It also requires only 2 bars of water pressure, similar to the pressure found in a typical home pressure cooker, to filter out the same type of contaminants. Yet it produces water that is almost as pure as through reverse osmosis.

This breakthrough technology took NTU‘s Nanyang Environment and Water Research Institute (NEWRI) about two years to develop and is now being commercialised by an NTU spin-off company De.Mem.

De.Mem which owns over a dozen water treatment plants in Vietnam and Singapore, will be building a pilot production plant in Singapore to manufacture the new membranes.

NTU Professor Ng Wun Jern, the executive director of NEWRI, said the new technology marks yet another huge step forward for Singapore, as it will be the first of its kind to hit the market.

“With the increasing urbanisation of cities and fast growing global population, more cities and communities will face an unprecedented challenge to meet its growing demand for clean water and wastewater treatment,” Prof Ng said.

“If we are to address the ever increasing demand for clean water, what the world needs are innovative technologies like NTU’s new nanofiltration hollow fibre membrane that allow us to treat and produce extremely clean water at a low cost, yet have high reliability and are easy to maintain.”

NTU Professor Wang Rong, the director of NEWRI’s Singapore Membrane Technology Centre who led the team in designing the new NF membrane, said they had designed it for commercial scale-up and production.

“One of the main challenges faced by the industry is that current reverse osmosis processes are energy intensive, with down time needed for maintenance,” explained Prof Wang, who is also the Chair of NTU’s School of Civil and Environmental Engineering.

“Our new membrane is also easy to manufacture using low-cost chemicals that are 30 times cheaper than conventional chemicals, making it suitable for mass production.”

Mr Andreas Kroell, Chief Executive Officer of De.Mem said the new membrane fills a gap in the current market for water treatment solutions.

“We have seen in the labs that when we treat industrial wastewater with the new nanofiltration membranes, the quality of clean water produced is comparable to reverse osmosis but requires much lower pressure, hence lowering costs,” Mr Kroell said.

“Such an effective and efficient technology has significant market potential and can be used in many of De.Mem’s projects that involve the treatment of industrial wastewater.”

De.Mem will test the new membrane modules in real world usage in its plants to verify its effectiveness and efficiency before scaling up to a full industrial production line.

NTU’s new membrane technology will also be showcased at the upcoming Singapore International Water Week, from 10 to 14 July.

Research Brings New Understanding of Chronic Inflammatory Disease

Research from life scientists at The University of Manchester has shone new light on the way cells tune in to different inflammatory signals to understand what is happening in the body.

Over recent years, scientists have discovered that chronic inflammatory diseases occur when the intricate coordination of the body’s natural immune system is disturbed, so that the immune response runs out of control.

Tuning the immune response relies on the concerted action of many different immune cells in order to achieve the desired outcome. These cells communicate through complex networks of signalling molecules called cytokines. Different cytokines enhance or suppress inflammation, and their balance defines severity of the response. Hence, imbalanced cytokine stimulation can activate immune cells to turn against their own body leading to tissue damage.

In a paper published in Nature Communications, a group led by Dr Pawel Paszek from Systems Microscopy Centre at The University of Manchester reveals that cells have a highly variable ability to react to cytokine stimulation and that this is dramatically influenced by other cytokines in their environment.

Dr Paszek said “There are dozens of cytokine molecules, and we have a good understanding of what they do in our bodies. However, how individual cells in our bodies can make sense of different signals eluded us. We were excited when we hit upon the new understanding.”

Dr Antony Adamson said “Cells are constantly bombarded by different messages. In our experiments we showed that different combinations of these cytokine messages resulted in drastically different behaviour. Essentially the cells are trying to gather and understand all the information around them, but rather than listening to multiple news bulletins playing at once, they can switch between different channels. “

Out-of-control cytokine signalling is associated with inflammatory conditions such as Crohn’s Disease and Ulcerative Colitis, known collectively as Inflammatory Bowel Disease. Clinically, a major drug for managing IBD targets is a cytokine called tumour necrosis factor alpha (TNF) and actions of TNF were investigated in the paper.

Though some years away, ‘systems medicine’ could save the NHS money, and protect patients from the trauma of trying medicines for months or even years which fail to impact on the distressing symptoms of IBD. This research by Dr Paszek is another step along the path of making this approach a reality

Professor Werner Muller

 

Professor Mike White said, “TNF is a very important molecule and our team has shone light on the way cells control excessive amounts of the TNF, which may be important for the progression of chronic inflammatory diseases”

Professor Dean Jackson said “Our immune systems are highly sophisticated and mechanisms of communication between different cells must be exquisitely controlled. In inflammatory diseases such as IBD this fine tuning is lost and the system runs out of control – like a snowball running down a hill. If we can develop better drugs to manipulate cell communication the outcome for patients should be improved.”

Insights into rare psoriasis gene mutations may help treat common causes of the disease

Scientists in Professor Steve Ley’s laboratory at the Crick, working in close collaboration with Professor Anne Bowcock at the National Heart and Lung Institute (Imperial College London), have revealed the mechanisms behind psoriasis in patients with mutations in a gene called CARD14.

These severe mutations in CARD14 are relatively rare, but the findings may have implications for treating people with common psoriasis, which affects two to four percent of adults in the UK.

Psoriasis is a chronic inflammatory disease of the skin, characterised by patches of inflammed skin, which are typically dry, scaly and itchy.

Professor Anne Bowcock (NHLI) has previously shown that people with specific mutations in CARD14 have a high probability of developing psoriasis. These mutations cause the CARD14 protein(which is encoded by the CARD14 gene and expressed in skin cells) to activate a family of nuclear proteins that control inflammatory gene expression. These are known as gain-of-function mutations, because the resulting protein product (in this case CARD14) is altered so that it continously activates a molecular pathway that drives inflammation.

In this new study, the scientists used biochemical and cellular techniques to find out more about how CARD14 mutations lead to increased inflammation in patients with psoriasis. They investigated how variants of the CARD14 protein interact with other proteins by co-expressing them in human cells grown in the laboratory and then determining which proteins could be isolated together as a complex. The team also looked at the biological activity of the CARD14 variants in different contexts by expressing them in human skin cells and looking at the activation of downstream signalling pathways and pro-inflammatory gene expression.

Their results showed that the mutations in the CARD14 gene result in its protein product forming ‘active signalling complexes’ with proteins called BCL10 and MALT1. This activates, or turns on, MALT1 enzyme activity, which further contributes to inflammatory signaling. The scientists found that using drugs to inhibit the activity of MALT1 reduced the inflammation caused by mutant variants of CARD14.

Professor Ley said: “Our findings suggest that MALT1 inhibitors might be therapeutically beneficial for psoriasis patients with gain-of-function CARD14 mutations.

“Although these severe CARD14 mutations are relatively rare, a common genetic variant of CARD14 present in the wider population is also associated with an increased risk of developing psoriasis. This raises the interesting possibility that MALT1 inhibitors may be useful for the treatment of more common forms of psoriasis.”

The paper, Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation, is published in the Biochemical Journal.

Identification of a novel control mechanism for degradation of cancer virus products

Expression of a cancer virus product, latent membrane protein 1 (LMP1), in cells leads to activation of caspase1, a type of protease, resulting in LMP1 degradation.

When expression of caspases that degrade the cancer virus product LMP1 is suppressed, activation of the transcription factor NF-κB2 and production of inflammatory cytokines are enhanced.

There are hopes for development of novel antiviral agents that target the mechanism that regulates protein levels of LMP1.

Background
Epstein-Barr virus, which is known to be a cancer virus, is a herpesvirus that infects most adults. It is known to be associated with nasopharyngeal carcinoma, Hodgkin lymphoma, and stomach cancer, and virus products expressed in association with Epstein-Barr viral infection are linked to cancer development.

We have identified a novel control mechanism for degradation of latent membrane protein 1 (LMP1), which is known to be an Epstein-Barr virus product with a particularly close connection with cancer development.

In cells that have been treated with caspase inhibitor, or with which gene knockdown3 has been performed, LMP1 degradation is suppressed, and NF-κB signals, which support inflammation, are found to be enhanced. We hope to develop novel antiviral agents that target LMP1 protein control.

Terms
Caspases: Caspases are a family of factors that induce apoptosis, or cell death. They are cysteine-aspartic proteases, with cysteine central to their activity, at the C-terminal ends of the aspartate residues (D) of matrix proteins. Fourteen types of caspase are known to occur in mammals, and among these it is primarily caspase-8 and caspase-9 that act in the initial phase of apoptosis induction, with caspase-3 and caspase-7 being active primarily in the apoptosis achievement phase.

Transcription factor NF-κB: Nuclear factor κB (NF-κB) was initially identified as a transcription factor that binds to the κ-light-chain-enhancer of immunoglobulins expressed selectively in B cells, but it has since been shown to be expressed by almost all cells, including the cells of invertebrates, such as urchins and fruit flies, as well as higher animals. In mammals in particular, five molecules that belong to the NF-κB family, also called as the Rel family, are known. Members of the NF-κB family are involved in various biological phenomena, such as the immune response and cell viability, through induction of expression of inflammatory cytokines, antiapoptotic factors, etc. In addition, NF-κB activation is dysregulated in various diseases, including inflammatory and autoimmune diseases, and cancer, and attention is therefore being given to NF-κB as target molecules for treatment of various diseases.

Gene knockdown: This refers to gene knockdown using small interfering RNA (siRNA). SiRNA is low-molecular-weight, double-stranded RNA containing 21 to 23 base pairs that is involved in the phenomenon of RNA interference (RNAi). In RNAi, breakdown of mRNA results in sequence-specific inhibition of gene expression, and it can therefore reduce the transcription levels of specific genes, and markedly weaken gene function. At the present time, RNAi using siRNA as a gene knockdown method is applied to fundamental research in the fields of biology and pharmacology, and it is hoped that clinical applications will also be found in future.

Inquiries
Professor Tadashi MATSUDA
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University