Amazing Science
779.6K views | +36 today
Amazing Science
Amazing science facts - 3D_printing • aging • AI • anthropology • art • astronomy • bigdata • bioinformatics • biology • biotech • chemistry • computers • cosmology • education • environment • evolution • future • genetics • genomics • geosciences • green_energy • history • language • map • material_science • math • med • medicine • microscopy • nanotech • neuroscience • paleontology • photography • photonics • physics • postings • robotics • science • technology • video
Your new post is loading...
Scooped by Dr. Stefan Gruenwald!

Huntington's disease trial test is 'major advance' due to neurofilament light chain

Huntington's disease trial test is 'major advance' due to neurofilament light chain | Amazing Science |

Experts describe the early research as a "major advance" in this field. The study, in the Lancet Neurology, suggests the prototype test could help in the hunt for new treatments. Huntington's disease is an inherited and incurable brain disorder that is currently fatal. Around 10,00 people in the UK have the condition and around 25,000 are at risk. It is passed on through genes, and children who inherit a faulty gene from parents have a 50% chance of getting the disease in later life. People can develop a range of problems including involuntary movements, personality changes and altered behavior and may be fully dependent on carers towards the end of their lives.


In this study, an international team - including researchers from University College London - looked at 200 people with genes for Huntington's disease - some of whom already had signs of the disease, and others at earlier stages. They compared them to some 100 people who were not at risk of getting the condition. Volunteers had several tests over three years, including brain scans and clinical check-ups to see how Huntington's disease affected people's thinking skills and movement as the condition became more severe. At the same time scientists looked for clues in blood samples - measuring a substance called neurofilament light chain (NFL) - released from damaged brain cells. They found levels of the brain protein were high in people with Huntington's disease and were even elevated in people who carried the gene for Huntington's disease but were many years away from showing any symptoms. And researchers found NFL levels rose as the condition worsened and as people's brains shrank over time.


Dr Edward Wild, at UCL, said: "Neurofilament light chain has the potential to serve as a speedometer in Huntington's disease, since a single blood test reflects how quickly the brain is changing. "We have been trying to identify blood biomarkers to help track the progression of Huntington's disease for well over a decade and this is the best candidate we have seen so far."

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Poison for cancer cells: New method identifies active agents in mixtures of hundreds of substances

Poison for cancer cells: New method identifies active agents in mixtures of hundreds of substances | Amazing Science |
The pharmaceutical industry is always on the lookout for precisely such substances to deploy them against threads like cancer. In the case of cancer, for example, when the proteasome is blocked, rapidly growing cancer cells choke on their own waste. The first medication of this kind is already generating annual revenues of over one billion US dollars. The scientists are now looking for further substances with lesser side effects.

Following preliminary studies, one such candidate was a toxic substance produced by the bacterium Photorhabdus luminescens. This is the poison that kills the larvae of the garden chafer. Using his new methodology, the scientists discovered that the bacterium lives inactively in the intestines of the threadworm. When it lays its eggs, the worm infects the larvae. The sudden change in environment causes the bacterium to emit toxins. After the larva dies, the bacterium ceases to produce toxins. Once the threadworms hatch from the protective egg membrane, they ingest the inactive bacterium into their intestines, and the cycle can start again.

Since the newly developed method also works in intensively colored solutions and in the presence of hundreds of other substances, the workgroup at the Chair of Biochemistry succeeded in isolating the unknown poison directly from the bacterial brew: It turned out to be two structurally very similar compounds, cepafungin I and glidobactin A. The latter was previously considered the strongest proteasome blocker. In spite of the resemblance, cepafungin I had never been tested as a proteasome blocking agent. The tests of the research group showed that Cepafungin I is indeed a strong Proteasomhemmer. In effect, it even surpasses the previous record holder.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Scientists Create Artificial Womb That Could Help Prematurely Born Babies

Scientists Create Artificial Womb That Could Help Prematurely Born Babies | Amazing Science |

Scientists have created an "artificial womb" in the hopes of someday using the device to save babies born extremely prematurely. So far the device has only been tested on fetal lambs. A study published Tuesday involving eight animals found the device appears effective at enabling very premature fetuses to develop normally for about a month.


"We've been extremely successful in replacing the conditions in the womb in our lamb model," says Alan Flake, a fetal surgeon at Children's Hospital of Philadelphia who led the study published in the journal Nature Communications.


"They've had normal growth. They've had normal lung maturation. They've had normal brain maturation. They've had normal development in every way that we can measure it," Flake says. Flake says the group hopes to test the device on very premature human babies within three to five years. "What we tried to do is develop a system that mimics the environment of the womb as closely as possible," Flake says. "It's basically an artificial womb."

No comment yet.
Scooped by Dr. Stefan Gruenwald!

DNA-based liquid biopsy can spot cancer recurrence a year before conventional CT scans

DNA-based liquid biopsy can spot cancer recurrence a year before conventional CT scans | Amazing Science |
‘Liquid biopsy’ diagnosed cancer recurrence up to a year before conventional scans in major lung cancer trial, and could buy crucial time for doctors


A revolutionary blood test has been shown to diagnose the recurrence of cancer up to a year in advance of conventional scans in a major lung cancer trial. The test, known as a liquid biopsy, could buy crucial time for doctors by indicating that cancer is growing in the body when tumors are not yet detectable on CT scans and long before the patient becomes aware of physical symptoms.


It works by detecting free-floating mutated DNA, released into the bloodstream by dying cancer cells. In the trial of 100 lung cancer patients, scientists saw precipitous rises in tumor DNA in the blood of patients who would go on to relapse months, or even a year, later.


The findings add to building anticipation that the technology, which is already in widespread use in non-invasive prenatal tests for Down’s syndrome, will have a major impact in cancer medicine.


Nitzan Rosenfeld of the Cancer Research UK Cambridge Institute, who was not involved in the latest trial, predicts that “most if not all” cancer patients will be given the DNA-based tests in future. “Even if only a fraction of cancers that are currently detected at a lethal stage will in future be detected at an early curable stage this will represent a great benefit in lives saved,” he said.


In the latest trial, reported in the journal Nature, 100 patients with non-small cell lung cancer were followed from diagnosis through surgery and chemotherapy, having blood tests every six to eight weeks.


By analyzing the patchwork of genetic faults in cells across each tumor, scientists created personalized genomic templates for each patient. This was then compared to the DNA floating in their blood, to assess whether a fraction of it matched that seen in their tumor.


Prof Charlie Swanton, a cancer geneticist at the Francis Crick Institute who led the work, described how circulating tumour DNA tracked the patient’s disease status with remarkable precision. Of patients who would remain in remission, he said that “Within 48 hours of surgery, the DNA drops down to undetectable.”


By contrast, rising tumour DNA levels were seen in patients whose disease would later recur, indicating that cancer remained in the lungs or had migrated to other organs, where it was lying dormant. When the tests of 24 patients were analyzed in detail, the scientists could say with 92% accuracy who would relapse.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Frog Skin Peptide Could Prevent the Next Influenza Pandemic

Frog Skin Peptide Could Prevent the Next Influenza Pandemic | Amazing Science |
New research from Emory University School of Medicine shows that a chemical in the mucus of South Indian frogs is capable of killing certain strains of the influenza virus. It’ll take a while for scientists to translate this finding into a useful medicine, but the discovery could lead to an entirely new source of powerful anti-viral drugs.


Skin slime from the South Indian frog Hydrophylax bahuvistara contains a compound that kills bacteria and viruses, according to a study published today in the journal Immunity. In tests on mice, a synthesized version of the molecule was successful at killing a variety of influenza viruses, namely the H1 pandemic strains that make the rounds each year. Eventually, a drug inspired by this compound could be used to attack an emerging H1 strain, or it could be used when vaccines are unavailable.


Unfortunately, this compound, dubbed “urumin,” doesn’t last very long in the body, so scientists are now trying to figure out how to make it more stable. That said, the discovery shows that amphibians, and possibly other animals, are a potential new source of disease-fighting compounds. The researchers who led the study are hopeful that similar frog-derived molecules can be used against other viruses, such as dengue and Zika.

Frogs can’t catch the flu, but they’re susceptible to bacterial infections and other diseases. Consequently, the Emory scientists had good reason to suspect that certain peptides produced by frogs—peptides are short chains of amino acids that form the building blocks of proteins—packed an anti-viral punch. The peptide attaches itself to the virus and literally dismantles it.
“Peptides derived from the skin of frogs have antibacterial activity. We hypothesized some peptides might also have antiviral activity and hence we tested them against flu viruses,” said lead researcher Joshy Jacob in an interview with Gizmodo. “The frogs secrete this peptide almost certainly to combat some pathogen in [their] niche. The flu virus most likely shares a common motif with whatever the peptide is targeted to.”
Indeed, the peptide seems to be pretty good at attacking influenza. It attaches itself to hemagglutinin, the major protein on the surface of influenza virus, resulting in the dismantling and eventual death of the virus.
No comment yet.
Scooped by Dr. Stefan Gruenwald!

Nanoparticle research tested in locusts focuses on new drug-delivery method

Nanoparticle research tested in locusts focuses on new drug-delivery method | Amazing Science |

Delivering life-saving drugs directly to the brain in a safe and effective way is a challenge for medical providers. One key reason: the blood-brain barrier, which protects the brain from tissue-specific drug delivery. Methods such as an injection or a pill aren’t as precise or immediate as doctors might prefer, and ensuring delivery right to the brain often requires invasive, risky techniques.


A team of engineers from Washington University in St. Louis has developed a new nanoparticle generation-delivery method that could someday vastly improve drug delivery to the brain, making it as simple as a sniff.


“This would be a nanoparticle nasal spray, and the delivery system could allow a therapeutic dose of medicine to reach the brain within 30 minutes to one hour,” said Ramesh Raliya, research scientist at the School of Engineering & Applied Science.


“The blood-brain barrier protects the brain from foreign substances in the blood that may injure the brain,” Raliya said. “But when we need to deliver something there, getting through that barrier is difficult and invasive. Our non-invasive technique can deliver drugs via nanoparticles, so there’s less risk and better response times.”


The novel approach is based on aerosol science and engineering principles that allow the generation of monodisperse nanoparticles, which can deposit on upper regions of the nasal cavity via diffusion. Working with Assistant Vice Chancellor Pratim Biswas, chair of the Department of Energy, Environmental & Chemical Engineering and the Lucy & Stanley Lopata Professor, Raliya developed an aerosol consisting of gold nanoparticles of controlled size, shape and surface charge. The nanoparticles were tagged with fluorescent markers, allowing the researchers to track their movement.


Next, Raliya and biomedical engineering postdoctoral fellow Debajit Saha exposed locusts’ antennae to the aerosol, and observed the nanoparticles travel from the antennas up through the olfactory nerves. Due to their tiny size, the nanoparticles passed through the brain-blood barrier, reaching the brain and suffusing it in a matter of minutes.

No comment yet.
Rescooped by Dr. Stefan Gruenwald from Melanoma BRAF Inhibitors Review!

Breakthrough research targets melanoma’s resistance to immunotherapy

Breakthrough research targets melanoma’s resistance to immunotherapy | Amazing Science |

Why do some tumors respond to immunotherapy and others don’t? That’s a question MD Anderson’s Weiyi Peng, M.D., Ph.D., and her team of investigators are getting closer to answering.

Peng, an assistant professor in Melanoma Medical Oncology, led a study that showed a link between the loss of a tumor-suppressor gene called PTEN and resistance to checkpoint inhibitor immunotherapy.


Patients with inactive PTEN had fewer T cells in their tumors, indicating that a lack of PTEN suppresses the immune response against melanoma. Patients with inactive PTEN also had worse outcomes when treated with checkpoint inhibitors compared to melanoma patients with intact PTEN.


These findings indicate PTEN loss may be an important biomarker to predict melanoma patients’ resistance to immunotherapy. The study also showed that treatment with an experimental drug that blocks a molecular pathway called PI3K improved the effectiveness of anti-PD-1 treatment in laboratory models of melanomas with loss of the PTEN gene.


“These results allowed us to devise a means of combating resistance to immunotherapy due to PTEN loss in melanoma patients,” Peng says.


Findings of the study have led to a Phase I and II clinical trial that will test a combination of immunotherapy and targeted therapy in patients with metastatic melanoma who lack the PTEN gene.

Via Krishan Maggon
No comment yet.
Scooped by Dr. Stefan Gruenwald!

Face2Gene: Thanks to AI, Computers Can Now See Your Health Problems

Face2Gene: Thanks to AI, Computers Can Now See Your Health Problems | Amazing Science |

Face2Gene takes advantage of the fact that so many genetic conditions have a tell-tale “face”—a unique constellation of features that can provide clues to a potential diagnosis. It is just one of several new technologies taking advantage of how quickly modern computers can analyze, sort, and find patterns across huge reams of data. They are built in fields of artificial intelligence known as deep learning and neural nets—among the most promising to deliver AI’s 50-year old promise to revolutionize medicine by recognizing and diagnosing disease.


Genetic syndromes aren’t the only diagnoses that could get help from machine learning. The RightEye GeoPref Autism Test can identify the early stages of autism in infants as young as 12 months—the crucial stages where early intervention can make a big difference. Unveiled January 2, 2017 at CES in Las Vegas, the technology uses infrared sensors test the child’s eye movement as they watch a split-screen video: one side fills with people and faces, the other with moving geometric shapes. Children at that age should be much more attracted to faces than abstract objects, so the amount of time they look at each screen can indicate where on the autism spectrum a child might fall.

In validation studies done by the test’s inventor, UC San Diego researcher Karen Pierce,1 the test correctly predicted autism spectrum disorder 86 percent of the time in more than 400 toddlers. That said, it’s still pretty new, and hasn’t yet been approved by the FDA as a diagnostic tool. “In terms of machine learning, it’s the simplest test we have,” says RightEye’s Chief Science Officer Melissa Hunfalvay. “But before this, it was just physician or parent observations that might lead to a diagnosis. And the problem with that is it hasn’t been quantifiable.”


A similar tool could help with early detection of America’s sixth leading cause of death: Alzheimer’s disease. Often, doctors don’t recognize physical symptoms in time to try any of the disease’s few existing interventions. But machine learning hears what doctor’s can’t: Signs of cognitive impairment in speech. This is how Toronto-based Winterlight Labs is developing a tool to pick out hints of dementia in its very early stages. Co-founder Frank Rudzicz calls these clues “jitters,” and “shimmers:” high frequency wavelets only computers, not humans, can hear.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Close to Half of All American Adults Are Infected With Genital HPV, Study Finds

Close to Half of All American Adults Are Infected With Genital HPV, Study Finds | Amazing Science |

More than 42 percent of Americans between the ages of 18 and 59 are infected with genital human papillomavirus, according to the first survey to look at the prevalence of the virus in the adult population. 


The report, published on Thursday by the National Center for Health Statistics, found that high-risk strains of the virus — a cause of cervical and vaginal cancers, and cancer of the penis, as well as cancers of the anus and throat in both sexes — infect 25.1 percent of men and 20.4 percent of women.


The virus is transmitted by skin to skin contact; people who are infected may pass the virus to sexual partners. “One of the most striking things that we really want people to know is that high-risk HPV is common — common in the general population — these are not people who are marginalized,” said the lead author, Geraldine McQuillan, an epidemiologist at the Centers for Disease Control and Prevention and the lead author of the new report.


She and her colleagues also found that 7.3 percent of Americans aged 18 to 69 are infected with oral HPV, and 4 percent are infected with the high-risk strains that can cause cancers of the mouth and pharynx. There are more than a hundred strains of this virus, and 40 of them are sexually transmitted. The body usually manages to rid itself of HPV, but for unclear reasons the infection can become chronic in certain individuals.


Many of the sexually transmitted strains do not cause serious health problems, but HPV-16 and -18 are the cause of almost all cervical cancers. Even low-risk strains cause warts, including genital warts.

Scott Baker's comment, April 7, 10:31 AM
You can't add these apx. 25% figures and get half (50%). It is still less than 25% if it is that much for two differtn subpopulations. This is a freshman math mistake and I'm surprised the MSM has made it.
Scooped by Dr. Stefan Gruenwald!

Lab-Grown Pancreas Reverses Diabetes In Mice

Lab-Grown Pancreas Reverses Diabetes In Mice | Amazing Science |
The success of a rat-to-mouse pancreas transplant suggests that such interspecies transplants could help meet the need for donor organs.


Mouse pancreases grown in rats generate functional, insulin-producing cells that can reverse diabetes when transplanted into mice with the disease, according to researchers at the Stanford University School of Medicine and the Institute of Medical Science at the University of Tokyo. These findings, published in Nature, suggest that a similar technique could one day be used to generate matched, transplantable human organs in large animals like pigs or sheep.


About 76,000 people in the United States are currently waiting for an organ transplant, but organs are in short supply. Generating genetically matched human organs in large animals could relieve the shortage and release transplant recipients from the need for lifelong immunosuppression, the researchers say. To conduct the work, the researchers implanted mouse pluripotent stem cells into early rat embryos. The rats had been genetically engineered to be unable to develop their own pancreas and were thus forced to rely on the mouse cells for the development of the organ. Once the rats were born and grown, the researchers transplanted the insulin-producing cells, which cluster together in groups called islets, from the rat-grown pancreases into mice genetically matched to the stem cells that formed the pancreas. These mice had been given a drug to cause them to develop diabetes.


“We found that the diabetic mice were able to normalize their blood glucose levels for over a year after the transplantation of as few as 100 of these islets,” said Hiromitsu Nakauchi, a professor of genetics at Stanford. “Furthermore, the recipient animals only needed treatment with immunosuppressive drugs for five days after transplantation, rather than the ongoing immunosuppression that would be needed for unmatched organs.”


The researchers’ current findings come on the heels of a previous study in which they grew rat pancreases in mice. Although the organs appeared functional, they were the size of a normal mouse pancreas rather than a larger rat pancreas. As a result, there were not enough functional islets in the smaller organs to successfully reverse diabetes in rats.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Herpes May Have Been Transmitted from Chimps to Humans 30,000 Years Ago

Herpes May Have Been Transmitted from Chimps to Humans 30,000 Years Ago | Amazing Science |
Researchers say the lineages of HSV-1 and HSV-2 show herpes viruses mixed genomes and moved from chimps to humans. How it was transmitted is a bit of a mystery.


There are two main types of herpes virus around today.

The herpes simplex virus 1 (HSV-1) is transmitted mostly by mouth and is found most often in cold sores. This ailment affects about two-thirds of the world’s population.


The herpes simplex virus 2 (HSV-2) is the main source for genital herpes. It affects about 11 percent of people around the globe. The HSV-2 strain has been used to help verify the “Out of Africa” theory that humans began migrating from that continent more than 50,000 years ago.


In general, HSV-1 and HSV-2 are considered cousins and have been thought to have evolved separately. However, the researchers of the study took a closer look at the evolution of the herpes virus, building on the work done in a 2014 study. The team, led by Sebastien Calvignac-Spencer, PhD, of the Robert Koch Institut in Germany, examined the whole genome sequencing data of 18 HSV-2 isolates.


The researchers say they determined the two main lineages of HSV-2 began diversifying about 30,000 years ago. One strain was restricted to Sub-Saharan Africa, while the other spread globally. Calvignac-Spencer told Healthline in an email that the HSV-2 strain eventually mixed its genome with the HSV-1 strain. He said this mixture did not occur in all HSV-2, but the HSV-2 lineage that spread around the world contains the presence of HSV-1 recombinant fragments.


“We don't know whether there is a causal relationships and these HSV-1 fragments provided a selective advantage to this lineage, but that is clearly one intriguing possibility,” Calvignac-Spencer said.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Funnel web spider venom can protect cells from being destroyed by a stroke

Funnel web spider venom can protect cells from being destroyed by a stroke | Amazing Science |

Doctors have stumbled on an unlikely source for a drug to ward off brain damage caused by strokes: the venom of one of the deadliest spiders in the world.


A bite from an Australian funnel web spider can kill a human in 15 minutes, but a harmless ingredient found in the venom can protect brain cells from being destroyed by a stroke, even when given hours after the event, scientists say. If the compound fares well in human trials, it could become the first drug that doctors have to protect against the devastating loss of neurons that strokes can cause.


Researchers discovered the protective molecule by chance as they sequenced the DNA of toxins in the venom of the Darling Downs funnel web spider (Hadronyche infensa) that lives in Queensland and New South Wales. Venom from three spiders was gathered for the study after scientists trapped and “milked exhaustively” three spiders on Orchid beach, about 400km north of Brisbane.


The molecule, called Hi1a, stood out because it looked like two copies of another brain cell-protecting chemical stitched together. It was so intriguing that scientists decided to synthesize the compound and test its powers. “It proved to be even more potent,” said Glenn King at the University of Queensland’s centre for pain research.


Strokes occur when blood flow to the brain is interrupted and the brain is starved of oxygen. About 85% of strokes are caused by blockages in blood vessels in the brain, with the rest due to bleeds when vessels rupture. Approximately six million people a year die from stroke, making it the second largest cause of death worldwide after heart attacks.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

First results of CRISPR gene editing of human embryos released from China

First results of CRISPR gene editing of human embryos released from China | Amazing Science |

A team in China has corrected genetic mutations in at least some of the cells in three normal human embryos using the CRISPR genome editing technique. The latest study is the first to describe the results of using CRISPR in viable human embryos, New Scientist can reveal.


While this study – which attempted to repair the DNA of six embryos in total – was very small, the results suggest CRISPR works much better in normal embryos than it did in previous tests on abnormal embryos that could not develop into children.

“It is encouraging,” says Robin Lovell-Badge of the Francis Crick Institute in London, who has contributed to several major reports on human genome editing. The numbers are far too low to make strong conclusions though, he cautions.


The CRISPR gene editing technique is a very efficient way of disabling genes, by introducing small mutations that disrupt the code of a DNA sequence. CRISPR can also be used to repair genes, but this is much more difficult.
Until now, results have only been published from experiments in which the CRISPR technique was used in abnormal embryos, made when two sperm fertilize the same egg. The idea behind this work was that it was more ethical to test the technique on embryos that could never fully develop.
In the first attempt to fix genes in human embryos, fewer than 1 in 10 cells were successfully repaired – an efficiency rate that is too low to make the method practical. A second study published in 2016 also had a low rate of efficiency. However, because these embryos were very genetically abnormal, these experiments may not have given an accurate indication of how well the technique would work in healthier embryos.
The Chinese team behind the latest study, at the Third Affiliated Hospital of Guangzhou Medical University, first carried out experiments with abnormal embryos, and found the repair rate was very low. But they had more success when they tried to repair mutations in normal embryos derived from immature eggs donated by people undergoing IVF.
No comment yet.
Scooped by Dr. Stefan Gruenwald!

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a | Amazing Science |
Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain.


As the Nav1.7 channel appears to be a highly important component in nociception, with null activity conferring total analgesia,[14] there has been immense interest in developing selective Nav1.7 channel blockers as potential novel analgesics.[27] Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene.[3][4][5] Since Nav1.7 is not present in heart tissue or the central nervous system, selective blockers of Nav1.7, unlike non-selective blockers such as local anesthetics, could be safely used systemically for pain relief. Moreover, selective Nav1.7 blockers may prove to be far more effective analgesics, and with fewer undesirable effects, relative to current pharmacotherapies.[27][28][29]


A number of selective Nav1.7 (and/or Nav1.8) blockers are in clinical development, including funapide (formerly TV-45070, XEN402), raxatrigine (formerly CNV1014802, GSK-1014802), PF-05089771, PF-04531083, DSP-2230, AZD-3161, NKTR-171, GDC-0276, and RG7893(formerly GDC-0287).[30][31][32] Ralfinamide (formerly NW-1029, FCE-26742A, PNU-0154339E) is a multimodal, non-selective Nav channel blocker which is under development for the treatment of pain.[33]


Spiders are the most successful venomous animals with an estimated 100,000 extant species [1]. The vast majority of spiders employ a lethal cocktail to rapidly subdue their prey, which are often many times their own size. However, despite their fearsome reputation, less than a handful of these insect assassins are harmful to humans [2,3]. Nevertheless, it is this small group of medically important species that first prompted scientists more than half a century ago to begin exploring the remarkable pharmacological diversity of spider venoms.


Amongst the ranks of animals that employ venom for their survival, spiders are the most successful, the most geographically widespread, and arguably consume the most diverse range of prey. Although the predominant items on a spider’s dinner menu are other arthropods, larger species will readily kill and feed on small fish, reptiles, amphibians, birds, and mammals. Thus, spider venoms contain a wealth of toxins that target a diverse range of receptors, channels, and enzymes in a wide range of vertebrate and invertebrate species.


Spider venoms are complex cocktails composed of a variety of compounds, including salts, small organic molecules, peptides, and proteins [4,5,6,7,8,9]. However, peptides are the primary components of spider venoms, and some species produce venom containing >1000 unique peptides of mass 2–8 kDa [10]. Based on the number of described spider species and a relatively conservative estimate of the complexity of their venom it has been estimated that the potential number of unique spider venom peptides could be upwards of 12 million [11]. In recent years there has been an exponential increase in the number of spider-toxin sequences being reported [12] due to the application of high-throughput proteomic [13,14] and transcriptomic [15,16,17] approaches, or a combination of these methods [10,18,19]. In the last 18 months alone the number of toxins in the ArachnoServer spider-toxin database [20,21] has more than doubled, and is now excess of 900 (see Nevertheless, our knowledge of the diversity of spider-venom peptides is still rudimentary, with less than 0.01% of potential peptides having been isolated and studied.


Although only a small number of spider venom peptides have been pharmacologically characterized, the array of known biological activities is impressive [9]. In addition to the well known neurotoxic effects of spider venoms, they contain peptides with antiarrhythmic, antimicrobial, analgesic, antiparasitic, cytolytic, haemolytic, and enzyme inhibitory activity. Furthermore, the crude venom of Macrothele raveni has antitumor activity, for which the responsible component has not yet been identified [22,23]. Finally, larger toxins such as the latrotoxins from the infamous black widow spider (Latrodectus mactans) and related species induce neurotransmitter release and they have played an important role in dissecting the process of synaptic vesicle exocytosis [24].


Since spiders employ their venom primarily to paralyse prey, it is no surprise that these venoms contain an abundance of peptides that modulate the activity of neuronal ion channels and receptors. Indeed, the majority of characterized spider-venom peptides target voltage-gated potassium (KV) [25], calcium (CaV) [26,27], or sodium (NaV) [26,28] channels. More recently, novel spider-venom peptides have been found that interact with ligand-gated channels (e.g., purinergic receptors [29]) and recently discovered families of channels such as acid sensing ion channels [30], mechanosensitive channels [31], and transient receptor potential channels [32]. Not only do most of these peptides have selectivity for a given class of ion channel, they can have anything from mild preference to exquisite selectivity for a given channel subtype. This potential for high target affinity and selectivity makes spider-venom peptides an ideal natural source for the discovery of novel therapeutic leads [33].


Despite the advent of automation and the rise of high-throughput and high-content screening in the pharmaceutical industry there has been a sharp decline in the rate of discovery and development of novel chemical entities [34,35]. A group of scientists reviewed the emerging role that venom-derived components can play in addressing this decline with an emphasis on technical advances that can aid the discovery process [36]. It is worth noting that two of the 20 FDA-approved peptide pharmaceuticals were derived from animal venoms (i.e., ziconitide and exendin-4) [37].

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Diabetes breakthrough increases insulin producing cells and could lead to a cure

A potential cure for Type 1 diabetes looms on the horizon in San Antonio, and the novel approach would also allow Type 2 diabetics to stop insulin shots.


The discovery, made at UT Health San Antonio, increases the types of pancreatic cells that secrete insulin. UT Health San Antonio researchers have a goal to reach human clinical trials in three years, but to do so they must first test the strategy in large-animal studies, which will cost an estimated $5 million.


Those studies will precede application to the U.S. Food and Drug Administration for Investigational New Drug (IND) approval, Bruno Doiron, Ph.D., a co-inventor, said. The scientists received a U.S. patent in January, and UT Health San Antonio is spinning out a company to begin commercialization. The strategy has cured diabetes in mice.


“It worked perfectly,” Dr. Doiron, assistant professor of medicine at UT Health, said. “We cured mice for one year without any side effects. That’s never been seen. But it’s a mouse model, so caution is needed. We want to bring this to large animals that are closer to humans in physiology of the endocrine system.”


Ralph DeFronzo, M.D., professor of medicine and chief of the Division of Diabetes at UT Health, is co-inventor on the patent. He described the therapy: “The pancreas has many other cell types besides beta cells, and our approach is to alter these cells so that they start to secrete insulin, but only in response to glucose [sugar],” he said. “This is basically just like beta cells.”


Insulin, which lowers blood sugar, is only made by beta cells. In Type 1 diabetes, beta cells are destroyed by the immune system and the person has no insulin. In Type 2 diabetes, beta cells fail and insulin decreases. At the same time in Type 2, the body doesn’t use insulin efficiently. The therapy is accomplished by a technique called gene transfer. A virus is used as a vector, or carrier, to introduce selected genes into the pancreas. These genes become incorporated and cause digestive enzymes and other cell types to make insulin.


Gene transfer using a viral vector has been approved nearly 50 times by the U.S. Food & Drug Administration to treat various diseases, Dr. DeFronzo said. It is proven in treating rare childhood diseases, and Good Manufacturing Processes ensure safety. Unlike beta cells, which the body rejects in Type 1 diabetes, the other cell populations of the pancreas co-exist with the body’s immune defenses. “If a Type 1 diabetic has been living with these cells for 30, 40 or 50 years, and all we’re getting them to do is secrete insulin, we expect there to be no adverse immune response,” Dr. DeFronzo said.


The therapy precisely regulates blood sugar in mice. This could be a major advance over traditional insulin therapy and some diabetes medications that drop blood sugar too low if not closely monitored. “A major problem we have in the field of Type 1 diabetes is hypoglycemia (low blood sugar),” Dr. Doiron said. “The gene transfer we propose is remarkable because the altered cells match the characteristics of beta cells. Insulin is only released in response to glucose.”


People don’t have symptoms of diabetes until they have lost at least 80 percent of their beta cells, Dr. Doiron said. “We don’t need to replicate all of the insulin-making function of beta cells,” he said. “Only 20 percent restoration of this capacity is sufficient for a cure of Type 1.”

No comment yet.
Rescooped by Dr. Stefan Gruenwald from Science and Global Education Trends!

Aspirin May Prevent Cancer from Spreading, New Research Shows

Aspirin May Prevent Cancer from Spreading, New Research Shows | Amazing Science |

If ever there was a wonder drug, aspirin might be it. Originally derived from the leaves of the willow tree, this mainstay of the family medicine cabinet has been used successfully for generations to treat conditions ranging from arthritis to fever, as well as to prevent strokes, heart attacks and even some types of cancer, among other ills. Indeed, the drug is so popular that annual consumption worldwide totals about 120 billion tablets.

Via Kathy Bosiak
No comment yet.
Rescooped by Dr. Stefan Gruenwald from Fragments of Science!

Using CRISPR to reverse retinitis pigmentosa and restore visual function by turning rods to cones

Using CRISPR to reverse retinitis pigmentosa and restore visual function by turning rods to cones | Amazing Science |

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa. The findings are published in the April 21 advance online issue of Cell Research.


Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes' photoreceptors, specialized cells in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells.


In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness.


In their published research, a team led by senior author Kang Zhang, MD, PhD, chief of ophthalmic genetics, founding director of the Institute for Genomic Medicine and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine, used CRISPR/Cas9 to deactivate a master switch gene called Nrland a downstream transcription factor called Nr2e3.


CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, allows researchers to target specific stretches of genetic code and edit DNA at precise locations, modifying select gene functions. Deactivating either Nrl or Nr2e3 reprogrammed rod cells to become cone cells.


"Cone cells are less vulnerable to the genetic mutations that cause RP," said Zhang. "Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision."


The scientists tested their approach in two different mouse models of RP. In both cases, they found an abundance of reprogrammed cone cells and preserved cellular architecture in the retinas.


Electroretinography testing of rod and cone receptors in live mice show improved function.

Via Mariaschnee
No comment yet.
Rescooped by Dr. Stefan Gruenwald from DNA and RNA research!

Lung cancer diagnosis with a simple breath test

Lung cancer diagnosis with a simple breath test | Amazing Science |
“Inhale deeply ... and exhale.” This is what a test for lung cancer could be like in future. Scientists at the Max Planck Institute for Heart and Lung Research in Bad Nauheim have developed a method that can detect the disease at an early stage. To this effect, they investigated the presence of traces of RNA molecules that are altered by cancer growth. In a study on healthy volunteers and cancer patients, the breath test correctly determined the health status of 98 percent of the participants. The method will now be refined in cooperation with licensing partners so that it can be used for the diagnosis of lung cancer.
Most lung cancer patients die within five years of diagnosis. One of the main reasons for this is the insidious and largely symptom-free onset of the disease, which often remains unnoticed. In the USA, high-risk groups, such as heavy smokers, are therefore routinely examined by CAT scan. However, patients can be wrongly classified as having the disease.
Together with cooperation partners, researchers at the Max Planck Institute for Heart and Lung Research have now developed a breath test that is much more accurate. In their research, the diagnosis of lung cancer was correct in nine out of ten cases. The method is therefore reliable enough to be used for the routine early detection of lung cancer.
The researchers analyzed RNA molecules released from lung tissue into expired breath, noting differences between healthy subjects and lung cancer patients. Unlike DNA, the RNA profile is not identical in every cell. Several RNA variants, and therefore different proteins, can arise from one and the same DNA segment. In healthy cells, such variants are present in a characteristic ratio. The scientists discovered that cancerous and healthy cells contain different amounts of RNA variants of the GATA6 and NKX2 genes. Cancer cells resemble lung cells in the embryonic stage.
The researchers developed a method to isolate RNA molecules. Not only is their concentration in expired breath extremely low, but they are also frequently highly fragmented. The researchers then investigated the RNA profile in subjects with and without lung cancer and from these data established a model for diagnosing the disease. In a test of 138 subjects whose health status was known, the test was able to identify 98 percent of the patients with lung cancer. 90 percent of the detected abnormalities were in fact cancerous.

Via Integrated DNA Technologies
No comment yet.
Scooped by Dr. Stefan Gruenwald!

Fang-Blenny's fish venom could help in development of new non-addictive painkillers

Fang-Blenny's fish venom could help in development of new non-addictive painkillers | Amazing Science |

Researchers have discovered a fish venom that contains opioid properties, which could help in the development of new pain-killing drugs. The fierce-looking fang blenny, also known as the poison-fang blenny or the saber-tooth blenny, fends off predators and competitors by injecting them with a heroin-like substance that impairs them rather than kills them.


"The venom causes the bitten fish to become slower in movement and dizzy by acting on their opioid receptors," said Bryan Fry, who led the study published Tuesday in the science journal Current Biology. Although used for defense, the venom "inhibits pain rather than causing it."


It's not the first time animal poison has been found to have analgesic properties: Ziconotide which was derived from cone snails, is used to treat chronic pain. But it's the first time scientists have identified opioid peptides in fish venom, Fry said. This venom is "chemically unique," which drives home the importance of biodiversity, said Fry of the University of


"This discovery is an excellent example as to why we must urgently protect all of nature," Fry told CBC News. "It is impossible to predict where the next wonder drug will come from."

No comment yet.
Rescooped by Dr. Stefan Gruenwald from DNA and RNA research!

New technology can detect tiny ovarian tumors of 2 mm size

New technology can detect tiny ovarian tumors of 2 mm size | Amazing Science |

“Synthetic biomarkers” could be used to diagnose ovarian cancer months earlier than now possible.


Most ovarian cancer is diagnosed at such late stages that patients’ survival rates are poor. However, if the cancer is detected earlier, five-year survival rates can be greater than 90 percent.


Now, MIT engineers have developed a far more sensitive way to reveal ovarian tumors: In tests in mice, they were able to detect tumors composed of nodules smaller than 2 millimeters in diameter. In humans, that could translate to tumor detection about five months earlier than is possible with existing blood tests, the researchers say.


The new test makes use of a “synthetic biomarker” — a nanoparticle that interacts with tumor proteins to release fragments that can be detected in a patient’s urine sample. This kind of test can generate a much clearer signal than natural biomarkers found in very small quantities in the patient’s bloodstream.


“What we did in this paper is engineer our sensor to be about 15 times better than a previous version, and then compared it against a blood biomarker in a mouse model of ovarian cancer to show that we could beat it,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and the senior author of the study.


This approach could also be adapted to work with other cancers. In this paper, which appears in the April 10 2017 issue of Nature Biomedical Engineering, the researchers showed they can detect colorectal tumors that metastasized to the liver. 

Via Integrated DNA Technologies
No comment yet.
Scooped by Dr. Stefan Gruenwald!

Creating Zika-Proof Mosquitoes Means Rigging Natural Selection

Creating Zika-Proof Mosquitoes Means Rigging Natural Selection | Amazing Science |
Gene drives, powered by Crispr, promise to wipe out mosquito-borne diseases. But first they'll have to beat nature at her own game: evolution.


Of the many great things promised by Crispr gene editing technology, the ability to eliminate disease by modifying organisms might just top the list. But doing that requires perfecting something called a gene drive. Think of gene drives as a means of supercharging evolution to, say, give an entire population of mosquitoes a gene that kills the Zika virus. The trouble is, organisms develop resistance to gene drives, much like they eventually outwit pesticides and antibiotics.


Researchers dedicate no small amount of time and thought to creating gene drives that can outsmart evolution because the potential payoffs are so great. The lowly mosquito transmits dozens of diseases that kill more than a million people every year, making it the deadliest animal in the world. Pesticides, mosquito nets, and medicine won’t solve the problem, but gene drives might—provided scientists can make them less likely to succumb to the genetic mutations that might render them useless. 


In a paper presented in Science Advances, Harvard scientists used computational models to test a means of doing just that. The resulting gene can spread to 99 percent of a population in as few as 10 generations, and persist for more than 200 generations without the mosquitoes (or any other population) developing a resistance. Although the researchers did not test their method by tinkering with real mosquitoes, their modeling creates a blueprint for anyone eager to build a more successful gene drive.


Simply put, a gene drive makes a specific gene spread through a population more rapidly than would happen through nature alone, something geneticists refer to as “super-Mendelian inheritance.” Typically, this means inserting a bit of DNA into the genome of an organism—say, Aedes aegypti, the primary transmitter of the Zika virus. When the modified, or transgenic, mosquito mates with a wild mosquito, their offspring carry one one copy of the “drive gene” directly opposite its natural counterpart. The drive gene snips out the normal gene and inserts a copy of itself, doing this over and over and over again until every mosquito carries two copies of the drive gene—and therefore, resistance to Zika. That’s the idea, anyway. But because nature is imperfect, mistakes happen. More specifically, mutations happen.


The very act of cutting out the normal gene makes the whole system more susceptible to mutations. And if enough of them add up over time and across a population, the drive gene can actually become recessive.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Japanese man is first to receive 'reprogrammed' stem cells from another person

Japanese man is first to receive 'reprogrammed' stem cells from another person | Amazing Science |

World-first transplant, used to treat macular degeneration, represents a major step forward in movement to create banks of ready-made stem cells.


On 28 March 2017, a Japanese man in his 60s became the first person to receive cells derived from induced pluripotent stem (iPS) cells donated by another person.  The surgery is expected to set the path for more applications of iPS-cell technology, which offers the versatility of embryonic stem cells without their ethical taint. Banks of iPS cells from diverse donors could make stem-cell transplants more convenient to perform, while slashing costs. iPS cells are created by removing mature cells from an individual (for example, from their skin) and reprogramming these cells back to an embryonic state. They can then be coaxed into a type of cell useful for treating a disease.


In the latest procedure, performed on a man from the Hyogo prefecture of Japan, skin cells from an anonymous donor were reprogrammed into iPS cells and then turned into a type of retinal cell, which was in turn transplanted onto the retina of the patient, who has age-related macular degeneration. Physicians hope that the cells will stop the progression of the disease, which can lead to blindness.


In September 2014 at the Kobe City Medical Center General Hospital, a Japanese woman underwent a similar procedure to receive retinal cells derived from iPS cells. But these were reprogrammed from cells taken from her own skin. Cells prepared in the same way for a second patient were found to contain genetic abnormalities, and were never implanted. Cells from macular degeneration patients, who tend to be elderly, might have also accumulated genetic defects that could increase the risk of the procedure.


The team decided to redesign the study according to new regulations, and so no more participants were recruited. This month, however, the researchers reported that the Japanese woman fared well1. The introduced cells remained intact one year after surgery, and her vision had not declined, as would usually be expected with macular degeneration.


In Tuesday's procedure — performed at the same hospital and by the same surgeon, Yasuo Kurimoto — doctors used iPS cells that had been taken from a donor’s skin cells, reprogrammed and banked. Japan’s health ministry approved the study, which plans to enroll a total of five patients, on 1 February. 

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Phenanthridine PJ34 Causes Fast Cell Death During Cancer Cell Mitosis and Spares Normal Cells

Phenanthridine PJ34 Causes Fast Cell Death During Cancer Cell Mitosis and Spares Normal Cells | Amazing Science |

Proteins that can be specifically modified during mitosis, the division process, to unleash an inherent death mechanism that self-eradicates duplicating cancer cells have been identified by researchers at Tel Aviv University. Many cancer patients struggle with the adverse effects of chemotherapy, still the most prescribed cancer treatment. For patients with pancreatic cancer and other aggressive cancers, the forecast is more grim: there is no known effective therapy.


Prof. Malka Cohen-Armon, study leader, said: “The discovery of an exclusive mechanism that kills cancer cells without impairing healthy cells, and the fact that this mechanism works on a variety of rapidly proliferating human cancer cells, is very exciting. According to the mechanism we discovered, the faster cancer cells proliferate, the faster and more efficiently they will be eradicated. The mechanism unleashed during mitosis may be suitable for treating aggressive cancers that are unaffected by traditional chemotherapy. Our experiments in cell cultures tested a variety of incurable human cancer types; breast, lung, ovary, colon, pancreas, blood, brain. This discovery impacts existing cancer research by identifying a new specific target mechanism that exclusively and rapidly eradicates cancer cells without damaging normally proliferating human cells.”


The newly-discovered mechanism involves the modification of specific proteins that affect the construction and stability of the spindle, the microtubular structure that prepares duplicated chromosomes for segregation into “daughter” cells during cell division. The researchers found that certain compounds called Phenanthridine derivatives were able to impair the activity of these proteins, which can distort the spindle structure and prevent the segregation of chromosomes. Once the proteins were modified, the cell was prevented from splitting, and this induced the cell’s rapid self-destruction.


“The mechanism we identified during the mitosis of cancer cells is specifically targeted by the Phenanthridine derivatives we tested,” Prof. Cohen-Armon said. “However, a variety of additional drugs that also modify these specific proteins may now be developed for cancer cell self-destruction during cell division. The faster the cancer cells proliferate, the more quickly they are expected to die.” The phenanthrenes PJ34, Phen and Tiq-A, the researchers found, modify kinesins (HSET/kifC1 and kif18A) and NuMA (nuclear mitotic apparatus protein) in a variety of human cancer cells. The most efficient cell killing activity was seen with phenanthridine PJ34, which caused significantly smaller aberrant spindles.


Reference: Visochek, L., Castiel, A., Mittelman, L., Elkin, M., Atias, D., Golan, T., Izraeli, S., Peretz, T., & Cohen-Armon, M. (2017) Exclusive destruction of mitotic spindles in human cancer cells Oncotarget, 8(13), 20813-20824

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Paralyzed man moves arm using power of thought in world first

Paralyzed man moves arm using power of thought in world first | Amazing Science |

A man who was paralysed from below the neck after crashing his bike into a truck can once again drink a cup of coffee and eat mashed potato with a fork, after a world-first procedure to allow him to control his hand with the power of thought.


Bill Kochevar, 53, has had electrical implants in the motor cortex of his brain and sensors inserted in his forearm, which allow the muscles of his arm and hand to be stimulated in response to signals from his brain, decoded by computer. After eight years, he is able to drink and feed himself without assistance.


“I think about what I want to do and the system does it for me,” Kochevar explained. “It’s not a lot of thinking about it. When I want to do something, my brain does what it does.” The experimental technology, pioneered by the Case Western Reserve University in Cleveland, Ohio, is the first in the world to restore brain-controlled reaching and grasping in a person with complete paralysis.


For now, the process is relatively slow, but the scientists behind the breakthrough say this is proof of concept and that they hope to streamline the technology until it becomes a routine treatment for people with paralysis. In the future, they say, it will also be wireless and the electrical arrays and sensors will all be implanted under the skin and invisible.


“Our research is at an early stage, but we believe that this neuroprosthesis could offer individuals with paralysis the possibility of regaining arm and hand functions to perform day-to-day activities, offering them greater independence,” said Dr Bolu Ajiboye, lead author of a paper detailing the research in the Lancet medical journal.

No comment yet.
Scooped by Dr. Stefan Gruenwald!

Whole-body vibration may be as effective as regular exercise

Whole-body vibration may be as effective as regular exercise | Amazing Science |

If you’re overweight and find it challenging to exercise regularly, now there’s good news: A less strenuous form of exercise known as whole-body vibration (WBV) can mimic the muscle and bone health benefits of regular exercise — at least in mice — according to a new study published in the Endocrine Society’s journal Endocrinology.


Lack of exercise is contributing to the obesity and diabetes epidemics, according to the researchers. These disorders can also increase the risk of bone fractures. Physical activity can help to decrease this risk and reduce the negative metabolic effects of these conditions.


But the alternative, WBV, can be experienced while sitting, standing, or even lying down on a machine with a vibrating platform. When the machine vibrates, it transmits energy to your body, and your muscles contract and relax multiple times during each second.


“Our study is the first to show that whole-body vibration may be just as effective as exercise at combating some of the negative consequences of obesity and diabetes,” said the study’s first author, Meghan E. McGee-Lawrence, Ph.D., ofAugusta University in Georgia. “While WBV did not fully address the defects in bone mass of the obese mice in our study, it did increase global bone formation, suggesting longer-term treatments could hold promise for preventing bone loss as well.”


Just as effective as a treadmill

Glucose and insulin tolerance testing revealed that the genetically obese and diabetic mice showed similar metabolic benefits from both WBV and exercising on a treadmill. Obese mice gained less weight after exercise or WBV than obese mice in the sedentary group, although they remained heavier than normal mice. Exercise and WBV also enhanced muscle mass and insulin sensitivity in the genetically obese mice.


The findings suggest that WBV may be a useful supplemental therapy to combat metabolic dysfunction in individuals with morbid obesity. “These results are encouraging,” McGee-Lawrence said. “However, because our study was conducted in mice, this idea needs to be rigorously tested in humans to see if the results would be applicable to people.”


The authors included researchers at the National Institute of Health’s National Institute of Aging (NIA). Funding was provided by the American Diabetes Association, the National Institutes of Health’s National Institute of Diabetes and Digestive Kidney Diseases, and the National Institute on Aging.

No comment yet.