#Missing link found between brain, immune system--with major disease implications Vessels directly connecting brain, lymphatic system exist despite decades of doctrine that they don't.
'In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of medicine have determined that the brain is connected directly to the immune system by vessels previously thought not to exist.
and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.""Instead of asking,'How do we study the immune response of the brain?''
''Why do multiple sclerosis patients have the immune attacks?''now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels,
"said Jonathan Kipnis, Phd, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG)."
"'Very well Hidden'The discovery was made possible by the work of Antoine Louveau, Phd, a postdoctoral fellow in Kipnis'lab. The vessels were detected after Louveau developed a method to mount a mouse's meninges-the membranes covering the brain-on a single slide
so that they could be examined as a whole.""It was fairly easy, actually, "he said.""There was one trick:
Harris, a Phd, is an assistant professor of neuroscience and a member of the BIG center.
Kipnis also saluted the"phenomenal"surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.
Alzheimer's, Autism, MS and Beyond The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it.
take Alzheimer's disease.""In Alzheimer's, there are accumulations of big protein chunks in the brain, "Kipnis said."
"We think they may be accumulating in the brain because they're not being removed efficiently by these vessels."
so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis,
that must be reconsidered in light of the presence of something science insisted did not exist t
A team of chemists and biologists at the Institute of Transformative Biomolecules (ITBM), Nagoya University have succeeded in finding new molecules that change the circadian rhythm in mammals by applying synthetic chemistry methods,
which makes use of highly selective metal catalysts. Most living organisms have a biological clock with an approximately 24-hour circadian rhythm,
Disruption of the circadian rhythm by genetic mutations and environmental factors such as jet lag, may lead to sleep disorders,
as well as lifestyle diseases such as obesity, cancer and mental disorders. The circadian rhythm is also related to seasonal reproduction,
Critical sites on the molecules for bioactivity have been uncovered and both period-lengthening/-shortening molecules have been utilized to investigate the regulation of the clock protein in the body's timekeeping mechanism.
which may overcome various circadian-related diseases and control reproductive activity in animals to provide solutions for food production.
Circadian clock research has accelerated rapidly since the discovery of clock genes in the 1990's. By genetic and molecular biology approaches,
The mechanism of the circadian clock works by circadian clock proteins CLOCK and BMAL1 heterodimers binding to a genetic sequence called E-box (CACGTG),
thus inhibiting the promotion of Per and Cry transcription. Activation and inhibition by the clock proteins constitutes a feedback loop,
"says Tsuyoshi Hirota, a chronobiologist and an associate professor at ITBM, who works with Steve Kay, a principal investigator at ITBM and a professor at the University of Southern California."
Our original palladium catalysts enable selective installation of functional groups at the desired positions on the heteroaromatic ring."
"Tsuyoshi Oshima is a graduate student in Itami's group and worked closely with the biologists at ITBM to synthesize molecules for studying structure-activity relationships (SARS)."Through SAR studies on the molecular derivatives of KL001,
we found the critical sites on the molecule for rhythm-changing activities, and succeeded in discovering active molecules that lengthens
or shortens the period of the circadian rhythm, "says Takashi Yoshimura, an animal biologist and professor at ITBM,
who also led this research from a biological perspective.""It was found that the carbazole moiety was critical for rhythm-changing activity
and that the substituents on the heteroaromatic ring are responsible for tuning the rhythm lengthening/shortening activities,
"says Stephan Irle, a theoretical chemist and a professor at ITBM, who also co-led this research."
"We are pleased extremely that C-H activation chemistry has played an important role in finding bioactive sites in KL001 derivatives
This is my first research outcome from the center's interdisciplinary collaboration between chemists and biologists,
which was made possible by ITBM's unique research environment, "says Itami. ITBM was established officially in 2013 at Nagoya University
and takes up a"Mix-Lab"style where chemists and animal/plant biologists from different research groups work in the same lab space."
"We hope we can make further use of synthetic chemistry to make bioactive molecules that can control the circadian rhythm of animals and gain further insight into the circadian clock mechanism,
which will surely contribute to medical applications, food production and advances in clock research. This has been a wonderful experience for
#Complex, large-scale genome analysis made easier The mset algorithm by Oliver Stegle at EMBL-EBI makes large-scale,
complex genome analyses easier. Researchers at EMBL-EBI have developed a new approach to studying the effect of multiple genetic variations on different traits.
The new algorithm, published in Nature Methods, makes it possible to perform genetic analysis of up to 500,000 individuals-and many traits-at the same time.
The relationship between genes and specific traits is complicated more than simple one-to-one relationships between genes and diseases.
Genome-wide association studies (GWAS) show that many genetic factors are at play for any given trait
but scientists are just beginning to explore how, specifically, genetic variations affect health and disease. Two major statistical challenges to finding these connections involve analysing associations between many different genetic variants and multiple traits,
and making the best use of data from large cohorts that include hundreds of thousands of individuals."
"It is very challenging to identify genetic variants that underlie phenotypes, or traits, and usually we do this by analysing each phenotype
and each variant one by one,"explains Oliver Stegle, Research Group Leader at EMBL-EBI.""But the simple models we use to do this are too simplistic to uncover the complex dependencies between sets of genetic variants and disease phenotypes."
"Complex models that let you look at the combined action of many different variants have involved, until now so much computation that it would take a year to run a single complex query."
"The breakthrough here is that we've made it possible to perform an integrative analysis involving many variants
The researchers tested their algorithm on data from two studies from public repositories, and compared the results with existing state-of-the-art tools.
and can explain a larger proportion of these traits in terms of the genetics that drive them."
"What's important about this work is that it improves statistical power and provides the tools people need to analyse multiple traits in very large cohorts,
"Our algorithm can be used to study up to half a million individuals-that hasn't been possible until now.""
The new algorithm provides much-needed methods for genomics, making large-scale, complex analysis a manageable and practical endeavour."
These methods will help researchers determine which specific aspects of our biology are inherited, and uncover new insights into the genetics behind our countless biological processes."
"Source: European Molecular biology Laborator r
#A microtubule'roadway'in the retina helps provide energy for vision Fluorescently labeled microtubules extend from the tips of the dendrites (top) into the axon and down into the giant synaptic terminal (bottom) of a single isolated goldfish retinal
bipolar cell. A loop of microtubules encircles the inner plasma membrane of the terminal and anchors mitochondria.
Researchers have discovered a thick band of microtubules in certain neurons in the retina that they believe acts as a transport road for mitochondria that help provide energy required for visual processing.
The findings appear in the July issue of The Journal of General Physiology. The retina is a layer of tissue in the back of the eye that converts light into nerve impulses.
They require a constant supply of energy to mediate the sustained release of the contents of an enormous number of synaptic vesicles,
which store the transmitters that convey information between neurons. An intriguing new study of their subcellular structure could help explain how bipolar synaptic terminals meet such excessive energy demands.
Using cutting-edge 3d microscopy, researchers from the National Heart Lung, and Blood Institute and Yale university examined the subcellular architecture of presynaptic terminals in retinal bipolar cells of live goldfish.
Goldfish retinal bipolar cells have giant presynaptic terminals that make them especially amenable for investigation.
Unexpectedly, the team discovered a thick band of microtubules, a component of the cell's cytoskeleton,
that extended from the axon of the neuron into the synaptic terminal and then looped around the interior periphery of the terminal.
The microtubule band appeared to associate with mitochondria--organelles known for providing energy to cells--in the synaptic terminal.
and never made it to the synaptic terminal. The findings suggest that these previously unknown microtubule structures provide a"roadway"for the transport of mitochondria crucial to maintain energy supplies into the synaptic terminals of these highly active neurons associated with vision.
Source: Rockefeller University Pres s
#Researchers discover how opium poppies synthesize morphine From left: Peter Facchini, professor in biological sciences, Jill Hagel, research associate,
and Scott Farrow, Phd student. Many people who live in developing countries do not have access to the pain relief that comes from morphine or other analgesics.
That's because opiates are derived primarily from the opium poppy plant (Papaver somniferum) and are dependent on the plant health and supply around the world.
After years of leading research on the opium poppy, University of Calgary scientists, Peter Facchini, his Phd student, Scott Farrow,
and research associate Jill Hagel, have characterized a novel gene that encodes the gateway enzyme in the formation of morphine
-which is to say, they've begun to understand how poppies synthesize the pain killing enzymes.
which encodes the gateway enzyme in the formation of morphine, "says Farrow.""It's really interesting to see these fused genes in a metabolic pathway.
"The findings were published July 1 in Nature Chemical Biology, and detail the missing step to morphine biosynthesis. Next steps Facchini says the isolation of this gene,
among many other things, is a key step toward the reassembly of the pathway to morphine in microorganisms such as yeast."
codeine and oxycodone,"says Facchini, professor of biological sciences in the Faculty of science and an internationally recognized expert on the opium poppy."
He likens this discovery to a box of Lego building blocks without a set of instructions-where the blocks are the genes along the pathway.
One of the next steps will be to"write the instruction manual"based on still unknown information about how the genes work,
University of Calgar r
#New cell division mechanism discovered Canadian and British researchers have discovered that chromosomes play an active role in animal cell division.
This occurs at a precise stage-cytokinesis-when the cell splits into two new daughter cells.
It was observed by a team of researchers including Gilles Hickson, an assistant professor at the University of Montreal's Department of Pathology and Cell biology and researcher at the CHU Sainte-Justine Research Centre, his assistant Silvana Jananji, in collaboration with Nelio
Rodrigues, a Phd student, and Sergey Lekomtsev, a postdoc, working in the group led by Buzz Baum of the MRC Laboratory for Molecular Cell biology at University college London.
Their findings were published today in Nature. Cell division is fundamental to all life forms: the human body develops from a single cell that divides billions of times to generate all tissue types,
and it was unknown until now that chromosomes could play an active role at this step in cytokinesis.
the separation of chromosomes followed by splitting of the cell into two new daughter cells by cytokinesis."
it can be a source for triggering cancer, for example,"said Hickson. It is well known that microscopic cable-like structures,
called microtubules, were involved in pulling chromosomes to opposite poles of the cell during the division process."
"At this time, microtubules physically separate the chromosomes via their central kinetochores while other microtubules signal to the cortex of the cell where its equator is, i e.,
Furthermore until now, it was believed that the chromosomes only played a passive role: that they were pulled by the microtubules
Chromosomes'active role Initially working with the cells of fruit flies using powerful genetic tools and sophisticated microscopy,
the research team discovered that chromosomes emit signals that influence the cortex of the cell to reinforce microtubule action.
This is what makes fruit flies such a powerful system for helping us to understand human biology.""When chromosomes are segregated,
they approach the membrane at the poles of the cell, and thanks to this enzyme's actions, this contributes to the softening of the polar membrane,
and to certain diseases,"said Hickson, who has devoted the last 15 years of his research life to cell biology.
In fact, all cancers are unchecked characterised by cell division, and the underpinning processes are potential targets for therapeutic interventions that prevent cancer onset and spread."
"But before we get there, we must continue to expand our knowledge about the basic processes
and signals involved in normal cell division to understand how they can go awry, or how they can be exploited..
Ultimately, this could help the rational design of more specific therapies to inhibit the division of cancer cells,
#Scientists find molecular switch that creates long-term immunity Melbourne researchers have identified a protein responsible for preserving the antibody-producing cells that lead to long-term immunity after infection or vaccination.
Dr Kim Good-Jacobson, Professor David Tarlinton and colleagues from the Walter and Eliza Hall Institute discovered the presence of a protein called Myb was essential for antibody-producing plasma cells to migrate into bone marrow,
Their findings were published in the Journal of Experimental Medicine. Dr Good-Jacobson said plasma cells were created
when the immune system was exposed to pathogens such as viruses or bacteria.""When our immune system encounters a new pathogen,
it can create plasma cells that secrete antibodies to specifically prevent future infections, generating immunity, "she said."
"Our bone marrow is like a long-term storage facility for plasma cells, allowing them to continue producing antibodies to protect against future infections.
Until now, it was known not why some plasma cells moved into the bone marrow, while others remained in the blood stream
and perished after a few days.""The research team discovered that when the gene that produces the protein Myb was removed,
plasma cells were no longer able to move into the bone marrow to provide long-term immunity.""Myb is a type of protein called a transcription factor,
we might be able to encourage the immune system to create long-term immunity for a range of infections."
improving the design of antibodies to better recognise invading pathogens in the future, "she said.""The Myb protein marks the plasma cells that produce high-quality antibodies for preservation."
"Professor Tarlinton said the discovery would mean researchers could now search for the trigger of Myb production
and find out what genes Myb controls.""Now that we know Myb is critical in creating long-term immunity,
we can begin dissecting the pathways it uses to mark plasma cells for storage and the genes involved in migrating to the bone marrow,
"Some pathogens, such as malaria, typically trigger the creation of short-lived plasma cells. If we don't create long-lived plasma cells,
we don't develop lasting immunity to the disease. If we can trigger the expression of Myb in plasma cells responding to pathogens
-either by infection or by immunisation-we might be able to convince the immune system to store these plasma cells in the bone marrow to offer protection against future infections
#Researchers create model of early human heart development from stem cells Researchers at the University of California, Berkeley,
in collaboration with scientists at the Gladstone Institutes, have developed a template for growing beating cardiac tissue from stem cells,
the researchers used biochemical and biophysical cues to prompt stem cells to differentiate and self-organize into micron-scale cardiac tissue,
"said Kevin Healy, a UC Berkeley professor of bioengineering, who is co-senior author of the study with Dr. Bruce Conklin, a senior investigator at the Gladstone Institute of Cardiovascular disease and a professor of medical genetics and cellular and molecular pharmacology at UC San francisco."
"This technology could help us quickly screen for drugs likely to generate cardiac birth defects, and guide decisions about
which drugs are dangerous during pregnancy.""Screening for drug toxicity To test the potential of the system as a drug-screening tool,
the researchers exposed the differentiating cells to thalidomide, a drug known to cause severe birth defects.
They found that at normal therapeutic doses, the drug led to abnormal development of microchambers, including decreased size,
problems with muscle contraction and lower beat rates compared with heart tissue that had not been exposed to thalidomide."
"We chose drug cardiac developmental toxicity screening to demonstrate a clinically relevant application of the cardiac microchambers,
"said Conklin.""Each year, as many as 280,000 pregnant women are exposed to drugs with evidence of potential fetal risk.
The most commonly reported birth defects involve the heart, and the potential for generating cardiac defects is of utmost concern in determining drug safety during pregnancy."
and other UC Berkeley researchers publicly debuted a system of beating human heart cells on a chip that could be used to screen for drug toxicity.
However, that heart-on-a-chip device used pre-differentiated cardiac cells to mimic adult-like tissue structure.
Location, location, location By the end of two weeks, the cells that began on a two-dimensional surface environment started taking on a 3d structure as a pulsating microchamber.
cells along the edge experienced greater mechanical stress and tension, and appeared more like fibroblasts,
"This spatial differentiation happens in biology naturally, but we demonstrated this process in vitro, "said study lead author Zhen Ma, a UC Berkeley postdoctoral researcher in bioengineering."
"The confined geometric pattern provided biochemical and biophysical cues that directed cardiac differentiation and the formation of a beating microchamber."
"Could eventually replace animal models Modeling early heart development is difficult to achieve in a petri dish and tissue culture plates,
"The fact that we used patient-derived human pluripotent stem cells in our work represents a sea change in the field,
which is an imperfect model for human disease.""The researchers pointed out that while this study focused on heart tissue,
University of California-Berkele e
#HIV uses the immune system's own tools to suppress it A Canadian research team at the IRCM in Montreal,
This breakthrough was published yesterday in the scientific journal PLOS Pathogens and will be presented at the upcoming IAS 2015 conference in Vancouver.
The findings pave the way for future HIV prevention or cure strategies. The study's goal was to determine how HIV manages to compromise antiviral responses in the initial period of infection,
also called the acute infection stage, during which the virus establishes itself in the body.
The acute infection is considered a critical period in determining the complexity, extent and progression of the disease.
It is also during this stage that HIV establishes latent infection in long-lasting cellular reservoirs.
These viral reservoirs, which harbour the virus out of sight from the immune system and antiviral drugs, represent the primary barrier to a cure."
"An important component in this process is a group of proteins collectively called type 1 Interferons,
which are the immune system's first line of defence against viral infections and are known to have a beneficial role in the early stages of HIV infection,
"says Dr. Cohen, Director of the Human Retrovirology research unit at the IRCM.""The problem is that HIV has developed mechanisms to suppress the Interferon response and, until now,
"Most of the Interferon is produced by a very small population of immune cells called pdcs (plasmacytoid dendritic cells), responsible for providing immediate defence against infections.
when they recognize the presence of a pathogen, they secrete Interferon. The Interferon then triggers a large array of defence mechanisms in nearby cells, creating an antiviral state that prevents the dissemination and, ultimately,
the expansion of the virus."When pdcs encounter HIV-infected cells, the production of Interferon is regulated by a protein located on the infected cell's surface called BST2,"
and leads to persistent infection, "adds Dr. Bego.""We found that HIV, through Vpu, takes advantage of the role played by BST2 by maintaining its ability to activate ILT7 and limit the production of Interferon,
""The hope for a definitive cure and an effective vaccine has been frustrated by HIV's endless propensity to subvert the host's defences
despite antiretroviral therapy,"describes Dr. Cohen, who also leads Cancure, a team of leading Canadian researchers working towards an HIV cure."
"Our findings can provide tools to enhance antiviral responses during the early stages of infection.
By blocking Vpu's action, we could prevent early viral expansion and dissemination, while also allowing pdcs to trigger effective antiviral responses.
We believe that such interventions during primary infection have the potential to limit the establishment and complexity of viral reservoirs,
a condition that seems required to achieve a sustained HIV remission.""""The discovery by Drs.
or wiped out during early periods of infection, will bring us closer to ending HIV/AIDS,
this new study will advance research for an HIV cure
#Malaria's key to the liver uncovered Scientists uncover a port of liver entry for malaria parasites in a report published in The Journal of Experimental Medicine.
If these results hold up in humans, drugs that target this entry protein might help prevent the spread of disease.
Malaria is caused by a parasite called Plasmodium falciparum, which is transmitted to humans via mosquito bite. Recent efforts to limit parasite transmission and increase treatment coverage has reduced the number of malaria-related deaths,
but the parasite still causes roughly 200 million new infections and half a million deaths worldwide each year.
The first stop for malaria parasites in humans is the liver where a few organisms multiply into tens of thousands,
which are released then into the bloodstream. Passage through the liver is essential for the parasite to establish a productive infection and cause disease,
and the bug's entry route has been traced to specialized liver cells called Kupffer cells. But exactly how the parasite traverses these cells is not clear.
A team of scientists at Johns Hopkins Bloomberg School of Public health now find that a Kupffer cell protein called CD68 is needed for parasite passage and efficient liver infection,
If this reduction is sufficient to substantially limit blood infections (and thus disease CD68 may represent a potential new drug target in the fight against malaria a
#Study finds non-genetic cancer mechanism Cancer can be caused solely by protein imbalances within cells,
a study of ovarian cancer has found. The discovery is a major breakthrough because, until now, genetic aberrations have been seen as the main cause of almost all cancer.
The research, published today in the journal Oncogene, demonstrates that protein imbalance is a powerful prognostic tool,
indicating whether or not patients are likely to respond to chemotherapy and whether a tumour is likely to spread to other sites.
The findings also open the possibility of new therapies aimed at measuring and preventing dangerous imbalances in cells.
Lead author Professor John Ladbury Dean of the University of Leeds'Faculty of Biological sciences and Professor of Mechanistic Biology, said:"
"There has been huge investment in sequencing the human genome with the idea that if we get all the relevant genetic information we can predict
whether you have a predisposition to cancer and, ultimately, use a precision medicine-based approach to develop a therapeutic approach.
Our study demonstrates that genetic screening alone is not enough.""The research, led by scientists at the University of Leeds and The University of Texas MD Anderson Cancer Center, focused on the"Akt pathway,
"a signalling pathway within cells that drives cancer formation and the spread of cancers through the body.
Under normal conditions, the cell receives external signals through a cell wall-bound receptor (FGFR2 in this study.
As a result of this stimulus the receptor is switched on'inside the cell. This results in the recruitment of signalling proteins and the initiation of the Akt pathway,
which is responsible for committing the cell to proliferate. In some cancerous cells, this pathway is switched permanently on.
A conventional approach to diagnosing this cancer would be to look for genetic modification of the receptor
(or recruited proteins), which could be responsible for maintaining the switched on state. The new study looked at isolated cancer cells without external stimulation
and found that the"Akt pathway"could be activated without genetic modifications. Two proteins; Plc? 1 (pronounced"plc-gamma-1")and Grb2 (pronounced"grab-2),
"compete for binding to FGFR2. The relative concentration of these proteins will dictate which one binds.
1 prevails, it triggers the Akt pathway. In this way, an imbalance in the amount of the two proteins can lead to cell proliferation and cancer formation.
Dr Zahra Timsah, University Academic Fellow at the University of Leeds'School of Molecular and Cellular biology,,
who was the lead researcher on the study, said:""This competition for binding to the receptor represents an unexpected way in
which cancer can occur. We found that in cells where Grb2 is depleted, FGFR2 was vulnerable to Plc?
"The researchers also looked at the process in a mouse model and found that Grb2 depletion results in the development of multiple tumours in the vicinity of a primary tumour,
indicating that protein imbalance can have a role in metastasis, the spread of a cancer through the body.
1 was predictive of the progress of ovarian cancers in patients. Measuring the levels of the proteins in patient tissues followed by database analysis of clinical information from The Cancer Genome Atlas
and other sources revealed that a high level of Grb2 relative to Plc? 1 and FGFR2 was associated with a significantly more favourable prognosis than patients with elevated levels of Plc?
1. Statistical data reveal that just under 40%of patients with a favourable balance were still alive seven years after samples were taken.
1 and FGFR2 binding sites survived the same length of time. Professor Ladbury said:""From the patient's point of view, the key findings are that these proteins are biomarkers.
They could offer information to clinicians on who is going to benefit from therapy and, just as importantly, who is not.
On the treatment side, the proteins'interaction could be a valid therapeutic target: you could, for instance, target Plc?
1 to ensure it does not overwhelm the cell.""Previous research findings have emphasised the roots of cancer in genetic mutation.
Some studies have pointed to cancers that occur without genetic causes, such as through epigenetic modifications of proteins,
however the present study reveals that signalling though cell wall-based receptors can occur without receptor activation
and therefore that non-genetic causes may be critical to understanding cancer in large numbers of patients.
The researchers are now working with clinicians at the University of Leeds to study the same mechanisms in other forms of cancer.
They are also exploring the possibility that other cell receptors could play a similar role to FGFR2 in sustaining oncogenic signalling without being activated themselves d
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