The Biology Lair

A tumblog for all things life sciences.

[biologylair]

Antibodies are the secreted form of B-lymphocyte receptors and are a part of adaptive immunity, but how are these proteins formed?

Above is a diagram illustrating Paul Ehlrich's Side Chain Theory of Antibody Formation. Ehlrich proposed that immunoglobulin molecules, a fundamental component of adaptive immunity, served as membrane bound proteins that bound to particular threats, similarly to the former "key in lock" view of enzymes in catalyzing biological reactions. Ehrlich also suggested that the action of binding a pathogenic molecule to the receptor would generate a signal to stimulate the production of more receptors of the same specificity. These "side chains" that were added on would then break off from the cell surface and become what we call antibodies.

 We now know, however, that soluble immunoglobulin receptors are specially manufactured to be secreted as antibody, rather than just "breaking off" of the lymphocyte, even though they have the same specificity as their membrane-bound counterparts.

[neurosciencestuff]

Shining Light on Brain Tumors

When operating on cancer, surgeons want to remove tumors and not healthy tissue. This is especially important and challenging when dealing with brain tumors, which are often spread out and mixed in with the healthy tissue. Now, researchers have shown that a well-established optics technique can reveal exactly where brain tumors are, producing images in less than a minute — unlike conventional methods that can take a whole day.

“The special thing about our images is that we showed they contain so much information,” said Marloes Groot of VU University Amsterdam, Netherlands. “When I showed these images to the pathologists that we work with, they were amazed.” Groot and her colleagues describe their work in the journal Biomedical Optics Express, from The Optical Society.

Pathologists typically use staining methods, in which chemicals like hematoxylin and eosin turn different tissue components blue and red, revealing its structure and whether there are any tumor cells. But for a definitive diagnosis this process can take up to 24 hours, which means surgeons may not realize some cancerous tissue has escaped from their attention until after surgery — requiring a second operation and more risk.

But with the new technique, the researchers don’t use any labeling or staining at all. Instead, they fire short, 200-femtosecond-long laser pulses into the tissue, and when three photons converge at the same time and place, the photons interact with the nonlinear optical properties of the tissue. Through well-known phenomena in optics called second and third harmonic generation, these interactions produce a single photon.

The key is that the incoming and outgoing photons have different wavelengths. The incoming photons are at 1200 nanometers, long enough to penetrate deep into the tissue. The single photon that is produced, however, is at 600 or 400 nanometers, depending on if it’s second or third harmonic generation. The shorter wavelengths mean the photon can scatter in the tissue. The scattered photon thus contains information about the tissue, and when it reaches a detector, in this case a high-sensitivity GaAsP photomultiplier tube, it reveals what the tissue looks like inside.

While other researchers have exploited this technique for other applications — to make images of insects and fish embryos, for example — this is the first time anyone has used it to analyze glial brain tumors. These tumors are particularly deadly because it’s hard to get rid of tumor cells by surgery, irradiation, and chemotherapy without substantial collateral damage to the surrounding brain tissue.

The researchers tested their method on samples of glial brain tumors from humans, finding that the histological detail in these images was as good — if not better — than those made with conventional staining techniques. They were able to make most images in under a minute. The smaller ones took less than a second, while larger images of a few square millimeters took five minutes. “This makes it possible to do it in real time in the operating room,” Groot said.

Now that they’ve shown their approach works, the researchers are developing a hand-held device that a surgeon can use to identify a tumor’s border during surgery. The incoming laser pulses can only reach a depth of about 100 micrometers into the tissue. To reach farther, Groot envisions attaching a needle that can pierce the tissue and deliver photons deeper.

“With our technique it’s potentially possible to diagnose not only during an operation but possibly before surgery,” she said.

[biologylair]

[neurosciencestuff]

Participants in novel drug intervention program have increased brain activation to healthy pleasures

How can people who are dependent on prescription opioids reduce their cravings? Learn to enjoy other aspects of their lives.

That’s the key finding in a new study published in the Journal of Behavioral Medicine by Eric L. Garland, associate professor at the University of Utah College of Social Work. Garland and colleagues studied how an intervention program for chronic pain patients called Mindfulness-Oriented Recovery Enhancement (MORE) decreased patients’ desire for prescription drugs.

The MORE intervention concentrates on helping people to recover a sense of meaning and fulfillment in everyday life, embracing its pleasures and pain without turning to substance use as a coping mechanism. It integrates the latest research on addiction, cognitive neuroscience, positive psychology and mindfulness. Participants in Garland’s study received eight weeks of instruction in applying mindfulness-oriented techniques to alleviate pain and craving while strengthening positive emotions and the sense of reward and meaning in life.

For example, to enhance their sense of reward in life, participants in Garland’s study were taught a “mindful savoring practice,” in which they focused attention on pleasant experiences such as a beautiful nature scene, sunset or feeling of connection with a loved one. In a meditation session, participants were taught to focus their awareness on colors, textures and scents of a bouquet of fresh flowers and to appreciate joy arising from the experience. As part of their daily homework, they were then asked to practice the meditation technique as a way to enjoy other pleasant life experiences.

Results from Garland’s new research shows that after a sample of chronic pain patients misusing opioids went through MORE, they exhibited increased brain activation on an EEG to natural healthy pleasures. The more their brains became active in response to natural healthy pleasure, the less the patients craved opioids.

“These findings are scientifically important because one of the major theories about how and why addiction occurs asserts that over time drug abusers become dulled to the experience of joy in everyday life, and this pushes them to use higher and higher doses of drugs to feel happiness,” said Garland.

“This study suggests that this process can be reversed. We can teach people to use mindfulness to appreciate and enjoy life more, and by doing that, they may feel less of a need for addictive drugs. It’s a powerful finding.”

Garland’s latest study builds on earlier work published in February in The Journal of Consulting and Clinical Psychology, in which the MORE intervention was found to reduce opioid misuse among a sample of chronic pain patients compared to another sample of chronic pain patients participating in a conventional support group.

The results are of particular interest in Utah, which claims one of the highest prescription drug abuse rates in the U.S. According to the most recent statistics available from the state Division of Substance Abuse and Mental Health, Utah ranks eighth in the U.S. for its number of deaths attributed to prescription drug overdose.

Garland, who developed MORE intervention, noted the method is also being tested on people who want to quit smoking or lose weight.

[ucsdhealthsciences-deactivated2]

Scientists Discover “Dimmer Switch” For Mood Disorders

Researchers at University of California, San Diego School of Medicine have identified a control mechanism for an area of the brain that processes sensory and emotive information that humans experience as “disappointment.”

The discovery of what may effectively be a neurochemical antidote for feeling let-down is reported Sept. 18 in the online edition of Science.

“The idea that some people see the world as a glass half empty has a chemical basis in the brain,” said senior author Roberto Malinow, MD, PhD, professor in the Department of Neurosciences and neurobiology section of the Division of Biological Sciences. “What we have found is a process that may dampen the brain’s sensitivity to negative life events.”

Because people struggling with depression are believed to register negative experiences more strongly than others, the study’s findings have implications for understanding not just why some people have a brain chemistry that predisposes them to depression but also how to treat it.

Specifically, in experiments with rodents, UC San Diego researchers discovered that neurons feeding into a small region above the thalamus known as the lateral habenula (LHb) secrete both a common excitatory neurotransmitter, glutamate, and its opposite, the inhibitory neurotransmitter GABA.

Excitatory neurotransmitters promote neuronal firing while inhibitory ones suppress it, and although glutamate and GABA are among two of the most common neurotransmitters in the mammalian brain, neurons are usually specialists, producing one but not both kinds of chemical messengers.

Indeed, prior to the study, there were only two other systems in the brain where neurons had been observed to co-release excitatory and inhibitory neurotransmitters – in a particular connection in the hippocampus and in the brainstem during development of the brain’s auditory map.

“Our study is one of the first to rigorously document that inhibition can co-exist with excitation in a brain pathway,” said lead author Steven Shabel, a postdoctoral researcher with Department of Neurosciences and neurobiology section of the Division of Biological Sciences. “In our case, that pathway is believed to signal disappointment.”

The LHb is a small node-like structure in the epithalamus region of the brain that is critical for processing a variety of inputs from the basal ganglia, hypothalamus and cerebral cortex and transmitting encoded responses (output) to the brainstem, an ancient part of the brain that mammals share with reptiles.

Experiments with primates have shown that activity in the LHb increases markedly when monkeys are expecting but don’t get a sip of fruit juice or other reward, hence the idea that this region is part of a so-called disappointment pathway.

Proper functioning of the LHb, however, is believed to be important in much more than just disappointment and has been implicated in regulating pain responses and a variety of motivational behaviors. It has also been linked to psychosis.

Depression, in particular, has been linked to hyperactivity of the LHb, but until this study, researchers had little empirical evidence as to how this overstimulation is prevented in healthy individuals given the apparent lack of inhibitory neurons in this region of the brain.

"The take-home of this study is that inhibition in this pathway is coming from an unusual co-release of neurotransmitters into the habenula," Shabel said. Researchers do not know why this region of the brain is controlled in this manner, but one hypothesis is that it allows for a more subtle control of signaling than having two neurons directly counter-acting each other.

Researchers were also able to show that neurons of rodents with aspects of human depression produced less GABA, relative to glutamate. When these animals were given an antidepressant to raise their brain’s serotonin levels, their relative GABA levels increased.

"Our study suggests that one of the ways in which serotonin alleviates depression is by rebalancing the brain’s processing of negative life events vis-à-vis the balance of glutamate and GABA in the habenula," Shabel said. "We may now have a precise neurochemical explanation for why antidepressants make some people more resilient to negative experiences."

Pictured: Basal ganglia neurons (green) feed into the brain and release glutamate (red) and GABA (blue) and sometimes a mix of both neurotransmitters (white).

[medicalschool]

Budd–Chiari syndrome is a condition caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins.

The acute syndrome presents with rapidly progressive severe upper abdominal pain, jaundice, hepatomegaly (enlarged liver), ascites, elevated liver enzymes, and eventually encephalopathy. The fulminant syndrome presents early with encephalopathy and ascites. Severe hepatic necrosis and lactic acidosis may be present as well. Caudate lobe hypertrophy is often present. The majority of patients have a slower-onset form of Budd–Chiari syndrome. This can be painless. A system of venous collaterals may form around the occlusion which may be seen on imaging as a “spider’s web.” Patients may progress to cirrhosis and show the signs of liver failure.

[ucsdhealthsciences-deactivated2]

Birthday Matters for Wiring-Up the Brain’s Vision Centers

Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.

The study is published online July 31 in Cell Reports.

“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.

A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.

The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.

To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.

For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.

The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.

“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”

The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.

In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.

“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

[neurosciencestuff]

A team of researchers at the Neuroscience Institute at Georgia State University has discovered that hidden differences in the properties of neural circuits can account for whether animals are behaviorally susceptible to brain injury. These results could have implications for the treatment of brain...

[ucsdhealthsciences-deactivated2]

“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”

To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase or MGMT. This protein dampens the cancer-killing effect of temozolomide. Tumors with high levels of MGMT are associated with a poor response to temozolomide therapy. 

The scientists systematically tested every microRNA in the human genome to identify those that suppressed MGMT expression, with the expectation that high-levels of these microRNAs in the tumor would predict improved therapeutic response to temozolomide.

“We showed that a signature of the MGMT-regulating microRNAs predicted temozolomide response in a cohort of glioblastoma patients.  Validation of these results should lead to diagnostic tools to enable us to determine which patients will benefit most from temozolomide therapy,” said Chen.

In the study, the scientists also discovered that injection of the MGMT-regulating microRNAs into glioblastoma cells increased tumor sensitivity to temozolomide treatment. 

“These findings establish the foundation for microRNAs-based therapies to increase the efficacy of temozolomide in glioblastoma patients,” said lead author, Valya Ramakrishnan, PhD, postdoctoral researcher, UC San Diego School of Medicine.

[biologylair]

Incredible scanning electron micrograph of an exposed axon terminal, loaded with synaptic vesicles (orange and blue). 

Image Credit: Tina Carvalho

[rhamphotheca]

Scientists uncover new marine mammal genus, represented by single endangered species

by Jeremy Hance

This is the story of three seals: the Caribbean, the Hawaiian, and the Mediterranean monk seals. Once numbering in the hundreds of thousands, the Caribbean monk seal was a hugely abundant marine mammal found across the Caribbean, and even recorded by Christopher Columbus during his second voyage, whose men killed several for food. Less than 500 years later the species would be extinct—due to overhunting. But scientists have long wondered how the extinct Caribbean monk seal was related to other monk seals: was it more closely related to the Mediterranean species or the Hawaiian one? Now, researchers have an answer and a new seal genus, as well. 

"Our paper is the first to firmly solve this riddle, both by producing and analyzing the first DNA evidence from the Caribbean monk seal, and by examining the anatomy of large series of monk seal specimens in museums, mostly from the Smithsonian," co-author and mammalogist Kristofer Helgen with the Smithsonian Institute told mongabay.com. "The answer is that the Caribbean monk seal is most closely related to the Hawaiian monk seal, demonstrating that the New World monk seals form a group to the exclusion of the Mediterranean monk seal." 

In fact, the New World monk seals are so genetically distinct—and physically different—from the Mediterranean monk seal that the researchers have proposed a new genus for the Caribbean and Hawaiian species: Neomonachus. Prior to this all three species were listed under one genus, Monachus…

(read more: MongaBay)

illustration of Caribbean Monk Seal by Peter Shouten

[bbsrc]

Food, famine and fungi

Ustilago maydis is a fungus that infects maize crops and causes the disease corn smut. In these images you can see the corn smut fungus (green) infecting a maize leaf (red). This infection will cause large plant ‘tumors’ and can eventually result in plant death.

Diseases like this pose a major threat to modern agriculture and therefore understanding fungal plant pathogens is of huge importance. 

BBSRC-funded scientists from The University of Exeter hope to understand the complex interplay between this fungal pathogen and its plant host. This knowledge will then help in the development of novel fungicides that can stop crop infection and keep food on our forks.

Images and research from Professor Gero Steinberg at the University of Exeter.

For more information on his research go to: http://bit.ly/1sbhNCo

For more plant related blog posts go to: http://tmblr.co/ZtJ7bq16IST19r

Or visit our Facebook at: https://www.facebook.com/bbsrcnews

[biologylair]

Okay seriously, with all the talk about Gluten-Free diets, what is it really? Get the scientific facts on whether gluten is actually bad for you.

[neurosciencestuff]

Controlling fear by modifying DNA

For many people, fear of flying or of spiders skittering across the lounge room floor is more than just a momentary increase in heart rate and a pair of sweaty palms.

It’s a hard-core phobia that can lead to crippling anxiety, but an international team of researchers, including neuroscientists from The University of Queensland’s Queensland Brain Institute (QBI), may have found a way to silence the gene that feeds this fear.

QBI senior research fellow Dr Timothy Bredy said the team had shed new light on the processes involved in loosening the grip of fear-related memories, particularly those implicated in conditions such as phobia and post-traumatic stress disorder.

Dr Bredy said they had discovered a novel mechanism of gene regulation associated with fear extinction, an inhibitory learning process thought to be critical for controlling fear when the response was no longer required.

“Rather than being static, the way genes function is incredibly dynamic and can be altered by our daily life experiences, with emotionally relevant events having a pronounced impact,” Dr Bredy said.

He said that by understanding the fundamental relationship between the way in which DNA functions without a change in the underlying sequence, future targets for therapeutic intervention in fear-related anxiety disorders could be developed.

“This may be achieved through the selective enhancement of memory for fear extinction by targeting genes that are subject to this novel mode of epigenetic regulation,” he said.

Mr Xiang Li, a PhD candidate and the study’s lead author, said fear extinction was a clear example of rapid behavioural adaptation, and that impairments in this process were critically involved in the development of fear-related anxiety disorders.

“What is most exciting is that we have revealed an epigenetic state that appears to be quite specific for fear extinction,” Mr Li said.

Dr Bredy said this was the first comprehensive analysis of how fear extinction was influenced by modifying DNA.

“It highlights the adaptive significance of experience-dependent changes in the chromatin landscape in the adult brain,” he said.

The collaborative research is being done by a team from QBI, the University of California, Irvine, and Harvard University.

The study was published this month in the Proceedings of the National Academy of Sciences of the United States of America.

[neurosciencestuff]

Functional brain imaging reliably predicts which vegetative patients have potential to recover consciousness

A functional brain imaging technique known as positron emission tomography (PET) is a promising tool for determining which severely brain damaged individuals in vegetative states have the potential to recover consciousness, according to new research published in The Lancet.

It is the first time that researchers have tested the diagnostic accuracy of functional brain imaging techniques in clinical practice.

“Our findings suggest that PET imaging can reveal cognitive processes that aren’t visible through traditional bedside tests, and could substantially complement standard behavioural assessments to identify unresponsive or “vegetative” patients who have the potential for long-term recovery”, says study leader Professor Steven Laureys from the University of Liége in Belgium.

In severely brain-damaged individuals, judging the level of consciousness has proved challenging. Traditionally, bedside clinical examinations have been used to decide whether patients are in a minimally conscious state (MCS), in which there is some evidence of awareness and response to stimuli, or are in a vegetative state (VS) also known as unresponsive wakefulness syndrome, where there is neither, and the chance of recovery is much lower. But up to 40% of patients are misdiagnosed using these examinations.

“In patients with substantial cerebral oedema [swelling of the brain], prediction of outcome on the basis of standard clinical examination and structural brain imaging is probably little better than flipping a coin,” writes Jamie Sleigh from the University of Auckland, New Zealand, and Catherine Warnaby from the University of Oxford, UK, in a linked Comment.

The study assessed whether two new functional brain imaging techniques—PET with the imaging agent fluorodeoxyglucose (FDG) and functional MRI (fMRI) during mental imagery tasks—could distinguish between vegetative and MCS in 126 patients with severe brain injury (81 in a MCS, 41 in a VS, and four with locked-in syndrome—a behaviourally unresponsive but conscious control group) referred to the University Hospital of Liége, in Belgium, from across Europe. The researchers then compared their results with the well-established standardised Coma Recovery Scale–Revised (CSR-R) behavioural test, considered the most validated and sensitive method for discriminating very low awareness.

Overall, FDG-PET was better than fMRI in distinguishing conscious from unconscious patients. Mental imagery fMRI was less sensitive at diagnosis of a MCS than FDG-PET (45% vs 93%), and had less agreement with behavioural CRS-R scores than FDG-PET (63% vs 85%). FDG-PET was about 74% accurate in predicting the extent of recovery within the next year, compared with 56% for fMRI.

Importantly, a third of the 36 patients diagnosed as behaviourally unresponsive on the CSR-R test who were scanned with FDG-PET showed brain activity consistent with the presence of some consciousness. Nine patients in this group subsequently recovered a reasonable level of consciousness.

According to Professor Laureys, “We confirm that a small but substantial proportion of behaviourally unresponsive patients retain brain activity compatible with awareness. Repeated testing with the CRS–R complemented with a cerebral FDG-PET examination provides a simple and reliable diagnostic tool with high sensitivity towards unresponsive but aware patients. fMRI during mental tasks might complement the assessment with information about preserved cognitive capability, but should not be the main or sole diagnostic imaging method.”

The authors point out that the study was done in a specialist unit focusing on the diagnostic neuroimaging of disorders of consciousness and therefore roll out might be more challenging in less specialist units.

Commenting on the study Jamie Sleigh and Catherine Warnaby add, “From these data, it would be hard to sustain a confident diagnosis of unresponsive wakefulness syndrome solely on behavioural grounds, without PET imaging for confirmation…[This] work serves as a signpost for future studies. Functional brain imaging is expensive and technically challenging, but it will almost certainly become cheaper and easier. In the future, we will probably look back in amazement at how we were ever able to practise without it.”

[zerostatereflex]

Just a Mantis Shrimp scrubbing it’s badass eye,

[amolecularmatter-blog]

Innervating the Brain

The Allen Brain Atlas is an online tool that combines structure, function, and gene expression data to create a comprehensive catalogue of histological sections and three-dimensional renderings of the human and mouse brains. While it was established primarily to accelerate neuroscience and neuroanatomy research, it is available free online. The images above are taken from renderings of the mouse brain showing the innervation of the olfactory bulb (bottom and top) and the expression of the App gene (middle) implicated in amyloid fibril formation in Alzheimer’s disease and, interestingly, mental retardation in Down Syndrome patients (APP, the human analogue to mouse App, is encoded on chromosome 21). 

Networks of neurons are not and cannot be wires like you would see on the side of a highway; they usually eminate from a point of origin and move to connect certain points of the brain, but they are in no way disorganised. For example, while the corpus collosum maintains extensive innervation throughout both hemispheres, other areas of the brain will not. It is this sort of macro-scale compartmentation that allows different parts of the brain to perform different functions - in vertebrates like us, for example, intense lateralisation of the hemispheres gives rise to lower-level organisation, namely the specific structures that perform fundamentally different tasks (the hippocampus, the cerebrum, and the cerebellum, for example). Before in situ hybridisation, the characteristic pattern of neuronal spread throughout the brain was probed by creating lesions in different areas and noting the resulting phenotype; this worked because without excitation, neurons die. This same reality makes it highly suboptimal for the brain to organise itself as a tangled mess of fibres if many of the pathways are likely to become redundant; it both necessitates and causes an organised structure built upon the frequency of signal transduction to particular areas.