Restoring IL-17 may treat skin infections related to chronic alcohol consumption

Summary:

Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report helps explain why this happens and what might be done to address it. "The clinical association between alcoholism and severe skin infection is well established," said one expert. "The ability to experimentally model skin immune deficiencies that occur in chronic alcoholics opens up new avenues to test immune-based therapies to better protect this population and thereby limit the spread of infectious disease to the broader community as well."

Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report appearing in the April 2015 issue of the Journal of Leukocyte Biology, helps explain why this happens and what might be done to address it. In the report, researchers used mice show how chronic alcohol intake compromises the skin's protective immune response. They also were able to show how certain interventions may improve the skin's immune response. Ultimately, the hope is that this research could aid in the development of immune-based therapies to combat skin infection in people who chronically consume alcohol.

"The clinical association between alcoholism and severe skin infection is well established," said Corey P. Parlet, Ph.D., a researcher involved in the work from the Department of Pathology at the University of Iowa, Carver College of Medicine, Iowa City, Iowa. "The ability to experimentally model skin immune deficiencies that occur in chronic alcoholics opens up new avenues to test immune-based therapies to better protect this population and thereby limit the spread of infectious disease to the broader community as well."

To make their discovery, scientists administered either drinking water consisting of a 20 percent ethanol/water solution or plain water. After 12 weeks on this fluid regimen, with a regular solid food diet, infection outcomes and host defense responses were assessed in mice that were given a skin infection with Staphylococcus aureus (S. aureus). They found that ethanol-consuming mice demonstrated increased illness, including greater weight loss, larger skin lesions and increased bacterial burden. The exacerbation of clinical disease corresponded with an inability to maintain immune cell numbers and activity at the site of infection, especially neutrophils, which are required to heal the infection. Interleukin-17 normally promotes the entry of neutrophils into the skin and their function there. This molecule was reduced in the skin of ethanol-consuming mice. By restoring IL-17 levels, the skin injury in mice was reduced and bacterial clearance defects were improved.

"Co-morbidities associated with chronic alcohol consumption often receive less research attention, yet have significant impact on overall quality of life, healthcare costs and potential infectious disease transmission," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "These new studies, together with greater understanding of how to clinically manipulate IL-17 mediated immune responses may lead to new treatment opportunities for alcoholism-associated skin infections.
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Body Mass Index In Adults (BMI Calculator for Adults)

The benefits of maintaining a healthy weight go far beyond improved energy and smaller clothing sizes. By losing weight or maintaining a healthy weight, you are also likely to enjoy these quality-of-life factors too.

• Fewer joint and muscle pains
• More energy and greater ability to join in desired activities
• Better regulation of bodily fluids and blood pressure
• Reduced burden on your heart and circulatory system
• Better sleep patterns
• Reductions in blood triglycerides, blood glucose, and risk of developing type 2 diabetes
• Reduced risk for heart disease and certain cancers

BMI is an indicator of the amount of body fat for most people. It is used as a screening tool to identify whether an adult is at a healthy weight. Find your BMI and what it means with our handy BMI Calculator. A separate BMI Percentile Calculator should be used for children and teens that takes a child’s age and gender into consideration.

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  BMI stands for Body Mass Index
  This is a numerical value of your weight in relation to your height. A BMI between 18.5 and 25 kg/m² indicates a normal weight. A BMI of less than 18.5 kg/m² is considered underweight. A BMI between 25 kg/m² and 29.9 kg/m² is considered overweight. A BMI of 30 kg/m² or higher is considered obese.
   
• Excess weight increases the heart's work.
  It also raises blood pressure and blood cholesterol and triglyceride levels and lowers HDL (good) cholesterol levels. It can make diabetes more likely to develop, too. Lifestyle changes that help you maintain a 3-5% weight loss are likely to result in clinically meaningful improvements in blood glucose, triglycerides, and risk of developing type 2 diabetes. Greater weight loss can even help reduce BP and improve blood cholesterol.
   
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'Lightning bolts' in brain show learning in action

SUMMARY:Researchers have captured images of the underlying biological activity within brain cells and their tree-like extensions, or dendrites, in mice that show how their brains sort, store and make sense out of information during learning "We believe our study provides important insights into how the brain deals with vast amounts of information continuously as the brain learns new tasks," says senior study investigator and neuroscientist Wen-Biao Gan, PhD.

Gan, a professor at NYU Langone and its Skirball Institute for Biomolecular Medicine, says, "we have long wondered how the brain can store new information continuously throughout life without disrupting previously acquired memories. We now know that the generation of calcium spikes in separate branches of nerve cells is critical for the brain to encode and store large quantities of information without interfering with each other."

Lead study investigator Joseph Cichon, a neuroscience doctoral candidate at NYU Langone, says their discoveries could have important implications for explaining the underlying neural circuit problems in disorders like autism and schizophrenia. Cichon says the team's next steps are to see if calcium ion spikes are malfunctioning in animal models of these brain disorders.

Among the study's key findings was that learning motor tasks such as running forward and backward induced completely separate patterns of lightning bolt-like activity in the dendrites of brain cells. These lightning bolts triggered a chain-like reaction, which changed the strength of connections between neurons.

The study also identified a unique cell type in the brain that controlled where the lightning bolts were generated. When these cells were turned off, lightning bolt patterns in the brain were disrupted, and as a result, the animal lost the information it had just learned

Long-standing mystery in membrane traffic solved

The Korea Advanced Institute of Science and Technology (KAIST)

Summary:

In 2013, James E. Rothman, Randy W. Schekman, and Thomas C. Südhof won the Nobel Prize in Physiology or Medicine for their discoveries of molecular machineries for vesicle trafficking, a major transport system in cells for maintaining cellular processes. SNARE proteins are known as the minimal machinery for membrane fusion. Scientists now report that NSF/?-SNAP disassemble a single SNARE complex using various single-molecule biophysical methods that allow them to monitor and manipulate individual protein complexes.

 2013, James E. Rothman, Randy W. Schekman, and Thomas C. Südhof won the Nobel Prize in Physiology or Medicine for their discoveries of molecular machineries for vesicle trafficking, a major transport system in cells for maintaining cellular processes. Vesicle traffic acts as a kind of "home-delivery service" in cells. Vesicles package and deliver materials such as proteins and hormones from one cell organelle to another. Then it releases its contents by fusing with the target organelle's membrane. One example of vesicle traffic is in neuronal communications, where neurotransmitters are released from a neuron. Some of the key proteins for vesicle traffic discovered by the Nobel Prize winners were N-ethylmaleimide-sensitive factor (NSF), alpha-soluble NSF attachment protein (α-SNAP), and soluble SNAP receptors (SNAREs).

SNARE proteins are known as the minimal machinery for membrane fusion. To induce membrane fusion, the proteins combine to form a SNARE complex in a four helical bundle, and NSF and α-SNAP disassemble the SNARE complex for reuse. In particular, NSF can bind an energy source molecule, adenosine triphosphate (ATP), and the ATP-bound NSF develops internal tension via cleavage of ATP. This process is used to exert great force on SNARE complexes, eventually pulling them apart. However, although about 30 years have passed since the Nobel Prize winners' discovery, how NSF/α-SNAP disassembled the SNARE complex remained a mystery to scientists due to a lack in methodology.

In a recent issue of Science, published on March 27, 2015, a research team, led by Tae-Young Yoon of the Department of Physics at the Korea Advanced Institute of Science and Technology (KAIST) and Reinhard Jahn of the Department of Neurobiology of the Max-Planck-Institute for Biophysical Chemistry, reports that NSF/α-SNAP disassemble a single SNARE complex using various single-molecule biophysical methods that allow them to monitor and manipulate individual protein complexes.

"We have learned that NSF releases energy in a burst within 20 milliseconds to "tear" the SNARE complex apart in a one-step global unfolding reaction, which is immediately followed by the release of SNARE proteins," said Yoon.

Previously, it was believed that NSF disassembled a SNARE complex by unwinding it in a processive manner. Also, largely unexplained was how many cycles of ATP hydrolysis were required and how these cycles were connected to the disassembly of the SNARE complex.

Yoon added, "From our research, we found that NSF requires hydrolysis of ATPs that were already bound before it attached to the SNAREs--which means that only one round of an ATP turnover is sufficient for SNARE complex disassembly. Moreover, this is possible because NSF pulls a SNARE complex apart by building up the energy from individual ATPs and releasing it at once, yielding a "spring-loaded" mechanism."

NSF is a member of the ATPases associated with various cellular activities family (AAA+ ATPase), which is essential for many cellular functions such as DNA replication and protein degradation, membrane fusion, microtubule severing, peroxisome biogenesis, signal transduction, and the regulation of gene expression. This research has added valuable new insights and hints for studying AAA+ ATPase proteins, which are crucial for various living being
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Kidney Stone....

Researchers master gene editing technique in mosquito that transmits deadly diseases

Researchers have successfully harnessed a technique, CRISPR-Cas9 editing, to use in an important and understudied species: the mosquito, Aedes aegypti, which infects hundreds of millions of people annually with the deadly diseases chikungunya, yellow fever, and dengue fever.

Mosquito larvae from two different lines fluoresce in different colors thanks to genetic tags that were inserted using the CRISPR-Cas9 gene editing system.

Credit: Vosshall Laboratory

Traditionally, to understand how a gene functions, a scientist would breed an organism that lacks that gene -- "knocking it out" -- then ask how the organism has changed. Are its senses affected? Its behavior? Can it even survive? Thanks to the recent advance of gene editing technology, this gold standard genetic experiment has become much more accessible in a wide variety of organisms. Now, researchers at Rockefeller University have harnessed a technique known as CRISPR-Cas9 editing in an important and understudied species: the mosquito, Aedes aegypti, which infects hundreds of millions of people annually with the deadly diseases chikungunya, yellow fever, and dengue fever.

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Researchers led by postdoctoral fellow Benjamin J. Matthews adapted the CRISPR-Cas9 system to Ae. aegypti and were able to efficiently generate targeted mutations and insertions in a number of genes. The immediate goal of this project, says Matthews, is to learn more about how different genes help the species operate so efficiently as a disease vector, and create new ways to control it. "To understand how the female mosquito actually transmits disease," says Matthews, "you have to learn how she finds humans to bite, and how she chooses a source of water to lay her eggs. Once you have that information, techniques for intervention will come."

In the study, published March 26 in Cell Reports, Matthews and research assistant Kathryn E. Kistler, both in Leslie B. Vosshall's Laboratory of Neurogenetics and Behavior, adapted the CRISPR-Cas9 system to introduce precise mutations in Ae. aegypti. Previously, to create these types of mutations, scientists relied on techniques that used engineered proteins to bind to specific segments of DNA they wanted to remove, a process that was both expensive and unreliable. CRISPR-Cas9, in contrast, consists of short stretches of RNA that bind to specific regions of the genome where a protein, Cas9, cleaves the DNA. Scientists have been studying how RNA binds to DNA for decades and "the targeting is done with rules that we have a good handle on," says Matthews, which makes it easy to reprogram CRISPR-Cas9 to target any gene.

"This amazing technique has worked in nearly every organism that's been tried," says Vosshall, who is Robin Chemers Neustein Professor and a Howard Hughes Medical Institute investigator. "There are lots of interesting animal species out there that could not be studied using genetics prior to CRISPR-Cas9, and as a result this technique is already revolutionizing biology."

This work opens the door to learning more about the role of specific genes the Vosshall lab suspects may help mosquitoes propagate, perhaps by finding the perfect spot to lay their eggs. Their protocols will likely also help other scientists apply the same technique to study additional organisms, such as agricultural pests or mosquitoes that carry malaria.

"Before starting this project, we thought it would be difficult to modify many genes in the mosquito genome in a lab setting" Matthews says. "With a little tweaking, we were able to make this technique routine and it's only going to get easier, faster, and cheaper from here on out."

International researchers reveal significance of water for functional protein dynamics

An international team of researchers from the CEA, the CNRS, the Institut Laue-Langevin, the Jülich Centre for Neutron Science, the University of California Irvine, the Australian Institute of Science and Technology Organisation, the Max Planck Institute Mülheim and the University of Perugia has shed light on the molecular mechanism behind the importance of water for functional protein dynamics. The scientists have discovered that water’s ability to flow on the surface of proteins makes them sufficiently dynamic to be biologically active. The results have just been published in Nature Communication on 16/03/2015.

In order to be biologically active, most soluble proteins require their surface to be covered with water. This so-called hydration water is generally acknowledged to enable a protein to undergo the internal motions that are so fundamental for its capacity to fulfill a specific biological function. Yet, the molecular mechanism behind water’s importance for functional protein dynamics has remained elusive. The team has now been able to observe the movements of water molecules on the surface of proteins. The study highlights how these movements correlate with protein dynamics that is essential to biological activity. Temperature turned out to be an essential parameter; since the motions of water molecules and, therefore, the behaviour of the proteins depend on it.

When "visualising" water movement on the protein surface, the team discovered that the molecules rotate around their own axes at temperatures below ‑30°C, temperatures at which proteins are inactive. Above ‑30°C however, whilst continuing to rotate, the water molecules also start to undergo translational diffusion. This is the temperature at which proteins start to be active and the researchers suggest that the capacity of water molecules to "dance" on the surface of proteins enables the dynamics they need to function.

To achieve these results, the scientists combined neutron scattering with molecular dynamics simulations. The neutron scattering technique provides detailed information on the movement and local arrangement of atoms and molecules in matter. The researchers had to first mask the scattering signal of the proteins, whilst preserving the signal from the water molecules on the protein surfaces. To achieve this they produced perdeuterated proteins (proteins in which all the hydrogen atoms are replaced by deuterium atoms) in ILL’s Life Sciences Group.

The study provides a better understanding of the conditions proteins require to be biologically active. An application of the results is the stabilization of protein drugs in the solid state, such as for example insulin that is used for treating diabetes.

First detailed picture of a cancer-related cell enzyme in action on a chromosome unit

29 October 2014 — A landmark study to be published in the October 30, 2014 print edition of the journal Nature provides new insight into the function of an enzyme related to the BRCA1 breast cancer protein. The study by a team at Penn State University is the first to produce a detailed working image of an enzyme in the Polycomb Repressive Complex 1 (PRC1) -- a group that regulates cell development and is associated with many types of cancer.

Enzymes like PRC1 turn on or turn off the activity of genes in a cell by manipulating individual chromosome units called nucleosomes. "The nucleosome is a key target of the enzymes that conduct genetic processes critical for life," saidSong Tan, professor of biochemistry and molecular biology at Penn State University and the leader of the study's research team.

The Penn State scientists obtained the first crystal structure of a gene regulation enzyme while it is working on a nucleosome. The image reveals previously unknown information about how the enzyme attaches to its nucleosome target. Before this study, scientists had been unable to picture exactly how cancer-related enzymes in the PRC1 group interacted with a nucleosome to control gene activity. The study is also the first to determine the crystal structure of a multisubunit protein complex bound to a nucleosome, which itself is a complex assembly of DNA and 4 histone proteins.

The research is the culmination of over 12 years of research by the Tan laboratory to capture an image of this important class of enzymes bound to the nucleosome. His lab earlier had determined the first structure of another nucleosome-bound protein, RCC1. "This is the second important structure from the Tan lab to date of a nucleosome in complex with a protein known to interact with and modify chromatin behavior, which in turn can influence human gene expression," said Peter Preusch, Ph.D., of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. "Along with Dr. Tan's previous work detailing a nucleosome bound to the key regulatory protein, RCC1, this new structure adds to our knowledge of how proteins can regulate the structure and function of our genetic material."

The study performed in the Penn State Center for Eukaryotic Gene Regulation provides unexpected insight into the workings of the BRCA1 breast-cancer-associated tumor-suppressor protein. Like PRC1, BRCA1 is a chromatin enzyme that shares a similar activity on the nucleosome. Tan said, “Our study suggests that BRCA1 and PRC1 employ a similar mechanism to anchor to the nucleosome”. Tan and his team now are working to visualize how BRCA1 and other disease-related chromatin enzymes interact with the nucleosome.The research project was proposed and executed by team member Robert K. McGinty, a Damon Runyon postdoctoral fellow at Penn State. McGinty andRyan C. Henrici, an undergraduate in the Penn State Schreyer Honors College, grew crystals of the PRC1 enzyme bound to the nucleosome. The team then solved the three-dimensional structure of this large molecular assembly by X-ray crystallography. "We are excited about this crystal structure because it provides new paradigms for understanding how chromatin enzymes function," McGinty said.

This research was supported by grants from the National Institutes of Health, the Damon Runyon Cancer Research Foundation and Penn State University.

Packaging Process for Genes Discovered in New Research

19 May 2011 — Scientists at Penn State University have achieved a major milestone in the attempt to assemble, in a test tube, entire chromosomes from their component parts. The achievement reveals the process a cell uses to package the basic building blocks of an organism's entire genetic code -- its genome. The evidence provided by early research with the new procedure overturns three previous theories of the genome-packaging process and opens the door to a new era of genome-wide biochemistry research. A paper describing the team's achievement will be published in the journal Scienceon 20 May 2011.

The research was accomplished with the help of a new laboratory procedure developed by the team of scientists led byB. Franklin Pugh, the Willaman Chair in Molecular Biology at Penn State. The procedure allows scientists, for the first time, to do highly controlled biochemical experiments with all the components of an organism's genome.

The team's research is designed to reveal the construction process for the chromosome -- the super-compressed marvel of molecular packaging that contains all an organism's DNA and associated proteins. "Our procedure starts with an entire genome of DNA from yeast cells that we propagate through bacteria, then purify, "Pugh said. "Next, we add equal parts of pure histones, the protein building blocks of chromosomes. Then we allow the assembly process to begin."

The result was that short sections of the lanky string of gene-containing DNA became wound around a series of histone proteins, forming a line of knots called nucleosomes separated by unknotted sections of DNA. Although earlier studies in other labs had shown that histones and DNA alone could construct a series of nucleosome knots along the DNA string, the overall structure of this construction was not nearly as organized as it needed to be in order to look like chromatin inside of a cell -- the material that the cell remodels to form chromosomes. Pugh's team sought out the recipe that would produce the actual, highly organized structure of chromatin.

"Just like baking a mixture of flour and water produces unleavened bread that lacks the texture of leavened bread, so too did the mixture of histones and DNA lack the texture of chromatin," explains Pugh.  To provide "texture" to the histone-DNA mix, graduate student Christian Wippo added yeast extract, under the guidance of laboratory head Philipp Korber at the University of Munich, Germany, and co-investigator on the project. "But, like adding yeast to flour and water without the sugar, this was not enough," Pugh said.  As Korber recounts, "Once we added ATP, 'the bread began to rise'." In other words, chromatin remodeling enzymes in the extract needed the energy from ATP to reposition the nucleosome knots along the DNA, thereby giving rise to the chromatin the texture that is seen inside of cells. "Chromatin-remodeling enzymes actively pack nucleosomes against barriers that sit at the beginning of every gene, and this process creates uniformly positioned nucleosome arrays," Pugh said.

A critical part of the study that allowed the scientists to "see" the chromatin texture was developed by Graduate Student Zhenhai Zhang, under Pugh's direction. "Because there are more than 60,000 nucleosomes that comprise chromosomes in yeast cells, seeing patterns in this texture would be impossible without the computational pattern-searching algorithms developed by Zhang," Pugh said. Zhang explained, "Remarkably, when all genes were aligned, nucleosomes at the beginning of the genes also aligned, rather being randomly scattered about. Without the yeast extract and ATP, only nucleosome-free zones could be seen at the beginning of genes."

This work is significant because it now allows scientists to experimentally probe the structure and function of chromosomes and their component genes in ways that simply were off limits before. "The cell protects chromosomes from the outside environment, including probing scientists," Pugh said. "We now have a way to study the components of the chromosome outside the protective confines of the cell." Because defects in chromatin organization lead to medical problems -- including certain cancers and developmental disorders -- more direct access to chromatin in its properly organized state is expected to help hasten the search for remedies to many human diseases

"Enabling Nerve Cell Regeneration" (latest research)

Nerve cells are amazing in their ability to regenerate themselves. How they do this is still a mystery. Researchers led by Melissa Rolls recently discovered that motor protein kinesin-2 is critical for this rebuilding. Nerve cells extend two long structures from their cell body: axons (sends signals) and dendrites (receives signals). For efficient nerve cell operations, microtubules (the neuronal highways) must line up in a specific way (polarity) in each part of the cell. 

Previously Rolls and her team found that when an axon is removed, microtubules in a dendrite reorient themselves in the axonal direction and enable growth of a new axon. Now by preventing kinesin-2 production in Drosophila, the dendrite microtubules were unable to be rebuilt in the correct polaity. Further understanding of this signal transport control may contribute toward the development of therapeutic treatments for neurodegenerative diseases and traumatic neural injury.

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"BIOCHEMICAL ENGINEERING"

Biochemical engineering is a branch of biotechnology engineering,chemical engineering, biomedical engineering and pharmaceutical engineering that mainly deals with the design and construction of unit processes that involve biological organisms or molecules, such asbioreactors.^{[citation needed]} Its applications are in the petrochemical industry, food, pharmaceutical, biotechnology, and water treatment industries.

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