Cyrus Moulton Telegram & Gazette Staff @MoultonCyrus

WORCESTER - Researchers have moved from the back row to the orchestra seats for the ballet of the cell, now that a new cryo-electron microscope is up and running at University of Massachusetts Medical School and attracting use and attention from all over the region.

Prior to this cryo-EM technology, it was like we were at the back of the arena with very poor vision, said Brian A. Kelch, assistant professor of biochemistry and molecular pharmacology at UMass Medical School. These microscopes now allow us to get 20/20 vision and move to the orchestra seats so we can now see all the dancers and see how they interact with each other. Then also when the dance gets out of synchrony, which could lead to disease, we can see how to bring those dancers back to synchrony which can fix that disease.

UMass Medical School held a ribbon cutting in October for a $12 million facility housing two powerful, high-resolution cryo-electron microscopes. The two microscopes - the roughly $5 million Titan Krios and the roughly $4 million Talos Arctica - will be the most advanced electron microscopes in New England and two of fewer than 50 such cryo-EM microscopes worldwide, according to Chen Xu, associate professor of biochemistry and molecular pharmacology and the core director of the Cryo-EM Facility at UMass Medical School.

The Titan Krios was acquired in collaboration with Harvard Medical School, supported by a grant of $5 million from the Massachusetts Life Sciences Center. The Talos-Arctica system was acquired with funding from the Howard Hughes Medical Institute. UMass Medical School has invested $3 million in renovations on its main campus to house the facility.

Now after lots of testing, calibration and training for staff, the Talos Arctica microscope is operational, and the Titan Krios is scheduled to come online this month.

The technology, known as cryo-Em, uses electron energy to produce images of samples that are cryogenically frozen with liquid nitrogen.

The technology not only allows scientists to see an object closer and more clearly than before but also allows scientists to see a sample frozen in many different positions.

Previous technology called X-ray crystallography required that samples be frozen in crystals that only allowed one position for samples. That process was also more time-consuming - it could take years to develop a sample, Mr. Xu said - and there was no guarantee that a sample that took so long to develop would be usable.

The new technology, however, can cut the time to develop a sample down to a month. It also requires less of a sample than the X-ray crystallography, according to Mr. Kelch.

Seeing the sample in multiple positions also enables two important developments.

It enables scientists to better reconstruct the sample in three dimensions and understand its function.

This is crucial for Mr. Kelch, whose lab is working on two projects.

In the first, he is studying the part of the cell that copies DNA and how that relates to cancer.

But without the cryo-EM, Mr. Kelch would not be able to look at the guardian proteins that are the target of the research. Although the study is in its infancy, Mr. Kelch hopes that understanding the structure of these proteins can lead to the development of chemotherapeutic drugs that work by interacting with the proteins.

In the second project, Mr. Kelchs lab is investigating how viruses become infectious particles. Again, being able to see the shape of proteins containing the virus is crucial to developing antiviral drugs.

Seeing the sample in multiple positions also enables scientists to discover how the sample can move.

Andrei A. Korostelev, associate professor of RNA therapeutics at UMass Medical School, described the process as like taking a picture of thousands of running horses and then arranging each horse in a sequence to show movement.

Here you freeze 1,000 horses, each of them moving differently, Mr. Korostelev said, continuing the analogy (the scientists actually freeze molecules). And then from that we try to reconstruct a smooth pathway of the movement.

Understanding movement is key to Mr. Korostelevs work studying the ribosome, the key machine in the cell that reads genetic code and converts it to proteins.

He has used cryo-EM to see how the parts of the ribosome move with respect to each other so the ribosome can perform its complex function.

Whats brand-new is that you can see the movements in such detail, said Mr. Korostelev, whose work has created movies of the ribosome in the process of making proteins.

But aside from their own research applications, scientists see the microscopes as a way to spark future collaborations among the different institutions and companies using the machines.

So far in addition to UMass Medical School, Harvard Medical School, Massachusetts General Hospital, biotechnology company Sanofi Genzyme and pharmaceutical company Vertex are some of the clients that are lining up to use the machine. The rates range from roughly $120 per hour for internal users to $300 an hour for industry partners, Mr. Xu said.

In addition, Mr. Korostelev said the microscopes are an attraction for students who are looking for the latest technology.

Mr. Kelch said the microscopes being at UMass is a boon for the entire state.

This whole facility can be an economic engine not just for academic science in Massachusetts, but also for the biotech industry as well, Mr. Kelch said. We get from them some money to help run the facility as well as make partnerships with those companies which helps our students and trainees to find new jobs once they leave here. The biotech industry gets access to the worlds state-of the art microscopes without having the burden of running that facility on their own. And all of that means a lot of growth, economic growth for the commonwealth.

Robert K. Coughlin, president and CEO of the Massachusetts Biotechnology Council, agreed.

It gives us a huge competitive advantage because this is state-of-the-art technology that is open source for many scientists to utilize, said Mr. Coughlin, whose organization represents more than 1,000 other organizations in the life-sciences cluster. If were going to continue in this region to be the best place for innovation, we need to stay ahead of the curve and constantly have access to cutting-edge equipment and technology.

Link:
Cyro-electron microscopes view 'ballet of the cell' at UMass Med School - Worcester Telegram

Thursday, April 6, 2017

By Nicholas Snow

The Rose Mercadante Chemistry Seminar series is pleased to present the final PhD seminar of Mariana Phillips, entitled "B7H6 Derived Peptides Trigger TNF- Dependent Immunostimulatory Activity of Lymphocytic NK92-MI Cells."

The seminar will be held at 5:45 p.m. on Tuesday April 11, 2017 in the Helen Lerner Amphitheater, McNulty Hall, Science and Technology Center, Seton Hall University. The University Community is invited.

Mariana Phillips was born in Mexico City, Mexico where she received her BSc in Food Chemistry from Universidad LaSalle, Mexico, in 1998. Phillips's academic career began as a science teacher of Physics and Chemistry, focusing particularly on developing a stimulating scientific learning environment for middle school students. Phillips relocated to the United States in 2005 with her family to pursue new scientific career goals. In 2012, she joined the Department of Chemistry and Biochemistry at Seton Hall University, to work on her PhD under the supervision of Profs. David Sabatino and Constantine Bitsaktsis. During her PhD studies, Phillips has developed methods in chemical biology for the production of novel immunstimulatory peptides. Phillips has also gained expertise in working with protein biologics, including antibody mimics for cancer-targeting immunotherapy applications. In 2015, Phillips received her MS degree in Biochemistry following her successful matriculation into the PhD program. In 2016-17, Phillips initiated a productive research collaboration with Dr. Robert Korngold at Hackensack UMC to investigate the biological properties of immunstimualtory constructs in vitro and in vivo. Taken together, Phillips accomplishments during her PhD studies have led to the generation of two publications, a book chapter currently in press, a research grant approved for funding, a travel grant award for attending the American Peptide Symposium in 2015 and more than five presentations and proceedings at local and national conferences. Phillips expects to receive her PhD in Biochemsitry in May 2017.

B7H6 has been identified as a cellular membrane protein expressed exclusively on tumor cells. Interestingly, B7H6 was found to bind selectively to NKp30, an activating receptor expressed on NK cells. B7H6:NKp30 binding stimulates NK cells' antitumor immune responses through the release of cytotoxic cytokines and chemokines, leading to tumor cell death. However, lower levels or the absence of cell surface B7H6 have correlated with the evolution of tumor resistance towards NK cells' immunosurveillance. Therefore, new B7H6 derived ligands that can bind and activate NK cells are expected to improve NK-dependent killing of resilient tumors. Towards this goal, this thesis work describes the rational design of a novel class of immunostimulatory peptides (IPs) derived from the binding site interface of B7H6:NKp30. The IPs were synthesized by conventional Fmoc solid phase peptide synthesis which also facilitated the incorporation of N-terminal fluorescein isothiocyanate (FITC) for structure-activity relationship studies. The secondary structures of the peptides were examined by CD spectroscopy which revealed versatile peptide structures which transitioned from random coil to -helical and turn-type conformations. Their biological properties were evaluated by flow cytometry, enzyme-linked immunosorbent assays (ELISAs) and cell death assays. The immunostimulatory effects of the IPs on the human NK92-MI cells were assessed by the production of TNF- alone as IFN- was undetectable. In a cell death assay, the IPs were found to be non-toxic, without any observable evidence of early or late stage apoptosis within the NK92-MI cells. Therefore, B7H6 derived peptides encompass an interesting class of ligands for activating NK cells' immune activities. The latter is a current focus of our on-going research program in cancer immunotherapy applications.

The Department of Chemistry and Biochemistry offers BS, MS and PhD degrees with specializations in all areas of chemistry. Our unique research environment, including traditional full-time students and part-time students is designed to foster collaborations with industry and colleagues in other disciplines. The Rose Mercadante Seminar Series is named for Rose Mercadante, the departmental secretary for over 40 years, in honor of our alumni, her "boys and girls".

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Chemistry - Final PhD Seminar - Mariana Phillips - Seton Hall University News & Events

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Global Biochemistry Analyzers Market 2017- URIT Medical ... - First Newshawk

by Mika Jehoon Lee | 4/4/17 2:15am

Students from local schools with an interest in science read weather maps, planted seedlings and examined sheep brain specimens at the fifth annual Science Day held this past Saturday, April 1 at various labs on campus.

According to fourth-year biochemistry graduate student and Science Day co-organizer Jessica DeSimone, this years attendance was the highest since its launch in 2013. A total of 171 adults accompanied 231 students at the event this year. DeSimone said that close to 200 adults and 300 students RSVPd for the event, but inclement weather may have accounted for the gap between expected and actual attendance.

Science Day is a free, drop-in event that features 15-minute long scientific demonstrations and hands-on activities geared toward students in sixth to ninth grade. According to DeSimone, Science Day was created to educate local community members about science and foster students passion for the subject. DeSimone said that Science Day was hosted by the group Graduate Women in Science and Engineering over the past few years, but this year it was independently organized by DeSimone, sixth-year biochemistry student Kelly Salmon and second-year biochemistry student Sarah Valles due to leadership changes in the group. They received funding for this years event from the School of Graduate and Advanced Studies. In addition to the three organizers, around 60 graduate students from eight different departments including biology, chemistry and psychology prepared 11 total activity stations for the event this year.

In the under the microscope station, students watched worms and flies glow under microscopes. According to third-year cellular and molecular biology graduate student Timothy Gauvin, a volunteer at the station, worms and flies provide a simple system for studying various human diseases, because the three species share a lot of similarities. Gauvin added that his love for microscopes got him interested in science and that he hoped students exposure to the activity would inspire their passion for science.

I thought it was cool to look at human cells under [microscopes] and as I investigated further, there was a lot of cool stuff you could do with this, Gauvin said. Im hoping kids of various ages can see that we have a lot of cool tricks.

Local middle school student Hope Cooper, who visited the under the microscope station, said that she enjoyed looking at worms under the microscope and learning about how worms hatch. Both Cooper and her father Adam Cooper attended Science Day two years ago and said that there were more microscopes and opportunities for students to use them this year than in years past.

Adam Cooper spoke highly of the benefit of such an event for students in exposing them to subjects they might study or pursue in the future.

The exposure for our kids to see what interests they may or may not have, to be able to see what they might want to do when they grow up and what they might not want to do when they grow up, [is] just a lot of good exposure to what their future might be, Adam Cooper said.

Meanwhile, in the soil and the world beneath our feet station, volunteers including ecology, evolution, ecosystems and society graduate student Ashley Lang Gr20 helped kids learn about mycorrhizal fungi and fossils. Lang said she wanted to introduce students to mycorrhizae, which grow in symbiotic relationships with plants, because it is poorly understood and many people are unaware of its existence.

Local elementary school student Nicholas Champine said that he enjoyed participating in Langs station and appreciated learning about fungis influence on plant growth.

Local elementary school student Charleigh Olmstead said that he specifically enjoyed playing the game Jet Stream Racer in the flowing rivers of air station. According to earth science graduate student Huanping Huang, the game allows students to become pilots and learn more about jet streams and gas. Jag Olmstead, Charleighs father, said that Science Day provided an opportunity of intellectual engagement for his children, as opposed to more typical recreational activities.

[Science Day] is something for the kids to enlighten their minds, learn something new and not play video games, Jag Olmstead said.

Rong Ding, whose elementary school-aged son participated in the flowing rivers of air station, said that the event provided his son with a unique opportunity to witness and participate in scientific experiments, which is not an everyday occurrence.

Science Day attendees were also given tours of the Thayer School of Engineering, where they visited the schools laboratories and made flubber, a rubbery polymer.

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Science Day brings students to campus - The Dartmouth

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The family of a 20-year-old student who died after he was hit by a car in Lenton have paid tribute to their 'fun-loving' son.

Andrew Robertson, of Berkshire, died at the scene of the crash on Derby Road at around 4.45pm last Thursday (March 30).

He was in his second year studying biochemistry at the University of Nottingham.

A statement from his family said: "He had a bright future ahead of him. He was a loving son, grandson, brother, nephew, cousin and boyfriend.

"He had many friends both at university and at home. Words cannot express how much he will be missed and we are extremely saddened by his death.

"Andrew was caring, fun-loving, sociable, supportive and very easy-going. He was a team player who always kept his word and looked out for others.

"We would appreciate privacy during this difficult time to allow us to grieve and come to terms with our loss."

Police are investigating and are appealing to anyone who might have seen anything in the area around the time of the collision, which happened between Clifton Boulevard and Priory Island.

Officers are particularly keen to speak to drivers with dashcam footage.

Hundreds of motorists were caught in gridlocked traffic after the incident occurred.

Retired Michael Fisher, who lives in Charles Avenue, said he was not surprised to hear that an incident had occurred on what he describes as a "dangerous road."

The 64-year-old told the Post: "That is sad to hear. It is a very busy road and I won't cross it without pressing the button.

"It does not surprise me at all but it is a shame."

A large section of the road was cordoned off for several hours while investigations were carried out at the scene.

Originally posted here:
Family pay tribute to student who died in Derby Road crash - Nottingham Post

10:23 Monday 03 April 2017

Our Lady of Sion School student Blaise Cloran was the only national finalist from Sussex at the The Big Bang Fair 2017.

Blaise, from year nine, was also the only Sussex student to achieve a weeks stay to study biochemistry at Oxford this summer and a NASA science camp in America for five days in the summer holidays.

Helen Davis, assistant head (academic), said: She did not win one of the major prizes but she did get a gold medal and a gold crest award. These are a fantastic achievement for a 13-year-old.

All of these events have been supported by the school but she has earned her place through merit alone. They are not places gained by a paid-for-place in any of these examples.

Blaise has achieved all this through her own determination her parents are not scientists. She is a fantastic role model for girls in science, something the nation sadly lacks.

Blaise said being selected for The Big Bang Fair at Birmingham NEC and representing Our Lady of Sion School was a truly amazing experience.

I showcased and competed with my project, A Quicker More Efficient Method of Diagnosis for Hepatitis. My project used an ELISA test combined with silk fibroin to create a cheap, under-two-hour diagnosis method that can be transported without refrigeration. It uses hepatitis to demonstrate how the process works but it could be applied to any disease.

I went up to the NEC at Birmingham and stayed for four days. On the first day, all 600 finalists went to a welcome ceremony, where we listened to talks from well-known scientists, such as Greg Foot, and were given information about the next few days. It was quite nerve-racking to be the only student from the whole of Sussex but the familiar scientific environment engrossed me and I soon felt at home.

On the Wednesday, the show was opened to the public and my day consisted of lots of judging. Judges would come round in groups of two or four and would listen and examine my project, which was displayed on a stand. I really enjoyed talking to people who were interested in my project and the questioning members of the public were good practice before I talked to the judges.

There were also many other stands at the fair such as JCB, SeaWorld, Airbus, Rolls Royce, many universities and, of course, other competitors. I learned lots from looking round and talking to those who occupied stands. Shows and experiments would go all day, which added to the all excitement.

The next day, the award ceremony was held and I was lucky enough to win a medal and a gold crest award. I felt honoured and I know I will definitely be trying to attend next year.

Later this summer, I will be attending an Oxbridge course in biochemistry that I had to pass a round of Skype interviews to gain a place at, followed by a NASA camp in America. I was lucky enough to get into both of these and cant wait to attend them.

I was interviewed for the Oxbridge course and got confirmed a place to study biochemistry at Oxford for a week. I am extremely excited to see what life is like at the university and experience studying at a higher level.

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Young scientist wins gold awards - Worthing Herald

How do your studies in biochemistry and music complement one another?

Both disciplines have helped me develop analytical skills. For instance, in biochemistry I often have to break down a molecular process by asking myself how I can connect this reaction to something I already know, so I can understand the concept more fully. And in music, the thought process is similar: How can I think of these notes what images or experiences can I tie to them so that I can maximize the expressivity of a phrase? The problem-solving I do in one subject stretches my capacity to do the same in the other.

What musical piece did you play in the BC Symphony Orchestra Concerto Competition? Do you prefer a particular composer?

I played Cello Concerto No. 1 in A minor by Camille Saint-Sans [which she also performed in the recent concert]. When it comes to solo repertoire, I love Edward Elgars Cello Concerto in E minor. The Elgar encompasses a broader range of expression both technically and musically and forces the performer to access and communicate raw, inner emotions in a very unique way.

Tell us about your experience with the BC Symphony Orchestra.

I have played with the Boston College Symphony Orchestra since freshman year. It has been great to have the opportunity to play significant symphonic works in a non-conservatory setting. [Director] John Finney has very realistic expectations of what the BCSO can do, and does an excellent job making the most of the skills that the orchestra members have. It was an incredibly rewarding experience rehearsing and performing alongside fellow BC musicians and friends, some of whom I have played with for the past four years here.

Have other BC faculty members have influenced you, and in what ways?

My conversations with [Music] Professor Thomas Oboe Lee led me to shift my conception of cello as an extracurricular to something that is a central aspect of my life. Professor Lee was the first to make me consider pursuing music. Now that I have embraced the idea of music as a very serious possibility for the future, I am much happier.

How did your semester in Italy contribute to your creative development?

I studied art history, Italian cinema, European history, and Italian language at the University of Parma, and did an internship at the Pietro Barilla Childrens Hospital. In Italy I was confronted with art everywhere I turned in the conventional forms of painting, sculpture, architecture, but also in terms of food, fashion, and language. Being exposed to art in this way distanced me from my stresses and allowed me return back to my normal life with the attitude of searching for beauty in what I see and what I do.

What are your post-graduate plans? Do they include music?

My post-graduate plans remain undecided. Medical school has always been a consideration, but for now I know that I would not be satisfied by simply doing cello for pleasure and allowing my skill level to stagnate. I would like to continue a serious study of the cello and see where it may take me.

Rosanne Pellegrini / University Communications

Excerpt from:
Q&A: Monica Grady '17 - Boston College Chronicle

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformation of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion,[1] or protein[2] which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. The instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number.

Binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The association of docking is actually reversible through dissociation. Measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is ambiguous whether the ligand generally binds at a metal site, as is the case in hemoglobin. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. The etymology stems from ligare, which means 'to bind'.

Ligand binding to a receptor protein alters the chemical conformation by affecting the three-dimensional shape orientation. The conformation of a receptor protein composes the functional state. Ligands include substrates, inhibitors, activators, and neurotransmitters. The rate of binding is called affinity, and this measurement typifies a tendency or strength of the effect. Binding affinity is actualized not only by host-guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution.[3] The solvent provides a chemical environment for the ligand and receptor to adapt, and thus accept or reject each other as partners.

Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies and for in vitro binding studies.

The interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity ligand binding results from greater intermolecular force between the ligand and its receptor while low-affinity ligand binding involves less intermolecular force between the ligand and its receptor. In general, high-affinity binding results in a higher degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding; the residence time (lifetime of the receptor-ligand complex) does not correlate. High-affinity binding of ligands to receptors is often physiologically important when some of the binding energy can be used to cause a conformational change in the receptor, resulting in altered behavior of an associated ion channel or enzyme.

A ligand that can bind to a receptor, alter the function of the receptor, and trigger a physiological response is called an agonist for that receptor. Agonist binding to a receptor can be characterized both in terms of how much physiological response can be triggered and in terms of the concentration of the agonist that is required to produce the physiological response. High-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. The lower the Ki concentration is, the more likely there will be a chemical reaction between the pending ion and the receptive antigen. Low-affinity binding (high Ki level) implies that a relatively high concentration of a ligand is required before the binding site is maximally occupied and the maximum physiological response to the ligand is achieved. In the example shown to the right, two different ligands bind to the same receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, can be defined as a full agonist. An agonist that can only partially activate the physiological response is called a partial agonist. In this example, the concentration at which the full agonist (red curve) can half-maximally activate the receptor is about 5 x 109Molar (nM = nanomolar). Ligands that bind to a receptor but fail to activate the physiological response are receptor antagonists.

In the example shown to the left, ligand-binding curves are shown for two ligands with different binding affinities. Ligand binding is often characterized in terms of the concentration of ligand at which half of the receptor binding sites are occupied, known as the IC50, which is related to but different from the dissociation constant. The ligand illustrated by the red curve has a higher binding affinity and smaller Kd than the ligand illustrated by the green curve. If these two ligands were present at the same time, more of the higher-affinity ligand would be bound to the available receptor binding sites. This is how carbon monoxide can compete with oxygen in binding to hemoglobin, resulting in carbon monoxide poisoning.

Binding affinity is most commonly determined using a radiolabeled ligand, known as a tagged ligand. Homologous competitive binding experiments involve binding competition between a tagged ligand and an untagged ligand.[4] Non-labelled methods such as surface plasmon resonance, dual polarization interferometry and Multi-Parametric Surface Plasmon Resonance (MP-SPR) can not only quantify the affinity from concentration based assays; but also from the kinetics of association and dissociation, and in the later cases, the conformational change induced upon binding. MP-SPR also enables measurements in high saline dissociation buffers thanks to a unique optical setup. Microscale Thermophoresis (MST), an immobilization-free method[5] was developed. This method allows the determination of the binding affinity without any limitation to the ligand's molecular weight.[6]

For the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article[7] on the configurational partition function.

Binding affinity data alone does not determine the overall potency of a drug. Potency is a result of the complex interplay of both the binding affinity and the ligand efficacy. Ligand efficacy refers to the ability of the ligand to produce a biological response upon binding to the target receptor and the quantitative magnitude of this response. This response may be as an agonist, antagonist, or inverse agonist, depending on the physiological response produced.[8]

Selective ligands have a tendency to bind to very limited kinds of receptor, whereas non-selective ligands bind to several types of receptors. This plays an important role in pharmacology, where drugs that are non-selective tend to have more adverse effects, because they bind to several other receptors in addition to the one generating the desired effect.

Bivalent ligands consist of two drug-like molecules (pharmacophores or ligands) connected by an inert linker. There are various kinds of bivalent ligands and are often classified based on what the pharmacophores target. Homobivalent ligands target two of the same receptor types. Heterobivalent ligands target two different receptor types. Bitopic ligands target an orthosteric binding sites and allosteric binding sites on the same receptor.

In scientific research, bivalent ligands have been used to study receptor dimers and to investigate their properties. This class of ligands was pioneered by Philip S. Portoghese and coworkers while studying the opioid receptor system.[9][10][11] Bivalent ligands were also reported early on by Micheal Conn and coworkers for the gonadotropin-releasing hormone receptor.[12][13] Since these early reports, there have been many bivalent ligands reported for various GPCR systems including cannabinoid,[14] serotonin,[15][16] oxytocin,[17] and melanocortin receptor systems.[18][19][20]

Bivalent ligands usually tend to be larger than their monovalent counterparts, and therefore, not drug-like. (See Lipinskis rule of five.) Many believe this limits their applicability in clinical settings.[21][22] In spite of these beliefs, their have been many ligands that have reported successful per-clinical animal studies.[19][23][24][25][26][27] Given that some bivalent ligands can have many advantages compared to their monovalent counterparts (such as tissue selectivity, increased binding affinity, and increased potency or efficacy), bivalents may offer some clinical advantages as well.

A privileged scaffold[28] is a molecular framework or chemical moiety that is statistically recurrent among known drugs or among a specific array of biologically active compounds. These privileged elements[29] can be used as a basis for designing new active biological compounds or compound libraries.

Main methods to study proteinligand interactions are principal hydrodynamic and calorimetric techniques, and principal spectroscopic and structural methods such as

Other techniques include: fluorescence intensity, bimolecular fluorescence complementation, FRET (fluorescent resonance energy transfer) / FRET quenching surface plasmon resonance, bio-layer interferometry, Coimmunopreciptation indirect ELIS, equilibrium dialysis, gel electrophoresis, far western blot, fluorescence polarization anisotropy, electron paramagnetic resonance, microscale thermophoresis

The dramatically increased computing power of supercomputers and personal computers has made it possible to study proteinligand interactions also by means of computational chemistry. For example, a worldwide grid of well over a million ordinary PCs was harnessed for cancer research in the project grid.org, which ended in April 2007. Grid.org has been succeeded by similar projects such as World Community Grid, Human Proteome Folding Project, Compute Against Cancer and Folding@Home.

See the original post here:
Ligand (biochemistry) - Wikipedia

Newswise PHILADELPHIA Kristen W. Lynch, PhD, has been appointed chair of the Department of Biochemistry and Biophysics, in the Perelman School of Medicine at the University of Pennsylvania, following eight years as a tenured faculty member in the department.

Dr. Lynch has a broad vision of the future of biochemistry and biophysics at Penn, said J. Larry Jameson, MD, PhD, executive vice president of the University of Pennsylvania for the Health System and dean of the Perelman School of Medicine. Her experience, talent, and collaborative spirit will foster strong ties among investigators within the department, as well as across Penn Medicine and the University. I am confident that under Dr. Lynchs leadership Penn will secure its place among the nations top biochemistry and biophysics departments.

Lynch, who is a professor of Biochemistry and Biophysics, also holds a secondary appointment in the department of Genetics and has expertise in RNA biology and immunology. Her laboratory focuses on understanding the biochemical mechanisms and regulatory networks that control alternative gene splicing in response to antigens. (Antigens are toxins and foreign substances, such as bacteria, viruses, and cells of transplanted organs, that stimulate the production of antibodies to protect an organism.)

Alternative splicing is a process in which a single gene codes for differentbut related forms of a given protein (called isoforms), each of which has similar functions. It eliminates the need for an organism to have large numbers of genes make distinctive proteins for carrying out similar functions throughout the body. Additionally, alternative splicing helps explain why humans have substantial genetic similarity with animals and insects, for example, yet such obvious physical and behavioral differences.

The Lynch laboratory specializes in understanding how alternative splicing is regulated in T cells when the cells are stimulated by an antigen during an immune response. Lynch and her team have identified more than 500 genes that undergo alternative splicing in response to T cell stimulation and have discovered some of the molecular mechanisms and signaling pathways that lead to this regulation.

She received her doctorate from Harvard University in 1996 and completed her postdoctoral training at the University of California, San Francisco. Lynch joined the Penn faculty as an associate professor in the department of Biochemistry and Biophysics in 2009, having been recruited from University of Texas Southwestern Medical Center, where she chaired the biological chemistry graduate program.

She is the author of more than 50 scientific papers in the leading journals in her field and the recipient of numerous awards and honors in recognition of her scientific achievements, including a National Science Foundation Career Award. Lynch founded and directs the campus-wide RNA Group, a central forum for investigators in and around Penn interested in RNA-related topics. Lynch has served as a director of the RNA Society, an international scientific organization; is an editor for Molecular and Cellular Biology; and has co-chaired several international meetings in the field of RNA processing.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

Link:
RNA Biologist Kristen Lynch Appointed Chair of Department of Biochemistry and Biophysics at Penn - Newswise (press release)

March 31, 2017 Credit: University of Oxford

An Oxford University spinout company is developing a molecular superglue for the rapid development of vaccines targeting a range of diseases.

SpyBiotech is using 'biochemical superglue' that can facilitate the rapid development of robust and novel vaccines. The company has raised 4m at launch in seed financing to develop the technology, led by Oxford Sciences Innovation with participation from GV.

The company gets its name from the bacterium Streptococcus pyogenes (Spy), the same organism behind a number of infections including strep throat and impetigo. The team behind SpyBiotech divided Spy into a peptide, SpyTag, and a protein partner, SpyCatcher. Naturally attracted to each other, the two form a covalent bond once combined.

SpyBiotech believes that this bond is the missing link to effective development and production of highly effective vaccines. The company will initially focus on virus-like particles (VLPs), a leading technology to induce immune responses by vaccination. Discovered in 1963, VLPs have become a cornerstone of a number of vaccines. Resembling viruses but without pathogenic material, VLPs can instead be coated with bug-busting antigens. However, the two most common ways in which a VLP can be paired with antigens genetic fusion and chemical conjugation are imprecise, expensive, prone to being misassembled, and consequently can result in the failure of a vaccine.

Conversely, SpyBiotech's SpyVLP can be easily and efficiently combined with a number of antigens, and used to produce stable vaccines that induce robust antibody responses. The company plans to target infectious diseases including major viral infections at first, with a view to developing SpyVLP into a universal platform that can be adapted to target a wide variety of conditions. In particular, owing to the versatile and easy-to-use nature of SpyVLP, the technology could underpin efforts to rapidly combat future outbreaks and pandemics.

SpyBiotech will use the seed funding to get its first candidates ready for Phase I trials. During that period, SpyBiotech's founders will receive support from its investors. The founders are aiming to start a further round of funding in the near future to catalyse the development of SpyVLP and expand into other disease areas. A leadership team, including the company's first CEO, will be announced in the coming months.

Sumi Biswas, Associate Professor at the Jenner Institute, Oxford University, said: 'Researchers in the vaccine field, including us, have struggled to make effective VLPs against many diseases for a long time. We view this superglue technology as a game changer to enable faster development of effective vaccines against major global diseases. We are excited to begin the journey of taking this versatile and innovative approach forward and moving our new vaccines from the laboratory to human clinical testing.'

Oxford Sciences Innovation (OSI), the patient capital investor for Oxford University, led the 4m investment, with GV (formerly Google Ventures), an independent venture capital arm of Alphabet, joining in participation.

Lachlan MacKinnon, Principal at OSI, said: 'We see the Spy technology as the missing link in rapid and robust VLP vaccine design and see GV as a natural co-investment partner to take this forward. We are privileged to be working with four founders who bring such an impressive combination of academic prowess and clinical stage experience to the company.'

Tom Hulme, General Partner at GV, added: 'SpyBiotech has established a novel approach using platform VLP vaccine technology that shows promise in a number of addressable markets. We're looking forward to working with a team of world class scientists with extensive experience in vaccine development spanning from vaccine design through to Phase II clinical trials to develop more effective vaccines for a wide range of global diseases.'

The research underpinning SpyBiotech was developed in conjunction between researchers at Oxford University's Department of Biochemistry and Jenner Institute, with four academics joining SpyBiotech at launch. The team includes: Mark Howarth, Professor of Protein Nanotechnology; Sumi Biswas, Associate Professor of Vaccinology; Simon Draper, Professor of Vaccinology; and Dr. Jing Jin. Combined, the founding team has taken twelve products to Phase I and II trials; filed nine patents on vaccines and other technologies; and has extensive experience in biotech and industrial collaborations and partnerships. The commercialisation of SpyBiotech's technology and company formation is supported by Oxford University Innovation, the research commercialisation company of Oxford University.

Carolyn Porter, Deputy Head of Technology Transfer at Oxford University Innovation, said: 'SpyBiotech punctuates research that's been developing for some time here at Oxford, and is a testament to the benefits of collaboration between our departments and institutes. Oxford is playing a leading role in developing the next generation of vaccines, and SpyBiotech and other spinouts working in this sector showcases the potential impact the University can have on the wider world.'

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Biochemical superglue opens new approach to vaccine development - Phys.Org