Institute of Chemical Biology

London, United Kingdom

Institute of Chemical Biology

London, United Kingdom

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Koleva M.V.,Institute of Chemical Biology | Koleva M.V.,Photonics Group | Koleva M.V.,UK National Heart and Lung Institute | Rothery S.,Imperial College London | And 5 more authors.
Molecular Membrane Biology | Year: 2015

Sonic hedgehog (Shh) is a morphogen active during vertebrate development and tissue homeostasis in adulthood. Dysregulation of the Shh signalling pathway is known to incite carcinogenesis. Due to the highly lipophilic nature of this protein imparted by two post-translational modifications, Shhs method of transit through the aqueous extracellular milieu has been a long-standing conundrum, prompting the proposition of numerous hypotheses to explain the manner of its displacement from the surface of the producing cell. Detection of high molecular-weight complexes of Shh in the intercellular environment has indicated that the protein achieves this by accumulating into multimeric structures prior to release from producing cells. The mechanism of assembly of the multimers, however, has hitherto remained mysterious and contentious. Here, with the aid of high-resolution optical imaging and post-translational modification mutants of Shh, we show that the C-terminal cholesterol and the N-terminal palmitate adducts contribute to the assembly of large multimers and regulate their shape. Moreover, we show that small Shh multimers are produced in the absence of any lipid modifications. Based on an assessment of the distribution of various dimensional characteristics of individual Shh clusters, in parallel with deductions about the kinetics of release of the protein from the producing cells, we conclude that multimerization is driven by self-assembly underpinned by the law of mass action. We speculate that the lipid modifications augment the size of the multimolecular complexes through prolonging their association with the exoplasmic membrane. © 2015 © 2015 Taylor & Francis.


Buyandelger B.,UK National Heart and Lung Institute | Buyandelger B.,Karolinska Institutet | Buyandelger B.,Imperial College London | Mansfield C.,UK National Heart and Lung Institute | And 50 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background-Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. Methods and Results-We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. Conclusions-We revealed new functions for ZBTB17 in the heart, a transcription factor that may play a role as a novel cardiomyopathy gene. © 2015 American Heart Association, Inc.


News Article | December 16, 2015
Site: www.nature.com

During the past two decades, Chinese science has undergone profound growth. China's investment in research and development surpassed that of the European Union in 2013, and it is predicted to overtake that of the United States by the end of the decade (see Nature http://doi.org/w5r; 2014).The proportion of published scientific papers that include Chinese co-authors has jumped from 2.4% in 1997 to 19% in 2014 — second only to the US contribution last year of 25%. Those statistics are impressive. But if China is to become a true scientific superpower, it must be able to produce great scientists who are not just knowledgeable but also creative and skilled in innovation. And great scientists need great mentors to lead the way. In recognition of the vision, dedication and hard work of those charged with nurturing the next generation of Chinese researchers, this year's Nature Awards for Mentoring in Science honour five researchers in China. The winners, feted in an 8 December ceremony, were chosen by panels composed of Chinese scientists and Springer Nature editorial representatives (see go.nature.com/hdi5k7). Submissions included statements from five people who had been mentored by the nominee and statements from the nominees reflecting their own thoughts on mentoring. Owing to China's size, submissions were divided into 'north' and 'south', with awards for lifetime and mid-career achievement in each. The 50,000-yuan (US$7,815) lifetime-achievement award for northern China was shared between immunologist Xuetao Cao, who is president of the Chinese Academy of Medical Sciences, and plant scientist Xingwang Deng, dean of the School of Advanced Agricultural Sciences at Peking University. The winner for southern China is Hongyuan Chen, an electroanalytical chemist and director of the Institute of Chemical Biology at Nanjing University. In the mid-career category, the 50,000-yuan awards for northern and southern China went, respectively, to Yigong Shi, a structural biologist and dean of life sciences at Tsinghua University in Beijing, and Hongbing Shu, an immunologist at Wuhan University. Like many Asian nations, China is often seen as a place of rigid hierarchies rooted in deference to power. One trait shared by all the winners, and indeed by all those nominated, is an understanding that the only authority in science is evidence — and that conventional wisdom must always be open to question. Shi, who was named a chair professor of molecular biology at Princeton University in New Jersey before he returned to China in 2008, thinks that most Chinese students are too wary of contradicting senior researchers and accepted scientific ideas. “I encourage my students to think critically and to challenge the authorities, including myself, so that they can learn that established rules can be broken, and with that, new fields of research can be built,” he says. Cao agrees. “We should inspire students to have confidence to challenge the dogma in the textbook and address fundamental questions in science,” he says. The lesson is not lost on the winners' protégés. “The scientific literature is a baffling mass of conflicting ideas and results, accepted wisdom and false assumptions,” notes Weilin Chen, a cancer immunologist at Zhejiang University and one of Cao's former PhD students at the Second Military Medical University in Shanghai. “Professor Cao often said that creativity comes from different directions with different views,” she says. “And he treats everyone, regardless of whether they are a PhD student or a visiting scholar, with the same high regard.” In the past, most Chinese labs were indeed quite rigid, with a single senior professor directing junior professors, postdocs and students along strictly hierarchical lines. With the rapid expansion of research institutes, however — fuelled by a large influx of researchers returning from overseas — the structure of many labs has begun to follow a less-hierarchical model, with many independent principal investigators all pursuing their own agendas and research directions. The mentors honoured by Nature have recognized the importance of instilling young researchers with the self-confidence that they need to establish their own intellectual identity and to make their own way in the world. “In my opinion, simply imparting knowledge is not enough,” says Hongyuan Chen. “A mentor should teach students the way of thinking. In the area of science, I guide my students to think in a scientific way, and give them the opportunity to solve problems independently.” He thinks that a good mentor must have a keen sense of when a student requires guidance and when he or she needs freedom. “For students who are just starting out, we need to give them more-detailed instructions to let them get used to research gradually,” he says. “And for those who have a solid knowledge base, strong independence and creativity, I let them think and practise in their own ways.” Jingjuan Xu, a former PhD student of Hongyuan Chen's and now an analytical chemist at Nanjing University, says that Chen provided an open environment that fostered imagination and creativity. “He encouraged us to read philosophy and literature, and think from different aspects,” recalls the chemist. “He said that every student is an independent, thinking being; a good mentor should nurture them to become 'horses' rather than 'sheep'.” Good mentors also recognize that it is not enough to produce successful scientists — it is just as important to teach others how to be effective, inspiring leaders themselves. Lei Li, a postdoc of Deng's at Yale University in New Haven, Connecticut, and now a professor in the School of Life Sciences at Peking University, recounts her own training in Deng's lab. “As I became more senior in the lab, Professor Deng started to ask me to help others in their lab techniques and in reading their manuscripts, which I soon realized was part of a system,” she says. “When he discovered performance issues, he never just criticized; he took time to find the root of the problem. And in several instances, he delegated me to do the pep talk.” The testimonials for the award winners all strongly reflect the scientists' unwavering dedication to the success of their protégés. But one story in particular stands out. In 2005, immunologist Bo Zhong, now at Wuhan University, applied to do a PhD in Hongbing Shu's lab after graduating with a major in English. “I was determined to study biology after graduation because I was interested in nature,” says Zhong. At Wuhan, “Dr Shu had recently been appointed as dean of life sciences, and his group [at the National Jewish Medical and Research Center in Denver, Colorado] had just published a milestone discovery in Molecular Cell. Every student with ambition wanted to join his lab — and so did I”. Zhong knew that it wouldn't be easy. “I had to admit that my background was much weaker than those who majored in biology,” he says. “I downloaded all his publications but found that I could hardly understand them. I knocked on the door to his office, and asked many naive questions. He patiently explained the details, recommended more publications to me and encouraged me to ask him if I had any difficulty in understanding the studies. Following his instructions, I read more papers, and wrote a five-page summary about pattern recognition and signalling, and asked whether I could join his lab. To my surprise, he agreed.” Shu admits that he was unsure about Zhong's potential at first, but after seeing his determination, Shu felt that Zhong deserved a chance to show what he could do. He doesn't regret the decision. “After I was convinced of his ambition and drive for a scientific career, I took him without hesitation. He has so far proved himself as one of the most successful students trained in my lab.” After taking him on, Shu asked Zhong to turn the summary that he had written into a full review paper, which became the first publication to come out of the newly formed lab. Shu thinks that patience and perseverance are among the most important traits of good mentorship, something he learnt from one of his own mentors: his PhD supervisor, Harish Joshi, a cell biologist at Emory University in Atlanta, Georgia. “I have always remembered what he told me when I was in his lab. 'Do not fire them; fire them up!',” Shu recalls. “In my 17- years' mentoring life, I have never given up on any one of my students.” A well-known Chinese saying goes, “If someone is your teacher for just one day, you should regard that person as your parent for the rest of your life.” The influence that great mentors have does indeed live long — and not just in their students, but in their students' students. “When I started my own lab in 2012, I often asked myself what Yigong would do,” says Liang Feng, a structural biologist at Stanford University in California and a former PhD student of Shi's. “I kept all e-mail communications Yigong sent to me or to the lab, and often went back to read them. They are like a 'how-to' guide for running a lab. For me and many others, Yigong was not only a great mentor and a role model, but also a relentless supporter and a lifelong friend.” The word used to describe the most revered teachers, shifu — a portmanteau of the words for teacher, laoshi, and father, fuqin — echoes the deep connection that forms between exceptional mentors and their protégés. None of the scientists who nominated their mentors for an award takes this filial bond for granted. In the words of Hongyuan Chen's protégé Jing-juan Xu, “I think that 'father' is really too high a standard to expect from a teacher. But we are the lucky children, because Professor Chen treated us like his own kids.”


News Article | December 12, 2016
Site: www.eurekalert.org

Ring molecules called cyclic depsipeptides play an important role in living organisms. Microbes make them as part of their chemical arsenal for attacking competitors and they have proven effective as antibiotics, anti-retrovirals and pesticides, among other applications. One problem, however, has been the difficulty of chemically synthesizing these biomolecules, particularly in larger ring-sizes. Current methods require a large number of chemical steps, each of which increases the time required and reduces the yield of the final product. Now a pair of chemists -- Stevenson Professor of Chemistry Jeffrey Johnston and doctoral student Suzanne Batiste from the department of chemistry and Institute of Chemical Biology at Vanderbilt University -- have developed a method that produces cyclic depsipeptides in a single step with high yields and in unusually large sizes, ranging up to rings with 60 atoms. They describe the new process in a paper titled "Rapid Synthesis of Cyclic Oligomeric Depsipeptides with Positional, Stereochemical and Macrocycle Size-Distribution Control" published this week in the online early edition of the Proceedings of the National Academy of Sciences. "I don't know of any chemist who wouldn't take a single-step synthesis over one that takes multiple steps," said Johnston. The Vanderbilt researchers achieved this result by adapting a standard tool in the synthetic organic chemist's toolbox called the "Mitsunobu reaction." Normally, this reaction is used to make one carbon-oxygen bond at a time. Johnston and Batiste modified it so it could be used to stitch monomers - small molecules that link to form molecular chains called oligomers -- together and then bind the ends together to form rings. The new method enables them to make rings in unusual and much larger sizes than those found in nature and to do so all in a single step. Once they have synthesized the basic monomer, using others with different chemical units, called decorations, to produce a variety of different bioactive molecules is relatively straightforward. In addition, the chemists found that they could control the size of the rings being formed by adding different salts to their recipe. For example, addition of salt sodium tetrafluoroborate tailored the reaction to produce only 24-atom rings. (This is the basic ring structure of the pesticide verticilide that normally requires 14 steps overall to synthesize, but now can be created in only six!) Similarly, the addition of the salt potassium tetrafluoroborate doubles the amount of 36-atom rings, while adding cesium chloride triples the amount of 60-atom rings produced from a single reaction. "The salts act as templates. So salts of different sizes encourage the formation of rings of different sizes," Johnston explained. The combination of their chemical make-up and ring structure account for cyclic depsipeptides' biological activity. They can be tailor-made to attach to specific receptors on cell surfaces. Receptors are large proteins with one end on the surface of a cell's outer membrane that respond to the presence of specific molecules in the cell's environment and trigger specific biochemical reactions within the cell. By capping a receptor's outer end, cyclic depsipeptides can either block the receptor or trigger it, depending on how they are designed. For example, verticilide blocks the activity of the ryanodine receptor, which controls the concentration of calcium ions within the cell, in insects but not in mammals. "There is speculation that large depsipeptide rings may exhibit unique biological properties but efforts to explore this are in the very early stages," said Johnston. "Our new process will help open this new chemical space." The research was funded by National Institute of General Medical Sciences grant NIH GM 063557.


Elani Y.,Imperial College London | Elani Y.,Institute of Chemical Biology | Solvas X.C.I.,Imperial College London | Solvas X.C.I.,ETH Zurich | And 6 more authors.
Chemical Communications | Year: 2016

Compartmentalised structures based on droplet interface bilayers (DIBs), including multisomes and compartmentalised vesicles, are seen by many as the next generation of biomimetic soft matter devices. Herein, we outline a microfluidic approach for the construction of miniaturised multisomes of pL volumes in high-throughput and demonstrate their potential as vehicles for in situ chemical synthesis. © The Royal Society of Chemistry 2016.


Liu Y.,Wuhan University of Technology | Guan J.,Wuhan University of Technology | Xiao Z.,Institute of Chemical Biology | Sun Z.,Wuhan University of Technology | Ma H.,Wuhan University of Technology
Materials Chemistry and Physics | Year: 2010

Chromium doped barium titanyl oxalate (BCTO) particles with sandwich-like morphologies were synthesized via a facile chemical co-precipitation method in the presence of acrylamide. The morphologies, structures as well as dielectric and electrorheological (ER) properties of the as-synthesized BCTO particles were studied as functions of the concentration of acrylamide. The results show that with increasing the concentration of acrylamide used in the chemical co-precipitation process, the morphologies of the as-synthesized products change from an irregular shape via sandwich-like structure to congeries of blocks, at the same time, the crystallinity and the BET surface area (SBET) exhibit maximal values. All these phenomena are reasonably explained in terms of the interaction between acrylamide and BCTO. Among the as-synthesized products with various morphologies, the BCTO sandwich-like particles show the strongest interfacial polarization and ER effect, which originate from their peculiar morphology and SBET. © 2010 Elsevier B.V. All rights reserved.


Miller R.M.,Institute of Chemical Biology | Miller R.M.,Imperial College London | Poulos A.S.,Imperial College London | Robles E.S.J.,Procter and Gamble | And 3 more authors.
Crystal Growth and Design | Year: 2016

The crystallization mechanisms and kinetics of micellar sodium dodecyl sulfate (SDS) solutions in water, under isothermal conditions, were investigated experimentally by a combination of reflection optical microscopy (OM), differential scanning calorimetry (DSC), and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). The rates of nucleation and growth were estimated from OM and DSC across temperatures ranging from 20 to -6 °C for 20% SDS-H2O, as well as for 10 and 30% SDS-H2O at representative temperatures of 6, 2, and -2 °C. A decrease in temperature increased both nucleation and growth rates, and the combined effect of the two processes on the morphology was quantified via both OM and ATR-FTIR. Needles, corresponding to the hemihydrate polymorph, become the dominant crystal form at ≤ -2 °C, while platelets, the monohydrate, predominate at higher temperatures. Above 8 °C, crystallization was only observed if seeded from crystals generated at lower temperatures. Our results provide quantitative and morphological insight into the crystallization of ubiquitous micellar SDS solutions and its phase stability below room temperature. © 2016 American Chemical Society.


PubMed | Institute of Chemical Biology
Type: Journal Article | Journal: Cytotechnology | Year: 2012

This paper describes the increase of antiproliferative activity toward tumor cell lines of liposome-delivered retinoids and aromatic polyamidines.


News Article | December 12, 2016
Site: phys.org

One problem, however, has been the difficulty of chemically synthesizing these biomolecules, particularly in larger ring-sizes. Current methods require a large number of chemical steps, each of which increases the time required and reduces the yield of the final product. Now a pair of chemists—Stevenson Professor of Chemistry Jeffrey Johnston and doctoral student Suzanne Batiste from the department of chemistry and Institute of Chemical Biology at Vanderbilt University—have developed a method that produces cyclic depsipeptides in a single step with high yields and in unusually large sizes, ranging up to rings with 60 atoms. They describe the new process in a paper titled "Rapid Synthesis of Cyclic Oligomeric Depsipeptides with Positional, Stereochemical and Macrocycle Size-Distribution Control" published this week in the online early edition of the Proceedings of the National Academy of Sciences. "I don't know of any chemist who wouldn't take a single-step synthesis over one that takes multiple steps," said Johnston. The Vanderbilt researchers achieved this result by adapting a standard tool in the synthetic organic chemist's toolbox called the "Mitsunobu reaction." Normally, this reaction is used to make one carbon-oxygen bond at a time. Johnston and Batiste modified it so it could be used to stitch monomers - small molecules that link to form molecular chains called oligomers—together and then bind the ends together to form rings. The new method enables them to make rings in unusual and much larger sizes than those found in nature and to do so all in a single step. Once they have synthesized the basic monomer, using others with different chemical units, called decorations, to produce a variety of different bioactive molecules is relatively straightforward. In addition, the chemists found that they could control the size of the rings being formed by adding different salts to their recipe. For example, addition of salt sodium tetrafluoroborate tailored the reaction to produce only 24-atom rings. (This is the basic ring structure of the pesticide verticilide that normally requires 14 steps overall to synthesize, but now can be created in only six!) Similarly, the addition of the salt potassium tetrafluoroborate doubles the amount of 36-atom rings, while adding cesium chloride triples the amount of 60-atom rings produced from a single reaction. "The salts act as templates. So salts of different sizes encourage the formation of rings of different sizes," Johnston explained. The combination of their chemical make-up and ring structure account for cyclic depsipeptides' biological activity. They can be tailor-made to attach to specific receptors on cell surfaces. Receptors are large proteins with one end on the surface of a cell's outer membrane that respond to the presence of specific molecules in the cell's environment and trigger specific biochemical reactions within the cell. By capping a receptor's outer end, cyclic depsipeptides can either block the receptor or trigger it, depending on how they are designed. For example, verticilide blocks the activity of the ryanodine receptor, which controls the concentration of calcium ions within the cell, in insects but not in mammals. "There is speculation that large depsipeptide rings may exhibit unique biological properties but efforts to explore this are in the very early stages," said Johnston. "Our new process will help open this new chemical space." More information: Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1616462114

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