Archive for the ‘Chemistry World Highlights’ Category

Zinc spark shows sperm the chequered flag

Researchers shed light on new explanation for how mammalian zygotes safeguard their survival

Bursts of zinc released within minutes of fertilisation stop reproductive chaos by preventing multiple sperm from binding to eggs, new research shows. 

A team led by Teresa Woodruff and Thomas O’Halloran at Northwestern University, US, first witnessed the almost immediate efflux of billions of zinc ions upon mammalian egg fertilisation with x-ray fluorescence microscopy in 2010. These zinc sparks look like supernovae, according to O’Halloran. Diffusing away from the cell’s membrane, the zinc ions encounter the zona pellucida, a glycoprotein matrix surrounding the egg. Now the team has revealed that zinc retained by the zona pellucida induces changes that harden its protein structure within 30–60 minutes of fertilisation, making it more resistant to sperm binding.

Read the full article in Chemistry World.


Zinc sparks induce physiochemical changes in the egg zona pellucida that prevent polyspermy

Emily L. Que, Francesca E. Duncan, Amanda R. Bayer, Steven J. Philips, Eric W. Roth, Reiner Bleher, Sophie C. Gleber, Stefan Vogt, Teresa K. Woodruff and Thomas V. O’Halloran

DOI: 10.1039/c6ib00212a

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A sound idea for treating lung disease

Scientists in Australia have made a portable device that gently vibrates stem cells with sound waves to turn them into an aerosol. The system could be an effective route for treating various pulmonary diseases.

Chan's device gently nebulises stem cells so they retain their viability after aerosolisation

Experts in microfluidics for bio-applications have praised the innovative idea. Ciprian Iliescu, at the Agency for Science, Technology and Research (A*STAR) in Singapore, describes this as a ‘breakthrough’ and ‘out of the box’ work. ‘Unlike a traditional aerosoliser which needs a nozzle, the design of the device is great as it is nozzle free, avoiding any blockage and contamination problems that are commonly encountered by a traditional aerosoliser,’ he adds. Praveen Vemula at the Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India, agrees that SAW nebulisation of cells ‘is a significant advance in inhaled cell delivery and generalisation of this platform technology to a wide range of cell types might lead to innovative ways to treat pulmonary diseases in the future’.

Read the full article in Chemistry World!

Read the original research paper in Integrative Biology for free*:

Assessment of the potential of a high frequency acoustomicrofluidic nebulisation platform for inhaled stem cell therapy
Layla Alhasan, Aisha Qi, Amgad R. Rezk, Leslie Y. Yeo and Peggy P. Y. Chan
Integr. Biol., 2016, Advance Article
DOI: 10.1039/C5IB00206K

*Access is free until 19/01/2016 through a registered RSC account

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Microfluidic approach to personalised cancer treatment

As part of the united effort to make healthcare technology smaller, better and cheaper, scientists in the US have developed an innovative microfluidic assay that can accurately predict how patients with a certain type of blood cancer will respond to an anticancer drug.

Cancer therapy, like the treatment of other medical conditions, often involves a degree of trial and error in the quest to find the best therapeutic option for each patient. What works for one individual will not necessarily work for another. The future of medicine lies in personalised diagnosis and treatments. Bypassing the use of often unsuccessful and sometimes potentially harmful drugs, and instead tailoring the treatment to each individual, will reduce the time and resources required to successfully treat patients.

Currently, chemosensitivity and resistance assays (CSRAs) are used to predict a patient’s response to a specific drug. However, these CSRAs are not always 100% reliable and do not take into account the influence of non-tumour cells in the overall prediction of treatment success. This is an important consideration as anticancer drugs will affect both tumour and non-tumour cells.

‘The validation of an ex vivo drug screen device for personalised medicine is a constant and tough challenge because an accurate standard just does not exist, and using patients’ clinical data for validation is an ultimate route we must go through’, explains Sihong Wang, a biomedical engineering expert at the City University of New York, US, who was not involved in the study.

To read more, check out Thadchajini Retneswaran’s Chemistry World article here or read the full paper online:

MicroC3: an ex vivo microfluidic cis-coculture assay to test chemosensitivity and resistance of patient multiple myeloma cells
Chorom Pak, Natalie S. Callander, Edmond W. K. Young, Benjamin Titz, KyungMann Kim, Sandeep Saha, Kenny Chng, Fotis Asimakopoulos, David J. Beebe and Shigeki Miyamoto
Integr. Biol., 2015
DOI: 10.1039/C5IB00071H

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Excess glucose limits blood transfusion success

Reducing the level of glucose in solutions used to process blood donations could benefit patients receiving blood transfusions, new research shows.

© Shutterstock

The storage of blood donations is a great challenge as the longer blood is stored, the more it deteriorates. Red blood cells (RBCs) are often collected in solutions containing glucose to preserve and extend their shelf-life, but these solutions may also be adversely affecting the blood as well as patients receiving it.

In the same way that untreated high blood sugar in diabetics can lead to serious medical conditions, complications associated with blood transfusions might be due to the high levels of glucose currently used to store RBCs after donation – often almost 10 times the bloodstream glucose level in a healthy person. This rationale was the motivation behind the research of Dana Spence and his team at Michigan State University in East Lansing, US, who used a microfluidic system to maintain a constant, low level of glucose in blood storage solutions, and then assessed the impact this had on the RBCs.

‘By reducing the glucose levels, we saw that the red blood cells were able to release increased amounts of ATP [adenosine triphosphate] which, in turn, can stimulate nitric oxide in other cell types,’ says Spence. He goes on to explain that nitric oxide is essential for maintaining blood flow and low nitric oxide bioavailability is a recognised problem associated with transfusion.

Christopher Silliman, an expert in blood banking and transfusions at the Bonfils Blood Center in Denver, Colorado, US, says the results are compelling and ‘may lead to improved storage techniques to ultimately make transfusions safer for patients’.

The team is now investigating the survival of RBCs after transfusion in vivo.

Read the full Chemistry World article, and others, on the website, or download the full paper here.

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Sorting the good from the bad

Healthy and cancerous cells attached to fibres

Stress applied to cancerous and non-cancerous cells stuck to nanofibres causes the cancerous cells to become unfixed

US scientists have found a way to separate cancerous cells from healthy cells by taking advantage of their adhesion properties. Separating cancer cells for analysis is a critical step for determining the recommended course of treatment for patients.

See the full article in Chemistry World

Or read the Integrative Biology paper:

Plasma surface modification of electrospun fibers for adhesion-based cancer cell sorting
B. N. Blackstone, J. J. Willard, C. H. Lee, M. T. Nelson, R. T. Hart, J. J. Lannutti and H. M. Powell
DOI: 10.1039/C2IB20025B

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Diabetes reduces antioxidant benefits

Scientists in China have discovered that the blood plasma proteins of type II diabetes patients reduce the beneficial effects of dietary polyphenols.

Blood

Raised glucose levels in the blood of diabetics affects the structure of their blood plasma proteins, which prevents the proteins carrying healthy antioxidants to cells and tissues

Polyphenols are antioxidants and are found in chocolate and red wine, for example. In the body, they scavenge cell damaging free radicals. They bind to proteins in blood plasma, constantly switching between the bound and unbound forms. This may be how polyphenols are delivered to cells and tissues, but this is unproven.

Diabetics have raised levels of glucose in their blood. Glucose can also bind to plasma proteins, says Jianbo Xiao of Shanghai Normal University, who led the research. ‘Exposing plasma proteins to glucose influences their structures and functions,’ he says. So, to investigate this influence, Xiao’s team studied the polyphenol-binding abilities of healthy plasma proteins and compared them to the binding abilities of type II diabetes plasma proteins using fluorescence spectroscopy.

The team found that type II diabetes plasma proteins have an affinity 1 to 10 times lower for polyphenols than healthy proteins. ‘The non-covalent interactions between polyphenols and plasma proteins are usually caused by four major forces: hydrogen bonding, van der Waals forces, hydrophobic interactions and electrostatic interactions,’ says Xiao. The difference between the affinities was larger when more hydrophobic polyphenols were tested. There was only a slight difference in the affinity when the polyphenol’s ability to form hydrogen bonds was changed. So, the main force in the interaction between polyphenols and blood proteins is the hydrophobic force and not hydrogen bonds. It could be that as glucose alters a protein’s structure, it is this hydrophobic interaction that is altered, decreasing the binding affinity.

Ann Hagerman, an expert in the interactions of proteins and polyphenols and their bioactivity at Miami University, US, says that as research has been focused for many years on unmodified proteins, seeing how such modifications affect the interaction is quite interesting. She would like to see the work extended to other small molecules, using methods in addition to fluorescence spectroscopy to study the interactions.

Xiao’s team will now investigate why hydrophobic polyphenols cause a larger difference between the binding affinities of healthy and type II diabetes plasma proteins. The findings may affect the use of polyphenols in diabetes therapies, they say.

Glycation of plasma proteins in type II diabetes lowers the non-covalent interaction affinities for dietary polyphenols
Yixie Xie, Jianbo Xiao, Guoyin Kai and Xiaoqing Chen
DOI: 10.1039/C2IB00185C

Read the original article at Chemistry World

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Early diagnosis for Alzheimer’s and Parkinson’s

US scientists have developed a biosensor that could detect the early stages of Alzheimer’s disease (AD) and Parkinson’s disease (PD) by measuring low concentrations of protein aggregates in cerebrospinal fluid (CSF).

Neurodegenerative diseases are challenging to diagnose in the early stages as they have similar symptoms. However, on a cellular level, aggregates of the proteins beta-amyloid and alpha-synuclein have been linked to AD and PD, respectively, and so have been suggested as good biomarkers for each disease. ‘Pre-symptomatic diagnosis is a problem,’ says lead researcher Shalini Prasad from the University of Texas at Dallas. ‘Current diagnostic tests don’t have the level of sensitivity and selectivity to detect protein binding. Our goal was to see if we could do both at ultra-low concentrations.’

The biosensor is made up of a printed circuit board overlaid with a porous alumina membrane. The team attached nanobodies (antibody fragments that are specific either for alpha-synuclein aggregates or beta-amyloid aggregates) inside the membrane’s pores. When they added CSF to the sensor, the aggregates bound to their specific nanobodies, causing a change in capacitance that was proportional to the aggregates’ concentration. Using their sensor, the team measured aggregate levels in CSF samples from people with autopsy-confirmed AD, PD and control samples with no neurodegenerative disease. They found that the sensor could distinguish between the samples based on the protein aggregates present, suggesting that it has potential in the early diagnosis of these diseases.

The biosensor microchip integrated with a nanoporous alumina membrane and a polydimethylsiloxane manifold. The sensor can achieve diagnosis of target analytes in under 15 minutes

The biosensor microchip integrated with a nanoporous alumina membrane and a polydimethylsiloxane manifold. The sensor can achieve diagnosis of target analytes in under 15 minutes

‘This looks like a very promising technological approach to the diagnosis of Alzheimer’s disease and Parkinson’s disease,’ says Seth Love, an expert in nerve cell damage and death in neurological disease at the Dementia Research Centre, University of Bristol, UK. However, he adds that ‘the applicability of the findings to ante-mortem disease remains to be demonstrated. It will be important to assess the utility of this approach for diagnosis of early-stage rather than end-stage disease.’

Prasad’s team is now working on a multiplex detection array that will give even greater resolution in distinguishing between forms of dementia and are hoping to put their technology into use in pre-clinical studies.

To read Helen Potter‘s original article see Chemistry World or read the full paper here:

CSF levels of oligomeric alpha-synuclein and beta-amyloid as biomarkers for neurodegenerative disease
Michael R. Sierks, Gaurav Chatterjee, Claire McGraw, Srinath Kasturirangan, Philip Schulz and Shalini Prasad
Integr. Biol., 2012, Advance Article
DOI: 10.1039/C1IB00018G

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Cell control to change cell function

US scientists can now control the reactions occurring inside cells. The technology could lead to the manipulation of cell functions in the future, they say. Cells could be triggered to release a therapeutic protein at disease sites, or could be stimulated to regenerate tissue, in response to external cues.

‘Cells respond to cues in their environment that influence or regulate their behaviour,’ explains Milan Mrksich from the University of Chicago who, together with Rafe Petty, carried out the work. ‘This is done by protein receptors on the cell surface that interact with ligands in the extracellular environment [outside the cell].’ For example, stem cells receive cues from growth factor proteins to become a particular cell type – a nerve, bone or skin cell.

Mrksich and Petty created cell-surface protein receptors and threaded them through a cell membrane so that the receptor was outside the cell and the protein within the cell. The team designed ligands to initiate and control phosphorylation reactions in the cell. ‘We could use this mechanism to signal a phosphorylation change in the receptor, which would be the first step in a series of molecular events that would lead to a change in cell function,’ says Mrksich.

Normally, when ligands are introduced to a cell, they bind to the receptors, causing them to dimerise. This brings the receptors closer together so that, with the aid of an enzyme already present in the cell, the proteins can phosphorylate each other. To control this effect, the researchers prepared a bead a couple of microns in size and attached the ligands to its surface, fixing them in place. As the ligands bound to the receptors, many receptors were brought closer together, increasing the phosphorylation rate.

‘The experiments provide further confirmation for the central role of ligand induced receptor dimerisation in cell signalling across the cell membrane,’ says Joseph Schlessinger, professor of pharmacology from the school of medicine at Yale University, US. But, he adds that research on how to make the synthetic receptor approach commercially viable is needed.

In the future, Mrksich hopes to regulate gene expression. If you can turn on or turn off the expression of a set of genes in a cell, you could control the cell function, he says. ‘So if we wanted to regulate gene expression in an animal, we could transplant cells that were engineered with our strategies with these protein receptors into an animal, have those cells function normally within the animal tissue in which they are inserted and then, when the cells see the cues that they are engineered to respond to, they would selectively take on a new function,’ he adds.

To read Elinor Richard‘s original article see Chemistry World or read the full paper here:

De novo motif for kinase mediated signaling across the cell membrane
Rafe T. Petty and Milan Mrksich
Integr. Biol., 2011, Advance Article
DOI: 10.1039/C1IB00009H

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3D model to study breast cancer

Slice from the normal acini model after 12 days. Green: membrane, blue: nuclei, red: dividing cells

Scientists from the US have made a computational model of the formation of breast acini, the sac-like part of the milk-producing glands, to understand complex events occurring during the progression of breast cancer.

Jonathan Tang from the University of California, Berkeley, and colleagues, made a 3D model of acini formation, for the first time, to study how three different cell activities – apoptosis (programmed cell death), proliferation (cell division) and polarisation (organisation of cell components) – work together to form the tissue. In doing so, they hoped to determine how changes to these activities cause cancer.

‘We believed that such a model would enable us to identify which perturbations cause disorganised structures that resemble tumours, giving us a deeper insight into the complex nature of cancer,’ says Tang.

To read more, check out Elinor Richards’ Chemistry World article here or read the full paper online:

Phenotypic transition maps of 3D breast acini obtained by imaging-guided agent-based modeling
Jonathan Tang, Heiko Enderling, Sabine Becker-Weimann, Christopher Pham, Aris Polyzos, Chen-Yi Chen and Sylvain V. Costes
Integr. Biol., 2011
DOI: 10.1039/c0ib00092b

This article was published as part of a themed issue in honor of Mina J. Bissell.

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Channelling deeper to target breast cancer

US scientists have developed a model of the breast ductal system that could be used to discover abnormal cells or deliver drugs at locations further along the ducts than other techniques. The model fits on a slide, enabling on-chip experiments.

The human mammary gland consists of branched ducts with channels of decreasing size that are increasingly more difficult to access to obtain cell samples. This is because the channels get too narrow so the liquid inside them does not move around enough for probes to pass through to collect the cells. Now, a team led by Sophie Lelièvre and James Leary at Purdue University, Indiana, have mimicked the ductal system by making branched channels from polydimethylsiloxane (PDMS). They then moved magnetic particles along the channels through static fluid using a magnet.

The team coated the PDMS with extracellular matrix – a protein scaffold that supports cells. From this, they formed a tubular structure in which to culture mammary epithelial cells. Due to stress from the tube walls, the cells did not survive in straight tubes, so the team engineered U-shaped half channels, or hemichannels, instead. They were then able to culture cells on them, and covered the channels with a PDMS membrane to form tubes.
 

Schematic of the branched channel system 

Link to journal articleBreast on-a-chip: mimicry of the channeling system of the breast for development of theranostics
Meggie M.G. Grafton, Lei Wang, Pierre-Alexandre Vidi, James Leary and Sophie A. Lelièvre
Integr. Biol., 2011, DOI: 10.1039/c0ib00132e

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