The sensitivity of the GLP-1 hormone, which is secreted by the gastrointestinal tract, can predict the metabolic efficacy of a gastric bypass. The use of a GLP1 challenge could thus function as a novel predictive biomarker for personalised treatment of type 2 diabetes and obesity
The gastric bypass is one of the most commonly performed surgical procedures in the treatment of obesity. In most patients, it quickly produces substantial body weight loss. Moreover, even before the weight loss, the procedure leads to improved glucose tolerance. However, these metabolic improvements vary considerably from patient to patient.
A hormone test may be able to predict the extent of metabolic improvement caused by the gastric bypass. These are the results of a study on a rodent model conducted by Prof. Dr. Matthias Tschöp and his colleagues from the Institute of Diabetes and Obesity (IDO), Helmholtz Diabetes Center at Helmholtz Zentrum München together with a team of researchers led by Dr. Kirk Habegger at the Metabolic Disease Institute of the University of Cincinnati.
After gastric bypass surgery, the concentration of the gut hormone GLP-1 (glucagon-like peptide 1) in the blood rises significantly. GLP-1 increases insulin secretion and contributes to improved blood glucose levels and blood lipids. As the rat studies by the Tschöp and Habegger research teams showed, GLP-1 responsiveness varied considerably with regard to glucose metabolism. More importantly, the more responsive the animals were to GLP-1, the greater the efficacy of the gastric bypass turned out to be regarding glucose metabolism improvements.
Thus, the responsiveness to GLP-1 could be a key indicator for the success of the gastric bypass. ‘If our results are confirmed in clinical trials with patients, the hormone response could be tested before the planned surgery and surgeons would be able to predict how much an individual patient’s glucose metabolism would benefit,’ said Tschöp. ‘This will contribute to the development of personalized therapies for type 2 diabetes and obesity. For surgical procedures such as gastric bypass this is particularly compelling because such operations are complex and cannot be easily reversed.’
The numerous secondary diseases related to excess weight and obesity, such as type 2 diabetes, are among the most common diseases in Germany. These diseases are the focus of research at Helmholtz Zentrum München, a partner in the German Center for Diabetes Research (DZD). Helmholtz Zentrum München

A way of using nanoparticles to investigate the mechanisms underlying ‘mystery’ cases of infertility has been developed by scientists at Oxford University.
The technique `could eventually help researchers to discover the causes behind cases of unexplained infertility and develop treatments for affected couples. The method involves loading porous silica nanoparticle ‘envelopes’ with compounds to identify, diagnose or treat the causes of infertility.
The researchers demonstrated that the nanoparticles could be attached to boar sperm with no detrimental effects on their function.
‘An attractive feature of nanoparticles is that they are like an empty envelope that can be loaded with a variety of compounds and inserted into cells,’ says Dr Natalia Barkalina, lead author of the study from the Nuffield Department of Obstetrics and Gynaecology at Oxford University. ‘The nanoparticles we use don’t appear to interfere with the sperm, making them a perfect delivery vessel.’
Dr Barkalina added: ‘We will start with compounds to investigate the biology of infertility, and within a few years may be able to explain or even diagnose rare cases in patients. In future we could even deliver treatments in a similar way.’
Sperm are difficult to study owing to their small size, unusual shape and short lifetime outside of the body. Yet this is a vital part of infertility research, as senior author Dr Kevin Coward explains: ‘To discover the causes of infertility, we need to investigate sperm to see where the problems start. Previous methods involved complicated procedures in animals and introduced months of delays before the sperm could be used.
‘Now, we can simply expose sperm to nanoparticles in a petri dish. It’s so simple that it can all be done quickly enough for the sperm to survive perfectly unharmed.’
The team, based at the Institute of Reproductive Sciences, used boar sperm because of its similarities to human sperm, as study co-author Celine Jones explains: ‘It is similar in size, shape and activity. Now that we have proved the system in boar sperm, we hope to replicate our findings in human sperm and eventually see if we can use them to deliver compounds to eggs as well.’ Oxford University

Headaches, anxiety, irritability—these and other symptoms of nicotine withdrawal can significantly deter smokers from being able to kick the habit. Now, in what may be a significant step toward alleviating those symptoms, UMass Medical School neuroscientist Andrew R. Tapper, PhD, and colleagues have identified the region of the brain in which they originate.
‘We were surprised to find that one population of neurons within a single brain region could actually control physical nicotine withdrawal behaviours,’ said Dr. Tapper, associate professor of psychiatry and interim director of the Brudnick Neuropsychiatric Research Institute at UMMS.
The Tapper lab discovered that physical nicotine withdrawal symptoms are triggered by activation of GABAergic neurons (neurons that secrete GABA, the brain’s predominant inhibitory neurotransmitter), in the interpeduncular nucleus, an area deep in the midbrain that has recently been shown to be involved in nicotine intake.
‘Most of the work in the field has been focused on the immediate effects of nicotine, the addictive component in tobacco smoke, on reward circuits in the brain,’ Tapper explained. ‘But much less is known regarding what happens when you take nicotine away from someone who has been smoking for a long time that causes all these terrible withdrawal symptoms. Our main goal was to understand what brain regions are activated—or deactivated—to cause nicotine withdrawal symptoms.
They did this through a series of experiments performed in mouse models with sophisticated neurochemistry and brain imaging methods, including recently developed optogenetics techniques in which specific neurons can be activated by light.
Most surprising was their discovery that nicotine withdrawal symptoms can be activated or deactivated independent of nicotine addiction. ‘When we activated the GABAergic neurons in the interpeduncular nucleus, mice suffered withdrawal symptoms even if they had no previous nicotine exposure,’ Tapper noted.
These findings are promising because existing treatments intended to help people quit smoking are not always effective. ‘There are very few treatments to help people quit smoking,’ Tapper said. ‘If you can dampen the activity of this brain region chemically during nicotine withdrawal then you would hopefully be able to help someone quit smoking because you could reduce some of the withdrawal symptoms that they are experiencing.’ University of Massachusetts

Massachusetts General Hospital (MGH) investigators have used a new sequencing method to identify a group of genes used by the brain’s immune cells – called microglia – to sense pathogenic organisms, toxins or damaged cells that require their response. Identifying these genes should lead to better understanding of the role of microglia both in normal brains and in neurodegenerative disorders and may lead to new ways to protect against the damage caused by conditions like Alzheimer’s and Parkinson’s diseases. The study also finds that the activity of microglia appears to become more protective with ageing, as opposed to increasingly toxic, which some previous studies had suggested.
‘We’ve been able to define, for the first time, a set of genes microglia use to sense their environment, which we are calling the microglial sensome,’ says Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and Division of Infectious Diseases, senior author of the study. ‘Identifying these genes will allow us to specifically target them in diseases of the central nervous system by developing ways to upregulate or downregulate their expression.’
A type of macrophage, microglia are known to constantly survey their environment in order to sense the presence of infection, inflammation, and injured or dying cells. Depending on the situation they encounter, microglia may react in a protective manner – engulfing pathogenic organisms, toxins or damaged cells – or release toxic substances that directly destroy microbes or infected brain cells. Since this neurotoxic response can also damage healthy cells, keeping it under control is essential, and excess neurotoxicity is known to contribute to the damage caused by several neurodegenerative disorders.
El Khoury’s team set out to define the transcriptome – the complete set of RNA molecules transcribed by a cell – of the microglia of healthy, adult mice and compared that expression profile to those of macrophages from peripheral tissues of the same animals and of whole brain tissue. Using a technique called direct RNA sequencing, which is more accurate than previous methods, they identified a set of genes uniquely expressed in the microglia and measured their expression levels, the first time such a gene expression ‘snapshot’ has been produced for any mammalian brain cell, the authors note.
Since ageing is known to alter gene expression throughout the brain, the researchers then compared the sensome of young adult mice to that of aged mice. They found that – contrary to what previous studies had suggested – the expression of genes involved in potentially neurotoxic actions, such as destroying neurons, was down-regulated as animals aged, while the expression of neuroprotective genes involved in sensing and removing pathogens was increased. El Khoury notes that the earlier studies suggesting increased neurotoxicity with ageing did not look at the cells’ full expression profile and often were done in cultured cells, not in living animals.
‘Establishing the sensome of microglia allows us to clearly understand how they interact with and respond to their environment under normal conditions,’ he explains. ‘The next step is to see what happens under pathologic conditions. We know that microglia become more neurotoxic as Alzheimer’s disease and other neurodegenerative disorders progress, and recent studies have identified two of the microglial sensome genes as contributing to Alzheimer’s risk. Our next steps should be defining the sensome of microglia and other brain cells in humans, identifying how the sensome changes in central nervous system disorders, and eventually finding ways to safely manipulate the sensome pharmacologically.’ Massachusetts General Hospital

Viruses cannot only cause illnesses in humans, they also infect bacteria. Those protect themselves with a kind of ‘immune system’ which – simply put – consists of specific sequences in the genetic material of the bacteria and a suitable enzyme. It detects foreign DNA, which may originate from a virus, cuts it up and thus makes the invaders harmless. Scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig have now shown that the dual-RNA guided enzyme Cas9 which is involved in the process has developed independently in various strains of bacteria. This enhances the potential of exploiting the bacterial immune system for genome engineering.
Even though it has only been discovered in recent years the immune system with the cryptic name ‘CRISPR-Cas’ has been attracting attention of geneticists and biotechnologists as it is a promising tool for genetic engineering. CRISPR is short for Clustered Regularly Interspaced Palindromic Repeats, whereas Cas simply stands for the CRISPR-associated protein. Throughout evolution, this molecule has developed independently in numerous strains of bacteria. This is now shown by Prof Emmanuelle Charpentier and her colleagues at the Helmholtz Centre for Infection Research (HZI) who published their finding in the international open access journal Nucleic Acids Research.

The CRISPR-Cas-system is not only valuable for bacteria but also for working in the laboratory. It detects a specific sequence of letters in the genetic code and cuts the DNA at this point. Thus, scientists can either remove or add genes at the interface. By this, for instance, plants can be cultivated which are resistant against vermins or fungi. Existing technologies doing the same thing are often expensive, time consuming or less accurate. In contrast to them the new method is faster, more precise and cheaper, as fewer components are needed and it can target longer gene sequences.

Additionally, this makes the system more flexible, as small changes allow the technology to adapt to different applications. ‘The CRISPR-Cas-system is a very powerful tool for genetic engineering,’ says Emmanuelle Charpentier, who came to the HZI from Umeå and was awarded with the renowned Humboldt Professorship in 2013. ‘We have analysed and compared the enzyme Cas9 and the dual-tracrRNAs-crRNAs that guide this enzyme site-specifically to the DNA in various strains of bacteria.’ Their findings allow them to classify the Cas9 proteins originating from different bacteria into groups. Within those the CRISPR-Cas systems are exchangeable which is not possible between different groups.

This allows for new ways of using the technology in the laboratory: The enzymes can be combined and thereby a variety of changes in the target-DNA can be made at once. Thus, a new therapy for genetic disorders caused by different mutations in the DNA of the patient could be on the horizon. Furthermore, the method could be used to fight the AIDS virus HIV which uses a receptor of the human immune cells to infect them. Using CRISPR-Cas, the gene for the receptor could be removed and the patients could become immune to the virus. However, it is still a long way until this aim will be reached.

Still those examples show the huge potential of the CRISPR-Cas technology. ‘Some of my colleagues already compare it to the PCR,’ says Charpentier. This method, developed in the 1980s, allows scientists to ‘copy’ nucleic acids and therefore to manifold small amounts of DNA to such an extent that they can be analysed biochemically. Without this ground-breaking technology a lot of experiments we consider to be routine would have never been possible. Helmholtz Ceentre for Infection Research