Potter group collaboration reveals atomic level mechanistic insight into an unusual protein tyrosine phosphatase
Data from a tripartite collaboration, from the Potter group at Oxford Pharmacology, the NIH and Freiburg University, just published in Nature Communications include the first multiple substrate/enzyme crystal complexes from a variety of pre-reactant-, reactant-, intermediate- and product-bound states for a Cys-based Arabidopsis thaliana protein tyrosine phosphate-phosphatase lacking a functional canonical catalytic acid.
Davis/Anthony paper describes system that enables enzyme-free site-selective cleavage of dehydroalanine tagged proteins
The ability of proteins to self-modify is rare, but the capability to design a chemically induced targeted proteolytic cleavage site would be enormously advantageous in many biotechnology applications and for the development of new medicines. In a proof-of-principle study, a team from the laboratories of Ben Davis and Daniel Anthony have designed and tested a system that enables enzyme-free site-selective cleavage of dehydroalanine tagged proteins. The reaction is promoted by diboron and is achievable under mild aqueous conditions. Usefully, it can be used to generate C-terminal amidation, which is essential for the activity of a number of important neuropeptides that are currently hard to synthesise. Indeed, drawing upon classical organ bath preparations that are available in Pharmacology, the team showed that it was possible to generate pharmacologically active neurokinin-A from a proteome lysate containing precursors following the incorporation of the chemically sensitive cleavage site. Professor Davis speculates that “this ability to achieve site-directed chemical modification of proteins sets the scene to stimulate new and exciting modes of synthetic biology and unpick some intriguing mechasnisms.”
The full paper, ‘Reductive site-selective atypical C,Z-type / N2–C2 cleavage allows C-terminal protein amidation’, is available open-access in Science Advances, a leading multidisciplinary journal with a global readership, which can be read at http://advances.sciencemag.org/.
Heart neurons use clock genes to control myocyte proliferation
© Image credit: Cassie H KwonA recent study involving the Minichiello group and international collaborators, principally at the Johns Hopkins University, Baltimore, USA, and the National Institutes of Health, Bethesda, USA, has uncovered an unknown link between cardiac neurons and clock genes in the regulation of heart size and cardiomyocyte proliferation. The lack of appropriate animal models has impaired addressing the precise effect of sympathetic neurons on heart development. The authors have used a novel mouse model based on the deletion of nerve growth factor (NGF) in smooth muscle cells disrupting cardiac sympathetic innervation to demonstrate that sympathetic innervation decreases cardiomyocyte proliferation through clock genes. These novel findings suggest neuronal modulation as a therapeutic strategy for cardiac regeneration.
Vasudevan lab identifies novel means of improving sensitivity and efficiency for PCR COVID testing
In collaboration with the infectious disease units at the John Radcliffe and Churchill Hospitals, the Vasudevan lab has identified a novel means of improving RT-qPCR sensitivity and efficiency for the detection of SARS-CoV-2 through the concentration of pooled patient lysates.
International collaboration by Potter group uncovers vital element in regulation of Na⁺/K⁺- ATPase-α1
Endogenous negative regulators of the Na/K-ATPase have been elusive for decades. The Potter group has coauthored a paper in Science Advances that identifies the myo-inositol polyphosphate pyrophosphate 5-InsP7 as an endogenous negative regulator of Na⁺/K⁺-ATPase-α1: “The inositol pyrophosphate 5-InsP7 drives sodium-potassium pump degradation by relieving an auto-inhibitory domain of PI3K p85α”
New Garland/Dora group paper provides a novel mechanism for the vasospasm underlying cardiovascular disease
The Vascular Pharmacology group has published a paper in Hypertension showing that loss of nitric oxide production by endothelial cells, a ubiquitous feature of cardiovascular disease, raises the electrical excitability of arterial smooth muscle by recruiting T-type voltage-gated calcium channels. This change switches physiological vasomotion to pathological vasospasm.
Optical method to study interaction between sympathetic nerves and heart muscle
Research led by Associate Professor Rebecca Burton at Oxford, together with Associate Professor Gil Bub at McGill University (Canada) and Professor Emilia Entcheva at George Washington University (USA), has demonstrated a purely optical method that makes it possible to stimulate cells and to directly observe both the effects of spatial distribution and functional connectivity between neurons and heart muscle cells. This model system provides a unique window into the relationship between the tissue health, neuron density and the excitability of the heart muscle. These insights are particularly relevant to understanding complications that arise after damage to the heart tissue, such as potentially lethal heart arrhythmias after a heart attack.
A NEW BIOMARKER FOR CARDIOVASCULAR DISEASES IN OLDER PEOPLE
A collaboration between the Smith/Refsum laboratory and the Aging Research Centre at the Karolinska Institute in Stockholm has led to the discovery of a new blood biomarker that predicts the development of cardiovascular diseases in older people. The marker is the ratio of the concentrations of methionine and homocysteine in blood plasma: the lower the ratio, the greater the risk of developing one or more diseases of the cardiovascular system. The findings were recently published in JAMA Network Open.
Interdisciplinary project could lead to a personalised approach for mood stabilisation for bipolar patients
The Vasudevan laboratory, in an interdisciplinary project with scientists and clinicians, across the Department of Psychiatry, Nuffield Department of Clinical Neuroscience, Warneford Hospital, Department of Pathology, Weatherall Institute of Molecular Medicine, and the Oxford StemBANCC, have used bipolar patient-derived fibroblasts to gain a deeper understanding into patient circadian rhythms, and how these rhythmic changes could predict lithium sensitivity in bipolar disorder.
BDNF-TRKB signalling is pivotal for the sequential maturation of intrinsic hippocampal circuits
The Minichiello laboratory through an excellent interdisciplinary collaborative effort, particularly with the laboratories of Prof E. Cherubini at the European Brain Research Institute (EBRI) in Rome, Italy, and Prof JM. Delgado-García at the University Pablo de Olavide, Seville, Spain, have now uncovered a novel essential role for BDNF-TrkB signalling in driving sequential maturation of intrinsic hippocampal circuits. They show the in vivo consequences of Ntrk2/Trkb selective deletion at a time-sensitive window both on postnatal development and adult brain.
Rhythms of the brain: uncovering a subcortical circuit that modulates cortical gabaergic neurons
Minas Salib, in the group led by Tim Viney and Peter Somogyi, has discovered a new type of neuronal pathway that may be important in memory.
For the encoding and recall of episodic memories, nerve cells in the cerebral cortex are activated in precisely timed sequences. Rhythmicity facilitates the coordination of neuronal activity and these rhythms are detected as oscillations of different frequencies, such as 5–12 Hz theta oscillations. Degradation of these rhythms, such as through neurodegeneration, causes memory deficits. The medial septum, a part of the basal forebrain that innervates the hippocampal formation, contains neurons that fire with a high degree of rhythmicity (HRNs) and others that fire with a low degree of rhythmicity (LRNs). These distinct types of neuron may contribute differentially to the coordination of cortical neuronal activity. Minas and colleagues discovered that GABAergic LRNs preferentially innervate the dentate gyrus and the CA3 area of the hippocampus, regions important for episodic memory. These neurons act in parallel with the HRNs mostly via transient inhibition of inhibitory neurons. A figure from the paper describing these results was chosen to illustrate the front cover of the June 5th issue of Journal of Neuroscience.
Gene therapy in utero for untreatable genetic disease
A recent study involving the Platt group and international collaborators, principally at UCL, but also in Singapore, US, Sweden and South Africa, has demonstrated proof-of principle for gene therapy in utero in a mouse model of acute neuronopathic Gaucher disease. This disease is an extremely severe, rapidly progressive, neurodegenerative lysosomal storage disorder resulting from a deficiency of the lysosomal enzyme beta-glucocerebrosidase. Most children with the disease die between two and four years of age. The authors used a mouse model of the disease to see if it was possible to prevent expression of the disease after birth by introducing the gene for beta-glucocerebrosidase into the brain of the mouse foetus.
Antiarrhythmic drugs – an updated classification after 50 years
In the late 1960s Miles Vaughan Williams, a member of the staff in the Oxford Department of Pharmacology and Fellow of Hertford College (1955-85), introduced a novel classification of drugs used to treat cardiac arrhythmias. This scheme has been very widely used around the world and has led to the development of new drugs that have saved countless lives. Our understanding of the control of cardiac rhythm has developed in that time and a group of cardiovascular scientists from Oxford, Cambridge and Beijing led by Dr.Ming Lei decided that the time was ripe to modernise the classification and to celebrate the centenary of the birth of Vaughan Williams (https://en.wikipedia.org/wiki/Miles_Vaughan_Williams).
Together they have now published a comprehensive modern classification, based upon the original version, in the leading journal ‘Circulation’.
Crystallography of new drug class facilitates structure-based design
The Potter group, leading an international collaboration, has discovered newly-designed synthetic microtubule disruptors with excellent activities and desirable drug-like profiles. This first example of a new drug class bound to tubulin to be explored crystallographically opens up new avenues for structure-based anti-cancer drug design.
Lipid accumulation in the brain may contribute to Parkinson's disease
A collaborative team of researchers from the Platt lab and the Isacson lab (McLean Hospital, Harvard Medical School) has found that elevated levels of certain types of lipids (fat molecules) in the brain, called glycosphingolipids, may be an early sign of Parkinson's disease.
RHYTHMIC BRAIN SIGNALS SUPPORTING MEMORY
Isn’t it extraordinary that we can record and retrieve memories of our lives all the time? The ability to make new memories and retrieve old ones is often associated with rhythmic electrical activity in a structure of the brain called hippocampus, as damage to this structure results in an impairment of memory. Abhilasha Joshi and her colleagues have discovered a novel population of nerve cells outside the hippocampus that regulate the rhythmic firing of specialised nerve cells within the hippocampus.
New endogenous cell signalling molecule discovered
The Potter group has been part of an interdisciplinary and international research team that has discovered a new endogenous cellular molecule called 2′-deoxyadenosine 5'-diphosphate ribose (dADPR) that may play an important role as a chemical signal in autoimmune and metabolic disorders, such as obesity and diabetes.
TRANSCRIPTOME ANALYSIS FROM A SMALL NUMBER OF NEURONS PURIFIED FROM THE AGED MOUSE BRAIN
The Minichiello Group in collaboration with the Nerlov laboratory and FACS facility at the MRC Weatherall Institute of Molecular Medicine, has established new methods to isolate brain neurons from the adult and aged mouse. This makes it possible to perform unbiased studies of aging brain neurons from relatively small numbers of neurons by quantitative transcriptome analysis, such as RNA sequencing, that offers higher resolution than other methods.
The heart’s own adrenaline-producing cells can control heart rhythm
The group led by Ming Lei has discovered that the heart can regulate its own rhythm by releasing adrenaline (epinephrine) from a specialised kind of heart muscle cell that contains the enzyme that makes adrenaline.
Rhythmic networks in the brain that help us find our way in the world
The Somogyi group discovered a rhythmic subcortical inhibitory (GABAergic) nerve cell population in a part of the mouse brain called the medial septum that projects to both the dorsal presubiculum and entorhinal cortex but avoids the hippocampus. As set out in a recent paper published in eLife, the group named these nerve cells ‘orchid cells’ based on the shape of the axonal trajectories