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Karnani M.M.,University of Cambridge | Szabo G.,Institute of Experimental Medicine | Erdelyi F.,Institute of Experimental Medicine | Burdakov D.,University of Cambridge | Burdakov D.,King's College London
Journal of Physiology | Year: 2013

GABAergic neurons are vital for brain function. Their neurochemical and electrical features have been classically characterized in the cortex, but in the lateral hypothalamic area (LHA), such knowledge is lacking, despite the emerging roles of LHA GABAergic cells in feeding and sleep. We used GAD65-GFP transgenic mice, developed for studies of cortical GABAergic cells, to determine fundamental properties of LHA GAD65 neurons, and compare them to 'classical' GABAergic cell types of the cortex, and to previously described classes of LHA cells. Whole-cell patch-clamp recordings in acute brain slices revealed that, unlike cortical GABAergic interneurons, LHA GAD65 neurons were intrinsically depolarized and fired action potentials spontaneously. Similar to cortical GABAergic cells, LHA GAD65 cells fell into four major subtypes based on evoked firing: fast spiking, late spiking, low threshold spiking and regular spiking. Three-dimensional reconstructions of biocytin-filled neurons, performed after the patch-clamp analysis, did not reveal striking morphological differences between these electrophysiological subtypes. Peptide transmitters expressed in known classes of LHA projection neurons, namely melanin-concentrating hormone (MCH) and hypocretin/orexin (hcrt/orx), were not detected in LHA GAD65 cells. Approximately 40% of LHA GAD65 cells were directly inhibited by physiological increases in extracellular glucose concentration. Glucose inhibition was most prevalent in the fast spiking subpopulation, although some glucose-responsive neurons were found in each electrophysiological subpopulation. These results suggest that LHA GAD65 neurons are electrically different from 'classical' GABAergic neurons of the cortex, are neurochemically distinct from LHA hcrt/orx and MCH cells, but partly resemble hcrt/orx cells in their glucose responses. © 2013 The Physiological Society.

Haller J.,Institute of Experimental Medicine | Harold G.,University of Sussex | Sandi C.,Ecole Polytechnique Federale de Lausanne | Neumann I.D.,University of Regensburg
Journal of Neuroendocrinology | Year: 2014

We review the impact of early adversities on the development of violence and antisocial behaviour in humans, and present three aetiological animal models of escalated rodent aggression, each disentangling the consequences of one particular adverse early-life factor. A review of the human data, as well as those obtained with the animal models of repeated maternal separation, post-weaning social isolation and peripubertal stress, clearly shows that adverse developmental conditions strongly affect aggressive behaviour displayed in adulthood, the emotional responses to social challenges and the neuronal mechanisms activated by conflict. Although similarities between models are evident, important differences were also noted, demonstrating that the behavioural, emotional and neuronal consequences of early adversities are to a large extent dependent on aetiological factors. These findings support recent theories on human aggression, which suggest that particular developmental trajectories lead to specific forms of aggressive behaviour and brain dysfunctions. However, dissecting the roles of particular aetiological factors in humans is difficult because these occur in various combinations; in addition, the neuroscientific tools employed in humans still lack the depth of analysis of those used in animal research. We suggest that the analytical approach of the rodent models presented here may be successfully used to complement human findings and to develop integrative models of the complex relationship between early adversity, brain development and aggressive behaviour. © 2014 British Society for Neuroendocrinology.

Sebens S.,Institute of Experimental Medicine | Schafer H.,Laboratory of Molecular Gastroenterology and Hepatology
Current Pharmaceutical Biotechnology | Year: 2012

Tumors irrespective of their origin are heterogenous cellular entities whose growth and progression greatly depend on reciprocal interactions between genetically altered (neoplastic) cells and their non-neoplastic microenvironment. Thus, microenvironmental factors promote many steps in carcinogenesis, e.g. proliferation, invasion, angiogenesis, metastasis and chemoresistance. Drug resistance, either intrinsic or acquired, essentially limits the efficacy of chemotherapy in many cancer patients. To some extent, this resistance is maintained by reduced drug accumulation, alterations in drug targets and increased repair of drug-induced DNA damage. However, the pivotal mechanism by which tumor cells elude the cytotoxic effect of chemotherapeutic drugs is their efficient protection from induction and excecution of apoptosis. It is meanwhile well established that cellular and non-cellular components of the tumoral microenvironment, e.g. myofibroblasts and extracellular matrix (ECM) proteins, respectively, contribute to the anti-apoptotic protection of tumor cells. Cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins and other ECM receptors which are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified as suitable molecular targets to overcome chemoresistance. Accordingly, several therapeutic strategies based on these targets have been already elaborated and tested in preclinical and clinical studies, including inhibitors and blocking antibodies for CD44/hyaluronan, integrins, L1CAM and CXCL12. Even though these approaches turned out to be promising, the upcoming challenge will be to prove the efficacy of these strategies in improving treatment and prognosis of cancer patients. © 2012 Bentham Science Publishers.

Milman B.L.,Institute of Experimental Medicine | Zhurkovich I.K.,Institute of Toxicology
Analytical Chemistry Research | Year: 2014

To gain perspective on the use of tandem mass spectral libraries for identification of toxic cyclic peptides, the new library was built from 263 mass spectra (mainly MS2 spectra) of 59 compounds of that group, such as microcystins, amatoxins, and some related compounds. Mass spectra were extracted from the literature or specially acquired on ESI-Q-ToF and MALDI-ToF/ToF tandem instruments. ESI-MS2 product-ion mass spectra appeared to be rather close to MALDI-ToF/ToF fragment spectra which are uncommon for mass spectral libraries. Testing of the library was based on searches where reference spectra were in turn cross-compared. The percentage of 1st rank correct identifications (true positives) was 70% in a general case and 88-91% without including knowingly defective ('one-dimension') spectra as test ones. The percentage of 88-91% is the principal estimate for the overall performance of this library that can be used in a method of choice for identification of individual cyclopeptides and also for group recognition of individual classes of such peptides. The approach to identification of cyclopeptides based on mass spectral library matching proved to be the most effective for abundant toxins. That was confirmed by analysis of extracts from two cyanobacterial strains. © 2014 Elsevier Ltd.

Marik S.A.,Rockefeller University | Yamahachi H.,Rockefeller University | McManus J.N.J.,Rockefeller University | Szabo G.,Institute of Experimental Medicine | Gilbert C.D.,Rockefeller University
PLoS Biology | Year: 2010

Cortical topography can be remapped as a consequence of sensory deprivation, suggesting that cortical circuits are continually modified by experience. To see the effect of altered sensory experience on specific components of cortical circuits, we imaged neurons, labeled with a genetically modified adeno-associated virus, in the intact mouse somatosensory cortex before and after whisker plucking. Following whisker plucking we observed massive and rapid reorganization of the axons of both excitatory and inhibitory neurons, accompanied by a transient increase in bouton density. For horizontally projecting axons of excitatory neurons there was a net increase in axonal projections from the non-deprived whisker barrel columns into the deprived barrel columns. The axon collaterals of inhibitory neurons located in the deprived whisker barrel columns retracted in the vicinity of their somata and sprouted long-range projections beyond their normal reach towards the non-deprived whisker barrel columns. These results suggest that alterations in the balance of excitation and inhibition in deprived and non-deprived barrel columns underlie the topographic remapping associated with sensory deprivation. © 2010 Marik et al.

Vasilyev V.B.,Institute of Experimental Medicine
Biochemical Society Transactions | Year: 2010

The first detailed report of a specific interaction of CP (caeruloplasmin) with another protein described its complex with LF (lactoferrin) in 2000. Since then, several protein-protein interactions involving CP have been reported, mostly concerning iron-containing proteins. The CP-LF complex was studied thoroughly, and evidence of reciprocal effects of CP and LF was obtained. Another specific interaction investigated in detail occurs between CP and MPO (myeloperoxidase). CP-LF, CP-MPO and CP-LF-MPO complexeswere found in sera of patients with inflammation. Modelling in vitro allowed understanding of which structural peculiarities of CP and partners allow the modification of their functions in a complex. The present paper reviews the latest data on complexes of CP with LF and MPO, and advances some suggestions about their role in health and disease. ©The Authors.

Cejka C.,Institute of Experimental Medicine | Cejkova J.,Institute of Experimental Medicine
Oxidative Medicine and Cellular Longevity | Year: 2015

Oxidative stress is involved in many ocular diseases and injuries. The imbalance between oxidants and antioxidants in favour of oxidants (oxidative stress) leads to the damage and may be highly involved in ocular aging processes. The anterior eye segment and mainly the cornea are directly exposed to noxae of external environment, such as air pollution, radiation, cigarette smoke, vapors or gases from household cleaning products, chemical burns from splashes of industrial chemicals, and danger from potential oxidative damage evoked by them. Oxidative stress may initiate or develop ocular injury resulting in decreased visual acuity or even vision loss. The role of oxidative stress in the pathogenesis of ocular diseases with particular attention to oxidative stress in the cornea and changes in corneal optical properties are discussed. Advances in the treatment of corneal oxidative injuries or diseases are shown. © 2015 Cestmir Cejka and Jitka Cejkova.

Haller J.,Institute of Experimental Medicine | Alicki M.,Institute of Experimental Medicine
Current Opinion in Psychiatry | Year: 2012

Purpose of Review: The perception that 'classical' anxiety tests are deficient was formulated in the mid-1990s. Recent clinical trials also demonstrate that the predictive power of such tests is low, which emphasizes the need for developing models of higher translational value. Several novel models are proposed each year. Here, we investigate their impact on anxiolytic-related studies performed in 2010 and 2011. Recent Findings: Here, we depict as 'classical' all the tests that were developed at the same time as or earlier than the elevated plus-maze test. No test equaled its success in the subsequent decades; therefore, we consider it the endpoint of the period when the methodological bases of current laboratory research were laid down. Fourteen classical tests were employed in the investigated period, which were used in more than 80% of studies. Concurrently, 36 'nonclassical' tests were used and six novel tests were also proposed. These accounted for fewer than 20% of studies. 'Classical' tests were often performed under unconventional conditions that putatively increased their translational value. Taken together, half of the studies involved at least one innovative step. Yet, the new procedures were infrequently used. Out of the 36 'nonclassical' tests, only 11 were used more than once, while the amendments to 'classical tests' were almost entirely laboratory specific. Summary: Our analysis shows that there is a large interest in performing anxiety research innovatively. However, efforts are highly divergent and result in large numbers of poorly validated and infrequently used novel approaches. Thus, models with increased translational value still need to be developed. © Lippincott Williams & Wilkins.

Milman B.L.,Institute of Experimental Medicine
TrAC - Trends in Analytical Chemistry | Year: 2015

The review is devoted to chemical identification using mass spectrometry as the most powerful technique of qualitative analysis. The review begins with consideration of basic principles and means of chemical identification. Following are sections covering techniques and instruments and metrological issues. Procedures for identification outlined next are divided into target identification by methods and unknown/non-target analysis. For the latter, information support, such as mass spectral libraries and chemical databases, programs of formula generation and spectral prediction/interpretation, are reviewed. Finally, identification of samples and some general trends are briefly noted. © 2014 Elsevier B.V.

Golubev A.,Institute of Experimental Medicine
Journal of Theoretical Biology | Year: 2010

Positively skewed distributions common in biology are often approximated with lognormal or gamma functions. It is shown here that for some classes of phenomena, including intermitotic time and protein expression variabilities, exponentially modified Gaussian (EMG) may provide better fit. EMG is generated by processes involving normally distributed entry rates and exponentially distributed exit rates; therefore, its parameters may be straightforwardly interpreted in biologically meaningful terms and thus may help to choose between theoretical models of the respective phenomena. In particular, EMG is consistent with the transition probability model of cell cycle and may be used to estimate its deterministic and probabilistic parts. EMG is also consistent with the assumption that the probabilistic part is determined by competing stochastic transcriptional events committing cells to proliferative mitoses, differentiation, or apoptosis. Discrete event simulation modelling of this situation suggests that cell differentiation rate is primarily increased by decreasing the frequencies of the events that result in the realisation of the competing options, including proliferation, rather than by the direct changes in the differentiation-inducing events. © 2009 Elsevier Ltd. All rights reserved.

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