Identification of Benzoxazolinone Derivatives Based Inhibitors for Depression and Pain Related Disorders Using Human Serotonin and Norepinephrine Transporter as Dual Therapeutic Target: A Computational Approach

Pain is commonly associated with depression. Both pain and depression share common biological pathways and neurotransmitters, which has implications for the treatment of both disorders. A drug that could ameliorate both pain and depression could be beneficial in the development of new therapeutics in the management of disorders associated with pain/depression dyad. Alterations in the neurotransmitters namely, serotonin and norepinephrine in the central nervous system (CNS) have been implicated in the pathophysiology of pain and depression. Serotonin and norepinephrine reuptake inhibitors (SNRIs) have been implicated as a novel therapeutic target for a wide range of biological functions, including pain, anxiety and depression. 2-benzoxazolinone (2-BOA) from the mangrove Acanthus ilicifolius and its derivatives have been reported for its analgesic and antidepressant activities. In the present work, docking studies were done on the crystal structure of human transporters of serotonin (hSERT) and on homology modeled human transporters of norepinephrine (hNET) as therapeutic targets of depression and pain related disorders using 2-BOA and its derivatives as potential candidates. A homology model for hNET was constructed using MODELLER and validated. Further docking studies were done on hSERT and hNET using 2-BOA and its structural analogs. The result of the study proposes the possible potential candidate among 2-BOA derivatives that may be further developed as a therapeutic lead compound for use in disorders associated with depression and pain

The cubicle warrior: the marionette of the digitalized warfare

In the last decade we have entered the era of remote controlled military technology. The excitement about this new technology should not mask the ethical questions that it raises. A fundamental ethical question is who may be held responsible for civilian deaths. In this paper we will discuss the role of the human operator or so-called ‘cubicle warrior’, who remotely controls the military robots behind visual interfaces. We will argue that the socio-technical system conditions the cubicle warrior to dehumanize the enemy. As a result the cubicle warrior is morally disengaged from his destructive and lethal actions. This challenges what he should know to make responsible decisions (the so-called knowledge condition). Nowadays and in the near future, three factors will influence and may increase the moral disengagement even further due to the decrease of locus of control orientation: (1) photo shopping the war; (2) the moralization of technology; (3) the speed of decision-making. As a result, cubicle warriors cannot be held reasonably responsible anymore for the decisions they make

Surface plasmon resonance imaging of cells and surface-associated fibronectin

<p>Abstract</p> <p>Background</p> <p>A critical challenge in cell biology is quantifying the interactions of cells with their extracellular matrix (ECM) environment and the active remodeling by cells of their ECM. Fluorescence microscopy is a commonly employed technique for examining cell-matrix interactions. A label-free imaging method would provide an alternative that would eliminate the requirement of transfected cells and modified biological molecules, and if collected nondestructively, would allow long term observation and analysis of live cells.</p> <p>Results</p> <p>Using surface plasmon resonance imaging (SPRI), the deposition of protein by vascular smooth muscle cells (vSMC) cultured on fibronectin was quantified as a function of cell density and distance from the cell periphery. We observed that as much as 120 ng/cm²of protein was deposited by cells in 24 h.</p> <p>Conclusion</p> <p>SPRI is a real-time, low-light-level, label-free imaging technique that allows the simultaneous observation and quantification of protein layers and cellular features. This technique is compatible with live cells such that it is possible to monitor cellular modifications to the extracellular matrix in real-time.</p

The role of virulence factors in the outcome of staphylococcal peritonitis in CAPD patients

<p>Abstract</p> <p>Background</p> <p>Peritonitis continues to be the most frequent cause of peritoneal dialysis (PD) failure, with an important impact on patient mortality. Gram-positive cocci such as <it>Staphylococcus epidermidis</it>, other coagulase-negative staphylococci (CoNS), and <it>Staphylococcus aureus </it>are the most frequent etiological agents of PD-associated peritonitis worldwide. The objective of the present study was to compare peritonitis caused by <it>S. aureus </it>and CoNS and to evaluate the factors influencing outcome.</p> <p>Methods</p> <p>Records of 86 new episodes of staphylococcal peritonitis that occurred between 1996 and 2000 in the Dialysis unit of a single university hospital were studied (35 due to <it>S. aureus</it>, 24 to <it>S. epidermidis </it>and 27 to other CoNS). The production of slime, lipase, lecithinase, nuclease (DNAse), thermonuclease (TNAse), α- and β-hemolysin, enterotoxins (SEA, SEB, SEC, SED) and toxic shock syndrome toxin-1 (TSST-1) was studied in <it>S. aureus </it>and CoNS. Antimicrobial susceptibility was evaluated based on the minimal inhibitory concentration determined by the E-test. Outcome predictors were evaluated by two logistic regression models.</p> <p>Results</p> <p>The oxacillin susceptibility rate was 85.7% for <it>S. aureus</it>, 41.6% for <it>S. epidermidis</it>, and 51.8% for other CoNS (p = 0.001). Production of toxins and enzymes, except for enterotoxin A and α-hemolysin, was associated with <it>S. aureus </it>episodes (p < 0.001), whereas slime production was positive in 23.5% of CoNS and 8.6% of <it>S. aureus </it>strains (p = 0.0047). The first model did not include enzymes and toxins due to their association with <it>S. aureus</it>. The odds of resolution were 9.5 times higher for <it>S. epidermidis </it>than for <it>S. aureus </it>(p = 0.02) episodes, and were similar for <it>S. epidermidis </it>and other CoNS (p = 0.8). The resolution odds were 68 times higher for non-slime producers (p = 0.001) and were not influenced by oxacillin resistance among vancomycin-treated cases (p = 0.89). In the second model, the resolution rate was similar for <it>S. aureus </it>and <it>S. epidermidis </it>(p = 0.70), and slime (p = 0.001) and α-hemolysin (p = 0.04) production were independent predictors of non-resolution.</p> <p>Conclusion</p> <p>Bacterial species and virulence factors rather than antibiotic resistance influence the outcome of staphylococcal peritonitis.</p

Hyperuricemia Is Independently Associated with Coronary Heart Disease and Renal Dysfunction in Patients with Type 2 Diabetes Mellitus

AIMS: To investigate the relationship between hyperuricemia (HUA) and the clinical backgrounds in Japanese patients with type 2 diabetes mellitus. METHODS: After a cross-sectional study evaluating the association of HUA with the clinical characteristics in 1,213 patients with type 2 diabetes mellitus, the estimated glomerular filtration rate (eGFR) and the incidence of diabetic macroangiopathies was investigated in a prospective observational study in 1,073 patients during a 3.5 year period. HUA was defined by serum uric acid levels >327 μmol/L or as patients using allopurinol. RESULTS: The frequency of HUA was significantly higher in the diabetic patients (32% in men and 15% in women) than in the normal controls (14% in men and 1% in women). In total, HUA was found in 299 (25%) of the patients during the cross-sectional study. Even after adjusting for sex, drinking status, treatment for diabetes mellitus, body mass index, hypertension, use of diuretics, hyperlipidemia, HbA1c and/or the eGFR, the HUA was independently associated with some diabetic complications. The eGFR was significantly reduced in HUA patients compared to those with normouricemia in the 12 months after observation was started. HUA was also an independent risk factor for coronary heart disease even after adjustment in the Cox proportional hazard model. CONCLUSIONS: HUA is a associated with diabetic micro- and macroangiopathies. HUA is a predictor of coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. However, the influence of HUA is considered to be limited

Shared neural representations of tactile roughness intensities by somatosensation and touch observation using an associative learning method

Previous human fMRI studies have reported activation of somatosensory areas not only during actual touch, but also during touch observation. However, it has remained unclear how the brain encodes visually evoked tactile intensities. Using an associative learning method, we investigated neural representations of roughness intensities evoked by (a) tactile explorations and (b) visual observation of tactile explorations. Moreover, we explored (c) modality-independent neural representations of roughness intensities using a cross-modal classification method. Case (a) showed significant decoding performance in the anterior cingulate cortex (ACC) and the supramarginal gyrus (SMG), while in the case (b), the bilateral posterior parietal cortices, the inferior occipital gyrus, and the primary motor cortex were identified. Case (c) observed shared neural activity patterns in the bilateral insula, the SMG, and the ACC. Interestingly, the insular cortices were identified only from the cross-modal classification, suggesting their potential role in modality-independent tactile processing. We further examined correlations of confusion patterns between behavioral and neural similarity matrices for each region. Significant correlations were found solely in the SMG, reflecting a close relationship between neural activities of SMG and roughness intensity perception. The present findings may deepen our understanding of the brain mechanisms underlying intensity perception of tactile roughness

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente