Feedforward Inhibition and Synaptic Scaling – Two Sides of the Same Coin?

Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing

Drosophila S2 Cells Are Non-Permissive for Vaccinia Virus DNA Replication Following Entry via Low pH-Dependent Endocytosis and Early Transcription

Vaccinia virus (VACV), a member of the chordopox subfamily of the Poxviridae, abortively infects insect cells. We have investigated VACV infection of Drosophila S2 cells, which are useful for protein expression and genome-wide RNAi screening. Biochemical and electron microscopic analyses indicated that VACV entry into Drosophila S2 cells depended on the VACV multiprotein entry-fusion complex but appeared to occur exclusively by a low pH-dependent endocytic mechanism, in contrast to both neutral and low pH entry pathways used in mammalian cells. Deep RNA sequencing revealed that the entire VACV early transcriptome, comprising 118 open reading frames, was robustly expressed but neither intermediate nor late mRNAs were made. Nor was viral late protein synthesis or inhibition of host protein synthesis detected by pulse-labeling with radioactive amino acids. Some reduction in viral early proteins was noted by Western blotting. Nevertheless, synthesis of the multitude of early proteins needed for intermediate gene expression was demonstrated by transfection of a plasmid containing a reporter gene regulated by an intermediate promoter. In addition, expression of a reporter gene with a late promoter was achieved by cotransfection of intermediate genes encoding the late transcription factors. The requirement for transfection of DNA templates for intermediate and late gene expression indicated a defect in viral genome replication in VACV-infected S2 cells, which was confirmed by direct analysis. Furthermore, VACV-infected S2 cells did not support the replication of a transfected plasmid, which occurs in mammalian cells and is dependent on all known viral replication proteins, indicating a primary restriction of DNA synthesis

Mechanisms of viral entry: sneaking in the front door

Recent developments in methods to study virus internalisation are providing clearer insights into mechanisms used by viruses to enter host cells. The use of dominant negative constructs, specific inhibitory drugs and RNAi to selectively prevent entry through particular pathways has provided evidence for the clathrin-mediated entry of hepatitis C virus (HCV) as well as the caveolar entry of Simian Virus 40. Moreover, the ability to image and track fluorescent-labelled virus particles in real-time has begun to challenge the classical plasma membrane entry mechanisms described for poliovirus and human immunodeficiency virus. This review will cover both well-documented entry mechanisms as well as more recent discoveries in the entry pathways of enveloped and non-enveloped viruses. This will include viruses which enter the cytosol directly at the plasma membrane and those which enter via endocytosis and traversal of internal membrane barrier(s). Recent developments in imaging and inhibition of entry pathways have provided insights into the ill-defined entry mechanism of HCV, bringing it to the forefront of viral entry research. Finally, as high-affinity receptors often define viral internalisation pathways, and tropism in vivo, host membrane proteins to which viral particles specifically bind will be discussed throughout

Changes in metabolism of TRH in euthyroid sick syndrome

Objective: The aim of this study was to examine the metabolism of a simple dose, intravenously administered TRH bolus of 200 mu g, in patients with euthyroid sick syndrome (ESS). Patients and Methods: A TRH test was performed on ten ESS patients and ten controls upon admission (d1) and after recovery (d2), Blood samples were collected at 0, 10, 20 and 30 min after TRH injection. We analyzed the Volume of distribution (V-d) the plasma clearance rate (PCR), the fractional clearance rate (FCR), the half-life (t(1/2)) and the TSH response to the injection of TRH. Results: All patients had lower tri-iodothyronine (T-3) levels compared with controls (0.9 +/- 0.1 nmol/l vs 1.9 +/- 0.1 nmol/l; P < 0.0001; mean +/- S.D.: paired t-test). In addition, the V-d (16.7 +/- 5.9/l vs 30.6 +/- 0.6/l: P < 0.0005) and PCR (2.0 +/- 0.80 l/min vs 3.3 +/- 0.25 l/min; P < 0.0005) were found statistically lowered in patients than in controls, whereas FCR (0.119 +/- 0.01 per min vs 0.110 +/- 0.01 per min: P < 0.025) was found increased in patients as opposed to controls, The t(1/2) Of exogenously administered TRH was increased in ESS compared with controls (7.2 +/- 0.7 min vs 6.3 +/- 0.6 min: P < 0.005). TSH response to TRH was found significantly repressed at 10, 20 and 30 min after TRH injection, On d2, these findings had reverted to normal and no changes regarding the kinetics of TRH and the response of TSH could be detected between patients and controls. Conclusions: The results demonstrate an impairment of TRH metabolism in ESS. The findings may suggest altered enzymatic activity, responsible for TRH degradation in states of acute ESS. These changes might be involved in the pathogenesis of ESS and represent part of an adaptive mechanism to this syndrome