Schwannoma of T12 Vertebra: Case Report and Review of Literature

We report a case of schwannoma of the twelfth thoracic vertebra that presented with paraparesis. The tumour was excised, and posterior and anterior stabilisation was performed. Eighteenmonths following this procedure, the patient has solid bony union, satisfactory neurological improvement and no recurrence

Lipid raft/caveolae signaling is required for Cryptococcus neoformans invasion into human brain microvascular endothelial cells

<p>Abstract</p> <p>Background</p> <p><it>Cryptococcus neoformans </it>has a predilection for central nervous system infection. <it>C. neoformans </it>traversal of the blood brain barrier, composed of human brain microvascular endothelial cells (HBMEC), is the crucial step in brain infection. However, the molecular mechanism of the interaction between <it>Cryptococcus neoformans </it>and HBMEC, relevant to its brain invasion, is still largely unknown.</p> <p>Methods</p> <p>In this report, we explored several cellular and molecular events involving the membrane lipid rafts and caveolin-1 (Cav1) of HBMEC during <it>C. neoformans </it>infection. Immunofluorescence microscopy was used to examine the roles of Cav1. The knockdown of Cav1 by the siRNA treatment was performed. Phosphorylation of Cav1 relevant to its invasion functions was investigated.</p> <p>Results</p> <p>We found that the host receptor CD44 colocalized with Cav1 on the plasma membrane, and knockdown of Cav1 significantly reduced the fungal ability to invade HBMEC. Although the CD44 molecules were still present, HBMEC membrane organization was distorted by Cav1 knockdown. Concomitantly, knockdown of Cav1 significantly reduced the fungal crossing of the HBMEC monolayer <it>in vitro</it>. Upon <it>C. neoformans </it>engagement, host Cav1 was phosphorylated in a CD44-dependent manner. This phosphorylation was diminished by filipin, a disrupter of lipid raft structure. Furthermore, the phosphorylated Cav1 at the lipid raft migrated inward to the perinuclear localization. Interestingly, the phospho-Cav1 formed a thread-like structure and colocalized with actin filaments but not with the microtubule network.</p> <p>Conclusion</p> <p>These data support that <it>C. neoformans </it>internalization into HBMEC is a lipid raft/caveolae-dependent endocytic process where the actin cytoskeleton is involved, and the Cav1 plays an essential role in <it>C. neoformans </it>traversal of the blood-brain barrier.</p

The BAT-Swift Science Software

The BAT instrument tells the Swift satellite where to point to make immediate follow-up observations of GRBs. The science software on board must efficiently process gamma-ray events coming in at up to 34 kHz, identify rate increases that could be due to GRBs while disregarding those from known sources, and produce images to accurately and rapidly locate new Gamma-ray sources.Comment: 4 pages, no figures, to appear in Santa Fe proceedings "Gamma-Ray Bursts: 30 Years of Discovery", Fenimore and Galassi (eds), AIP, 200

Effect of Backgrounding System on Steer Performance and Carcass Characteristics

The impact of 3 backgrounding systems: grazing corn residue with distillers grains supplementation at 0.86% BW/d, grazing an oats-brassica forage, or feeding a grower ration in a drylot on finishing performance and carcass characteristics were evaluated. Backgrounding phase gains were greatest for steers fed a grower ration in the drylot (3.58 lb/d), intermediate for steers grazing oats-brassica forage and then fed the grower ration for short period (2.65 lb/d), and least for steers grazing corn residue while supplemented distillers grains and then fed the grower ration for short period (2.22 lb/d). These backgrounding treatment differences did not affect ADG during the finishing period (3.73 lb/d). However, the 2 grazing treatments had greater DMI resulting in poorer F:G. Overall, these backgrounding systems did not affect carcass quality. Increased finishing phase cost for the 2 grazing treatments due to poorer F:G, can be off set by less input cost during backgrounding, but ultimately the cost effectiveness is dependent on the production resources and scenarios of each individual producer

A Fully-Configurable Open-Source Software-Defined Digital Quantized Spiking Neural Core Architecture

We introduce QUANTISENC, a fully configurable open-source software-defined digital quantized spiking neural core architecture to advance research in neuromorphic computing. QUANTISENC is designed hierarchically using a bottom-up methodology with multiple neurons in each layer and multiple layers in each core. The number of layers and neurons per layer can be configured via software in a top-down methodology to generate the hardware for a target spiking neural network (SNN) model. QUANTISENC uses leaky integrate and fire neurons (LIF) and current-based excitatory and inhibitory synapses (CUBA). The nonlinear dynamics of a neuron can be configured at run-time via programming its internal control registers. Each neuron performs signed fixed-point arithmetic with user-defined quantization and decimal precision. QUANTISENC supports all-to-all, one-to-one, and Gaussian connections between layers. Its hardware-software interface is integrated with a PyTorch-based SNN simulator. This integration allows to define and train an SNN model in PyTorch and evaluate the hardware performance (e.g., area, power, latency, and throughput) through FPGA prototyping and ASIC design. The hardware-software interface also takes advantage of the layer-based architecture and distributed memory organization of QUANTISENC to enable pipelining by overlapping computations on streaming data. Overall, the proposed software-defined hardware design methodology offers flexibility similar to that of high-level synthesis (HLS), but provides better hardware performance with zero hardware development effort. We evaluate QUANTISENC using three spiking datasets and show its superior performance against state-of the-art designs

Positive allosteric modulation of the muscarinic M1 receptor improves efficacy of antipsychotics in mouse glutamatergic deficit models of behavior

Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M1 muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. This study investigated the effect of the M1 mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], alone or in combination with haloperidol (a first-generation antipsychotic), clozapine (a second-generation atypical antipsychotic), or aripiprazole (a third-generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-d-aspartate receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]. Sensorimotor gating and spatial memory induction are two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (an operational measure of sensorimotor gating), BQCA alone had minimal effects but exhibited different levels of efficacy in reversing MK-801–induced prepulse inhibition disruptions when combined with a subeffective dose of each of the three (currently prescribed) antipsychotics. Furthermore, the combined effect of BQCA and clozapine was absent in M1−/− mice. Interestingly, although BQCA alone had no effect in reversing MK-801–induced memory impairments in a Y-maze spatial test, we observed a reversal upon the combination of BQCA with atypical antipsychotics, but not with haloperidol. These findings provide proof of concept that a judicious combination of existing antipsychotics with a selective M1 mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior

Selecting an Anti-Malarial Clinical Candidate from Two Potent Dihydroisoquinolones

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. RESULTS: Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. CONCLUSION: SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators

Groundwater residence time distributions in peatlands: implications for peat decomposition and accumulation

Peat soils consist of poorly decomposed plant detritus, preserved by low decay rates, and deep peat deposits are globally significant stores in the carbon cycle. High water tables and low soil temperatures are commonly held to be the primary reasons for low peat decay rates. However, recent studies suggest a thermodynamic limit to peat decay, whereby the slow turnover of peat soil pore water may lead to high concentrations of phenols and dissolved inorganic carbon. In sufficient concentrations, these chemicals may slow or even halt microbial respiration, providing a negative feedback to peat decay. We document the analysis of a simple, one-dimensional theoretical model of peatland pore water residence time distributions (RTDs). The model suggests that broader, thicker peatlands may be more resilient to rapid decay caused by climate change because of slow pore water turnover in deep layers. Even shallow peat deposits may also be resilient to rapid decay if rainfall rates are low. However, the model suggests that even thick peatlands may be vulnerable to rapid decay under prolonged high rainfall rates, which may act to flush pore water with fresh rainwater. We also used the model to illustrate a particular limitation of the diplotelmic (i.e., acrotelm and catotelm) model of peatland structure. Model peatlands of contrasting hydraulic structure exhibited identical water tables but contrasting RTDs. These scenarios would be treated identically by diplotelmic models, although the thermodynamic limit suggests contrasting decay regimes. We therefore conclude that the diplotelmic model be discarded in favor of model schemes that consider continuous variation in peat properties and processes

Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978)

The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins