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Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes., Competing Interests: Competing Financial Interests No competing financial interests are reported by the authors.

The success of antibody-based drugs has led to an increased demand for predictive computational tools to assist antibody engineering efforts surrounding the six hypervariable loop regions making up the antigen binding site. Accurate computational modeling of isolated protein loop regions can be quite difficult; consequently, modeling an antigen binding site that includes six loops is particularly challenging. In this work, we present a method for automatic modeling of the FV region of an immunoglobulin based upon the use of a precompiled antibody x-ray structure database, which serves as a source of framework and hypervariable region structural templates that are grafted together. We applied this method (on common desktop hardware) to the Second Antibody Modeling Assessment (AMA-II) target structures as well as an experimental specialized CDR-H3 loop modeling method. The results of the computational structure predictions will be presented and discussed., (© 2014 The Authors. Proteins published by Wiley Periodicals, Inc.)

Purpose: The proposed method is aimed at reducing eddy current (EC) induced distortion in diffusion weighted echo planar imaging, without the need to perform further image coregistration between diffusion weighted and T2 images. These ECs typically have significant high order spatial components that cannot be compensated by preemphasis., Theory and Methods: High order ECs are first calibrated at the system level in a protocol independent fashion. The resulting amplitudes and time constants of high order ECs can then be used to calculate imaging protocol specific corrections. A combined prospective and retrospective approach is proposed to apply correction during data acquisition and image reconstruction., Results: Various phantom, brain, body, and whole body diffusion weighted images with and without the proposed method are acquired. Significantly reduced image distortion and misregistration are consistently seen in images with the proposed method compared with images without., Conclusion: The proposed method is a powerful (e.g., effective at 48 cm field of view and 30 cm slice coverage) and flexible (e.g., compatible with other image enhancements and arbitrary scan plane) technique to correct high order ECs induced distortion and misregistration for various diffusion weighted echo planar imaging applications, without the need for further image post processing, protocol dependent prescan, or sacrifice in signal-to-noise ratio., (Copyright © 2013 Wiley Periodicals, Inc.)

Many neurons adapt their spike output to accommodate the prevailing sensory environment. Although such adaptation is thought to improve coding of relevant stimulus features, the relationship between adaptation at the neural and behavioral levels remains to be established. Here we describe improved discrimination performance for an auditory spatial cue (interaural time differences, ITDs) following adaptation to stimulus statistics. Physiological recordings in the midbrain of anesthetized guinea pigs and measurement of discrimination performance in humans both demonstrate improved coding of the most prevalent ITDs in a distribution, but with highest accuracy maintained for ITDs corresponding to frontal locations, suggesting the existence of a fovea for auditory space. A biologically plausible model accounting for the physiological data suggests that neural tuning is stabilized by inhibition to maintain high discriminability for frontal locations. The data support the notion that adaptive coding in the midbrain is a key element of behaviorally efficient sound localization in dynamic acoustic environments.

In order to investigate whether performance in an auditory spatial discrimination task depends on the prevailing listening conditions, we tested the ability of human listeners to discriminate target sounds with and without presentation of a preceding sound. Target sounds were either lateralized by means of interaural time differences (ITDs) of +400, 0, or -400 micros or interaural level differences (ILDs) with the same subjective intracranial locations. The preceding sound was always lateralized by means of ITD. This allowed for testing whether the effects of a preceding sound were location- or cue-specific. Preceding sounds and target sounds were randomly paired across trials. Listeners had to discriminate whether they perceived the target sounds as coming from the same or different intracranial locations. Finally, stimuli were selected so that, without any preceding sound, ITD and ILD cues were equally discriminable at all target lateralizations. Stimuli were 800 Hz-wide, 400-ms duration bands of noise centered at 500 Hz, presented over headphones. The duration of the preceding sound was randomly selected from a uniform distribution spanning from 1s to 2s. Results show that discriminability of both binaural cues was improved for midline target positions when preceding sound and targets were co-located, whereas it was impaired when preceding sound and targets came from different positions. No effect of the preceding sound was found for left or right target positions. These results are compatible with a purely bottom-up mechanism based on adaptive coding of ITD around the midline that may be combined with top-down mechanisms to increase localization accuracy in realistic listening conditions.

Inhibitory inputs to the binaural brainstem nuclei medial and lateral superior olives (MSO and LSO, respectively) are thought to be important for sound localization in mammals. Here, we investigate whether aged gerbils that typically exhibit degenerative changes in auditory nuclei providing inhibition to MSO and LSO show diminished localization ability. We also tested the localization ability in gerbils reared in omni-directional white noise during hearing onset, a treatment that affects the adjustment of inhibitory inputs to MSO neurons possibly resulting in weakened sensitivity to interaural time difference. Localization ability of both groups was compared to that of young gerbils raised under control conditions. Stimuli had a duration of 125 ms and were pure tones of 0.5, 1, 2, 4 and 8 kHz, 300-Hz-bands of noise centered at 0.5, 2 and 8 kHz or broad-band noise. Gerbils trained in a two-alternative-forced-choice procedure indicated if sounds were presented from the left or from the right by choosing the respective response compartment of a Y-shaped experimental setup. The minimum resolvable angle (MRA) was calculated as the minimum angle between two loudspeaker locations that a gerbil was able to discriminate. MRAs for aged gerbils were higher compared to controls, whereas MRAs of noise-reared gerbils did not differ from those of the control group. Results are discussed with respect to the progressive degeneration affecting the gerbil's auditory system, changes in the anatomical arrangement of inhibitory inputs on binaural neurons in the MSO, and hearing thresholds.

The neuronal apoptosis inhibitory protein (NAIP) gene, also known as the baculovirus inhibitor of apoptosis repeat-containing protein 1 (BIRC1) gene, is a member of the inhibitors of apoptosis (IAP) family and was first characterized as a candidate gene for spinal muscular atrophy (SMA). The expression of NAIP has been thoroughly studied in the central nervous system and overlaps the pattern of neurodegeneration in SMA. Recent studies have pointed to a role for NAIP in non-neuronal cells. We report here the production of a specific anti-NAIP antibody and the profile of NAIP expression in human adult tissues by Western blot and immunohistochemical detection methods. NAIP was detected in a number of tissues by Western blot analysis, but immunohistochemistry revealed that NAIP's presence in certain tissues, such as liver, lung, and spleen, is most likely due to macrophage infiltration. In the small intestine, the expression of NAIP coincides with the expression of p21(WAF1). This observation, coupled with findings from other groups, suggests a role for NAIP in increasing the survival of cells undergoing terminal differentiation as well as the possibility that the protein serves as an intestinal pathogen recognition protein. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Minimum resolvable angles (MRAs) for sound localization in azimuth in the gerbil were determined in a behavioral study using tones, 300-Hz bands of noise centered at frequencies between 500 Hz and 8 kHz and broad-band noise of on average 60 dB SPL overall level. Using the method of constant stimuli, seven gerbils were trained in a two-alternative-forced-choice procedure to indicate if sounds were presented to them from the left or from the right by choosing the left or right arm of a Y-shaped cage. The MRA is the minimum angle between two loudspeaker locations that the gerbils discriminated. Animals were either stimulated from the front (N=4) or from the back (N=3). The MRA for broad-band noise randomly varying in level by +/- 6 dB was 23 degrees and 45 degrees for gerbils stimulated from the front or back, respectively. Generally a gerbil's MRA for tones declined up to 2 kHz reaching 20 degrees and 31 degrees for gerbils stimulated from the front or back, respectively, and the MRA was generally increased above this frequency. Results for narrow-band noise stimuli were similar. Results are discussed with respect to the available interaural cues and physiological mechanisms of sound localization in the gerbil.

The neuronal apoptosis inhibitory protein (NAIP) was identified as a candidate gene for the inherited neurodegenerative disorder spinal muscular atrophy. NAIP is the founding member of a human protein family that is characterized by highly conserved N-terminal motifs called baculovirus inhibitor of apoptosis repeats (BIR). Five members of the human family of inhibitor of apoptosis proteins including NAIP have been shown to be antiapoptotic in various systems. To date, a mechanism for the antiapoptotic effect of NAIP has not been elucidated. To investigate NAIP function, we found cytoprotection of NAIP-expressing primary cortical neurons treated to undergo caspase-3-dependent apoptosis. The additional treatment of these neurons with the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone did not result in increased survival. Similar cytoprotective effects were obtained using HeLa cells transiently transfected with a NAIP N-terminal construct and treated to undergo a caspase-3-dependent cell death. To examine whether NAIP inhibits caspases directly, recombinant N-terminal NAIP protein containing BIR domains was overexpressed, purified, and tested for caspase inhibition potential. Our results demonstrate that inhibition of caspases is selective and restricted to the effector group of caspases, with K(i) values as low as approximately 14 nm for caspase-3 and approximately 45 nm for caspase-7. Additional investigations with NAIP fragments containing either one or two NAIP BIRs revealed that the second BIR and to a lesser extent the third BIR alone are sufficient to mediate full caspase inhibition.

When a linear magnetic field gradient is used, spatially higher-order magnetic fields are produced to satisfy the Maxwell equations. It has been observed that the higher-order magnetic field produced by the readout gradient causes axial echo planar images acquired with a horizontal solenoid magnet to shift along the phase-encoding direction and lose image intensities. Both the shift and intensity reduction become increasingly severe as the slice offset from the isocenter increases. These phenomena are quantitatively analyzed, and good correlation between experiments and theory has been established. The analysis also predicts a previously unreported Nyquist ghost on images with very large slice offsets. This ghost has been verified with computer simulations. Based on the analysis, several methods have been developed to eliminate the image shift, the intensity reduction, and the ghost. Selected methods have been implemented on a commercial scanner and proved effective in removing these image artifacts.

A highly interactive MRI scanner interface has been developed that allows, for the first time, real-time graphic control of one-dimensional (1D) and two-dimensional (2D) cardiac MRI exams. The system comprises a Mercury array processor (AP) in a Sun SPARCserver with two connections to the MRI scanner, a data link that passes the NMR data directly to the AP as they are collected, and a control link that passes commands from the Sun to the scanner to redirect the imaging pulse sequence in real time. In the 1D techniques, a cylinder or "pencil" of magnetization is repeatedly excited using gradient-echo or spin-echo line-scan sequences, with the magnetization read out each time along the length of the cylinder, and a scrolling display generated on the Sun monitor. Rubber-band lines drawn on the scout image redirect the pencil or imaging slice to different locations, with the changes immediately visible in the display. M-mode imaging, 1D flow imaging, and 2D fast cardiac imaging have been demonstrated on normal volunteers using this system. This platform represents an operator-"friendly" way of directing real-time imaging of the heart.

We describe a system for performing interactive MRI in real time. Using a TR/TE 7.1/3.5 ms sequence, the operator may alter a scan parameter and observe the effects of the alteration on the image within a few hundred milliseconds. With this system, we can interactively control the oblique scan slice orientation and, using inversion pulses, the image contrast.

Temporal filtering methods were applied to iodine signal-to-noise ratio (SNR) restoration in intravenous hybrid subtraction digital subtraction angiography (DSA). For equal detected exposure rates hybrid subtraction had approximately 35% of the SNR of temporal subtraction. When matched filtering was applied to a DSA run, the filtered result had approximately two times higher SNR than the peak contrast image in the run. Thus, when matched filtering techniques were applied to the hybrid image sequence, the resultant SNR increased to about 70% of that of temporal subtraction. With an additional factor-of-two increase in exposure rate for the hybrid run, SNR parity with temporal subtraction could be achieved. This compared with a factor-of-nine increase in exposure that would be required if no filtering were performed. Experimental hybrid matched filter results, generated with intravenous canine DSA studies, supported the predictions in SNR performance.

The technical characteristics of a new digital fluorographic image processing method called matched filtering are presented. This technique, a type of extensive temporal integration, takes a weighted sum of images acquired during passage of a contrast bolus through some area of interest. The weight of each image is governed by the magnitude of the contrast bolus in that image. An essential requirement of the matched filter is that its integral be zero. It is shown for equal exposure rates and typical bolus characteristics that matched filtering provides a factor of two higher signal-to-noise ratio (SNR) than conventional methods for bolus transit times of 10 s or higher. Equilvalently, matched filtering can yield images with quality comparable to conventional digital subtraction angiography (DSA) at a factor of four less patient exposure. The SNR obtained with matched filtering is shown to be within 30% of an ideal bound. Comparisons of matched filtering to standard recursive methods and simple integration are made. Experimental canine studies are presented which compare matched filtering with conventional DSA.

Using computer calculations and assumed contrast bolus curves, several aspects of the application of temporal integration methods and matched filtering to intravenous digital subtraction angiography (IV-DSA) were studied. The topics included the improvement in signal-to-noise ratio (SNR) of the final image provided by simple integration, a comparison of the SNR performance of matched filtering and extensive integration, the degradation of SNR caused by the motion of noniodinated objects and the sensitivity of SNR to variations in DSA bolus dynamics from patient to patient. Additionally the dependence of matched filter SNR on exposure position and duration was both estimated and demonstrated with clinical DSA images. The results indicate that a substantial improvement in SNR can be obtained with only moderate integration increasing to a two X improvement for longer durations. Integration methods are able to withstand moderate durations (2 seconds) of motion and still provide image quality superior to more conventional DSA results.