Four-Hour-Delayed Gadolinium 3D REAL IR and SPACE FLAIR MRI Correlated to Meniere Disease Histology.

Objectives: This study aims to showcase the complementary nature of utilizing both histopathology and magnetic resonance imaging (MRI) in understanding the otologic pathophysiology of Meniere disease. In addition, it seeks to raise awareness of the value of preserving and curating historical temporal bone collections which continue to inform our understanding of otologic diseases. Methods: The essential anatomical feature of Meniere disease-the distended membranous labyrinth-is explored through a comparison of early temporal bone studies with contemporary MRI techniques. The histopathologic photomicrographs are of inner ear specimens from deceased patients with symptoms consistent with Meniere disease. The MRI sequences from living patients exhibiting classic Meniere disease symptoms during life are captured 4 hours post-administration of gadolinium. Results: Both histopathologic examination and MRI imaging reveal consistent distention of the saccule, utricle, and scala media in patients with Meniere disease. The study shows the histologic photomicrographs of actual Meniere patients compared to the MRIs and successfully demonstrates the correlation between postmortem histological findings and MRI evidence of distension in living patients. Conclusions: A corresponding distension of the membranous labyrinth is seen in both the histologic specimens and the Meniere MRIs. This correlation suggests the potential utility of utilizing MRI to aid in diagnosing atypical Meniere disease and distinguishing it from other disease processes, such as migraine equivalent vertigo. The integration of historical temporal bone studies with modern MRI techniques offers valuable insights into the pathophysiology of otologic diseases. In addition, it emphasizes the importance of preserving and curating historical temporal bone collections for continued research and medical education purposes. Previous studies of delayed MRIs did not use Meniere disease temporal bone histopathology images.

Coherent control of an opsin in living brain tissue.

Retinal-based opsins are light-sensitive proteins. The photoisomerization reaction of these proteins has been studied outside cellular environments using ultrashort tailored light pulses1-5. However, how living cell functions can be modulated via opsins by modifying fundamental nonlinear optical properties of light interacting with the retinal chromophore has remained largely unexplored. We report the use of chirped ultrashort near-infrared pulses to modulate light-evoked ionic current from Channelrhodopsin-2 (ChR2) in brain tissue, and consequently the firing pattern of neurons, by manipulating the phase of the spectral components of the light. These results confirm that quantum coherence of the retinal-based protein system, even in a living neuron, can influence its current output, and open up the possibilities of using designer-tailored pulses for controlling molecular dynamics of opsins in living tissue to selectively enhance or suppress neuronal function for adaptive feedback-loop applications in the future.

Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC.

The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and distinct antibiotic profiles. The vast majority of these compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly effective in suppressing the activity of Escherichia coli LpxC (EcLpxC) but not divergent orthologs such as Pseudomonas aeruginosa LpxC (PaLpxC) in vitro. The molecular basis for such promiscuous inhibition of EcLpxC has remained poorly understood. Here, we report the crystal structure of EcLpxC bound to L-161,240, providing the first molecular insight into L-161,240 inhibition. Additionally, structural analysis of the EcLpxC/L-161,240 complex together with the EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I ßa-ßb loop in EcLpxC in comparison with previously reported crystal structures of EcLpxC complexes with l-threonyl-hydroxamate-based broad-spectrum inhibitors. Such a conformational switch, which has only been observed in EcLpxC but not in divergent orthologs such as PaLpxC, results in expansion of the active site of EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head groups, including compounds containing single (R- or S-enantiomers) or double substitutions at the neighboring Cα atom of the hydroxamate warhead group. These results highlight the importance of understanding inherent conformational plasticity of target proteins in lead optimization.

Long-distance integration of nuclear ERK signaling triggered by activation of a few dendritic spines.

The late phase of long-term potentiation (LTP) at glutamatergic synapses, which is thought to underlie long-lasting memory, requires gene transcription in the nucleus. However, the mechanism by which signaling initiated at synapses is transmitted into the nucleus to induce transcription has remained elusive. Here, we found that induction of LTP in only three to seven dendritic spines in rat CA1 pyramidal neurons was sufficient to activate extracellular signal-regulated kinase (ERK) in the nucleus and regulate downstream transcription factors. Signaling from individual spines was integrated over a wide range of time (>30 minutes) and space (>80 micrometers). Spatially dispersed inputs over multiple branches activated nuclear ERK much more efficiently than clustered inputs over one branch. Thus, biochemical signals from individual dendritic spines exert profound effects on nuclear signaling.