Ultrabroadband 3D invisibility with fast-light cloaks.

An invisibility cloak should completely hide an object from an observer, ideally across the visible spectrum and for all angles of incidence and polarizations of light, in three dimensions. However, until now, all such devices have been limited to either small bandwidths or have disregarded the phase of the impinging wave or worked only along specific directions. Here, we show that these seemingly fundamental restrictions can be lifted by using cloaks made of fast-light media, termed tachyonic cloaks, where the wave group velocity is larger than the speed of light in vacuum. On the basis of exact analytic calculations and full-wave causal simulations, we demonstrate three-dimensional cloaking that cannot be detected even interferometrically across the entire visible regime. Our results open the road for ultrabroadband invisibility of large objects, with direct implications for stealth and information technology, non-disturbing sensors, near-field scanning optical microscopy imaging, and superluminal propagation.

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.

The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.

The crystal structure of methylglyoxal synthase from Escherichia coli.

BACKGROUND: The reaction mechanism of methylglyoxal synthase (MGS) is believed to be similar to that of triosephosphate isomerase (TIM). Both enzymes utilise dihydroxyacetone phosphate (DHAP) to form an enediol(ate) phosphate intermediate as the first step of their reaction pathways. However, the second catalytic step in the MGS reaction pathway is characterized by the elimination of phosphate and collapse of the enediol(ate) to form methylglyoxal instead of reprotonation to form the isomer glyceraldehyde 3-phosphate. RESULTS: The crystal structure of MGS bound to formate and substoichiometric amounts of phosphate in the space group P6522 has been determined at 1.9 A resolution. This structure shows that the enzyme is a homohexamer composed of interacting five-stranded beta/alpha proteins, rather than the hallmark alpha/beta barrel structure of TIM. The conserved residues His19, Asp71, and His98 in each of the three monomers in the asymmetric unit bind to a formate ion that is present in the crystallization conditions. Differences in the three monomers in the asymmetric unit are localized at the mouth of the active site and can be ascribed to the presence or absence of a bound phosphate ion. CONCLUSIONS: In agreement with site-directed mutagenesis and mechanistic enzymology, the structure suggests that Asp71 acts as the catalytic base. Further, Asp20 and Asp101 are involved in intersubunit salt bridges. These salt bridges may provide a pathway for transmitting allosteric information.

Temporal bone findings in Alzheimer's disease.

Sensorineural hearing loss has been reported in Alzheimer's disease (AD) and a topographically specific pattern of degeneration in the central auditory system has been described. Although peripheral visual and olfactory systems have been extensively studied, there is no report of peripheral auditory system abnormalities in AD patients. Comparison of temporal bones from eight AD patients with those from eight non-AD controls revealed a significant difference in the percentage of remaining hair cells, peripheral processes, and spiral ganglion cells in the basal cochlear turn but no significant differences in the overall percentage between the two groups. Furthermore, special stains (thioflavin S and Bielschowsky's silver impregnation) of temporal bone nervous tissue from AD patients did not show neuritic plaques and neurofibrillary tangles. It is unclear whether the differences between the two groups in the basal portion of the cochlea are due to AD or some other process, such as presbycusis. However, lack of significant degeneration in other parts of the cochlea and absence of neurofibrillary tangles and neuritic plaques in all eight patients may suggest that the peripheral auditory system, unlike the peripheral visual and olfactory systems, is not involved in AD. A larger sample of AD patients is necessary to clarify the peripheral auditory system findings in the present study.

Comparison of vestibular autorotation and caloric testing.

The two most common stimuli of the vestibular system for diagnostic purposes are caloric and rotational head movements. Caloric stimulation, by delivering thermal energy to the lateral semicircular canal, is a well-studied method of vestibular testing, and its clinical usefulness has been established. Vestibular autorotation testing uses high-frequency (2 to 6 Hz), active head movements to stimulate the horizontal and vertical vestibulo-ocular reflex to produce measurable eye movements that can be used to calculate gain and phase. We compared the alternate bilateral bithermal caloric results with the vestibular autorotation test results obtained from 39 patients with peripheral vestibular disorders and from 10 patients with acoustic neuroma. In the peripheral disorder group, only 2 of 14 patients with equal caloric response (< 20% reduced vestibular response) had a normal vestibular autorotation test result. No patients with a reduced vestibular response greater than 21% had a normal vestibular autorotation test result. In the acoustic neuroma group, four patients had a normal reduced vestibular response, but all patients had an abnormal vestibular autorotation test result. We conclude that testing both the horizontal and vertical vestibulo-ocular reflexes in their physiologic frequency range with the vestibular autorotation test provides additional information that could be missed by conventional caloric testing. Therefore high-frequency rotational testing is a valuable addition to the vestibular test battery.

The relationship between vasopressin and endolymphatic hydrops in the guinea pig.

Clinical studies have shown that plasma vasopressin level is significantly elevated in patients with Meniere's disease. Other reports indicated that histamine induced a very quick and high elevation of vasopressin level and caused nystagmus in experimentally produced endolymphatic hydrops. We became interested in further investigating the details of this relationship by studying the effect of experimental endolymphatic hydrops and histamine upon plasma vasopressin level in the guinea pig. The results are as follows: 1) Histamine increased the plasma vasopressin level in normal guinea pigs. 2) There was no statistically significant difference in the plasma vasopressin level between the hydrops model and normal guinea pigs. 3) Histamine increased the plasma vasopressin level more in the hydrops model group than in normals. 4) Plasma vasopressin level was elevated in the vertiginous model caused by inner ear anesthesia. Our results support those of clinical investigators who reported that the plasma vasopressin level was elevated more in the Meniere's disease group than any other equilibrium disorder group. It is possible that vasopressin is in someway involved in the development of endolymphatic hydrops.

Mirroring perfection: the structure of methylglyoxal synthase complexed with the competitive inhibitor 2-phosphoglycolate.

The crystal structure of the transition-state analogue 2-phosphoglycolate (2PG) bound to methylglyoxal synthase (MGS) is presented at a resolution of 2.0 A. This structure is very similar to the previously determined structure of MGS complexed to formate and phosphate. Since 2PG is a competitive inhibitor of both MGS and triosephosphate isomerase (TIM), the carboxylate groups of each bound 2PG from this structure and the structure of 2PG bound to TIM were used to align and compare the active sites despite differences in their protein folds. The distances between the functional groups of Asp 71, His 98, His 19, and the carboxylate oxygens of the 2PG molecule in MGS are similar to the corresponding distances between the functional groups of Glu 165, His 95, Lys 13, and the carboxylate oxygens of the 2PG molecule in TIM. However, these spatial relationships are enantiomorphic to each other. Consistent with the known stereochemical data, the catalytic base Asp 71 is positioned on the opposite face of the 2PG-carboxylate plane as Glu 165 of TIM. Both His 98 of MGS and His 95 of TIM are in the plane of the carboxylate of 2PG, suggesting that these two residues are homologous in function. While His 19 of MGS and Lys 13 of TIM appear on the opposite face of the 2PG carboxylate plane, their relative location to the 2PG molecule is quite different, suggesting that they probably have different functions. Most remarkably, unlike the coplanar structure found in the 2PG molecule bound to TIM, the torsion angle around the C1-C2 bond of 2PG bound to MGS brings the phosphoryl moiety out of the molecule's carboxylate plane, facilitating elimination. Further, the superimposition of this structure with the structure of MGS bound to formate and phosphate suggests a model for the enzyme bound to the first transition state.

Identification of catalytic bases in the active site of Escherichia coli methylglyoxal synthase: cloning, expression, and functional characterization of conserved aspartic acid residues.

Methylglyoxal synthase provides bacteria with an alternative to triosephosphate isomerase for metabolizing dihydroxyacetone phosphate (DHAP). In the present studies, the methylglyoxal synthase gene in Escherichia coli has been cloned and sequenced. The identified open reading frame (ORF) codes for a polypeptide of 152 amino acids, consistent with the 17 kDa purified protein. The sequence of this protein is not similar to any other protein of known function, including the functionally similar protein triosephosphate isomerase. The methylglyoxal synthase gene was amplified by PCR, subcloned into the pET16B expression vector, and expressed in the host E. coli BL21(DE3). Sequence comparison of the methylglyoxal protein and related ORFs from four different bacterial species revealed that four aspartic acid and no glutamic acid residues are absolutely conserved. The function of the four aspartic acid residues was tested by mutating them to either asparagine or glutamic acid. Thermal denaturation, CD spectroscopy, and gel filtration experiments showed that the mutant enzymes had the same secondary and quaternary structure as the wild-type enzyme. Kinetic characterization of both Asp 71 and Asp 101 mutant proteins shows reduced kcat/Km by 10(3)- and 10(4)-fold respectively, suggesting that they are both intimately involved in catalysis. A time-dependent inhibition of both Asp 20 and Asp 91 asparagine mutants by DHAP suggests that these two residues are involved with protecting the enzyme from DHAP or reactive intermediates along the catalytic pathway. In combination with the results of 2-phosphoglycolate binding studies, a catalytic mechanism is proposed.

Managing the emergency airway in Le Fort fractures.

Le Fort fractures are a part of the facial fracture spectrum, sustained from significant forces of impact to the midface. The mechanism of airway obstruction in Le Fort fractures is attributed to midface instability with posterior inferior displacement into the oropharyngeal airway. Otolaryngologists often participate in the evaluation and management of such patients, securing the airway, if necessary. It is important, therefore, to understand the mechanisms responsible for acute airway obstruction in these types of fractures. A retrospective review of 64 cases of Le Fort fractures, representing a 3-year period, was performed to determine the factors responsible for acute airway obstruction. The review disclosed that airway obstruction is due most often to hemorrhage into the upper airway from multiple sources, with inability to handle blood and the oral secretions. An emergency airway was required by one third of the patients with Le Fort fractures in this review.