In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection

Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21)-1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1-21)-1c was more efficacious than Esc(1-21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1-21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infection

Valley Dependent Optoelectronics from Inversion Symmetry Breaking

Inversion symmetry breaking allows contrasted circular dichroism in different k-space regions, which takes the extreme form of optical selection rules for interband transitions at high symmetry points. In materials where band-edges occur at noncentral valleys, this enables valley dependent interplay of electrons with light of different circular polarizations, in analogy to spin dependent optical activities in semiconductors. This discovery is in perfect harmony with the previous finding of valley contrasted Bloch band features of orbital magnetic moment and Berry curvatures from inversion symmetry breaking [Phys. Rev. Lett. 99, 236809 (2007)]. A universal connection is revealed between the k-resolved optical oscillator strength of interband transitions, the orbital magnetic moment and the Berry curvatures, which also provides a principle for optical measurement of orbital magnetization and intrinsic anomalous Hall conductivity in ferromagnetic systems. The general physics is demonstrated in graphene where inversion symmetry breaking leads to valley contrasted optical selection rule for interband transitions. We discuss graphene based valley optoelectronics applications where light polarization information can be interconverted with electronic information.Comment: Expanded version, to appear in Phys. Rev.

Functional roles of SPLUNC1 in the innate immune response against Gram-negative bacteria

Abstract PLUNC (palate, lung and nasal epithelium clone)-associated gene originally referred to one gene, but now has been extended to represent a gene family that consists of a number of genes with peptide sequence homologies and predicted structural similarities. PLUNC-like proteins display sequence homology with BPI (bactericidal/permeability-increasing protein), a 456-residue cationic protein produced by precursors of polymorphonuclear leucocytes that have been shown to possess both bactericidal and LPS (lipopolysaccharide)-binding activities. The human PLUNC is also known as LUNX (lung-specific X protein), NASG (nasopharyngeal carcinoma-related protein) and SPURT (secretory protein in upper respiratory tract). The gene originally named PLUNC is now recognized as SPLUNC1. Its gene product SPLUNC1 is a secretory protein that is abundantly expressed in cells of the surface epithelium in the upper respiratory tracts and secretory glands in lung, and in the head and the neck region. The functional role of SPLUNC1 in innate immunity has been suggested but not clearly defined. The present review describes recent findings that support antimicrobial and anti-inflammatory functions of SPLUNC1 in Gram-negative bacteria-induced respiratory infection

A Longitudinal Cline Characterizes the Genetic Structure of Human Populations in the Tibetan Plateau

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their de- mography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with world- wide genetic variation data. We found a clear signal of genetic stratification across the east- west axis within Tibetan samples. Samples from more eastern locations tend to have higher genetic affinity with lowland East Asians, which can be explained by more gene flow from lowland East Asia onto the plateau. Our findings corroborate a previous report of admixture signals in Tibetans, which were based on a subset of the samples analyzed here, but add evidence for isolation by distance in a broader geospatial context

Private Collaborative Business Benchmarking in the Cloud

Collaborative business benchmarking helps organizations to evaluate their performance against current and future-state business goals. Cloud-based business benchmarking provides valuable insight for organizations to understand and compare their efficiency and effectiveness against peers. However, collaborative benchmarking entails sharing sensitive data, privacy of the benchmarking is very critical for organizations. We present a privacy-preserving prototype for collaborative business benchmarking in the cloud. Sensitive business’s data is encrypted and can only be decrypted by a set of parties through a threshold group decryption scheme

Climbing the Jaynes-Cummings Ladder and Observing its Sqrt(n) Nonlinearity in a Cavity QED System

The already very active field of cavity quantum electrodynamics (QED), traditionally studied in atomic systems, has recently gained additional momentum by the advent of experiments with semiconducting and superconducting systems. In these solid state implementations, novel quantum optics experiments are enabled by the possibility to engineer many of the characteristic parameters at will. In cavity QED, the observation of the vacuum Rabi mode splitting is a hallmark experiment aimed at probing the nature of matter-light interaction on the level of a single quantum. However, this effect can, at least in principle, be explained classically as the normal mode splitting of two coupled linear oscillators. It has been suggested that an observation of the scaling of the resonant atom-photon coupling strength in the Jaynes-Cummings energy ladder with the square root of photon number n is sufficient to prove that the system is quantum mechanical in nature. Here we report a direct spectroscopic observation of this characteristic quantum nonlinearity. Measuring the photonic degree of freedom of the coupled system, our measurements provide unambiguous, long sought for spectroscopic evidence for the quantum nature of the resonant atom-field interaction in cavity QED. We explore atom-photon superposition states involving up to two photons, using a spectroscopic pump and probe technique. The experiments have been performed in a circuit QED setup, in which ultra strong coupling is realized by the large dipole coupling strength and the long coherence time of a superconducting qubit embedded in a high quality on-chip microwave cavity.Comment: ArXiv version of manuscript published in Nature in July 2008, 5 pages, 5 figures, hi-res version at http://www.finkjohannes.com/SqrtNArxivPreprint.pd

Structural Features Essential to the Antimicrobial Functions of Human SPLUNC1

SPLUNC1 is an abundantly secreted innate immune protein in the mammalian respiratory tract that exerts bacteriostatic and antibiofilm effects, binds to lipopolysaccharide (LPS), and acts as a fluid-spreading surfactant. Here, we unravel the structural elements essential for the surfactant and antimicrobial functions of human SPLUNC1 (short palate lung nasal epithelial clone 1). A unique α-helix (α4) that extends from the body of SPLUNC1 is required for the bacteriostatic, surfactant, and LPS binding activities of this protein. Indeed, we find that mutation of just four leucine residues within this helical motif to alanine is sufficient to significantly inhibit the fluid spreading abilities of SPLUNC1, as well as its bacteriostatic actions against Gram-negative pathogens Burkholderia cenocepacia and Pseudomonas aeruginosa. Conformational flexibility in the body of SPLUNC1 is also involved in the bacteriostatic, surfactant, and LPS binding functions of the protein as revealed by disulfide mutants introduced into SPLUNC1. In addition, SPLUNC1 exerts antibiofilm effects against Gram-negative bacteria, although α4 is not involved in this activity. Interestingly, though, the introduction of surface electrostatic mutations away from α4 based on the unique dolphin SPLUNC1 sequence, and confirmed by crystal structure, is shown to impart antibiofilm activity against Staphylococcus aureus, the first SPLUNC1-dependent effect against a Gram-positive bacterium reported to date. Together, these data pinpoint SPLUNC1 structural motifs required for the antimicrobial and surfactant actions of this protective human protein

On the Propagation of Slip Fronts at Frictional Interfaces

The dynamic initiation of sliding at planar interfaces between deformable and rigid solids is studied with particular focus on the speed of the slip front. Recent experimental results showed a close relation between this speed and the local ratio of shear to normal stress measured before slip occurs (static stress ratio). Using a two-dimensional finite element model, we demonstrate, however, that fronts propagating in different directions do not have the same dynamics under similar stress conditions. A lack of correlation is also observed between accelerating and decelerating slip fronts. These effects cannot be entirely associated with static local stresses but call for a dynamic description. Considering a dynamic stress ratio (measured in front of the slip tip) instead of a static one reduces the above-mentioned inconsistencies. However, the effects of the direction and acceleration are still present. To overcome this we propose an energetic criterion that uniquely associates, independently on the direction of propagation and its acceleration, the slip front velocity with the relative rise of the energy density at the slip tip.Comment: 15 pages, 6 figure

Ischemia-Related Lesion Characteristics in Patients With Stable or Unstable Angina

Background Postmortem-derived findings support the common beliefs that lipid-rich coronary plaques with a thin, fibrous cap are prone to rupture and that rupture and superimposed thrombosis are the primary mechanisms causing acute coronary syndromes. In vivo imaging with intracoronary techniques may disclose differences in the characterization of atherosclerotic plaques in patients with stable or unstable angina and thus may provide clues to which plaques may rupture and whether rupture and thrombosis are active. Methods and Results We assessed the characteristics of the ischemia-related lesions with coronary angiography and intracoronary angioscopy and determined their compositions with intracoronary ultrasound in 44 patients with unstable and 23 patients with stable angina. The angiographic images were classified as noncomplex (smooth borders) or complex (irregular borders, multiple lesions, thrombus). Angioscopic images were classified as either stable (smooth surface) or thrombotic (red thrombus). The ultrasound characteristics of the lesion were classified as poorly echo-reflective, highly echo-reflective with shadowing, or highly echo-reflective without shadowing. There was a poor correlation between clinical status and angiographic findings. An angiographic complex lesion (n=33) was concordant with unstable angina in 55% (24 of 44); a noncomplex lesion (n=34) was concordant with stable angina in 61% (14 of 23). There was a good correlation between clinical status and angioscopic findings. An angioscopic thrombotic lesion (n=34) was concordant with unstable angina in 68% (30 of 44); a stable lesion (n=33) was concordant with stable angina in 83% (19 of 23). The ultrasound-obtained composition of the plaque was similar in patients with unstable and stable angina. Conclusions Angiography discriminates poorly between lesions in stable and unstable angina. Angioscopy demonstrated that plaque rupture and thrombosis were present in 17% of stable angina and 68% of unstable angina patients. Currently available ultrasound technology does not discriminate stable from unstable plaques

Synergistic Biophysical Techniques Reveal Structural Mechanisms of Engineered Cationic Antimicrobial Peptides in Lipid Model Membranes

In the quest for new antibiotics, two novel engineered cationic antimicrobial peptides (eCAPs) have been rationally designed. WLBU2 and D8 (all 8 valines are the d-enantiomer) efficiently kill both Gram-negative and -positive bacteria, but WLBU2 is toxic and D8 nontoxic to eukaryotic cells. We explore protein secondary structure, location of peptides in six lipid model membranes, changes in membrane structure and pore evidence. We suggest that protein secondary structure is not a critical determinant of bactericidal activity, but that membrane thinning and dual location of WLBU2 and D8 in the membrane headgroup and hydrocarbon region may be important. While neither peptide thins the Gram-negative lipopolysaccharide outer membrane model, both locate deep into its hydrocarbon region where they are primed for self-promoted uptake into the periplasm. The partially α-helical secondary structure of WLBU2 in a red blood cell (RBC) membrane model containing 50 % cholesterol, could play a role in destabilizing this RBC membrane model causing pore formation that is not observed with the D8 random coil, which correlates with RBC hemolysis caused by WLBU2 but not by D8.Fil: Heinrich, Frank. University of Carnegie Mellon; Estados UnidosFil: Salyapongse, Aria. University of Carnegie Mellon; Estados UnidosFil: Kumagai, Akari. University of Carnegie Mellon; Estados UnidosFil: Dupuy, Fernando Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Shukla, Karpur. University of Carnegie Mellon; Estados UnidosFil: Penk, Anja. Universitat Leipzig; AlemaniaFil: Huster, Daniel. Universitat Leipzig; AlemaniaFil: Ernst, Robert K.. University of Maryland; Estados UnidosFil: Pavlova, Anna. Georgia Institute Of Techology. School Of Chemical & Biomolecular Engineering; Estados UnidosFil: Gumbart, James C.. Georgia Institute Of Techology. School Of Chemical & Biomolecular Engineering; Estados UnidosFil: Deslouches, Berthony. University of Pittsburgh; Estados UnidosFil: Di, Y. Peter. University of Pittsburgh; Estados UnidosFil: Tristram-Nagle, Stephanie. University of Carnegie Mellon; Estados Unido