Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate how the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure

Variation in life history traits and transcriptome associated with adaptation to diet shifts in the ladybird Cryptolaemus montrouzieri

Background: Despite the broad diet range of many predatory ladybirds, the mechanisms involved in their adaptation to diet shifts are not completely understood. Here, we explored how a primarily coccidophagous ladybird Cryptolaemus montrouzieri adapts to feeding on aphids. Results: Based on the lower survival rate, longer developmental time, and lower adult body weight and reproduction rate of the predator, the aphid Megoura japonica proved being less suitable to support C. montrouzieri as compared with the citrus mealybug Planococcus citri. The results indicated up-regulation of genes related to ribosome and translation in fourth instars, which may be related to their suboptimal development. Also, several genes related to biochemical transport and metabolism, and detoxification were up-regulated as a result of adaptation to the changes in nutritional and non-nutritional (toxic) components of the prey. Conclusion: Our results indicated that C. montrouzieri succeeded in feeding on aphids by regulation of genes related to development, digestion and detoxification. Thus, we argue that these candidate genes are valuable for further studies of the functional evolution of ladybirds led by diet shifts

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

The Hubbard model within the equations of motion approach

The Hubbard model has a special role in Condensed Matter Theory as it is considered as the simplest Hamiltonian model one can write in order to describe anomalous physical properties of some class of real materials. Unfortunately, this model is not exactly solved except for some limits and therefore one should resort to analytical methods, like the Equations of Motion Approach, or to numerical techniques in order to attain a description of its relevant features in the whole range of physical parameters (interaction, filling and temperature). In this manuscript, the Composite Operator Method, which exploits the above mentioned analytical technique, is presented and systematically applied in order to get information about the behavior of all relevant properties of the model (local, thermodynamic, single- and two- particle ones) in comparison with many other analytical techniques, the above cited known limits and numerical simulations. Within this approach, the Hubbard model is shown to be also capable to describe some anomalous behaviors of the cuprate superconductors.Comment: 232 pages, more than 300 figures, more than 500 reference

Frequency Hopping Joint Radar-Communications with Hybrid Sub-Pulse Frequency and Duration Modulation

Frequency-hopping (FH) joint radar-communications (JRC) can offer excellent security for integrated sensing and communication systems. However, existing JRC schemes mainly embed information using only the sub-pulse frequencies and hence the data rate is limited. In this letter, we propose to use both sub-pulse frequencies and durations for information modulation, leading to higher communication data rates. For information demodulation, we propose a novel scheme by using the time-frequency analysis (TFA) technique and a 'you only look once' (YOLO)-based detection system. As such, our system does not require channel estimation, simplifying the transmission signal frame design. Simulation results demonstrate the effectiveness of our scheme, and show that it is robust against the Doppler shift and timing offset between the transceiver and the communication receiver

An integrative approach to discovering cryptic species within the Bemisia tabaci whitefly species complex

Bemisia tabaci is a cryptic whitefly-species complex that includes some of the most damaging pests and plant-virus vectors of a diverse range of food and fibre crops worldwide. We combine experimental evidence of: (i) differences in reproductive compatibility, (ii) hybrid verification using a specific nuclear DNA marker and hybrid fertility confirmation and (iii) high-throughput sequencing-derived mitogenomes, to show that the “Mediterranean” (MED) B. tabaci comprises at least two distinct biological species; the globally invasive MED from the Mediterranean Basin and the “African silver-leafing” (ASL) from sub-Saharan Africa, which has no associated invasion records. We demonstrate that, contrary to its common name, the “ASL” does not induce squash silver-leafing symptoms and show that species delimitation based on the widely applied 3.5% partial mtCOI gene sequence divergence threshold produces discordant results, depending on the mtCOI region selected. Of the 292 published mtCOI sequences from MED/ASL groups, 158 (54%) are low quality and/or potential pseudogenes. We demonstrate fundamental deficiencies in delimiting cryptic B. tabaci species, based solely on partial sequences of a mitochondrial barcoding gene. We advocate an integrative approach to reveal the true species richness within cryptic species complexes, which is integral to the deployment of effective pest and disease management strategies

Non-antibiotic quorum sensing inhibitors acting against N-acyl homoserine lactone synthase as druggable target

YesN-acylhomoserine lactone (AHL)-based quorum sensing (QS) is important for the regulation of proteobacterial virulence determinants. Thus, the inhibition of AHL synthases offers non-antibiotics-based therapeutic potentials against QS-mediated bacterial infections. In this work, functional AHL synthases of Pseudomonas aeruginosa LasI and RhlI were heterologously expressed in an AHL-negative Escherichia coli followed by assessments on their AHLs production using AHL biosensors and high resolution liquid chromatography–mass spectrometry (LCMS). These AHL-producing E. coli served as tools for screening AHL synthase inhibitors. Based on a campaign of screening synthetic molecules and natural products using our approach, three strongest inhibitors namely are salicylic acid, tannic acid and trans-cinnamaldehyde have been identified. LCMS analysis further confirmed tannic acid and trans-cinnemaldehyde efficiently inhibited AHL production by RhlI. We further demonstrated the application of trans-cinnemaldehyde inhibiting Rhl QS system regulated pyocyanin production in P. aeruginosa up to 42.06%. Molecular docking analysis suggested that trans-cinnemaldehyde binds to the LasI and EsaI with known structures mainly interacting with their substrate binding sites. Our data suggested a new class of QS-inhibiting agents from natural products targeting AHL synthase and provided a potential approach for facilitating the discovery of anti-QS signal synthesis as basis of novel anti-infective approach.University of Malaya High Impact Research (HIR) Grant (UM-MOHE HIR Grant UM.C/625/1/HIR/MOHE/CHAN/14/1, no. H-50001-A000027) given to K.G.C. and National Natural Science Foundation of China (no. 81260481) given to H.W

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy

INTRODUCTION/AIMS: Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). METHODS: Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. RESULTS: Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p  .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. DISCUSSION: In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients

Emergence of carbapenem-resistant Acinetobacter baumannii as the major cause of ventilator-associated pneumonia in intensive care unit patients at an infectious disease hospital in southern Vietnam.

Ventilator-associated pneumonia (VAP) is a serious healthcare-associated infection that affects up to 30 % of intubated and mechanically ventilated patients in intensive care units (ICUs) worldwide. The bacterial aetiology and corresponding antimicrobial susceptibility of VAP is highly variable, and can differ between countries, national provinces and even between different wards in the same hospital. We aimed to understand and document changes in the causative agents of VAP and their antimicrobial susceptibility profiles retrospectively over an 11 year period in a major infectious disease hospital in southern Vietnam. Our analysis outlined a significant shift from Pseudomonas aeruginosa to Acinetobacter spp. as the most prevalent bacteria isolated from quantitative tracheal aspirates in patients with VAP in this setting. Antimicrobial resistance was common across all bacterial species and we found a marked proportional annual increase in carbapenem-resistant Acinetobacter spp. over a 3 year period from 2008 (annual trend; odds ratio 1.656, P = 0.010). We further investigated the possible emergence of a carbapenem-resistant Acinetobacter baumannii clone by multiple-locus variable number tandem repeat analysis, finding a blaOXA-23-positive strain that was associated with an upsurge in the isolation of this pathogen. We additionally identified a single blaNDM-1-positive A. baumannii isolate. This work highlights the emergence of a carbapenem-resistant clone of A. baumannii and a worrying trend of antimicrobial resistance in the ICU of the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam