A Spontaneously Electrical State of Matter.

ConspectusMolecular deposition on solid surfaces forms crystalline or amorphous/glassy thin solid films. Intermolecular interactions govern the packing and dynamics of these films. The connection between molecular structure and intermolecular interactions is based on understanding electrostatic forces, dispersion forces and hydrogen bonding. Recently, an entire class of dipolar molecular species have demonstrated counterintuitive self-organization such that the dipole moments of individual molecules are oriented in thin films. This leads to the spontaneous generation of polarized molecular films manifesting a polarization charge equivalent to tens to hundreds of volts in strength at the film-vacuum interface, relative to the film-substrate interface. These voltages, and the corresponding electric fields present in such films, result from a collective and spontaneous orientation of molecular dipoles throughout the film during film growth and represent a metastable state of polarized material. The existence of these materials should encourage reconsideration of the importance of solid-state intermolecular electrostatic interactions.This account will detail observations of the spontaneous electric fields in molecular solids, provide insights into the dynamics and structure of molecular materials that the emergence of these electric fields can facilitate, and present a dipole-alignment based mean-field model that reproduces the temperature dependence of the electric field strength. Species as diverse as carbon monoxide, nitrous oxide, freons, simple alcohols, and cis-methyl formate have been demonstrated to spontaneously generate electric fields. We have reported electric fields more than 108 V m-1, have shown how field strength varies with the film deposition temperature, and have reported temperature-dependent Stark shifts observable in both infrared and ultraviolet absorption spectra. The latter has led to the reporting of large Wannier-Mott excitons in wide band gap molecular materials, such as solid carbon monoxide and ammonia.Changes in the field strength with time, at specific temperatures, can be related to the structural dynamics of glassy molecular solids. Measurement of surface potentials is a very sensitive technique by which to observe the rotation and translation of molecular species buried in thin films. This is particularly true for polarized, supercooled molecular glasses, where surface potentials have been used to report on secondary relaxation processes that have hitherto been hidden from measurement.Characterizing spontaneously electric molecular films, and understanding their behavior, requires the inclusion of nonlocal and nonlinear effects. The mean-field model that we present describes the data by connecting the energy of interaction of an average dipole with the mean effective field in the film, where this field is itself a function of the degree of polarization. This feedback loop produces a smooth function with a nonintuitive, discontinuous differential. The condensation of thin molecular films is an important means by which molecular solids are generated in the interstellar medium and represents a key pathway for the generation of organic optically and electrically active materials. It may also be possible to manipulate chemistry with the intense, localized electric fields acting as or acting on catalysts. The repercussions of the spontaneous generation of bound surface charges and the presence of electric fields in molecular solids will be discussed in these contexts.

Hidden singularities in spontaneously polarized molecular solids.

Films of dipolar molecules formed by physical vapor deposition are, in general, spontaneously polarized, with implications ranging from electron transfer in molecular optoelectronic devices to the properties of astrochemical ices in the interstellar medium. Polarization arises from dipole orientation, which should intuitively decrease with increasing deposition temperature, T. However, it is experimentally found that minimum or maximum values in polarization vs T may be observed for cis-methyl formate, 1-propanol, and ammonia. A continuous analytic form of polarization vs T is developed, which has the property that it is not differentiable at all T. The minima and maxima in polarization vs T are marked by singularities in the differential of this analytic form. This exotic behavior is presently unique to films of dipolar species and has not been reported, for example, in the related magnetic phases of spin glasses.

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

The sputum microbiome, airway inflammation, and mortality in chronic obstructive pulmonary disease.

BACKGROUND: The sputum microbiome has a potential role in disease phenotyping and risk stratification in chronic obstructive pulmonary disease (COPD), but few large longitudinal cohort studies exist. OBJECTIVE: Our aim was to investigate the COPD sputum microbiome and its association with inflammatory phenotypes and mortality. METHODS: 16S ribosomal RNA gene sequencing was performed on sputum from 253 clinically stable COPD patients (4-year median follow-up). Samples were classified as Proteobacteria or Firmicutes (phylum level) and Haemophilus or Streptococcus (genus level) dominant. Alpha diversity was measured by using Shannon-Wiener diversity and Berger-Parker dominance indices. Survival was modeled by using Cox proportional hazards regression. A subset of 78 patients had label-free liquid chromatography with tandem mass spectrometry performed, with partial least square discriminant analysis integrating clinical, microbiome, and proteomics data. RESULTS: Proteobacteria dominance and lower diversity was associated with more severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease classification system (P = .0015), more frequent exacerbations (P = .0042), blood eosinophil level less than or equal to 100 cells/µL (P < .0001), and lower FEV1 (P = .026). Blood eosinophil counts showed a positive relationship with percent of Firmicutes and Streptococcus and a negative association with percent Proteobacteria and Haemophilus. Proteobacteria dominance was associated with increased mortality compared with Firmicutes-dominated or balanced microbiome profiles (hazard ratio = 2.58; 95% CI = 1.43-4.66; P = .0017 and hazard ratio = 7.47; 95% CI = 1.02-54.86; P = .048, respectively). Integrated omics analysis showed significant associations between Proteobacteria dominance and the neutrophil activation pathway in sputum. CONCLUSION: The sputum microbiome is associated with clinical and inflammatory phenotypes in COPD. Reduced microbiome diversity, associated with Proteobacteria (predominantly Haemophilus) dominance, is associated with neutrophil-associated protein profiles and an increased risk of mortality.

Low temperature aging in a molecular glass: the case of cis-methyl formate.

Glassy films of cis-methyl formate show spontaneous dipole orientation on deposition from the vacuum, the so-called 'spontelectric effect', creating surface potentials and electric fields within the films. We follow the decay of these fields, and their accompanying dipole orientation, on the hours timescale at deposition temperatures between 40 K and 55 K. Our data trace the low temperature 'secondary decay' mechanism, at tens of degrees below the glass transition temperature of 90 K. We show that secondary decay is due to molecular rotation, with associated activation energies lying between 0.1 and 0.2 eV. Diffusion is absent, as established from published neutron reflectivity data. Using an analytical model for the spontelectric effect, data are placed on a quantitative footing, showing that angular motion in excess of 50° reproduces the observed values of activation energies. Exploitation of the spontelectric effect is new in the study of glass aging and is shown here to give insight into the elusive processes which take place far from the molecular glass transition temperature.

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis.

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.

The optical absorption spectra of spontaneously electrical solids: the case of nitrous oxide.

Absorption spectra of films of N2O, in the range 115-160 nm, are presented for deposition temperatures between 33 K and 64 K. Observed shifts in the absorption energy vs. deposition temperature are analysed in terms of the temperature-dependent spontaneously electrical ('spontelectric') fields present in the films. Using a simple electrostatic theory, we suggest that (i) spectra are associated with Wannier-Mott excitons, (ii) the action of the electric field upon the excitons suffers a blockade at ≤54 K for the C-state and ≤52 K for the D-state of N2O, (iii) the blockade may be attributed to structural defects, which trap excitons, limiting their size and (iv) films form with defect-free regions containing 324 ± 3, 168 ± 46 and 95 ± 1 molecules of N2O at 54 K, 52 K and 50 K respectively, yielding an experimental indication of the scale size of regular periodicity associated with Wannier-Mott excitons. Results demonstrate how the spontelectric effect can be used as a tool for exploring the structure of solids and give a graphic image of the structural changes that take place close to the known phase change at 47 K/48 K.

Convolutional networks for fast, energy-efficient neuromorphic computing.

Deep networks are now able to achieve human-level performance on a broad spectrum of recognition tasks. Independently, neuromorphic computing has now demonstrated unprecedented energy-efficiency through a new chip architecture based on spiking neurons, low precision synapses, and a scalable communication network. Here, we demonstrate that neuromorphic computing, despite its novel architectural primitives, can implement deep convolution networks that (i) approach state-of-the-art classification accuracy across eight standard datasets encompassing vision and speech, (ii) perform inference while preserving the hardware's underlying energy-efficiency and high throughput, running on the aforementioned datasets at between 1,200 and 2,600 frames/s and using between 25 and 275 mW (effectively >6,000 frames/s per Watt), and (iii) can be specified and trained using backpropagation with the same ease-of-use as contemporary deep learning. This approach allows the algorithmic power of deep learning to be merged with the efficiency of neuromorphic processors, bringing the promise of embedded, intelligent, brain-inspired computing one step closer.

Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Neutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined. OBJECTIVE: We sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function. METHODS: NET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation. RESULTS: Sputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD. CONCLUSION: NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

Cell-type specific RNA-Seq reveals novel roles and regulatory programs for terminally differentiated Dictyostelium cells.

BACKGROUND: A major hallmark of multicellular evolution is increasing complexity by the evolution of new specialized cell types. During Dictyostelid evolution novel specialization occurred within taxon group 4. We here aim to retrace the nature and ancestry of the novel "cup" cells by comparing their transcriptome to that of other cell types. RESULTS: RNA-Seq was performed on purified mature spore, stalk and cup cells and on vegetative amoebas. Clustering and phylogenetic analyses showed that cup cells were most similar to stalk cells, suggesting that they share a common ancestor. The affinity between cup and stalk cells was also evident from promoter-reporter studies of newly identified cell-type genes, which revealed late expression in cups of many stalk genes. However, GO enrichment analysis reveal the unexpected prominence of GTPase mediated signalling in cup cells, in contrast to enrichment of autophagy and cell wall synthesis related transcripts in stalk cells. Combining the cell type RNA-Seq data with developmental expression profiles revealed complex expression dynamics in each cell type as well as genes exclusively expressed during terminal differentiation. Most notable were nine related hssA-like genes that were highly and exclusively expressed in cup cells. CONCLUSIONS: This study reveals the unique transcriptomes of the mature cup, stalk and spore cells of D. discoideum and provides insight into the ancestry of cup cells and roles in signalling that were not previously realized. The data presented in this study will serve as an important resource for future studies into the regulation and evolution of cell type specialization.

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD. METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD. FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

Patterned formation of enolate functional groups on the graphene basal plane.

Chemical functionalization of graphene is one method pursued to engineer new properties into a graphene sheet. Graphene oxide is the most commonly used chemical derivative of graphene. Here we present experimental evidence for the formation of enolate moieties when oxygen atoms are added to the graphene basal plane. The exotic functional groups are stabilized by simultaneous bond formation between the graphene sheet and the underlying Ir(111) substrate. Scanning tunneling microscopy images demonstrate the patterned nature of C-O bond formation and X-ray photoelectron spectroscopy and high-resolution electron energy loss spectroscopy are used to characterize the enolate moiety. The results present a new mechanism for the formation of patterned graphene oxide and provide evidence of a functional group rarely considered for graphene oxide materials.

Spontaneous polarization of solid CO on water ices and some astrophysical implications.

Reflection absorption infrared spectroscopy (RAIRS) is used to show that when 20 monolayer (ML) films of solid CO are laid down on solid water substrates at 20 to 24 K, the films polarize spontaneously. CO films were prepared on three types of water ice: porous amorphous solid water (CO-pASW), crystalline water (CO-CSW) and compact amorphous solid water (CO-cASW) with corresponding fields of 3.76 ± 0.15 × 10(7) V m(-1) for CO-pASW, 2.87 ± 0.15 × 10(7) V m(-1) for CO-CSW and 1.98 ± 0.15 × 10(7) V m(-1) for CO-cASW. For comparison, CO laid down on SiO2 yields 3.8 ± 0.15 × 10(7) V m(-1). Our results are of relevance to an understanding of the chemistry and physics of dense star-forming regions in the interstellar medium, in which dust particles become coated with solid CO on a layer of cASW. The polarization charge which accumulates on the CO surface acts as a catalyst for the removal of electrons and ions from the medium and may account for the low degree of ionization observed in these regions, a feature which is an important factor for the rate of star formation.

Novel TGM5 mutations in acral peeling skin syndrome.

Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase-5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study, we report both European and non-European families carrying other mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity, we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse-transcribed PCR analysis and used databases and in silico prediction tools.

Graphene as an anti-corrosion coating layer.

Graphene, a single layer of carbon atoms arranged in an aromatic hexagonal lattice, has recently drawn attention as a potential coating material due to its impermeability, thermodynamic stability, transparency and flexibility. Here, the effectiveness of a model system, a graphene covered Pt(100) surface, for studying the anti-corrosion properties of graphene, has been evaluated. Chemical vapour deposition techniques were used to cover the single crystal surface with a complete layer of high-quality graphene and the surface was characterised after exposure to corrosive environments with scanning tunnelling microscopy (STM) and Raman spectroscopy. Graphene covered Pt samples were exposed to: (i) ambient atmosphere for 6 months at room temperature and 60 °C for 75 min, (ii) Milli-Q water for 14 hours at room temperature and 60 °C for 75 min, and (iii) saltwater (0.513 M NaCl) for 75 min at room temperature and 60 °C. STM provides atomic resolution images, which show that the graphene layer and the underlying surface reconstruction on the Pt(100) surface remain intact over the majority of the surface under all conditions, except exposure to saltwater when the sample is kept at 60 °C. Raman spectroscopy shows a broadening of all graphene related peaks due to hybridisation between the surface Pt d-orbitals and the graphene π-bands. This hybridisation also survives exposure to all environments except saltwater on the hot surface, with the latter leading to peaks more representative of a quasi free-standing graphene layer. A mechanism explaining the corrosive effect of hot saltwater is suggested. Based on these experiments, graphene is proposed to offer protection against corrosion in all tested environments, except saltwater on a hot surface, and Raman spectroscopy is proposed as a useful method for indirectly assessing the chemical state of the Pt surface.

Developments in in situ hybridisation.

In situ hybridisation (ISH) is an established family of closely related methods for the detection and visualisation of specific nucleic acid sequences (DNA, RNA) in tissue sections, cytological preparations and whole organisms. The technique has a history of refinements and applications going back over several decades and is routinely employed in laboratories where visualisation of gene expression directly within the tissue of interest is necessary. This article will focus on ISH methods for the demonstration of messenger RNA (mRNA) and micro RNA (miRNA) in formalin-fixed paraffin-embedded (FFPE) tissues with emphasis on non-radioactive signal detection strategies currently available.

Spontaneously electrical solids in a new light.

Reflection-absorption infrared spectroscopy (RAIRS) of nitrous oxide (N2O) thin films is shown to provide an independent means of observing the spontelectric state, the first new structural phase of matter, with unique electrical properties, to have emerged in decades. The presence of a spontaneous and powerful static electric field within the film, the defining characteristic of spontelectric solids, is demonstrated through observations of longitudinal-transverse optical (LO-TO) splitting in RAIR spectra, using an analysis based on the vibrational Stark effect. In particular the dependence of the LO-TO splitting on the film deposition temperature may be wholly attributed to the known temperature dependence of the spontelectric field.

Spontaneous electric fields in solid carbon monoxide.

Reflection-absorption infrared spectroscopy (RAIRS) is shown to provide a means of observing the spontelectric phase of matter, the defining characteristic of which is the occurrence of a spontaneous and powerful static electric field within a film of material. The presence of such a field is demonstrated here through the study of longitudinal-transverse optical splitting in RAIR spectra in films of carbon monoxide, based upon the deposition temperature dependence of this splitting. Analysis of spectral data, in terms of the vibrational Stark effect, allows the measurement of the polarization of spontelectric films, showing for example that solid carbon monoxide at 20 K may maintain a spontelectric field of 3.78 × 10(7) V m(-1), representing a polarization of 3.34 × 10(-4) cm(-2). We comment on the astrophysical implications of polarized carbon monoxide ices, on the surface of cosmic grains in star-forming regions.

Functionalisation and immobilisation of an Au(110) surface via uracil and 2-thiouracil anchored layer.

We study surface functionalisation by uracil and 2-thiouracil, and immobilisation of several DNA moieties on functionalised gold surfaces. The combination of X-ray photoelectron and near-edge X-ray absorption spectroscopy allowed us to obtain a complete understanding of complex interfacial processes, starting from adsorption of biomolecules onto the metallic surface and progressing towards a specific surface functionality for interactions with other biologically related adsorbates. Au(110) surfaces were functionalised by deposition of uracil and 2-thiouracil molecules under vacuum conditions, and then tested for their selectivity by immobilisation of different DNA moieties deposited from aqueous solutions. We observed that adenine, adenosine, and RNA polymer (polyadenylic acid) from saturated solutions were immobilized successfully on the 2-thiouracil, but those from dilute (1%) solutions were not. However, cytosine failed to adsorb even from saturated solution. The chemical states of the biologically related adsorbates were investigated and the geometrical orientation of uracil and 2-thiouracil on the Au(110) surface was determined using both spectroscopic techniques.

Regional copy number-independent deregulation of transcription in cancer.

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.