bluuebunny/crossref_metadata_2025 huggingface dataset:
Atomic-Level EELS Mapping Using High-Energy Edges in Dualeels™ Mode
Authors: Longo Paolo , Thomas Paul J. , Twesten Ray D.
Published: July 2012

With advancements in aberration correction, the spatial resolution of scanning transmission electron microscopy (STEM) has been enormously improved. In addition to the reduction of the STEM probe size, a dramatic increase in the STEM probe current has been realized, leading to the routine acquisition of high-resolution elemental and chemical maps using electron energy loss spectrometry (EELS). Using EELS combined with these advanced STEM instruments, atomic-level resolution information can be obtained from various types of materials, revealing the nature of interfaces, elemental distribution, presence of defects, and much more. In addition to simple elemental composition distributions, EELS is capable of delivering information about the chemical bonding, local atomic coordination, oxidation states, band gaps, and chemical phases of a broad range of materials at the fundamental resolution limit of the property being probed. Atomic-level EELS maps of these fundamental material properties can now be obtained with the acquisition time, to a large extent, limited only by the speed of the EELS spectrometer and not by the signal being measured. The availability of fast EELS spectrometers with large angular collection efficiencies has closed the gap between the rate of signal generation in the specimen and the speed at which this signal can be detected. This significantly increases the amount of information that can be acquired using EELS. Using the most recent generation of spectrometers, EELS data can be acquired at well over 1,000 spectra per second with a high-duty cycle. Fifth-order spectral aberration correction in this generation of spectrometers allows the use of the large collection angles needed to match the increased convergence angle that Cs-probe-corrected systems present, improving collection efficiency while maintaining energy resolution. These advances, when taken together, result in a well matched source/detector system capable of recording high-energy EELS edges at atomic resolution at a rate fast enough to limit electron beam damage to the sample.
Equipment Funding Opportunities and Strategies for Success (Part 1)
Authors: Sherman Debby
Published: July 2012

I think most of you probably know me. I tend to be rather vocal about things, whether it be on the Microscopy Listserver or through the years on problems of facility management, so I'm going to very briefly go over some of my experiences. I direct a core facility that has independent users, has a service component, is basically life sciences, but we do imaging for everybody. They can be from civil engineering, vet school, aeronautics, chemistry…who knows what will come in the door. So, some of the challenge has been to obtain major instrumentation that is versatile enough to handle a broad, broad range of users, but is initially justified based on a critical core research group. This is integral for obtaining any type of federal funding. So, we need new instrumentation for numerous reasons.
Calendar
Authors: Webster Paul
Published: July 2012

Following is a list of microscopy related meetings and courses. The editors would greatly appreciate input to this list via the electronic submission form under “events/other microscopy events” at the MSA webpage: www.microscopy.org. We will gladly add hypertext links to the notice on the web and insert a listing of the meeting in the next issue.
Complement C1q production by osteoclasts and its regulation of osteoclast development
Authors: Teo Boon Heng Dennis , Bobryshev Yuri V. , Teh Boon King , Wong Siew Heng , Lu Jinhua
Published: July 2012

C1q deficiency is the strongest known risk factor for SLE (systemic lupus erythematosus) but its endogenous cellular origin remains limitedly understood. In the present study we investigate the production of C1q by both cultured and endogenous bone osteoclasts. Blood monocytes were cultured with RANKL (receptor activator of nuclear factor κB ligand) and M-CSF (macrophage colony-stimulating factor) to generate osteoclasts and these cells expressed C1Q mRNA and also secreted C1q protein. Intracellular C1q was detectable in developing osteoclasts at day 3 by Western blotting and was also detectable by flow cytometry. By immunofluorescence microscopy, C1q was preferentially detected in immature osteoclasts. By multiple detection methods, C1q expression was markedly increased after IFNγ (interferon γ) treatment. By immunohistochemistry, C1q was also detected in endogenous bone osteoclasts. When osteoclasts were cultured on immobilized C1q, these cells exhibited 2–7-fold increases in the expression of signature osteoclast genes [TRAP (tartrate-resistant acid phosphatase), cathepsin K, calcitonin receptor, carbonic anhydrase II and NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1)], suggesting an osteoclastogenic capability. This is the first report of C1q production by osteoclasts. Its ability to enhance osteoclast development implies reduced osteoclastogenesis in patients with SLE as they often experience decreased C1q levels. This is consistent with the non-erosive nature of lupus arthritis.
Pharmacological chaperones increase the cell-surface expression of intracellularly retained mutants of the melanocortin 4 receptor with unique rescuing efficacy profiles
Authors: Ward Natalie-Anne , Hirst Simon , Williams John , Findlay John B.C.
Published: July 2012

Mutated versions of membrane proteins often fail to express at the plasma membrane, but instead are trapped in the secretory pathway, resulting in disease. The retention of these mutant proteins is thought to result from local misfolding, which prevents export from the ER (endoplasmic reticulum), targeting the receptor for degradation via the ER-associated quality control system. The rhodopsin-like G-protein-coupled MC4R (melanocortin 4 receptor) is an example of such a membrane protein. Over 100 natural MC4R mutations are linked with an obese phenotype and to date represent the most common monogenic cause of severe early-onset obesity. More than 80% of these mutations result in a substantial proportion of MC4R being retained intracellularly. If these receptors were expressed at the plasma membrane, many could be functional, as mutations often occur in regions distinct from those associated with ligand or G-protein binding. Our aim is to show proof of concept that selective compounds can rescue the function of MC4R mutants by increasing their cell-surface expression, and further to this, examine whether the rescue profile differs between mutants. Whole-cell ELISA and 96-well fluorescence-based assays with N-terminally HA (haemagglutinin)-tagged and C-terminally mCherry-tagged mutant MC4Rs were used to screen a number of novel MC4R-selective compounds. A total of four related compounds increased the cell-surface expression of wild-type and three intracellularly retained mutant MC4Rs, thus acting as pharmacological chaperones. There appears to be a unique rescue efficacy profile for each compound that does not correlate with potency, suggesting distinct receptor conformations induced by the different mutations. A degree of functionality of V50M and S58C was also rescued following relocation to the cell surface.
Building droplet-based microfluidic systems for biological analysis
Authors: Niu Xize , deMello Andrew J.
Published: July 2012

In the present paper, we review and discuss current developments and challenges in the field of droplet-based microfluidics. This discussion includes an assessment of the basic fluid dynamics of segmented flows, material requirements, fundamental unit operations and how integration of functional components can be applied to specific biological problems.
Looking for novel functions of tau
Authors: Avila Jesus , de Barreda Elena Gomez , Fuster-Matanzo Almudena , Simón Diana , Llorens-Martín María , Engel Tobias , Lucas Jose J. , Díaz-Hernández Miguel , Hernández Félix
Published: July 2012

The lack or excess of the protein tau can be deleterious for neurons. The absence of tau can result in retarded neurogenesis and neuronal differentiation, although adult mice deficient in tau are viable, probably because of the compensation of the loss of tau by other MAPs (microtubule-associated proteins). On the contrary, the overexpression of tau can be toxic for the cell. One way to reduce intracellular tau levels can be achieved by its secretion through microvesicles to the extracellular space. Furthermore, tau can be found in the extracellular space because of the neuronal cell death occurring in neurodegenerative disorders such as Alzheimer's disease. The presence of toxic extracellular tau could be the mechanism for the spreading of tau pathology in these neurodegenerative disorders.
Exploiting amyloid: how and why bacteria use cross-β fibrils
Authors: Sawyer Elizabeth B. , Claessen Dennis , Gras Sally L. , Perrett Sarah
Published: July 2012

Many bacteria produce protein fibrils that are structurally analogous to those associated with protein misfolding diseases such as Alzheimer's disease. However, unlike fibrils associated with disease, bacterial amyloids have beneficial functions including conferring stability to biofilms, regulating development or imparting virulence. In the present review, we consider what makes amyloid fibrils so suitable for these roles and discuss recent developments in the study of bacterial amyloids, in particular the chaplins from Streptomyces coelicolor. We also consider the broader impact of the study of bacterial amyloids on our understanding of infection and disease and on developments in nanotechnology.
The self-perpetuating tau truncation circle
Authors: Zilka Norbert , Kovacech Branislav , Barath Peter , Kontsekova Eva , Novák Michal
Published: July 2012

Pathological truncations of human brain proteins represent the common feature of many neurodegenerative disorders including AD (Alzheimer's disease), Parkinson's disease and Huntington's disease. Protein truncations significantly change the structure and function of these proteins and thus can engender their pathological metamorphosis. We have shown previously that truncated forms of tau protein are contained in the core of the paired helical filaments that represent the main constituent of neurofibrillary pathology. Recently, we have identified truncated tau species of a different molecular signature. We have found that tau truncation is not produced by a random process, but rather by highly specific proteolytic cleavage and/or non-enzymatic fragmentation. In order to characterize the pathophysiology of AD-specific truncated tau species, we have used a transgenic rat model for AD expressing human truncated tau. Expression of the tau protein induces the formation of novel truncated tau species that originate from both transgenic human tau and endogenous rat tau proteins. Moreover, these truncated tau proteins are found exclusively in the misfolded fraction of tau, suggesting that they actively participate in the tau misfolding process. These findings corroborate further the idea that the appearance of truncated tau species starts a self-perpetuating cycle of further tau protein truncation leading to and accelerating tau misfolding and formation of neurofibrillary pathology.
Alternatively folded proteins with unexpected beneficial functions
Authors: Min Soyoung , Meehan James , Sullivan Louise M. , Harte Níal P. , Xie Yongjing , Davey Gavin P. , Svanborg Catharina , Brodkorb André , Mok K. Hun
Published: July 2012

HAMLET (human α-lactalbumin made lethal to tumour cells) and its related partially unfolded protein–fatty acid complexes are novel biomolecular nanoparticles that possess relatively selective cytotoxic activities towards tumour cells. One of the key characteristics is the requirement for the protein to be partially unfolded, hence endowing native proteins with additional functions in the alternatively folded states. Beginning with the history of its discovery and development, the cellular targets that appear to be strongly correlated with tumour cell death are introduced in the present article.
Prion processing: a double-edged sword?
Authors: McMahon Hilary E.M.
Published: July 2012

The events leading to the degradation of the endogenous PrPC (normal cellular prion protein) have been the subject of numerous studies. Two cleavage processes, α-cleavage and β-cleavage, are responsible for the main C- and N-terminal fragments produced from PrPC. Both cleavage processes occur within the N-terminus of PrPC, a region that is significant in terms of function. α-Cleavage, an enzymatic event that occurs at amino acid residues 110 and 111 on PrPC, interferes with the conversion of PrPC into the prion disease-associated isoform, PrPSc (abnormal disease-specific conformation of prion protein). This processing is seen as a positive event in terms of disease development. The study of β-cleavage has taken some surprising turns. β-Cleavage is brought about by ROS (reactive oxygen species). The C-terminal fragment produced, C2, may provide the seed for the abnormal conversion process, as it resembles in size the fragments isolated from prion-infected brains. There is, however, strong evidence that β-cleavage provides an essential process to reduce oxidative stress. β-Cleavage may act as a double-edged sword. By β-cleavage, PrPC may try to balance the ROS levels produced during prion infection, but the C2 produced may provide a PrPSc seed that maintains the prion conversion process.
The roles of miRNAs in wing imaginal disc development in Drosophila
Authors: Waldron Joseph A. , Newbury Sarah F.
Published: July 2012

During development, it is essential for gene expression to occur in a very precise spatial and temporal manner. There are many levels at which regulation of gene expression can occur, and recent evidence demonstrates the importance of mRNA stability in governing the amount of mRNA that can be translated into functional protein. One of the most important discoveries in this field has been miRNAs (microRNAs) and their function in targeting specific mRNAs for repression. The wing imaginal discs of Drosophila are an excellent model system to study the roles of miRNAs during development and illustrate their importance in gene regulation. This review aims at discussing the developmental processes where control of gene expression by miRNAs is required, together with the known mechanisms of this regulation. These developmental processes include Hox gene regulation, developmental timing, growth control, specification of SOPs (sensory organ precursors) and the regulation of signalling pathways.
Non-coding RNAs in Saccharomyces cerevisiae: what is the function?
Authors: Wu Jian , Delneri Daniela , O'Keefe Raymond T.
Published: July 2012

New sequencing technologies and high-resolution microarray analysis have revealed genome-wide pervasive transcription in many eukaryotes, generating a large number of RNAs with no coding capacity. The focus of current debate is whether many of these ncRNAs (non-coding RNAs) are functional, and if so, what their function is. In this review, we describe recent discoveries in the field of ncRNAs in the yeast Saccharomyces cerevisiae. Newly identified ncRNAs in this budding yeast, their functions in gene regulation and possible mechanisms of action are discussed.
Defining the roles and interactions of PTB
Authors: Kafasla Panagiota , Mickleburgh Ian , Llorian Miriam , Coelho Miguel , Gooding Clare , Cherny Dmitry , Joshi Amar , Kotik-Kogan Olga , Curry Stephen , Eperon Ian C. , Jackson Richard J. , Smith Christopher W.J.
Published: July 2012

PTB (polypyrimidine tract-binding protein) is an abundant and widely expressed RNA-binding protein with four RRM (RNA recognition motif) domains. PTB is involved in numerous post-transcriptional steps in gene expression in both the nucleus and cytoplasm, but has been best characterized as a regulatory repressor of some ASEs (alternative splicing events), and as an activator of translation driven by IRESs (internal ribosome entry segments). We have used a variety of approaches to characterize the activities of PTB and its molecular interactions with RNA substrates and protein partners. Using splice-sensitive microarrays we found that PTB acts not only as a splicing repressor but also as an activator, and that these two activities are determined by the location at which PTB binds relative to target exons. We have identified minimal splicing repressor and activator domains, and have determined high resolution structures of the second RRM domain of PTB binding to peptide motifs from the co-repressor protein Raver1. Using single-molecule techniques we have determined the stoichiometry of PTB binding to a regulated splicing substrate in whole nuclear extracts. Finally, we have used tethered hydroxyl radical probing to determine the locations on viral IRESs at which each of the four RRM domains bind. We are now combining tethered probing with single molecule analyses to gain a detailed understanding of how PTB interacts with pre-mRNA substrates to effect either repression or activation of splicing.
Copy number variations involving the microtubule-associated protein tau in human diseases
Authors: Rovelet-Lecrux Anne , Campion Dominique
Published: July 2012

Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.
UPF1 involvement in nuclear functions
Authors: Varsally Wazeer , Brogna Saverio
Published: July 2012

UPF1 (up-frameshift 1) is a protein conserved in all eukaryotes that is necessary for NMD (nonsense-mediated mRNA decay). UPF1 mainly localizes to the cytoplasm and, via mechanisms that are linked to translation termination but not yet well understood, stimulates rapid destruction of mRNAs carrying a PTC (premature translation termination codon). However, some studies have indicated that in human cells UPF1 has additional roles, possibly unrelated to NMD, which are carried out in the nucleus. These might involve telomere maintenance, cell cycle progression and DNA replication. In the present paper, we review the available experimental evidence implicating UPF1 in nuclear functions. The unexpected view that emerges from this literature is that the nuclear functions primarily stem from UPF1 having an important role in DNA replication, rather than NMD affecting the expression of proteins involved in these processes. Our bioinformatics survey of the interaction network of UPF1 with other human proteins, however, highlights that UPF1 also interacts with proteins associated with nuclear RNA degradation and transcription termination; therefore suggesting involvement in processes that could also impinge on DNA replication indirectly.
The role of microRNA in the response to cisplatin treatment
Authors: Drayton Ross M.
Published: July 2012

Resistance to the cytotoxic effects of cisplatin can be mediated through changes in a wide variety of cellular processes and signalling pathways. The discovery of microRNAs as regulators of protein expression through the targeting of mRNA has led to a number of studies on the effect of cisplatin treatment on microRNA expression, and the ability of microRNAs to modulate cisplatin resistance.
BLF1, the first Burkholderia pseudomallei toxin, connects inhibition of host protein synthesis with melioidosis
Authors: Hautbergue Guillaume M. , Wilson Stuart A.
Published: July 2012

Melioidosis is a disease caused by infection with Burkholderia pseudomallei. The molecular basis for the pathogenicity of B. pseudomallei is poorly understood. However, recent work has identified the first toxin from this bacterium and shown that it inhibits host protein synthesis. Here, we review the illness that is potentially associated with biological warfare, the pathogen and its deadly molecular mechanism of action, as well as therapeutic developments that may follow.
Quantum dot–nucleic acid/aptamer bioconjugate-based fluorimetric biosensors
Authors: Zhou Dejian
Published: July 2012

Over the last 10 years, fluorescent semiconductor QD (quantum dot)–biomolecule conjugates have emerged as a powerful new sensing platform showing great potential in a wide range of applications in biosensing, environmental monitoring and disease diagnosis. The present mini-review is a brief account of the recent developments in QD–NA (nucleic acid), particularly NA aptamer, conjugate-based biosensors using the FRET (Förster resonance energy transfer) readout mechanism. It starts with a brief introduction to the NA aptamer and QD-FRET, followed by example approaches to compact QD–DNA conjugates, target readout strategies and sensing performance, and concludes with challenges and outlook for the QD–NA/aptamer bioconjugate sensors.
The role of MAPT sequence variation in mechanisms of disease susceptibility
Authors: Caffrey Tara M. , Wade-Martins Richard
Published: July 2012

The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse group of neurodegenerative dementias and movement disorders. The genomic architecture in the region spanning the MAPT locus contains a ~1.8 Mb block of linkage disequilibrium characterized by two major haplotypes: H1 and H2. Recent studies have established strong genetic association between the MAPT locus and neurodegenerative disease and uncovered haplotype-specific differences in expression and alternative splicing of MAPT transcripts. Integrating genetic association data and gene expression data to understand how non-coding genetic variation at a gene locus affects gene expression and leads to susceptibility to disease is a high priority in disease genetics, and the MAPT locus provides an excellent paradigm for this. In the absence of protein-coding changes caused by haplotype sequence variation, altered levels of protein expression or altered ratios of isoform expression are excellent candidate mechanisms to link the MAPT genetic disease association with biological function. The use of novel transgenic and endogenous genetic models are required to understand the role of MAPT sequence variation in mechanisms of disease susceptibility.
Cytoplasmic mRNA 3′ tagging in eukaryotes: does it spell the end?
Authors: Morozov Igor Y. , Caddick Mark X.
Published: July 2012

Although functional RNA is generally protected against degradation, defects or irregularity during RNA biogenesis lead to rapid degradation. Cellular surveillance mechanisms therefore need to distinguish aberrant, erroneous, damaged or aging transcripts from normal RNAs in order to maintain fidelity and control of gene expression. The detection of defects seems to be primarily based on functionality or aberrant rates of a given step in RNA biogenesis, allowing efficient detection of many different errors without recognition of their specific nature. We propose that the addition of non-templated nucleotides to the 3′ end of mRNAs and small non-coding RNAs, 3′ tagging, is the primary means by which malfunctioning RNAs are labelled, promoting their functional repression and degradation. However, the addition of non-templated nucleotides to transcripts can have diverse effects which vary with location, length, substrate and sequence.
Choosing and usingDrosophilamodels to characterize modifiers of Huntington's disease
Authors: Green Edward W. , Giorgini Flaviano
Published: July 2012

HD (Huntington's disease) is a fatal inherited gain-of-function disorder caused by a polyQ (polyglutamine) expansion in the htt (huntingtin protein). Expression of mutant htt in model organisms is sufficient to recapitulate many of the cellular defects found in HD patients. Many groups have independently developed Drosophila models of HD, taking advantage of its rapid life cycle, carefully annotated genome and well-established molecular toolkits. Furthermore, unlike simpler models, Drosophila have a complex nervous system, displaying a range of carefully co-ordinated behaviours which offer an exquisitely sensitive readout of neuronal disruption. Measuring HD-associated changes in behaviour in Drosophila therefore offers a window into the earliest stages of HD, when therapeutic interventions might be particularly effective. The present review describes a number of recently developed Drosophila models of HD and offers practical guidance on the advantages and disadvantages of various experimental approaches that can be used to screen these models for modifiers of mutant htt-mediated toxicity.
Human papillomavirus gene expression is controlled by host cell splicing factors
Authors: Klymenko Tetyana , Graham Sheila V.
Published: July 2012

HPVs (human papillomaviruses) infect stratified epithelia and cause a variety of lesions ranging from benign warts to invasive tumours. The virus life cycle is tightly linked to differentiation of the keratinocyte it infects: papillomaviruses modulate host gene expression to ensure efficient virus replication. For example, the viral transcription factor E2 can directly up-regulate, in an epithelial differentiation-dependent manner, cellular SRSFs [SR (serine/arginine-rich) splicing factors] that control constitutive and alternative splicing. Changes in alternative splicing and the mechanisms controlling this for viral mRNAs have been the subject of intense exploration. However, to date experiments have only been carried out in model systems because the genetic systems suitable for studying alternative splicing of viral RNAs in the context of the virus life cycle are relatively recent and technically challenging. Now using these life cycle-supporting systems, our laboratory has identified SR proteins as important players in differentiation-dependent regulation of HPV gene expression. Better understanding of the role of cellular factors in regulating the virus life cycle is needed as it may help development of novel diagnostic approaches and antiviral therapies in the future.
Nanomechanics of superbugs and superdrugs: new frontiers in nanomedicine
Authors: McKendry Rachel A.
Published: July 2012

The alarming rise in drug-resistant hospital ‘superbugs’ and the associated increase in fatalities is driving the development of technologies to search for new antibiotics and improve disease diagnostics. One of the most successful drug targets is the bacterial cell wall, an evolutionary feature of virtually all prokaryotes and vital for their survival by providing mechanical strength. The recent discovery of bacterial cytoskeletal proteins analogous to the key force-bearing machinery in eukaryotes also provides new opportunities for drug discovery, but little is known about their mechanical role in bacteria. In the present short article, I review recent developments in the field of nanotechnology to investigate the mechanical mechanisms of action of potent antibiotics on cell wall and cytoskeletal targets with unprecedented spatial, temporal and force resolution and the development of a new generation of nanomechanical devices to detect pathogens for point-of-care diagnostics.
The role of mammalian poly(A)-binding proteins in co-ordinating mRNA turnover
Authors: Brook Matthew , Gray Nicola K.
Published: July 2012

The function of cytoplasmic PABPs [poly(A)-binding proteins] in promoting mRNA translation has been intensively studied. However, PABPs also have less clearly defined functions in mRNA turnover including roles in default deadenylation, a major rate-limiting step in mRNA decay, as well as roles in the regulation of mRNA turnover by cis-acting control elements and in the detection of aberrant mRNA transcripts. In the present paper, we review our current understanding of the complex roles of PABP1 in mRNA turnover, focusing on recent progress in mammals and highlighting some of the major questions that remain to be addressed.
Solid-state nanopores for biosensing with submolecular resolution
Authors: Bahrami Azadeh , Doğan Fatma , Japrung Deanpen , Albrecht Tim
Published: July 2012

Biological cell membranes contain various types of ion channels and transmembrane pores in the 1–100 nm range, which are vital for cellular function. Individual channels can be probed electrically, as demonstrated by Neher and Sakmann in 1976 using the patch-clamp technique [Neher and Sakmann (1976) Nature 260, 799–802]. Since the 1990s, this work has inspired the use of protein or solid-state nanopores as inexpensive and ultrafast sensors for the detection of biomolecules, including DNA, RNA and proteins, but with particular focus on DNA sequencing. Solid-state nanopores in particular have the advantage that the pore size can be tailored to the analyte in question and that they can be modified using semi-conductor processing technology. This establishes solid-state nanopores as a new class of single-molecule biosensor devices, in some cases with submolecular resolution. In the present review, we discuss a few of the most important recent developments in this field and how they might be applied to studying protein–protein and protein–DNA interactions or in the context of ultra-fast DNA sequencing.
Tau oligomers and tau toxicity in neurodegenerative disease
Authors: Ward Sarah M. , Himmelstein Diana S. , Lancia Jody K. , Binder Lester I.
Published: July 2012

AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid β-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course analysis and antibody labelling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labelling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the molecular chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease.
Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease
Authors: Royce Simon G. , Sedjahtera Amelia , Samuel Chrishan S. , Tang Mimi L. K.
Published: July 2012

Although CSs (corticosteroids) demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and AHR (airway hyper-responsiveness) despite optimal treatment with these agents, probably due to progressive airway remodelling. Identifying novel therapies that can target airway remodelling and/or airway reactivity may improve symptom control in these patients. We have demonstrated previously that the anti-fibrotic hormone RLN (relaxin) can reverse airway remodelling (epithelial thickening and subepithelial fibrosis) and AHR in a murine model of AAD (allergic airways disease). In the present study, we compared the effects of RLN with a CS (methylprednisolone) on airway remodelling and AHR when administered independently or in combination in the mouse AAD model. Female mice at 6–8 weeks of age were sensitized and challenged to OVA (ovalbumin) over a 9-week period and treated with methylprednisolone, RLN, a combination of both treatments or vehicle controls. Methylprednisolone was administered intraperitoneally on the same day as nebulization for 6 weeks, whereas recombinant human RLN-2 was administered via subcutaneously implanted osmotic mini-pumps from weeks 9–11. RLN or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; whereas RLN but not methylprednisolone significantly decreased epithelial thickness and AHR. Additionally, combination therapy with CS and RLN more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that RLN can modulate a broader range of airway remodelling changes and AHR than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.
Fehlererfassung in Dialyseeinrichtungen – Eine Basisfunktion für Patientensicherheit
Authors: Lückerath Hedi
Published: July 2012

Dass Fehler auch in Dialyseeinrichtungen vorkommen, ist eine Binsenweisheit. Einmal vorgekommen, ist jeder Fehler zunächst ein Einzelfall, der für sich alleine steht. Erst die systematische Fehlererfassung gibt die Möglichkeit, Häufungen, Systematiken, beeinflussende Faktoren oder bisher unbekannte Fehlervarianten zu erkennen. Fehlersammellisten, Reportingsysteme und Beobachtungen von Arbeitsabläufen lassen sich in allen Dialyseeinrichtungen anwenden; sie haben unterschiedliche Zielsetzungen und methodische Grenzen. In Kombination sind die genannten Methoden die Basisfunktion von Patientensicherheit, denn verhindern lassen sich nur bekannte Gefahren.
Therapie des shuntassoziierten Stealsyndroms V – Autologe Proximalisierung ohne Bypass
Authors: Krönung Gerhard
Published: July 2012

Die shunterhaltende Therapie des Stealsyndroms beim Normo-Flow-Shunt ist die Proximalisierung des arteriellen Lecks ohne Erhöhung des Shuntflusses. PAI und DRIL benutzen für die Proximalisierung einen freien autologen/alloplastischen Bypass. Bei einer geeigneten Anatomie mit einem kräftigen Stamm der Vena brachialis kann dieser alternativ erfolgreich als drainierender „In-situ-Bypass“ zur Proximalisierung eingesetzt werden.
Transient Rayleigh-Bénard-Marangoni solutal convection
Authors: Trouette Benoît , Chénier Eric , Doumenc Frédéric , Delcarte Claudine , Guerrier Béatrice
Published: July 2012

Solutal driven flow is studied for a binary solution submitted to solvent evaporation at the upper free surface. Evaporation induces an increase in the solute concentration close to the free surface and solutal gradients may induce a convective flow driven by buoyancy and/or surface tension. This problem is studied numerically, using several assumptions deduced from previous experiments on polymer solutions. The stability of the system is investigated as a function of the solutal Rayleigh and Marangoni numbers, the evaporative flux and the Schmidt number. The sensitivity of the thresholds to initial perturbations is analyzed. The effect of viscosity variation during drying is also investigated. At last numerical simulations are presented to study the competition between buoyancy and Marangoni effects in the nonlinear regime.
Mechanical and piezoresistive properties of thin silicon films deposited by plasma-enhanced chemical vapor deposition and hot-wire chemical vapor deposition at low substrate temperatures
Authors: Gaspar J. , Gualdino A. , Lemke B. , Paul O. , Chu V. , Conde J. P.
Published: July 2012

This paper reports on the mechanical and piezoresistance characterization of hydrogenated amorphous and nanocrystalline silicon thin films deposited by hot-wire chemical vapor deposition (HWCVD) and radio-frequency plasma-enhanced chemical vapor deposition (PECVD) using substrate temperatures between 100 and 250 °C. The microtensile technique is used to determine film properties such as Young’s modulus, fracture strength and Weibull parameters, and linear and quadratic piezoresistance coefficients obtained at large applied stresses. The 95%-confidence interval for the elastic constant of the films characterized, 85.9 ± 0.3 GPa, does not depend significantly on the deposition method or on film structure. In contrast, mean fracture strength values range between 256 ± 8 MPa and 600 ± 32 MPa: nanocrystalline layers are slightly stronger than their amorphous counterparts and a pronounced increase in strength is observed for films deposited using HWCVD when compared to those grown by PECVD. Extracted Weibull moduli are below 10. In terms of piezoresistance, n-doped radio-frequency nanocrystalline silicon films deposited at 250 °C present longitudinal piezoresistive coefficients as large as −(2.57 ± 0.03) × 10−10 Pa−1 with marginally nonlinear response. Such values approach those of crystalline silicon and of polysilicon layers deposited at much higher temperatures.
Interfacial properties of free-standing poly(3-hexylthiophene) films
Authors: Yimer Yeneneh Y. , Dhinojwala Ali , Tsige Mesfin
Published: July 2012

Using full atomistic classical molecular dynamics simulations, the interfacial properties of free-standing poly(3-hexylthiophene) (P3HT) films have been investigated. The orientations of different parts of the P3HT chain and the surface tensions of the films were calculated in a temperature range of 540 K–600 K. At the liquid/vacuum interface, the P3HT chain shows ordering by exposing hexyl groups at the interface, while the chain backbone lays flat with the thiophene ring preferentially tilt toward the surface. At the interface, the terminal methyl groups of hexyl side chains are in excess compared to the methylene groups or thiophene rings. The surface tension of P3HT in its melt state shows similar temperature dependence to that of polymers that have long alkyl side chains. The surface tension values are comparable to those polymers that expose methyl or methylene groups on the surface. The surface tension values determined for the melt state are lower than the experimental reported values for crystalline P3HT films, as expected.
Some algebro-geometric solutions for the coupled modified Kadomtsev-Petviashvili equations arising from the Neumann type systems
Authors: Chen Jinbing
Published: July 2012

A treatment is described for getting some algebro-geometric solutions of the coupled modified Kadomtsev-Petviashvili (cmKP) equations and a hierarchy of 1+1 dimensional integrable nonlinear evolution equations (INLEEs) by using the Neumann type systems through three steps: (i) according to the nonlinearization of Lax pair, the cmKP equations and the 1+1 dimensional INLEEs are reduced to a family of compatible Neumann type systems on a symplectic submanifold, whose involutive solutions give rise to the finite parametric solutions of the INLEEs in both 2+1 and 1+1 dimensions; (ii) from the holomorphic differentials and the Abel map on a hyperelliptic curve of Riemman surface, the Abel-Jacobi variables are introduced to straighten out the Neumann type flows, the 1+1 and 2+1 dimensional flows giving the Abel-Jacobi solutions; (iii) based on the Riemann theorem and the trace formulas, the Jacobi inversion is applied to the straightened flows for getting some new algebro-geometric solutions of the cmKP equations and the 1+1 dimensional integrable hierarchy.
Global rate coefficients for ionization and recombination of carbon, nitrogen, oxygen, and argon
Authors: Annaloro Julien , Morel Vincent , Bultel Arnaud , Omaly Pierre
Published: July 2012

The flow field modeling of planetary entry plasmas, laser-induced plasmas, inductively coupled plasmas, arcjets, etc., requires to use Navier-Stokes codes. The kinetic mechanisms implemented in these codes involve global (effective) rate coefficients. These rate coefficients result from the excited states coupling during a quasi-steady state. In order to obtain these global rate coefficients over a wide electron temperature (Te) range for ionization and recombination of carbon, nitrogen, oxygen, and argon, the behavior of their excited states is investigated using a zero-dimensional (time-dependent) code. The population number densities of these electronic states are considered as independent species. Their relaxation is studied within the range 3000  K≤Te≤20 000  K and leads to the determination of the ionization (ki) and recombination (kr) global rate coefficients. Comparisons with existing data are performed. Finally, the ratio ki/kr is compared with the Saha equilibrium constant. This ratio increases more rapidly than the equilibrium constant for Te>15 000  K.
Effect of stochasticity in mean field dynamo models
Authors: Newton Andrew P. L. , Kim Eun-Jin
Published: July 2012

We present a comprehensive investigation into the effect of choosing the stochastic control parameters in a simplified—Parker dynamo model. Through considering the manifold of marginal stability, i.e., the region of parameter space where the mean growth rate is zero, we show that stochastic fluctuations are not prohibitive to dynamo. Furthermore, by directly comparing results obtained by periodic and Gaussian coloured noise alpha with identical characteristic time-scales and fluctuating amplitudes, we find that the transition to dynamo is significantly eased for stochastically fluctuating alpha. The effect of stochasticity in magnetic diffusion is also investigated, highlighting the importance of resonance between poloidal and toroidal magnetic fields on the growth rate. Furthermore, we show that probability density functions of the growth-rate, magnetic field, and magnetic energy can provide a wealth of useful information regarding the dynamo behaviour/intermittency. Finally, the statistical properties of the dynamo such as temporal correlation and fluctuating amplitude are found to be dependent on the distribution of the fluctuations in stocastic parameters.
Detachment-induced electron production in the early afterglow of pulsed cc-rf oxygen plasmas
Authors: Küllig C. , Dittmann K. , Meichsner J.
Published: July 2012

Line integrated electron densities are measured by 160.28 GHz Gaussian beam microwave interferometry in a 10 Hz pulsed (50% duty cycle) cc-rf oxygen discharge, operating at 13.56 MHz. Depending on the processing parameters, the oxygen rf discharge displays two different operation modes regarding its electronegativity. For higher rf power with negative self-bias voltage above −220 V, the oxygen discharge acts as electropositive plasma (n-/ne≪1), whereas at lower rf power and self-bias voltage the plasma becomes strongly electronegative (n-/ne>2). In the latter mode, a significant electron density increase is measured in the early afterglow (<100 μs) within a pressure range from 20 to 100 Pa. By use of a simple rate equation model, the temporal behavior of the electron density could be reproduced for both modes of electronegativity. The electron production in the early afterglow is mainly caused due to the detachment of negative atomic oxygen ions by metastable oxygen molecules.
Collision of invariant bundles of quasi-periodic attractors in the dissipative standard map
Authors: Calleja Renato , Figueras Jordi-Lluís
Published: July 2012

We perform a numerical study of the breakdown of hyperbolicity of quasi-periodic attractors in the dissipative standard map. In this study, we compute the quasi-periodic attractors together with their stable and tangent bundles. We observe that the loss of normal hyperbolicity comes from the collision of the stable and tangent bundles of the quasi-periodic attractor. We provide numerical evidence that, close to the breakdown, the angle between the invariant bundles has a linear behavior with respect to the perturbing parameter. This linear behavior agrees with the universal asymptotics of the general framework of breakdown of hyperbolic quasi-periodic tori in skew product systems.
Approximating the electrical enhancement effects in a nano-patterned, injection-limited, single-layer organic light-emitting diode
Authors: Fina Michael , Mao Samuel S.
Published: July 2012

Numerical analysis of the electrical effects accompanying nanocolumn patterning at the cathode-organic interface in an injection-limited, single-layer organic light-emitting diode (SLOLED) is conducted. We introduce a carrier-decoupled framework based on the Scott-Malliaras current injection mechanism in the double-sided, injection-limited current regime to simplify the multi-dimensional semiconductor equations in order to analyze the device function in the presence of a periodic nanocolumn array. A semi-analytical treatment is developed to solve the drift-diffusion equations. A common problem in SLOLEDs is unbalanced carrier currents arising from asymmetric injection and transport characteristics. The numerical results for the cathode nanopatterned device predict increased current injection with strongly asymmetrical current enhancement, which is shown to promote carrier injection parity in electron-deficient, single-layer devices by preferentially augmenting cathode-side injection current. Finally, the recombination current enhancement is attained and is shown to be increased by a factor of 8.52 and 3.00 when comparing the nanopatterned SLOLED device with planar devices of thicknesses equal to the unpatterned thickness and nanoimprint-thickness-reduced devices, respectively.
Effects of domain, grain, and magnetic anisotropy distributions on magnetic permeability: Monte-Carlo approach
Authors: Chun Jaehun , Mark Jones A. , McCloy John S.
Published: July 2012

We have investigated the effects of domain and grain anisotropy on spin-resonance in magnetic permeability, implementing a Monte-Carlo approach and a coupled Landau-Lifshitz-Gilbert equation. The Monte-Carlo approach provides great flexibility by employing different probability density functions, allowing modeling of material texture differences that may occur due to different preparation methods. Changes in the permeability tensor result from variations in grain demagnetization and domain demagnetization as well as the anisotropy field relative to saturation magnetization. Experimental permeability measurements on demagnetized polycrystalline yttrium iron garnet show for the first time that the best fit to measured data requires a complex distribution of both grain and domain demagnetization factors. Assuming that grain and domain demagnetizations are decoupled, it was found that the grain structure (i.e., grain demagnetization distribution) has a smaller effect on the frequency-dependent permeability than does the same distribution of domains (i.e., domain demagnetization distribution). Implications for modeling experimental data assuming particular phenomenological loss coefficients or linewidths are also offered.