Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes.

Ergosterol is essential for fungal cell membrane integrity and growth, and numerous antifungal drugs target ergosterol. Inactivation or modification of ergosterol biosynthetic genes can lead to changes in antifungal drug susceptibility, filamentation and stress response. Here, we found that the ergosterol biosynthesis gene ERG251 is a hotspot for point mutations during adaptation to antifungal drug stress within two distinct genetic backgrounds of Candida albicans. Heterozygous point mutations led to single allele dysfunction of ERG251 and resulted in azole tolerance in both genetic backgrounds. This is the first known example of point mutations causing azole tolerance in C. albicans. Importantly, single allele dysfunction of ERG251 in combination with recurrent chromosome aneuploidies resulted in bona fide azole resistance. Homozygous deletions of ERG251 caused increased fitness in low concentrations of fluconazole and decreased fitness in rich medium, especially at low initial cell density. Dysfunction of ERG251 resulted in transcriptional upregulation of the alternate sterol biosynthesis pathway and ZRT2, a Zinc transporter. Notably, we determined that overexpression of ZRT2 is sufficient to increase azole tolerance in C. albicans. Our combined transcriptional and phenotypic analyses revealed the pleiotropic effects of ERG251 on stress responses including cell wall, osmotic and oxidative stress. Interestingly, while loss of either allele of ERG251 resulted in similar antifungal drug responses, we observed functional divergence in filamentation regulation between the two alleles of ERG251 (ERG251-A and ERG251-B) with ERG251-A exhibiting a dominant role in the SC5314 genetic background. Finally, in a murine model of systemic infection, homozygous deletion of ERG251 resulted in decreased virulence while the heterozygous deletion mutants maintain their pathogenicity. Overall, this study provides extensive genetic, transcriptional and phenotypic analysis for the effects of ERG251 on drug susceptibility, fitness, filamentation and stress responses.

Early vs. late enoxaparin for the prevention of venous thromboembolism in patients with ICH: A double blind placebo controlled multicenter study.

BACKROUND: Venous thromboembolism (VTE) after primary intracerebral hemorrhage (ICH) worsens patient prognosis. Administering low-molecular weight heparins (LMWH) to prevent VTE early (24 h) may increase the risk of hematoma enlargement, whereas administering late (72 h) after onset may decrease its effect on VTE prevention. The authors investigated when it is safe and effective to start LMWH in ICH patients. METHODS: In the setting of double blinded, placebo controlled randomization, patients >18 years of age with paretic lower extremity, and admitted to the emergency room within 12 h of the onset of ICH, were randomized into two groups. Patients in the enoxaparin group received 20 mg twice a day 24 h (early) after the onset of ICH and in the placebo group 72 h (late) after onset respectively. Both groups immediately received intermittent pneumatic compression stockings at the ER. Patients were prospectively and routinely screened for VTE and hemorrhagic complications 1 day after entering the study and again before discharge. RESULTS: 139 patients were included for randomization in this study. Only 3 patients developed VTE, 2 in the early enoxaparin group and one in the late enoxaparin group. No patients developed PE. Thromboembolic events (p = 0.901), risk of hematoma enlargement (p = 0.927) and overall outcome (P = 0.904) did not differ significantly between the groups. CONCLUSION: Administering 40 mg/d LMWH for prevention of VTE to a spontaneous ICH patient is safe regardless of whether it is started 24 h (early) or 72 h (late) after the hemorrhage. Risk of hemorrhage enlargement is not associated with early LMWH treatment. Administering LMWH late did not increase VTEs.

A recurrent nova super-remnant in the Andromeda galaxy.

The accretion of hydrogen onto a white dwarf star ignites a classical nova eruption1,2-a thermonuclear runaway in the accumulated envelope of gas, leading to luminosities up to a million times that of the Sun and a high-velocity mass ejection that produces a remnant shell (mainly consisting of insterstellar medium). Close to the upper mass limit of a white dwarf3 (1.4 solar masses), rapid accretion of hydrogen (about 10-7 solar masses per year) from a stellar companion leads to frequent eruptions on timescales of years4,5 to decades6. Such binary systems are known as recurrent novae. The ejecta of recurrent novae, initially moving at velocities of up to 10,000 kilometres per second7, must 'sweep up' the surrounding interstellar medium, creating cavities in space around the nova binary. No remnant larger than one parsec across from any single classical or recurrent nova eruption is known8-10, but thousands of successive recurrent nova eruptions should be capable of generating shells hundreds of parsecs across. Here we report that the most frequently recurring nova, M31N 2008-12a in the Andromeda galaxy (Messier 31 or NGC 224), which erupts annually11, is indeed surrounded by such a super-remnant with a projected size of at least 134 by 90 parsecs. Larger than almost all known remnants of even supernova explosions12, the existence of this shell demonstrates that the nova M31N 2008-12a has erupted with high frequency for millions of years.

Dimethylformamide is a novel nitrilase inducer in Rhodococcus rhodochrous.

Nitrilases are of commercial interest in the selective synthesis of carboxylic acids from nitriles. Nitrilase induction was achieved here in three bacterial strains through the incorporation of a previously unrecognised and inexpensive nitrilase inducer, dimethylformamide (DMF), during cultivation of two Rhodococcus rhodochrous strains (ATCC BAA-870 and PPPPB BD-1780), as well as a closely related organism (Pimelobacter simplex PPPPB BD-1781). Benzonitrile, a known nitrilase inducer, was ineffective in these strains. Biocatalytic product profiling, enzyme inhibition studies and protein sequencing were performed to distinguish the nitrilase activity from that of sequential nitrile hydratase-amidase activity. The expressed enzyme, a 40-kDa protein with high sequence similarity to nitrilase protein Uniprot Q-03217, hydrolyzed 3-cyanopyridine to produce nicotinic acid exclusively in strains BD-1780 and BD-1781. These strains were capable of synthesising both the vitamin nicotinic acid as well as ß-amino acids, a compound class of pharmaceutical interest. The induced nitrilase demonstrated high enantioselectivity (> 99%) in the hydrolysis of 3-amino-3-phenylpropanenitrile to the corresponding carboxylic acid.

Proper-motion age dating of the progeny of Nova Scorpii AD 1437.

'Cataclysmic variables' are binary star systems in which one star of the pair is a white dwarf, and which often generate bright and energetic stellar outbursts. Classical novae are one type of outburst: when the white dwarf accretes enough matter from its companion, the resulting hydrogen-rich atmospheric envelope can host a runaway thermonuclear reaction that generates a rapid brightening. Achieving peak luminosities of up to one million times that of the Sun, all classical novae are recurrent, on timescales of months to millennia. During the century before and after an eruption, the 'novalike' binary systems that give rise to classical novae exhibit high rates of mass transfer to their white dwarfs. Another type of outburst is the dwarf nova: these occur in binaries that have stellar masses and periods indistinguishable from those of novalikes but much lower mass-transfer rates, when accretion-disk instabilities drop matter onto the white dwarfs. The co-existence at the same orbital period of novalike binaries and dwarf novae-which are identical but for their widely varying accretion rates-has been a longstanding puzzle. Here we report the recovery of the binary star underlying the classical nova eruption of 11 March AD 1437 (refs 12, 13), and independently confirm its age by proper-motion dating. We show that, almost 500 years after a classical-nova event, the system exhibited dwarf-nova eruptions. The three other oldest recovered classical novae display nova shells, but lack firm post-eruption ages, and are also dwarf novae at present. We conclude that many old novae become dwarf novae for part of the millennia between successive nova eruptions.

Hydrolysis of nitriles by soil bacteria: variation with soil origin.

AIMS: The aim of this study was to explore bacterial soil diversity for nitrile biocatalysts, in particular, those for hydrolysis of ß-substituted nitriles, to the corresponding carboxamides and acids that may be incorporated into peptidomimetics. To achieve this, we needed to compare the efficiency of isolation methods and determine the influence of land use and geographical origin of the soil sample. METHODS AND RESULTS: Nitrile-utilizing bacteria were isolated from various soil environments across a 1000 km long transect of South Africa, including agricultural soil, a gold mine tailing dam and uncultivated soil. The substrate profile of these isolates was determined through element-limited growth studies on seven different aliphatic or aromatic nitriles. A subset of these organisms expressing broad substrate ranges was evaluated for their ability to hydrolyse ß-substituted nitriles (3-amino-3-phenylpropionitrile and 3-hydroxy-4-phenoxybutyronitrile) and the active organisms were found to be Rhodococcus erythropolis from uncultivated soil and Rhodococcus rhodochrous from agricultural soils. CONCLUSIONS: The capacity for hydrolysis of ß-substituted nitriles appears to reside almost exclusively in Rhodococci. Land use has a much greater effect on the biocatalysis substrate profile than geographical location. SIGNIFICANCE AND IMPACT OF THE STUDY: Enzymes are typically substrate specific in their catalytic reactions, and this means that a wide diversity of enzymes is required to provide a comprehensive biocatalysis toolbox. This paper shows that the microbial diversity of nitrile hydrolysis activity can be targeted according to land utilization. Nitrile biocatalysis is a green chemical method for the enzymatic production of amides and carboxylic acids that has industrial applications, such as in the synthesis of acrylamide and nicotinamide. The biocatalysts discovered in this study may be applied to the synthesis of peptidomimetics which are an important class of therapeutic compounds.

Systematics of molecular self-assembled networks at topological insulators surfaces.

The success of topological insulators (TI) in creating devices with unique functionalities is directly connected to the ability of coupling their helical spin states to well-defined perturbations. However, up to now, TI-based heterostructures always resulted in very disordered interfaces, characterized by strong mesoscopic fluctuations of the chemical potential that make the spin-momentum locking ill-defined over length scales of few nanometers or even completely destroy topological states. These limitations call for the ability to control topological interfaces with atomic precision. Here, we demonstrate that molecular self-assembly processes driven by inherent interactions among the constituents offer the opportunity to create well-defined networks at TIs surfaces. Even more remarkably, we show that the symmetry of the overlayer can be finely controlled by appropriate chemical modifications. By analyzing the influence of the molecules on the TI electronic properties, we rationalize our results in terms of the charge redistribution taking place at the interface. Overall, our approach offers a precise and fast way to produce tailor-made nanoscale surface landscapes. In particular, our findings make organic materials ideal TIs counterparts, because they offer the possibility to chemically tune both electronic and magnetic properties within the same family of molecules, thereby bringing us a significant step closer toward an application of this fascinating class of materials.

Protective and pathological roles of tissue factor in the heart.

UNLABELLED: Tissue factor (TF) is expressed in the heart where it is required for haemostasis. High levels of TF are also expressed in atherosclerotic plaques and likely contribute to atherothrombosis after plaque rupture. Indeed, risk factors for atherothrombosis, such as diabetes, hypercholesterolaemia, smoking and hypertension, are associated with increased TF expression in circulating monocytes, microparticles and plasma. Several therapies that reduce atherothrombosis, such as statins, ACE inhibitors, beta-blockers and anti-platelet drugs, are associated with reduced TF expression. In addition to its haemostatic and pro-thrombotic functions, the TF : FVIIa complex and downstream coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). In mice, deficiencies in either PAR-1 or PAR-2 reduce cardiac remodelling and heart failure after ischaemia-reperfusion injury. This suggests that inhibition of coagulation proteases and PARs may be protective in heart attack patients. In contrast, the TF/thrombin/PAR-1 pathway is beneficial in a mouse model of Coxsackievirus B3-induced viral myocarditis. We found that stimulation of PAR-1 increases the innate immune response by enhancing TLR3-dependent IFN-ß expression. Therefore, inhibition of the TF/thrombin/PAR-1 pathway in patients with viral myocarditis could have detrimental effects. CONCLUSION: The TF : FVIIa complex has both protective and pathological roles in the heart.

Slowly progressive frontotemporal lobar degeneration caused by the C9ORF72 repeat expansion: a 20-year follow-up study.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient's cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.

Probing the electronic properties of individual MnPc molecules coupled to topological states.

Hybrid organic/inorganic interfaces have been widely reported to host emergent properties that go beyond those of their single constituents. Coupling molecules to the recently discovered topological insulators, which possess linearly dispersing and spin-momentum-locked Dirac fermions, may offer a promising platform toward new functionalities. Here, we report a scanning tunneling microscopy and spectroscopy study of the prototypical interface between MnPc molecules and a Bi2Te3 surface. MnPc is found to bind stably to the substrate through its central Mn atom. The adsorption process is only accompanied by a minor charge transfer across the interface, resulting in a moderately n-doped Bi2Te3 surface. More remarkably, topological states remain completely unaffected by the presence of the molecules, as evidenced by the absence of scattering patterns around adsorption sites. Interestingly, we show that, while the HOMO and LUMO orbitals closely resemble those of MnPc in the gas phase, a new hybrid state emerges through interaction with the substrate. Our results pave the way toward hybrid organic-topological insulator heterostructures, which may unveil a broad range of exciting and unknown phenomena.

Combined DaT imaging and olfactory testing for differentiating parkinsonian disorders.

OBJECTIVE: Dopamine transporter (DaT) imaging with single photon emission computed tomography (SPECT) detects loss of striatal dopaminergic innervation with very high sensitivity. It cannot readily distinguish idiopathic Parkinson's disease (iPD) and dementia with Lewy bodies (DLB) from atypical disorders (aPD). However, most iPD/DLB patients are hyposmic, whereas the majority of aPD patients were reported to have intact olfaction. For this reason, we conducted a longitudinal follow-up study to investigate the power of combined DaT imaging and olfactory testing to predict the final diagnosis of the patients. MATERIALS AND METHODS: A total of 129 patients received [123I]FP-CIT SPECT and olfactory testing at baseline assessment. Clinical follow-up 30 ± 12 months later was the diagnostic standard of truth. A normative dataset of 24 healthy controls was used for comparison. RESULTS: Baseline DaT imaging predicted a dopamine-deficient diagnosis with 98% sensitivity and 98% specificity. The combined DaT/olfactory testing correctly classified 91% of patients as iPD/DLB (PPV 91%). The PPV rose to 97% or greater in anosmic patients. In contrast, only 45% of aPD patients were categorised correctly by combined DaT/olfactory testing - mainly because of the presence of normosmic iPD patients. CONCLUSIONS: In patients with an abnormal DaT SPECT, hyposmia yields an a posteriori likelihood of iPD/DLB of > 90%. In contrast, a finding of normosmia only increases the a posteriori likelihood of aPD to approximately the 50%.

Quantum interference mapping of Rashba-split Bloch states in Bi/Ag(111).

We report on low-temperature scanning tunneling spectroscopy investigations of the (sqrt[3]×sqrt[3]) Bi/Ag(111)R30° surface alloy which provides a giant Rashba-type spin splitting. We observed spectroscopic features that are assigned to two Rashba-split bands. Quantum interference mapping shows that backscattering is not only allowed below but also above the Rashba energy. We argue that the observed behavior can be understood within the Bloch picture where k refers to the crystal momentum and the velocity of an electronic state is defined as v(n)(E) = 1/ℏ ∇(k)E(n)(k). The analysis of the energy dispersion of scattering channels reveals a conventional Rashba splitting for the unoccupied Rashba bands, while hybridization is observed in the occupied states.

Combining scanning tunneling microscopy and synchrotron radiation for high-resolution imaging and spectroscopy with chemical, electronic, and magnetic contrast.

The combination of high-brilliance synchrotron radiation with scanning tunneling microscopy opens the path to high-resolution imaging with chemical, electronic, and magnetic contrast. Here, the design and experimental results of an in-situ synchrotron enhanced x-ray scanning tunneling microscope (SXSTM) system are presented. The system is designed to allow monochromatic synchrotron radiation to enter the chamber, illuminating the sample with x-ray radiation, while an insulator-coated tip (metallic tip apex open for tunneling, electron collection) is scanned over the surface. A unique feature of the SXSTM is the STM mount assembly, designed with a two free-flex pivot, providing an angular degree of freedom for the alignment of the tip and sample with respect to the incoming x-ray beam. The system designed successfully demonstrates the ability to resolve atomic-scale corrugations. In addition, experiments with synchrotron x-ray radiation validate the SXSTM system as an accurate analysis technique for the study of local magnetic and chemical properties on sample surfaces. The SXSTM system's capabilities have the potential to broaden and deepen the general understanding of surface phenomena by adding elemental contrast to the high-resolution of STM.

Imaging findings and accuracy of core needle biopsy in mucinous carcinoma of the breast.

BACKGROUND: Diagnosis of mucinous carcinoma can be difficult due to its benign appearance on mammograms and ultrasonographic (US) images. In the light of the rather scarce literature, core needle biopsy (CNB) has proved useful in diagnosing mucinous lesions. PURPOSE: To assess mammographic, US, and CNB findings of mucinous breast tumors and to correlate them with final histology obtained in therapeutic surgery. MATERIAL AND METHODS: From 2000-2006, 25 mucinous carcinomas detected with CNB were surgically removed. The mammography, US, and CNB results were analyzed and correlated with final histology. RESULTS: Ninety-six percent of the mucinous carcinomas (24/25) were visible with US. All except two of the 24 tumors were solid masses. All the mixed-type lesions (group 2) were hypoechoic and had irregular or lobulated margins and heterogeous internal echotexture. The US features were more variable among the 14 pure mucinous carcinomas (group 1) and the six US visible mucinous carcinomas with cancerous cells outside the tumor (group 3). Fifty-seven percent of group 1 and 50% of group 3 tumors had clearly lobulated or irregular margins. Fifty-seven percent of group 1 and 67% of group 3 cancers were hypoechoic. A vast majority of these tumors had heterogenous echotexture. Seventy-one percent (17/24) of the lesions visible with US had posterior acoustic enhancement. Eighty percent (20/25) of the mucinous carcinomas were classified as BI-RADS 4 lesions in US. All the lesions with images available were visible on mammograms, where most of the tumors were seen as a high-density circumscribed lesion and classified as BI-RADS 4 lesions, while none were classified as BI-RADS 1, 2 or 5. The sensitivity and positive predictive value of CNB regarding mucinous carcinoma was 100%. CONCLUSION: CNB was found to be a highly reliable diagnostic tool for diagnosing mucinous carcinoma in this selected material. US findings of pure mucinous carcinoma were variable, however, all reached BI-RADS 4 category. The presence of posterior acoustic enhancement beneath a solid breast lesion should raise suspicion of mucinous carcinoma. Most of the tumors appeared as BI-RADS 4 lesions in US and in mammography thus making both a useful tool for raising a suspicion of malignancy in mucinous cancers.

Polarization-modulated rectification at ferroelectric surfaces.

By correlating room temperature conductive atomic force microscopy with low temperature electrostatic force microscopy images of the same sample region, we demonstrate that nanoscale electric conduction between a sharp tip and the surface of ferroelectric HoMnO3 is intrinsically modulated by the polarization of ferroelectric domains. Conductance spectra reveal that the electric conduction is described by polarization-induced Schottky-like rectification at low bias, but dominated by a space-charge limited conduction mechanism at high bias. Our observation demonstrates visualization of ferroelectric domain structure by electric conduction, which may be used for nondestructive readout of nanoscale ferroelectric memories and/or ferroelectric sensors.

Phenotype-environment mismatches reduce connectivity in the sea.

The connectivity of marine populations is often surprisingly lower than predicted by the dispersal capabilities of propagules alone. Estimates of connectivity, moreover, do not always scale with distance and are sometimes counterintuitive. Population connectivity requires more than just the simple exchange of settlers among populations: it also requires the successful establishment and reproduction of exogenous colonizers. Marine organisms often disperse over large spatial scales, encountering very different environments and suffering extremely high levels of post-colonization mortality. Given the growing evidence that such selection pressures often vary over spatial scales that are much smaller than those of dispersal, we argue that selection will bias survival against exogenous colonizers. We call this selection against exogenous colonizers a phenotype-environment mismatch and argue that phenotype-environment mismatches represent an important barrier to connectivity in the sea. Crucially, these mismatches may operate independently of distance and thereby have the potential to explain the counterintuitive patterns of connectivity often seen in marine environments. We discuss how such mismatches might alter our understanding and management of marine populations.

Temperature and size dependence of antiferromagnetism in mn nanostructures.

We report on variable-temperature STM investigations of the spontaneous long-range magnetic order of Mn monolayer nanostructures epitaxially grown on stepped W(110). The measurements reveal that the onset of the antiferromagnetic order is closely related to the Mn nanostructure width along the [001] direction, with a decreasing Néel temperature as we move from a 2D toward a quasi-1D system. In contrast, lateral confinement along the [110] direction seems to play a less important role. The results are discussed in terms of anisotropic exchange coupling and of boundary effects, both potentially stabilizing long-range magnetic order in nanostructures confined in the [110] direction.

Magnetization reversal of nanoscale islands: how size and shape affect the arrhenius prefactor.

The thermal switching behavior of individual in-plane magnetized Fe/W(110) nanoislands is investigated by a combined study of variable-temperature spin-polarized scanning tunneling microscopy and Monte Carlo simulations. Even for islands consisting of less than 100 atoms the magnetization reversal takes place via nucleation and propagation. The Arrhenius prefactor is found to strongly depend on the individual island size and shape, and based on the experimental results a simple model is developed to describe the magnetization reversal in terms of metastable states. Complementary Monte Carlo simulations confirm the model and provide new insight into the microscopic processes involved in magnetization reversal of smallest nanomagnets.

Ultrasonography-guided core needle biopsy in differential diagnosis of papillary breast tumors.

BACKGROUND: Papillary lesions of the breast are considered diagnostically challenging for various reasons. A relatively high malignancy rate in final pathological analysis has in many cases necessitated excision of these lesions, regardless of core needle biopsy (CNB). PURPOSE: To assess mammographic, sonographic, and CNB findings of papillary lesions, and to correlate them with final histology obtained by surgical excision. MATERIAL AND METHODS: From 2000-2006, 29 benign and 19 malignant papillary tumors examined with CNB were surgically removed. Mammographic, sonographic, and CNB results were analyzed and correlated with final histology. RESULTS: On ultrasonography (US), 69% (20/29) of the benign lesions were solid and 31% (9/29) were cystic, and 47% of the malignant lesions (9/19) were solid and 53% (10/19) were cystic. The mammographic findings were nonspecific, although most of the malignant tumors (67%, 12/18) were categorized as BI-RADS 4 lesions. The sensitivity, specificity, and positive predictive value of the core needle biopsy histology was 32% (6/19), 100% (29/29), and 100% (6/6), respectively, for papillary carcinoma. A negative predictive value of 91% (21/23) for malignancy and 48% (11/23) for either atypia or malignancy was shown. Of the lesions with CNB diagnosis of benign papillary lesion with atypia, 58% (11/19) turned out to be malignant and 11% (2/19) were benign on surgery. CONCLUSION: The probability of malignancy is low when the CNB result shows a benign papillary lesion with no atypia. However, the only way to reliably diagnose atypical papillary lesions is to surgically remove all papillary tumors, irrespective of the CNB result. Differentiation between benign and malignant lesions or malignant noninvasive and invasive tumors is not possible based on sonographic or mammographic appearance.

[Perianal fistulas in Crohn's disease--biologicals and surgery: is it worthwhile?]. / Perianales Fistelleiden bei Morbus Crohn - Biologika und Chirurgie: Ein lohnendes Konzept?

Perianal fistulas and abscesses are a common manifestation in Crohn's disease (CD), seen in about 30 - 40 % of the patients. Often they are combined with CD of the anal canal and occur as a complex system of fistulas. The evaluation of these fistulas can be done with endoscopic ultrasound or magnetic resonance imaging, the conceptual accuracy of both methods is high. There are accepted therapeutic concepts for surgery and for the conventional drug therapy according to the classification of the fistulas. In contrast, the therapeutic regimens for a complex perianal fistulising CD are not convincing, especially not for maintainance therapy. However, several studies about therapy with anti-TNF-alpha antibodies have shown good results while long-time results with other recent anti-TNF-alpha antibodies apart from infliximab are still lacking. In this review article we analyse the current literature and develop a stage-adapted therapy for the use of biologicals and surgery in fistulising perianal CD.