Ubiquitous formation of bulk Dirac cones and topological surface states from a single orbital manifold in transition-metal dichalcogenides.

Transition-metal dichalcogenides (TMDs) are renowned for their rich and varied bulk properties, while their single-layer variants have become one of the most prominent examples of two-dimensional materials beyond graphene. Their disparate ground states largely depend on transition metal d-electron-derived electronic states, on which the vast majority of attention has been concentrated to date. Here, we focus on the chalcogen-derived states. From density-functional theory calculations together with spin- and angle-resolved photoemission, we find that these generically host a co-existence of type-I and type-II three-dimensional bulk Dirac fermions as well as ladders of topological surface states and surface resonances. We demonstrate how these naturally arise within a single p-orbital manifold as a general consequence of a trigonal crystal field, and as such can be expected across a large number of compounds. Already, we demonstrate their existence in six separate TMDs, opening routes to tune, and ultimately exploit, their topological physics.

Fermiology and Superconductivity of Topological Surface States in PdTe_{2}.

We study the low-energy surface electronic structure of the transition-metal dichalcogenide superconductor PdTe_{2} by spin- and angle-resolved photoemission, scanning tunneling microscopy, and density-functional theory-based supercell calculations. Comparing PdTe_{2} with its sister compound PtSe_{2}, we demonstrate how enhanced interlayer hopping in the Te-based material drives a band inversion within the antibonding p-orbital manifold well above the Fermi level. We show how this mediates spin-polarized topological surface states which form rich multivalley Fermi surfaces with complex spin textures. Scanning tunneling spectroscopy reveals type-II superconductivity at the surface, and moreover shows no evidence for an unconventional component of its superconducting order parameter, despite the presence of topological surface states.

Cerebrospinal fluid biomarkers of neurodegeneration in patients with juvenile and classic myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of ß-amyloid (Aß42 ) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients. METHODS: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aß42. RESULTS: The CSF level of Aß42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aß42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aß42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aß42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aß42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing. CONCLUSION: The CSF level of Aß42 was decreased in patients with jDM1, whilst the Aß42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aß42 , T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary.

Characteristics of local recurrence of lung cancer and possibilities for surgical management.

PURPOSE: To investigate the correlation between stage and histopathological characteristics of patients with lung cancer and local recurrence, as well as the incidence and the characteristics of local recurrence along with the possibility of surgical retreatment. METHODS: Studied were 51 patients with locally relapsing lung cancer, initially treated surgically from 2003 to 2007. The operations performed ranged from conservative wedge resections, standard lobectomies and pneumonectomies to extensive resections of the entire lung and chest wall. All patients underwent regular follow-up including thoracic CT scan every 3 months. RESULTS: All patients were diagnosed with local recurrence after a median of 10 months (range 1-30) after primary surgery with curative intent. There was no statistically significant link between type of surgery and time to local recurrence. Patients with pathological stage I,II, and IIIa had a significantly longer time to local recurrence than those with stage IIIb and IV. Local recurrence sites were the bronchial stump, mediastinal lymph nodes, the remaining lung parenchyma, chest wall and a combination of these. Surgical retreatment was possible in 20 of 51 patients (39.27percnt;). Chest wall was the commonest localization (20 of 51; 39.2%), also the most frequent in the group of surgically retreated patients (13 of 20; 65%). Squamous cell cancer (SCC) was the predominant histological type (38 of 51; 74.5%), followed by adenocarcinoma (9 of 51; 17.7%). CONCLUSION: SCC is the commonest locally relapsing lung cancer. The type of the initial surgical procedure didn't have any impact on the incidence of local recurrence, but the extent and completeness of surgery did. The time to local recurrence heavily depended on the primary tumor pathological stage. Chest wall was the commonest relapse site, and the most suitable for surgical retreatment, which was related to the quality of surgery.

A spatially resolved optical method to measure thermal diffusivity.

We describe an optical method to directly measure the position-dependent thermal diffusivity of reflective single crystal samples across a broad range of temperatures for condensed matter physics research. Two laser beams are used, one as a source to locally modulate the sample temperature, and the other as a probe of sample reflectivity, which is a function of the modulated temperature. Thermal diffusivity is obtained from the phase delay between source and probe signals. We combine this technique with a microscope setup in an optical cryostat, in which the sample is placed on a three-axis piezo-stage, allowing for spatially resolved measurements. Furthermore, we demonstrate experimentally and mathematically that isotropic in-plane diffusivity can be obtained when overlapping the two laser beams instead of separating them in the traditional way, which further enhances the spatial resolution to a micron scale, especially valuable when studying inhomogeneous or multidomain samples. We discuss in detail the experimental conditions under which this technique is valuable and demonstrate its performance on two stoichiometric bilayer ruthenates: Sr3Ru2O7 and Ca3Ru2O7. The spatial resolution allowed us to study the diffusivity in single domains of the latter, and we uncovered a temperature-dependent in-plane diffusivity anisotropy. Finally, we used the enhanced spatial resolution enabled by overlapping the two beams to measure the temperature-dependent diffusivity of Ti-doped Ca3Ru2O7, which exhibits a metal-insulator transition. We observed large variations of transition temperature over the same sample, originating from doping inhomogeneity and pointing to the power of spatially resolved techniques in accessing inherent properties.

Tomographic mapping of the hidden dimension in quasi-particle interference.

Quasiparticle interference (QPI) imaging is well established to study the low-energy electronic structure in strongly correlated electron materials with unrivalled energy resolution. Yet, being a surface-sensitive technique, the interpretation of QPI only works well for anisotropic materials, where the dispersion in the direction perpendicular to the surface can be neglected and the quasiparticle interference is dominated by a quasi-2D electronic structure. Here, we explore QPI imaging of galena, a material with an electronic structure that does not exhibit pronounced anisotropy. We find that the quasiparticle interference signal is dominated by scattering vectors which are parallel to the surface plane however originate from bias-dependent cuts of the 3D electronic structure. We develop a formalism for the theoretical description of the QPI signal and demonstrate how this quasiparticle tomography can be used to obtain information about the 3D electronic structure and orbital character of the bands.

Probing spin correlations using angle-resolved photoemission in a coupled metallic/Mott insulator system.

A nearly free electron metal and a Mott insulating state can be thought of as opposite ends of the spectrum of possibilities for the motion of electrons in a solid. Understanding their interaction lies at the heart of the correlated electron problem. In the magnetic oxide metal PdCrO2, nearly free and Mott-localized electrons exist in alternating layers, forming natural heterostructures. Using angle-resolved photoemission spectroscopy, quantitatively supported by a strong coupling analysis, we show that the coupling between these layers leads to an "intertwined" excitation that is a convolution of the charge spectrum of the metallic layer and the spin susceptibility of the Mott layer. Our findings establish PdCrO2 as a model system in which to probe Kondo lattice physics and also open new routes to use the a priori nonmagnetic probe of photoemission to gain insights into the spin susceptibility of correlated electron materials.

Membrane fusion mediated by baculovirus gp64 involves assembly of stable gp64 trimers into multiprotein aggregates.

The baculovirus fusogenic activity depends on the low pH conformation of virally-encoded trimeric glycoprotein, gp64. We used two experimental approaches to investigate whether monomers, trimers, and/or higher order oligomers are functionally involved in gp64 fusion machine. First, dithiothreitol (DTT)- based reduction of intersubunit disulfides was found to reversibly inhibit fusion, as assayed by fluorescent probe redistribution between gp64-expressing and target cells (i.e., erythrocytes or Sf9 cells). This inhibition correlates with disappearance of gp64 trimers and appearance of dimers and monomers in SDS-PAGE. Thus, stable (i.e., with intact intersubunit disulfides) gp64 trimers, rather than independent monomers, drive fusion. Second, we established that merger of membranes is preceded by formation of large (greater than 2 MDa), short-lived gp64 complexes. These complexes were stabilized by cell-surface cross-linking and characterized by glycerol density gradient ultracentrifugation. The basic structural unit of the complexes is stable gp64 trimer. Although DTT-destabilized trimers were still capable of assuming the low pH conformation, they failed to form multimeric complexes. The fact that formation of these complexes correlated with fusion in timing, and was dependent on (a) low pH application, (b) stable gp64 trimers, and (c) cell-cell contacts, suggests that such multimeric complexes represent a fusion machine.

Synchronized activation and refolding of influenza hemagglutinin in multimeric fusion machines.

At the time of fusion, membranes are packed with fusogenic proteins. Do adjacent individual proteins interact with each other in the plane of the membrane? Or does each of these proteins serve as an independent fusion machine? Here we report that the low pH-triggered transition between the initial and final conformations of a prototype fusogenic protein, influenza hemagglutinin (HA), involves a preserved interaction between individual HAs. Although the HAs of subtypes H3 and H2 show notably different degrees of activation, for both, the percentage of low pH-activated HA increased with higher surface density of HA, indicating positive cooperativity. We propose that a concerted activation of HAs, together with the resultant synchronized release of their conformational energy, is an example of a general strategy of coordination in biological design, crucial for the functioning of multiprotein fusion machines.

Weyl-like points from band inversions of spin-polarised surface states in NbGeSb.

Band inversions are key to stabilising a variety of novel electronic states in solids, from topological surface states to the formation of symmetry-protected three-dimensional Dirac and Weyl points and nodal-line semimetals. Here, we create a band inversion not of bulk states, but rather between manifolds of surface states. We realise this by aliovalent substitution of Nb for Zr and Sb for S in the ZrSiS family of nonsymmorphic semimetals. Using angle-resolved photoemission and density-functional theory, we show how two pairs of surface states, known from ZrSiS, are driven to intersect each other near the Fermi level in NbGeSb, and to develop pronounced spin splittings. We demonstrate how mirror symmetry leads to protected crossing points in the resulting spin-orbital entangled surface band structure, thereby stabilising surface state analogues of three-dimensional Weyl points. More generally, our observations suggest new opportunities for engineering topologically and symmetry-protected states via band inversions of surface states.

Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in vitro by anticancer drugs.

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.

Human fetal islet transplantation in type 1 diabetics: comparison of immunological effects between multiple implantation regimens.

Previous studies have suggested that the multiple transplants might be equally metabolically efficient to a single regimen for human adult islets. The aim of this study was to compare immunological and metabolic parameters after each of the two regimens of human fetal islets (HFI). Group A single transplants (n = 9) had 180 +/- 20 x 1000 HFI equivalents (IEQs) implanted via a single intramuscular injection. In group B multiple transplants (n = 8) islets were implanted by three consecutive injections of 60 +/- 10 x 1000 IEQs at 7-day intervals. We analyzed the immunological parameters of CD4/CD8 T lymphocyte ratios; islet cell antibodies (ICAs) and insulin antibodies (IAs). We estimated insulin secreting capacity (ISC) as the metabolic parameter. We observed that the CD4+/CD8+ T-cell ratio increased, peaking on day 90, in similar fashion in both groups: day -1: A = 1.18 +/- 0.03 versus B = 1.19 +/- 0.04; on day 90: A = 1.79 +/- 0.09, versus B = 1.75 +/- 0.08 (P = NS) immediately before the decrease in C-peptide levels. Thereafter the ratios rapidly decreased without statistical differences. The levels of ICAs did not change. The levels of IAs, which were increased before transplant, then decreased without statistical differences between the groups. The values of ISC increased after transplant and then decreased similar to the T-cell ratio. Our results demonstrated that regimens of multiple and single HFIs did not show differences in the kinetics of the immunological response presumably mediating graft destruction. The CD4/CD8 ratio increased as the C-peptide level decreased, peaking on day 90 at the time of a decrease in C-peptide. These results may be useful for clinical studies of HFIs for type 1 diabetic patients.

The characteristics of nucleobase transport and metabolism by the perfused sheep choroid plexus.

The uptake of nucleobases was investigated across the basolateral membrane of the sheep choroid plexus perfused in situ. The maximal uptake (U(max)) for hypoxanthine and adenine, was 35.51+/-1.50% and 30.71+/-0.49% and for guanine, thymine and uracil was 12.00+/-0.53%, 13.07+/-0.48% and 12.30+/-0.55%, respectively with a negligible backflux, except for that of thymine (35.11+/-5.37% of the U(max)). HPLC analysis revealed that the purine nucleobase hypoxanthine and the pyrimidine nucleobase thymine can pass intact through the choroid plexus and enter the cerebrospinal fluid CSF so the lack of backflux for hypoxanthine was not a result of metabolic trapping in the cell. Competition studies revealed that hypoxanthine, adenine and thymine shared the same transport system, while guanine and uracil were transported by a separate mechanism and that nucleosides can partially share the same transporter. HPLC analysis of sheep CSF collected in vivo revealed only two nucleobases were present adenine and hypoxanthine; with an R(CSF/Plasma) 0.19+/-0.02 and 3.43+/-0.20, respectively. Xanthine and urate, the final products of purine catabolism, could not be detected in the CSF even in trace amounts. These results suggest that the activity of xanthine oxidase in the brain of the sheep is very low so the metabolic degradation of purines is carried out only as far as hypoxanthine which then accumulates in the CSF. In conclusion, the presence of saturable transport systems for nucleobases at the basolateral membrane of the choroidal epithelium was demonstrated, which could be important for the distribution of the salvageable nucleobases, adenine and hypoxanthine in the central nervous system.

The characteristics of basolateral nucleoside transport in the perfused sheep choroid plexus and the effect of nitric oxide inhibition on these processes.

The single pass paired dilution technique was used to measure the uptake of nucleosides across the basolateral face of the isolated in situ perfused sheep choroid plexus (CP). The uptake of labelled adenosine and guanosine into the CP was large (approximately 35%) whereas that of thymidine was less (approximately 15%). The addition of 0.5 mM unlabelled adenosine to the perfusate inhibited the uptake of labelled adenosine by 66%, guanosine by 100% and that of thymidine by 50%, whereas the addition of 0.5 mM unlabelled thymidine caused complete self-inhibition. The backflux of adenosine was very small which may indicate a high rate of cellular metabolism or a flux into cerebrospinal fluid (CSF). The addition of 0.5 mM unlabelled adenosine did not alter the backflux of adenosine, but increased that of guanosine and thymidine. The entry of radioactivity derived from adenosine across the apical side of the CP cells into the newly formed CSF was determined as a 'CSF uptake index' relative to [14C]butanol and found to be about 25%; however, HPLC analysis revealed that the majority of this activity was hypoxanthine, and not adenosine. The complete inhibition of nitric oxide synthase caused a significant reduction in adenosine uptake into the CP and an increase in backflux for this molecule. It would appear that the uptake for adenosine by the CP is governed by the rate of cellular metabolism and not by the rate of transport into the cells of the choroid plexus whereas for guanosine and thymidine, transport is of greater importance.

Tiazofurine uptake by the isolated guinea pig heart.

Tiazofurine is a selective inhibitor of the enzyme inosine monophosphate dehydrogenase, and exhibits potent antitumor activity. Considering the potential side effects on the heart, [3H] tiazofurine uptake into the cardiomyocytes, as well as the mechanism of transport, were studied in the isolated perfused guinea pig heart, using the rapid single circulation, paired-tracer technique. The maximal cellular uptake (Umax) of [3H] tiazofurine ranged from 19% to 25% of the injected dose, with total cellular uptake (Utot) ranging 12.1-15.6%. The addition of unlabeled tiazofurine caused inhibition of [3H] tiazofurine uptake, with a Umax value of 9.06 +/- 4.6%. Therefore, the uptake of tiazofurine into cardiomyocytes could be considered a saturable process. The inhibition of [3H] tiazofurine uptake caused by adenosine and dipyridamole was of the same degree as the inhibition by unlabeled tiazofurine. Thus, it can be assumed that nucleosides' transport system(s) are involved in transport of tiazofurine into myocardial cells.

Human fetal islet transplantation in type 1 diabetic patients: comparison of metabolic effects between single and multiple implantation regimens.

Previous studies suggest that multiple transplantations might be equally efficient to a single regimen for human adult islets. The aim of this study was to compare metabolic parameters after each of the two regimens of human fetal islet (HFI) transplantation in type 1 diabetics. In group A (single transplant, n = 9), 180 +/- 20 x 1000 HFI equivalents (IEQs) were implanted by a single IM injection; in group B (multiple transplants, n = 8) islets were implanted as three consecutive injections (60 +/- 10 x 1000 IEQs) at 7-day intervals. We analyzed the metabolic parameters on days -1, 30, 60, 90, 120, 150, and 180 after the procedure. Among the metabolic parameters, we evaluated insulin secretion capacity-ISC (C peptide, RIA), metabolic control (HbA1c, chromatography), and insulin daily dose IDD. We found that C peptide levels increased, peaking on day 90 (A: 0.38 +/- 0.15; B: 0.34 +/- 0.19 nmol/L, P = NS) and then rapidly decreasing without differences, the HbA1c levels and IDD decreased in the same manner without differences between the groups. Our results demonstrate that multiple and single islet transplant regimens are equally efficient to temporarily restore a significant ISC with improvement of metabolic and clinical parameters. The results imply that the two regimens have an equal clinical value.

Penetration of [3H] tiazofurin into guinea pig eye by a saturable mechanism.

This study investigated the transport of tiazofurin (2-beta-D-ribofuranosyl thiazole-4-carboxamide) across the blood-aqueous humor barrier, using the vascular perfusion method in the guinea pig. Volume of distribution (Vd) of [3H] tiazofurin increased almost linearly in time, from 4% of its plasma concentration at 3 min to 10% after 12 min of perfusion. Unidirectional transport constant, K(in) was 7.01 +/- 1.06 x 10(-3) ml/min/g. These results indicate that tiazofurin penetrates the aqueous humor to a considerable extent. Addition of unlabelled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labelled tiazofurin (K(in) = 2.60 +/- 0.91 x 10(-3) ml/min/g). Therefore, penetration of tiazofurin from blood into aqueous humor seems to be a saturable process with a diffusional component that cannot be disregarded. Such findings could be of considerable importance since this molecule is known to affect tissue metabolism.

The kinetics of tiazofurin uptake by the isolated perfused choroid plexus of the sheep.

Tiazofurin (TZF-beta-D-ribofuronosyl thiazole-4-carboxamide, NSC-286193) is a synthetic nucleoside analog with potent antitumor activity. Isolated choroid plexuses (CP) of sheep were perfused in situ and the uptake of [3H]-tiazofurin was determined in relation to the recovery of [14C]-mannitol by means of the paired indicator dilution technique. The maximal uptake of tiazofurin was 8.29 +/- 0.84% and was shown to be both carrier-mediated, sodium-dependent and inhibited by adenosine which suggests that it uses the carrier for endogenous nucleosides. However, the total tiazofurin uptake into the choroid plexus was negligible (0.93 +/- 1.97%) as a result of a high backflux, indicating that tiazofurin is not trapped within the cells of the CP to any significant degree. The kinetics for the uptake into the CP were more favorable than for its passage across the blood-brain barrier with a Km of 7.71 +/- 1.42 microM, a Vmax of 1.30 +/- 0.05 microM/min/g and a negligible constant of a free diffusion (Kd) which suggests that the CP/CSF route may act as an alternative pathway into the brain.

Slow penetration of [3H] tiazofurin into guinea pig brain by a saturable mechanism.

The aim of this study was to investigate the transport of tiazofurin (2-beta-D-ribofuranosyl thiazole-4-carboxamide) across the blood-brain barrier (BBB) using brain vascular perfusion and capillary depletion method in the guinea pig. Values for volume of distribution of [3H] tiazofurin in brain increased slowly and almost linearly in time, from 1% of its plasma concentration at 1 min to 5% after 15 min of perfusion. Unidirectional transport constant Kin was 2.61 +/- 0.21 x 10(-3) ml/min/g. According to these results, it is evident that tiazofurin slowly penetrates the BBB. Addition of unlabeled tiazofurin to the perfusing medium caused a significant decrease in the uptake of [3H] labeled tiazofurin (Kin = 0.77 +/- 0.1 x 10(-3) ml/min/g). Therefore, penetration of tiazofurin from blood into brain seems to be a saturable process. Presence of potential inhibitors of tiazofurin blood-to-brain transport (adenosine and dipyridamole) did not cause complete inhibition of tiazofurin brain uptake. Thus, it could be assumed that transport of tiazofurin from blood into brain is only partially mediated by the nucleosides transport system. The results obtained using capillary depletion method show that tiazofurin that passes across the BBB is accumulated mostly in the brain tissue and not in brain capillaries endothelial cells.