Spin-Dependent ππ

We present a detailed analysis of the electronic properties of graphene/Eu/Ni(111). By using angle- and spin-resolved photoemission spectroscopy and ab initio calculations, we show that the intercalation of Eu in the graphene/Ni(111) interface gives rise to a gapped freestanding dispersion of the ππ^{*} Dirac cones at the K[over ¯] point with an additional lifting of the spin degeneracy due to the mixing of graphene and Eu states. The interaction with the magnetic substrate results in a large spin-dependent gap in the Dirac cones with a topological nature characterized by a large Berry curvature and a spin-polarized Van Hove singularity, whose closeness to the Fermi level gives rise to a polaronic band.

How long does it take to diagnose young-onset dementia? A comparison with late-onset dementia.

INTRODUCTION: Dementia occurring in young people may be difficult to recognize. We compared the time to diagnosis between young- (YOD, age < 65) and late-onset dementia (LOD). METHODS: Time between the onset of symptoms and the diagnosis was measured in YOD and LOD patients consecutively seen in a cognitive neurology clinic. Multivariable regression analyses were performed to identify determinants of time to diagnosis. RESULTS: Mean time to diagnosis in 95 YOD patients was 11.2 months longer than in 73 LOD patients (p = 0.022). The delay was driven by a longer time taken by YOD patients to be seen in the specialist centre, which in turn was related to the presence of language disturbances and coexisting depression. DISCUSSION: Young people take longer than elderly people to receive a dementia diagnosis because they take longer to be referred to dementia specialist centres. More awareness on YOD is needed in primary care and the public.

New insights into vitamin D regulation: is there a role for alkaline phosphatase?

PURPOSE: The diagnosis of vitamin D deficiency is based on the determination of total plasma 25-hydroxyvitamin D (25-OHD) concentrations, but the regulation of vitamin D 25-hydroxylation is not a major consideration and very little information is available on this activity. To check what factors could interfere with the activity of vitamin D-25-hydroxylase and thus alter the 25-OHD concentrations, we looked for potential correlations between 25-OHD and results of liver function tests in healthy adults. METHODS: This single-centre study was retrospective and consisted of evaluating the correlations between 25-OHD and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and bone alkaline phosphatase (BALP) in 349 healthy subjects aged from 18 to 65 years. In particular, in Group 1 (n = 119), we looked for correlations between 25OHD and all liver function tests and in Group 2 (n = 230) the correlation between 25OHD and BALP. RESULTS: In Group 1, we found no correlation between 25OHD and AST (r = - 0.03; p = 0.8), ALT (r = - 0.02; p = 0.91), GGT (r = - 0.08; p = 0.68), direct bilirubin (r = - 0.02; p = 0.89), indirect bilirubin (r = - 0.24; p = 0.21), and total bilirubin (r = - 0.24; p = 0.21) but one between 25OHD and ALP (r = - 0.2; p = 0.007); in Group 2, we found a significant negative correlation between 25-OHD and BALP (r = - 0.2; p = 0.0008). CONCLUSIONS: The correlations that we found suggest that ALP and BALP might be involved in the regulation of vitamin D-25-hydroxylase activity, but further studies are mandatory to confirm our assumptions.

3D printing in the design of pharmaceutical dosage forms.

Three-dimensional (3D) printing technologies are manufacturing approaches with widespread use in industry (e.g. automotive, automobile, pharmaceutical industries). With regard to its use in pharmaceutical industry, 3D printing is demonstrating to be of added value attributed to the possibility of printing tailored pharmaceutical products, namely personalized medical devices, such as implants and other dosage forms. However, with the approval of the first 3D-printed drug-product in 2015, a new perspective has arisen, i.e. the use of this technology to produce solid oral dosage forms exhibiting complex drug release profiles and allowing for individual dosing. Technological hurdles and regulatory issues still have to be overcome before this technology can truly find its place in the healthcare sector, where it can certainly contribute to a personalized and patient-centered healthcare. This manuscript offers a comprehensive analysis of the most extensively used methods of 3D printing in the pharmaceutical field, with examples of solid oral dosage forms and other medical devices currently under development or already marketed.

Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.

BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Evidence of ß-antimonene at the Sb/Bi2Se3 interface.

We report a study of the interface between antimony and the prototypical topological insulator Bi2Se3. Scanning tunnelling microscopy measurements show the presence of ordered domains displaying a perfect lattice match with bismuth selenide. Density functional theory calculations of the most stable atomic configurations demonstrate that the ordered domains can be attributed to stacks of ß-antimonene.

Revisiting the role of sucrose in PLGA-PEG nanocarrier for potential intranasal delivery.

The efficient design of nanocarriers is a major challenge and must be correlated with the route of administration. Intranasal route is studied for local, systemic or cerebral treatments. In order to develop nanocarriers with suitable properties for intranasal delivery, to achieve brain and to market the product, it is extremely important the simplification of the formulation in terms of raw materials. Surfactants and cryoprotectants are often added to improve structuration and/or storage of polymeric nanoparticles. PLGA-PEG nanocarriers were prepared by nanoprecipitation method evaluating the critical role of sucrose as surfactant-like and cryoprotectant, with the aim to obtain a simpler formulation compared to those proposed in other papers. Photon correlation spectroscopy and Turbiscan analysis show that sucrose is a useful excipient during the preparation process and it effectively cryoprotects nanoparticles. Among the investigated nanocarriers with different degree of PEG, PEGylated PLGA (5%) confers weak interaction between nanoparticles and mucin as demonstrated by thermal analysis and mucin particle method. Furthermore, in vitro biological studies on HT29, as epithelium cell line, does not show cytotoxicity effect for this nanocarrier at all texted concentrations. The selected nanosystem was also studied to load docetaxel, as model drug, and characterized by a technological point of view.

Innovative oral spray-dried Idebenone systems to improve patient compliance.

Idebenone is a high permeable drug with very slight water solubility that affects the dissolution rate in the biological fluids, causing an irregular and limited in vivo absorption after oral administration. Moreover, it is marketed in Europe as tablets equivalent to 150 mg, with the consequent administration of multiple dose of solid unit to obtain the correct dose, a deterrent for the patients' compliance. According to these considerations, our goal was to develop spray-dried microparticles using a soluble ß-cyclodextrin (CD) polymer and an enhancer of dissolution rate, such as carboxymethyl cellulose, to obtain a formulation easily dosable and soluble in water. The complex in solution was evaluated by phase solubility studies and the Idebenone/CD molar ratio selected was 1:1. According to Higuchi and Connors, adding carboxymethyl cellulose, a Bs-type profile was obtained. This result was due to the presence of carboxymethyl cellulose that competes with the CD in forming Idebenone microsystems, reducing of 10-fold the formulation bulk. UV-Vis absorption, (1)H nuclear magnetic resonance and circular dichroism showed the formation of the CD/Idebenone inclusion complex confirmed also by differential scanning calorimetry, Fourier transform infrared spectroscopy and fluorescence microscope (FM). The water solubility data and the in vitro dissolution tests performed in simulated gastric fluid, showed an increase of the drug water interaction due to the presence of the CD and carboxymethyl cellulose, both able to improve drug wettability, water solubility and dissolution rate. This approach seems to be suitable to produce microsystems which are able to enhance the in vivo absorption of Idebenone after oral administration and to increase the patient compliance.

TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

BACKGROUND: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor ß activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. METHODS: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT-PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. RESULTS: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively). CONCLUSIONS: The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.

Low-radiation environment affects the development of protection mechanisms in V79 cells.

Very little is known about the influence of environmental radiation on living matter. In principle, important information can be acquired by analysing possible differences between parallel biological systems, one in a reference-radiation environment (RRE) and the other in a low-radiation environment (LRE). We took advantage of the unique opportunity represented by the cell culture facilities at the Gran Sasso National Laboratories of the Istituto Nazionale di Fisica Nucleare, where environment dose rate reduction factors in the underground (LRE), with respect to the external laboratory (RRE), are as follows: 10(3) for neutrons, 10(7) for directly ionizing cosmic rays and 10 for total γ-rays. Chinese hamster V79 cells were cultured for 10 months in both RRE and LRE. At the end of this period, all the cultures were kept in RRE for another 6 months. Changes in the activities of antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GPX) and spontaneous mutation frequency at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus were investigated. The results obtained suggest that environmental radiation might act as a trigger of defence mechanisms in V79 cells, specifically those in reference conditions, showing a higher degree of defence against endogenous damage as compared to cells grown in a very low-radiation environment. Our findings corroborate the hypothesis that environmental radiation contributes to the development of defence mechanisms in today living organisms/systems.

Excitation spectra of transition-metal atoms on the Ag (100) surface controlled by Hund's exchange.

We report photoemission experiments revealing the valence electron spectral function of Mn, Fe, Co, and Ni atoms on the Ag (100) surface. The series of spectra shows splittings of higher energy features which decrease with the filling of the 3d shell and a highly nonmonotonic evolution of spectral weight near the Fermi edge. First principles calculations demonstrate that two manifestations of Hund's exchange J are responsible for this evolution. First, there is a monotonic reduction of the effective exchange splittings with increasing filling of the 3d shell. Second, the amount of charge fluctuations and, thus, the weight of quasiparticle peaks at the Fermi level varies nonmonotonically through this 3d series due to a distinct occupancy dependence of effective charging energies U(eff).

Case Report: Post-gastrectomy reactive hyperinsulinemic hypoglicaemia: glucose trends before and after canagliflozin treatment.

The pathogenesis of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia is not yet fully clarified. Recent studies suggest an up-regulation of the intestinal glucose transporter SGLT-1 aimed to prevent carbohydrate malabsorption. The overexpression of SGLT-1 could therefore represents one of the mechanisms underlying the wide glycemic excursions found in patients after gastrectomy, but studies investigating the use of SGLT-1/SGLT-2 inhibitors in patients with post-gastrectomy reactive hyperinsulinemic hypoglycaemia are very scant in the literature. We report the case of a 37-year-old non diabetic man who frequently presented symptoms of hypoglycaemia in the postprandial period. In 2012, he underwent Roux en-Y gastric bypass (RYGB) and after two years, he started to experience typical symptoms of reactive hyperinsulinaemic hypoglycaemia. We suggested healthy modifications of dietary habits and periodic follow-up visits with a dietitian. After three months, the patient still presented symptoms of reactive hypoglycaemia; we provided him with Flash Glucose Monitoring (FGM) to assess trend of glucose levels in interstitial fluid during the day and we decided to introduce canagliflozin 300 mg/day before the main meal. Hypoglycaemic events previously referred by the patient and clearly recorded by FGM completely disappeared taking canagliflozin. We found a reduction of time spent in hypoglycaemia, an improvement of glycemic variability and an increase of time in target range. It was also noted a reduction of time spent in hyperglicemia with consequent improvement of average glucose values and of glucose main indicator. This is the first report with FGM supporting a role of canagliflozin in the management of post-gastrectomy reactive hyperinsulinaemic hypoglycaemia. Our preliminary results are very limited but in line with those of the literature and showed for the first time a reduction of hypoglycaemic events and an improvement of glycemic variability through a flash glucose monitoring system. Further studies are mandatory to confirm this therapeutic opportunity.

Controlling the topology of Fermi surfaces in metal nanofilms.

The properties of metal crystals are governed by the electrons of the highest occupied states at the Fermi level and determined by Fermi surfaces, the Fermi energy contours in momentum space. Topological regulation of the Fermi surface has been an important issue in synthesizing functional materials, which we found to be realized at room temperature in nanometer-thick films. Reducing the thickness of a metal thin film down to its electron wavelength scale induces the quantum size effect and the electronic system changes from three to two-dimensional, transforming the Fermi surface topology. Such an ultrathin film further changes its topology through one-dimensional (1D) structural deformation of the film when it is grown on a 1D substrate. In particular, when the interface has 1D metallic bands, the system is additionally stabilized by forming an electron energy gap by hybridization between 1D states of the film and substrate.

Spectral functions of isolated Ce adatoms on paramagnetic surfaces.

We report photoemission experiments revealing the full valence electron spectral function of Ce adatoms on Ag(111), W(110), and Rh(111) surfaces. A transfer of Ce 4f spectral weight from the ionization peak towards the Fermi level is demonstrated upon changing the substrate from Ag(111) to Rh(111). In the intermediate case of Ce on W(110) the ionization peak is found to be split. This evolution of the spectra is explained by means of first-principles theory, which clearly demonstrates that a reliable understanding of magnetic adatoms on metal surfaces requires simultaneous low and high energy spectroscopic information.

Transition from unclassified Ktedonobacterales to Actinobacteria during amorphous silica precipitation in a quartzite cave environment.

The orthoquartzite Imawarì Yeuta cave hosts exceptional silica speleothems and represents a unique model system to study the geomicrobiology associated to silica amorphization processes under aphotic and stable physical-chemical conditions. In this study, three consecutive evolution steps in the formation of a peculiar blackish coralloid silica speleothem were studied using a combination of morphological, mineralogical/elemental and microbiological analyses. Microbial communities were characterized using Illumina sequencing of 16S rRNA gene and clone library analysis of carbon monoxide dehydrogenase (coxL) and hydrogenase (hypD) genes involved in atmospheric trace gases utilization. The first stage of the silica amorphization process was dominated by members of a still undescribed microbial lineage belonging to the Ktedonobacterales order, probably involved in the pioneering colonization of quartzitic environments. Actinobacteria of the Pseudonocardiaceae and Acidothermaceae families dominated the intermediate amorphous silica speleothem and the final coralloid silica speleothem, respectively. The atmospheric trace gases oxidizers mostly corresponded to the main bacterial taxa present in each speleothem stage. These results provide novel understanding of the microbial community structure accompanying amorphization processes and of coxL and hypD gene expression possibly driving atmospheric trace gases metabolism in dark oligotrophic caves.

Highly anisotropic Dirac cones in epitaxial graphene modulated by an island superlattice.

We present a new method to engineer the charge carrier mobility and its directional asymmetry in epitaxial graphene by using metal cluster superlattices self-assembled onto the moiré pattern formed by graphene on Ir(111). Angle-resolved photoemission spectroscopy reveals threefold symmetry in the band structure associated with strong renormalization of the electron group velocity close to the Dirac point giving rise to highly anisotropic Dirac cones. We further find that the cluster superlattice also affects the spectral-weight distribution of the carbon bands as well as the electronic gaps between graphene states.

Direct spectroscopic evidence of spin-dependent hybridization between Rashba-split surface states and quantum-well states.

The electronic structure of ultrathin Ag(111) films covered with a square root(3) x square root(3)-Bi/Ag ordered alloy was investigated by means of spin- and angle-resolved photoemission spectroscopy. Surface-state (SS) bands, spin split by the Rashba interaction, selectively couple to the quantum-well state (QWS) bands, originally spin degenerate, in the metal film. Gaps are found to open between QWS and SS with parallel spins, while free-electron-like QWS dispersions are observed for antiparallel spin configurations. The present results demonstrate that in a nonmagnetic metal film the spin degeneracy of the valence levels can be lifted by hybridization with Rashba-type SS bands.

Correlated electrons step by step: itinerant-to-localized transition of fe impurities in free-electron metal hosts.

High-resolution photoemission spectroscopy and ab initio calculations have been employed to analyze the onset and progression of d-sp hybridization in Fe impurities deposited on alkali metal films. The interplay between delocalization, mediated by the free-electron environment, and Coulomb interaction among d electrons gives rise to complex electronic configurations. The multiplet structure of a single Fe atom evolves and gradually dissolves into a quasiparticle peak near the Fermi level with increasing host electron density. The effective multiorbital impurity problem within the exact diagonalization scheme describes the whole range of hybridizations.

Prevalence of antibodies against Kilham virus in experimental rat colonies of Argentina.

The Kilham rat virus (KRV) is a parvovirus originally isolated from a rat sarcoma in the late 1950s. The clinical signs associated with a natural KRV infection include foetal resorption in dams, runting, ataxia, cerebellar hypoplasia and jaundice in suckling rats, and sudden death, scrotal cyanosis, abdominal swelling and dehydration in juvenile rats. The ability of this virus to produce persistent infections has resulted in a high frequency of contamination of cell cultures and transplantable-tumor system. In addition, the virus may interfere with research in other ways. The remarkable resistance to environmental conditions determines the importance of the detection and control of this agent, especially in the laboratory animal production. This study determines the seroprevalence of Kilham antibodies from sera of adult rats from conventional facilities, using the haemagglutination inhibition test. The seroprevalence varied between 27.8% and 75%. This result confirms that the virus is circulating in Argentinean conventional facilities and might be interfering with research. The recognized Kilham virus may be prevented from supply sources by implementing a health monitoring schedule including a regular serological surveillance, and by keeping the animals under barrier systems.