Substrate temperature dependence of structure and optical properties of ZnTiO3:Er3+/Yb3+ thin films synthesized by pulsed laser deposition.

ZnTiO3:Er3+,Yb3+ thin film phosphors were successfully deposited by pulsed laser deposition (PLD) at different substrate temperatures. The distribution of the ions in the films was investigated and the chemical analysis showed that the doping ions were homogeneously distributed in the thin films. The optical response of the phosphors revealed that the reflectance percentages of the ZnTiO3:Er3+,Yb3+ vary with the silicon substrate temperature due to the differences in the thickness and morphological roughness of the thin films. Under 980 nm diode laser excitation, the ZnTiO3:Er3+,Yb3+ film phosphors displayed up-conversion emission from the Er3+ electronic transitions, with violet, blue, green, and red emission lines at 410, 480, 525, 545 and 660 nm from 2H9/2 â†’ 4I15/2, 4F7/2 â†’ 4I15/2, 2H11/2 â†’ 4I15/2, 4S3/2 â†’ 4I15/2 and 4F9/2 â†’ 4I15/2 transitions, respectively. The up-conversion emission was enhanced by increasing the silico (Si) substrate temperature during the deposition. Based on the photoluminescence properties and decay lifetime analysis, the energy level diagram was established and the up-conversion energy-transfer mechanism was discussed in detail.

Encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: real-life data from an Italian multicenter experience.

BACKGROUND: Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage. PATIENTS AND METHODS: This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019. RESULTS: Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome. CONCLUSIONS: Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

First Directional Measurement of Sub-MeV Solar Neutrinos with Borexino.

We report the measurement of sub-MeV solar neutrinos through the use of their associated Cherenkov radiation, performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The measurement is achieved using a novel technique that correlates individual photon hits of events to the known position of the Sun. In an energy window between 0.54 to 0.74 MeV, selected using the dominant scintillation light, we have measured 10 887_{-2103}^{+2386}(stat)±947(syst) (68% confidence interval) solar neutrinos out of 19 904 total events. This corresponds to a ^{7}Be neutrino interaction rate of 51.6_{-12.5}^{+13.9} counts/(day·100 ton), which is in agreement with the standard solar model predictions and the previous spectroscopic results of Borexino. The no-neutrino hypothesis can be excluded with >5σ confidence level. For the first time, we have demonstrated the possibility of utilizing the directional Cherenkov information for sub-MeV solar neutrinos, in a large-scale, high light yield liquid scintillator detector. This measurement provides an experimental proof of principle for future hybrid event reconstruction using both Cherenkov and scintillation signatures simultaneously.

Improved Measurement of Solar Neutrinos from the Carbon-Nitrogen-Oxygen Cycle by Borexino and Its Implications for the Standard Solar Model.

We present an improved measurement of the carbon-nitrogen-oxygen (CNO) solar neutrino interaction rate at Earth obtained with the complete Borexino Phase-III dataset. The measured rate, R_{CNO}=6.7_{-0.8}^{+2.0} counts/(day×100 tonnes), allows us to exclude the absence of the CNO signal with about 7σ C.L. The correspondent CNO neutrino flux is 6.6_{-0.9}^{+2.0}×10^{8} cm^{-2} s^{-1}, taking into account the neutrino flavor conversion. We use the new CNO measurement to evaluate the C and N abundances in the Sun with respect to the H abundance for the first time with solar neutrinos. Our result of N_{CN}=(5.78_{-1.00}^{+1.86})×10^{-4} displays a ∼2σ tension with the "low-metallicity" spectroscopic photospheric measurements. Furthermore, our result used together with the ^{7}Be and ^{8}B solar neutrino fluxes, also measured by Borexino, permits us to disfavor at 3.1σ C.L. the "low-metallicity" standard solar model B16-AGSS09met as an alternative to the "high-metallicity" standard solar model B16-GS98.

AEgIS at ELENA: outlook for physics with a pulsed cold antihydrogen beam.

The efficient production of cold antihydrogen atoms in particle traps at CERN's Antiproton Decelerator has opened up the possibility of performing direct measurements of the Earth's gravitational acceleration on purely antimatter bodies. The goal of the AEgIS collaboration is to measure the value of g for antimatter using a pulsed source of cold antihydrogen and a Moiré deflectometer/Talbot-Lau interferometer. The same antihydrogen beam is also very well suited to measuring precisely the ground-state hyperfine splitting of the anti-atom. The antihydrogen formation mechanism chosen by AEgIS is resonant charge exchange between cold antiprotons and Rydberg positronium. A series of technical developments regarding positrons and positronium (Ps formation in a dedicated room-temperature target, spectroscopy of the n=1-3 and n=3-15 transitions in Ps, Ps formation in a target at 10 K inside the 1 T magnetic field of the experiment) as well as antiprotons (high-efficiency trapping of [Formula: see text], radial compression to sub-millimetre radii of mixed [Formula: see text] plasmas in 1 T field, high-efficiency transfer of [Formula: see text] to the antihydrogen production trap using an in-flight launch and recapture procedure) were successfully implemented. Two further critical steps that are germane mainly to charge exchange formation of antihydrogen-cooling of antiprotons and formation of a beam of antihydrogen-are being addressed in parallel. The coming of ELENA will allow, in the very near future, the number of trappable antiprotons to be increased by more than a factor of 50. For the antihydrogen production scheme chosen by AEgIS, this will be reflected in a corresponding increase of produced antihydrogen atoms, leading to a significant reduction of measurement times and providing a path towards high-precision measurements.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.

Co-evolution of hydrological components under climate change scenarios in the Mediterranean area.

The Mediterranean area is historically characterized by high human pressure on water resources. Today, while climate is projected to be modified in the future, through precipitation decrease and temperature increase, that jointly and non-linearly may affect runoff, concerns about water availability are increasing. For these reasons, quantitative assessment of future modifications in the mean annual water availability are important; likewise, the description of the future interannual variability of some hydrological components such as runoff and evapotranspiration are highly wished for water management and ecosystems dynamics analyses. This study investigates at basin spatial scale future runoff and evapotranspiration, exploring their probability density functions and their interdependence as functions of climatic changes. In order to do that, a parsimonious conceptual lumped model is here used. The model is forced by different future climate scenarios, generated through a weather generator based on a stochastic downscaling of an ensemble of General Circulation Models (GCMs) realizations. The use of the adopted hydrological model, under reliable stochastic future climate scenarios, allows to project future values of evapotranspiration and runoff in a probabilistic framework and, at the same time, the evaluation of their bivariate frequency distributions for changes through the Multivariate Kernel Density Estimation method. As a case study, a benchmark Mediterranean watershed has been proposed (Imera Meridionale, Italy). Results suggest a radical shift and shape modification of the annual runoff and evapotranspiration probability density functions. Possible implications and impacts on water resources management are here addressed and discussed.

Test of Electric Charge Conservation with Borexino.

Borexino is a liquid scintillation detector located deep underground at the Laboratori Nazionali del Gran Sasso (LNGS, Italy). Thanks to the unmatched radio purity of the scintillator, and to the well understood detector response at low energy, a new limit on the stability of the electron for decay into a neutrino and a single monoenergetic photon was obtained. This new bound, τ≥6.6×10^{28} yr at 90% C.L., is 2 orders of magnitude better than the previous limit.

A moiré deflectometer for antimatter.

The precise measurement of forces is one way to obtain deep insight into the fundamental interactions present in nature. In the context of neutral antimatter, the gravitational interaction is of high interest, potentially revealing new forces that violate the weak equivalence principle. Here we report on a successful extension of a tool from atom optics--the moiré deflectometer--for a measurement of the acceleration of slow antiprotons. The setup consists of two identical transmission gratings and a spatially resolving emulsion detector for antiproton annihilations. Absolute referencing of the observed antimatter pattern with a photon pattern experiencing no deflection allows the direct inference of forces present. The concept is also straightforwardly applicable to antihydrogen measurements as pursued by the AEgIS collaboration. The combination of these very different techniques from high energy and atomic physics opens a very promising route to the direct detection of the gravitational acceleration of neutral antimatter.

Investigating the changes in extreme rainfall series recorded in an urbanised area.

The aim of this study is to investigate and quantify changes in the rainfall regime of the metropolitan area of Palermo characterised by increasingly strong urbanisation. The rainfall data, considered in this study, were collected on a yearly basis from eight rain gauges within and outside the metropolitan area of Palermo, Sicily, Italy. A preliminary analysis made on the annual total rainfall depths showed a global reduction of total annual rainfall, with two different trends: more regular for the series observed in the rain gauges within the urbanised area and more variable for the series observed in the rain gauges outside the area. A further analysis has been performed using the series of maximum intensity for fixed duration (1, 3, 6, 12, 24 hrs) and annual daily maxima. The analysis of the trend in the extreme rainfall series has been performed by estimating the maximum rainfall depth corresponding to a fixed return period using the EV1 distribution with parameters estimated using L-moments. The analysis of all series indicates a global reduction of rainfall intensities, both for internal and external series, in disagreement with the results obtained by other authors.

Impaired activation of islet-reactive CD4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice.

Despite the impressive protection of B cell-deficient (muMT(-/-)) nonobese diabetic (NOD) mice from spontaneous diabetes, existence of mild pancreatic islet inflammation in these mice indicates that initial autoimmune targeting of beta cells has occurred. Furthermore, muMT(-/-) NOD mice are shown to harbor a latent repertoire of diabetogenic T cells, as evidenced by their susceptibility to cyclophosphamide-induced diabetes. The quiescence of this pool of islet-reactive T cells may be a consequence of impaired activation of T lymphocytes in B cell-deficient NOD mice. In this regard, in vitro anti-CD3-mediated stimulation demonstrates impaired activation of lymph node CD4 T cells in muMT(-/-) NOD mice as compared with that of wild-type counterparts, a deficiency that is correlated with an exaggerated CD4 T cell:APC ratio in lymph nodes of muMT(-/-) NOD mice. This feature points to an insufficient availability of APC costimulation on a per T cell basis, resulting in impaired CD4 T cell activation in lymph nodes of muMT(-/-) NOD mice. In accordance with these findings, an islet-reactive CD4 T cell clonotype undergoes suboptimal activation in pancreatic lymph nodes of muMT(-/-) NOD recipients. Overall, the present study indicates that B cells in the pancreatic lymph node microenvironment are critical in overcoming a checkpoint involving the provision of optimal costimulation to islet-reactive NOD CD4 T cells.

Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice.

Diabetes in nonobese diabetic (NOD) mice results from the activation of I-A(g7)-restricted, islet-reactive T cells. This study delineates several characteristics of NOD CD4 T cell activation, which, independent of I-A(g7), are likely to promote a dysregulated state of peripheral T cell tolerance. NOD CD4 T cell activation was found to be resistant to antigenic stimulation via the TCR complex, using the progression of cell division as a measure. The extent of NOD CD4 T cell division was highly sensitive to changes in Ag ligand density. Moreover, even upon maximal TCR complex-mediated stimulation, NOD CD4 T cell division prematurely terminated. Maximally stimulated NOD CD4 T cells failed to achieve the threshold number of division cycles required for optimal susceptibility to activation-induced death, a critical mechanism for the regulation of peripheral T cell tolerance. Importantly, these aberrant activation characteristics were not T cell-intrinsic but resulted from reliance on B cell costimulatory function in NOD mice. Costimulation delivered by nonautoimmune strain APCs normalized NOD CD4 T cell division and the extent of activation-induced death. Thus, by disrupting the progression of CD4 T cell division, polarization of APC costimulatory function to the B cell compartment could allow the persistence and activation of diabetogenic cells in NOD mice.

Disulfide-cross-linked tau and MAP2 homodimers readily promote microtubule assembly.

The neuronal proteins Tau and MAP2 use homologous C-terminal MT-binding regions (MTBRs) to interact with microtubules, F-actin, and intermediate filaments. Although Tau-MTBR is the principal component of pronase-treated Alzheimer paired helical filaments, both Tau and MAP2 form filaments in vitro from disulfide-linked homodimers. That the critical thiol lies within a domain needed for MT binding raised the question: Does disulfide formation block Tau-Tau or MAP2-MAP2 dimer binding to microtubules, thereby acting to divert dimers toward filament formation? We now report that cross-linked Tau and MAP2 homodimers readily promote tubulin polymerization and that monomer and dimer affinity for MTs is surprisingly similar. Therefore, disulfide cross-bridging into homodimers is unlikely to be a drive force for filament formation in Alzheimer's disease.

I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice.

B cell-deficient nonobese diabetic (NOD) mice are protected from the development of spontaneous autoimmune diabetes, suggesting a requisite role for Ag presentation by B lymphocytes for the activation of a diabetogenic T cell repertoire. This study specifically examines the importance of B cell-mediated MHC class II Ag presentation as a regulator of peripheral T cell tolerance to islet beta cells. We describe the construction of NOD mice with an I-Ag7 deficiency confined to the B cell compartment. Analysis of these mice, termed NOD BCIID, revealed the presence of functionally competent non-B cell APCs (macrophages/dendritic cells) with normal I-Ag7 expression and capable of activating Ag-reactive T cells. In addition, the secondary lymphoid organs of these mice harbored phenotypically normal CD4+ and CD8+ T cell compartments. Interestingly, whereas control NOD mice harboring I-Ag7-sufficient B cells developed diabetes spontaneously, NOD BCIID mice were resistant to the development of autoimmune diabetes. Despite their diabetes resistance, histologic examination of pancreata from NOD BCIID mice revealed foci of noninvasive peri-insulitis that could be intentionally converted into a destructive process upon treatment with cyclophosphamide. We conclude that I-Ag7-mediated Ag presentation by B cells serves to overcome a checkpoint in T cell tolerance to islet beta cells after their initial targeting has occurred. Overall, this work indicates that the full expression of the autoimmune potential of anti-islet T cells in NOD mice is intimately regulated by B cell-mediated MHC class II Ag presentation.

Some educational implications for students with profound disabilities at risk for inadequate nutrition and the nontherapeutic effects of medication.

The educational relevance for students with profound disabilities of being at risk for poor nutrition and the potential problems caused by the nontherapeutic effects of some medications were examined, examples of their significance presented, some reasons for their occurrence discussed, and some suggestions for instructional personnel offered. Two classroom-based cases were included that described the resolution of a nutritional and a medication problem, including the role of the teacher and health-related personnel.

[Metabolic aspects of intestinal urinary diversion. Comparison with ileo-cecal bladder substitution and ileal conduct]. / Aspetti metabolici della derivazione urinaria intestinale. Confronto tra vescica ileo-cecale di sostituzione e condotto ileale.

The aim of this study was the metabolic evaluation of 10 patients with 2 different types of urinary diversions, after cystectomy for infiltrating carcinoma. The patients were divided into two groups, homogeneous for age and follow up, according to the type of urinary diversion: group A (5 patients with ileo-cecal bladder) and group B (5 patients with ileal conduit). The follow up duration was 16.8 +/- 7.3 months in group A and 25.4 +/- 7.8 months, in group B. Even though the glomerular filtration rate (GFR) in both groups was within the normal limits, however - on closer evaluation - patients of A group revealed a slight functional damage, shown by reduced creatinine secretion, lower bicarbonatemia and lower urinary acid secretion when compared with ileal conduit patients. According to this study, the ileal conduit seems to be associated with a fairly good metabolic status while the ileo-cecal bladder could require closer clinical-metabolic follow up and bicarbonate supplementation.

P-glycoprotein expression in bladder cancer.

Multi-drug resistance is a phenomenon by which tumor cells express resistance to a variety of chemically unrelated chemotherapeutic drugs. The classical form of multi-drug resistance is mediated through the expression of P-glycoprotein, which acts as an energy dependent drug efflux pump. P-glycoprotein expression was evaluated in 29 cystectomy specimens from patients with bladder cancer with no prior exposure to chemotherapeutic drugs, and in bladder biopsies from 9 subjects before treatment with intravesical doxorubicin. Furthermore, the strategy of circumvention of P-glycoprotein-mediated resistance using the combination of doxorubicin and verapamil intravesically was tested in 5 patients. P-glycoprotein was expressed in 75% of the cystectomy specimens. In the doxorubicin treated patients no correlation was noted between P-glycoprotein expression on the initial tumors and subsequent response to doxorubicin. The pilot trial of verapamil and doxorubicin was well tolerated but did not suggest increased efficacy of this combination. P-glycoprotein can be expressed on bladder cancer cells without prior chemotherapy. The role of P-glycoprotein mediated multi-drug resistance in bladder cancer treatment failure remains to be defined.

Metabolic complications of the urinary intestinal diversion: ileo-caecal bladder compared with ileal conduit.

Five patients with an ileal conduit and 5 with an ileo-caecal bladder substitute have been studied metabolically. All had undergone cystectomy for infiltrating carcinoma and they formed 2 homogeneous groups in terms of age and follow-up. Function in both groups was within normal limits but closer examination of patients with an ileo-caecal bladder revealed mild functional damage as shown by reduced creatinine secretion, a lower level of bicarbonate and lower urinary acid valency secretion. It was concluded that the ileal conduit is more satisfactory from a metabolic point of view than the ileo-caecal bladder, which requires closer follow-up and treatment with bicarbonates if necessary.

Uretero-ileocecocapsuloplasty. Preliminary reports.

A uretero-ileocecocapsulaplasty and ileal patch operation was performed on seven patients following cystectomy. All the patients were carefully selected cases of unifocal T2, T3 vesical carcinoma localized at least 2-3 cm from the bladder neck. Vesical mapping and intraoperative histological examination of resection edges were negative. The operative technique is described together with early clinical and urodynamic findings.