Prominence of the training data preparation in geomagnetic storm prediction using deep neural networks.

The direct interaction between large-scale interplanetary disturbances emitted from the Sun and the Earth's magnetosphere can lead to geomagnetic storms representing the most severe space weather events. In general, the geomagnetic activity is measured by the Dst index. Consequently, its accurate prediction represents one of the main subjects in space weather studies. In this scenario, we try to predict the Dst index during quiet and disturbed geomagnetic conditions using the interplanetary magnetic field and the solar wind parameters. To accomplish this task, we analyzed the response of a newly developed neural network using interplanetary parameters as inputs. We strongly demonstrated that the training procedure strictly changes the capability of giving correct forecasting of stormy and disturbed geomagnetic periods. Indeed, the strategy proposed for creating datasets for training and validation plays a fundamental role in guaranteeing good performances of the proposed neural network architecture.

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the Madin-Darby canine kidney cell line. In silico models trained on these data are used in drug discovery efforts to prioritize novel chemical targets for synthesis; however, their proprietary nature and the limited validation available, which is usually restricted to predicting in vitro permeability, are barriers to widespread adoption. Because of the categorical nature of the in vitro permeability assay, intrinsic assay variability, and the challenges often encountered when translating in vitro data to an in vivo drug property, validation based solely on in vitro data might not be a good characterization of the usefulness of the in silico tool. In this work, we analyze the performance of three different in silico models in predicting the in vitro and in vivo permeability of 300 marketed drugs and 86 discovery compounds. The models differ in their approach (mechanistic vs quantitative structure-activity relationship) and the degree of complexity; one of them is a linear equation based on seven simple physicochemical descriptors and is presented for the first time in this work. Results show that in silico models can be successfully used to complement the discovery toolbox for characterizing in vivo intestinal permeability, defined using fraction of dose absorbed in human (Fa) and human jejunal permeability (Peff). While the in vitro permeability models outperformed the in silico approach at predicting each of the in vivo end points explored, the gap in predictivity between the in vitro and the in vivo data was generally comparable to the gap between in silico and in vitro data. The in vitro and in silico approaches shared many of the same outliers, which can often be explained by the route of drug absorption (paracellular vs transcellular, active vs passive). Data suggest that the discovery process can greatly benefit from an early adoption of in silico models for predicting permeability as well as from a careful analysis of the in silico to in vivo disconnects.

The Pathology of Aging 129S6/SvEvTac Mice.

The 129 mouse strain is commonly used for the generation of genetically engineered mice. Genetic drift or accidental contamination during outcrossing has resulted in several 129 substrains. Comprehensive data on spontaneous age-related pathology exist for the 129S4/SvJae substrain, whereas only limited information is available for other 129 substrains. This longitudinal aging study describes the life span and spontaneous lesions of 44 male and 18 female mice of the 129S6/SvEvTac substrain. Median survival time was 778 and 770 days for males and females, respectively. Tumors of lung and Harderian gland were the most common neoplasms in both sexes. Hepatocellular tumors occurred mainly in males. Hematopoietic tumors were observed at low frequency. Suppurative and ulcerative blepharoconjunctivitis was the most common nonneoplastic condition in both sexes. Corynebacteria (primarily Corynebacterium urealyticum and C. pseudodiphtheriticum) were isolated from animals with blepharoconjunctivitis and in some cases from unaffected mice, although a clear causal association between corynebacterial infections and blepharoconjunctivitis could not be inferred. Polyarteritis occurred only in males and was identified as the most common nonneoplastic contributory cause of death. Eosinophilic crystalline pneumonia occurred in both sexes and was a relevant cause of death or comorbidity. Epithelial hyalinosis at extrapulmonary sites was noted at higher frequency in females. This study contributes important data on the spontaneous age-related pathology of the 129S6/SvEvTac mouse substrain and is a valuable reference for evaluation of the phenotype in genetically engineered mice obtained with this 129 substrain.

Pathologic and Environmental Studies Provide New Pathogenetic Insights Into Ringtail of Laboratory Mice.

Ringtail is a pathologic condition of laboratory rodents characterized by annular constrictions of the tail. Traditionally, it is classified as an environmental disorder caused by low relative humidity, but other factors (temperature, dietary deficiencies, genetic susceptibility, and caging type) have also been proposed. Twenty litters of mice with ringtail lesions occurred from September 2010 to August 2013 in a facility located in the northern Italy. Mice were maintained under controlled environmental conditions and fed a standard diet. Retrospective analysis of environmental data (relative humidity, temperature) was carried out. Gross, histopathologic, scanning, and transmission electron microscopy examination of tails and limbs was performed. The incidence of ringtail was 0.075% (20/26 800) of all weaned litters over the 3-year period of examination. Temperature and relative humidity remained within accepted limits in all cases except one. We observed annular constrictions in tail, digits of pes, crus, and antebrachium in 116 (100.0%), 47 (40.5%), 11 (9.5%), and 2 (1.7%) of 116 affected mice, respectively. Histologic and ultrastructural examination revealed abnormal keratin desquamation and presence of a keratin ring encircling the tail, causing progressive strangulation of the growing tail with subsequent compression and ulceration of underlying soft tissues, resulting in circulatory changes (edema, hyperemia, thrombosis, hemorrhages), ischemic necrosis, and eventually auto-amputation distal to the constriction. On the basis of our findings, we suggest a disorder of cornification as the primary lesion of ringtail in mice. The cause of these cases, however, remained undetermined, even though traditional etiologic factors (relative humidity, temperature, diet, caging type) were reasonably excluded.

Growth and surface characterization of TiNbZr thin films deposited by magnetron sputtering for biomedical applications.

Low modulus of elasticity and the presence of non-toxic elements are important criteria for the development of materials for implant applications. Low modulus Ti alloys can be developed by designing ß-Ti alloys containing non-toxic alloying elements such as Nb and Zr. Actually, most of the metallic implants are produced with stainless steel (SS) because it has adequate bulk properties to be used as biomaterials for orthopedic or dental implants and is less expensive than Ti and its alloys, but it is less biocompatible than them. The coating of this SS implants with Ti alloy thin films may be one alternative to improve the biomaterial properties at a relatively low cost. Sputtering is a physical deposition technique that allows the formation of nanostructured thin films. Nanostructured surfaces are interesting when it comes to the bone/implant interface due to the fact that both the surface and the bone have nanoscale particle sizes and similar mechanical properties. TiNbZr thin films were deposited on both Si(111) and stainless steel (SS) substrates. The TiNbZr/Si(111) film was used as a model system, while the TiNbZr/SS film might improve the biocompatibility and extend the life time of stainless steel implants. The morphology, chemical composition, Young's modulus, and hardness of the films were analyzed by atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDS), and nanoindentation.

Diffuse scaling dermatitis in an athymic nude mouse.

This report describes the clinicopathological features of a case of diffuse scaling dermatitis that occurred in a 16-week-old female athymic nude (CrTac:NCr-Foxn1(nu)) mouse. Gross presentation was suggestive of Corynebacterium bovis infection (scaly skin disease). However, C. bovis was not isolated from the skin of the affected animal or from the skin of unaffected CrTac:NCr-Foxn1(nu) mice housed in the same cage or room. Staphylococcus xylosus was instead isolated in high numbers from the skin lesion, whereas only a few colonies were recovered from the skin of unaffected mice. Microscopically, the affected skin was characterized by chronic hyperplastic and hyperkeratotic dermatitis with focal ulcerations, extensive serocellular crusts, and intralesional clusters of Gram-positive coccoid bacteria. Although gross presentation of the reported case was suggestive of C. bovis infection, epidemiological, histopathological, and bacteriological findings definitively ruled out an outbreak of scaly skin disease. A diagnostic hypothesis of hyperplastic and hyperkeratotic dermatitis associated with opportunistic S. xylosus infection was formulated based on increased bacterial burden and presence of intralesional Gram-positive coccoid bacteria.

Micro-reactors for characterization of nanostructure-based sensors.

Fabrication and testing of micro-reactors for the characterization of nanosensors is presented in this work. The reactors have a small volume (100 µl) and are equipped with gas input/output channels. They were machined from a single piece of kovar in order to avoid leaks in the system due to additional welding. The contact pins were electrically insulated from the body of the reactor using a borosilicate sealing glass and the reactor was hermetically sealed using a lid and an elastomeric o-ring. One of the advantages of the reactor lies in its simple assembly and ease of use with any vacuum/gas system, allowing the connection of more than one device. Moreover, the lid can be modified in order to fit a window for in situ optical characterization. In order to prove its versatility, carbon nanotube-based sensors were tested using this micro-reactor. The devices were fabricated by depositing carbon nanotubes over 1 µm thick gold electrodes patterned onto Si/SiO(2) substrates. The sensors were tested using oxygen and nitrogen atmospheres, in the pressure range between 10(-5) and 10(-1) mbar. The small chamber volume allowed the measurement of fast sensor characteristic times, with the sensors showing good sensitivity towards gas and pressure as well as high reproducibility.

Development of a disposable amperometric biosensor for salicylate based on a plastic electrochemical microcell.

The use of an amperometric biosensor for rapid salicylate determination in blood is described. Photolitography was used to make gold electrodes on a polyester film. The plastic microcell was characterized using cyclic voltammetry to demonstrate the electrochemical performance of the system. The biosensor was constructed by immobilizing salicylate hydroxylase onto the working electrode of the plastic electrochemical microcell. The optimized working conditions were 0.1 mol L(-1) phosphate buffer at pH 7.6 with 0.5 mmol L(-1) of NADH and 300 mV vs. Au as the applied potential. The resulting biosensor exhibited a high sensitivity (97.4 nA/mmol L(-1) salicylate) and an adequate linear response range (1.2x10(-4) to 1.0x10(-3)mol(-1)). The biosensor performance was verified by determining salicylate in spiked blood samples and the results were statistically equivalent to the values obtained from the standard Trinder spectrophotometric method, with a 95% confidence level. This study shows the potential development of a portable, inexpensive and disposable device for point-of-care monitoring.

Immunohistochemical detection of Ym1/Ym2 chitinase-like lectins associated with hyalinosis and polypoid adenomas of the transitional epithelium in a mouse with acute myeloid leukemia.

An 8-month-old PML/RARalpha knock-in female mouse developed a promyelocytic-like myeloid leukemia with an expected latency. At necropsy, besides the typical findings associated with myeloid leukemia, a severe unilateral hydronephrosis was observed. By histopathologic examination, 2 polypoid adenomas arising from the transitional epithelium of the renal pelvis and ureter were detected. The epithelial cells of the polypoid adenomas showed accumulation of hyaline eosinophilic material within the cytoplasm. Large amounts of extracellular eosinophilic crystals were also associated with the transitional cell adenomas. Immunohistochemical analysis revealed that the eosinophilic intracytoplasmic material and the extracellular eosinophilic crystals were composed of Ym proteins. A unilateral hyaline droplet tubular nephropathy was associated with the myeloid leukemia. Expression of Ym proteins characterized both the neoplastic myeloid infiltrates and the tubular hyaline droplets. In the present PML/RARalpha knock-in female mouse, the accumulation of Ym proteins associated with the myeloid leukemia and with the polypoid adenomas of the transitional epithelium underlies 2 distinct pathogenetic mechanisms.

Physiological characteristics of top level off-road motorcyclists.

OBJECTIVES: The study aims to analyse the physiological characteristics of top level off-road motocross, enduro, and desert rally motorcyclists to facilitate the design of a specific training program. METHODS: Twenty seven off-road top level riders participated in this study which measured anthropometric data, maximum aerobic power with incremental tests of both arms and legs, isokinetic dynamometry of the knee and elbow, handgrip strength, heart rate, and blood lactate concentrations during competition. RESULTS: The physical demands of the various races appear to influence the development of distinct musculoskeletal characteristics, as well as aerobic and anaerobic metabolism. Motocross riders have more muscle mass, higher isokinetic handgrip strength, and greater aerobic power than enduro and desert rally riders. However, there are no significant anthropometric and physiological differences between desert rally and enduro riders. Desert rally riders tend to be overweight with maximum aerobic power similar to that of healthy individuals. The mechanical characteristics of the motorcycle and the technical and tactical skills of the riders seem to be more important for race success than the metabolic capabilities of the rider. CONCLUSIONS: Desert rally and enduro riders present similar anthropometric and physiological characteristics. Both have a maximum aerobic power similar to that of healthy normal individuals, although desert rally riders tend to be overweight. Motocross riders on the other hand, have more muscle mass, more strength, and greater aerobic power. The differences observed suggest the need for a specific training program to address the requirements of different riders to reduce the possibility of injury.

Energetics of midvelocity emissions in peripheral heavy ion collisions at Fermi energies.

Peripheral and semiperipheral collisions have been studied in the system 93Nb+93Nb at 38A MeV. The evaporative and midvelocity components of the light charged particle and intermediate mass fragment emissions have been carefully disentangled. In this way it was possible to obtain the average amount not only of charge and mass, but also of energy, pertaining to the midvelocity emission, as a function of an impact parameter estimator. This emission has a very important role in the overall balance of the reaction, as it accounts for a large fraction of the emitted mass and for more than half of the dissipated energy. As such, it may give precious clues on the microscopic mechanism of energy transport from the interaction zone toward the target and projectile remnants.

Nuclear stopping from 0.09A to 1.93A GeV and its correlation to flow.

We present a complete systematics (excitation functions and system-size dependences) of global stopping and side flow for heavy ion reactions in the energy range between 0.09A and 1.93A GeV. For the heaviest system, Au+Au, we observe a plateau of maximal stopping extending from about 0.2A to 0.8A GeV with a fast drop on both sides. The degree of stopping, which is shown to remain significantly below the expectations of a full stopping scenario, is found to be highly correlated to the amount of side flow.

Eosinophilic crystals as a distinctive morphologic feature of a hyaline droplet nephropathy in a mouse model of acute myelogenous leukaemia.

Eosinophilic crystals have been described in the upper and lower respiratory tract, gall bladder, intrahepatic bile ducts and glandular stomach of different laboratory mice strains. They have been recently identified as chitinase-like (Ym1/Ym2) proteins. Here we describe the occurrence of eosinophilic crystals in the renal tubules of mice with experimentally induced acute myelogenous leukaemia. Fourteen FVB/N and 29 129Sv mice of both sexes, 8-10 weeks of age, were employed to establish a model of human acute myelogenous leukaemia. Nine mice that developed a widespread acute myelogenous leukaemia revealed the presence of eosinophilic crystals in renal tubules. The presence of eosinophilic crystals in the kidneys was constantly associated with a hyaline droplet nephropathy. Immunohistochemistry showed that the crystals and the hyaline droplets were composed of chitinase-like (Ym1/Ym2) proteins. Furthermore, immunoreactivity for Ym1/Ym2 proteins was also detected in the crystalline material stored in the cytoplasm of large macrophage-like cells or in extracellular localization within the leukaemic infiltrates. On the basis of our results we hypothesize that the detection of the Ym1/Ym2 proteins in the urine of mice might represent a feasible indicator of the burden and progression of the leukaemic condition in our murine model.

Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma.

Circulating endothelial cells (CECs) were evaluated by flow cytometry in immunodeficient mice bearing human lymphoma. A trend toward higher CEC values was observed on days 7 and 14 after transplant, and differences versus controls were highly significant on day 21 (P = 0.0061). A strong correlation was found between CEC and tumor volume (r, 0.942; P = 0.004) and between CEC and tumor-generated VEGF (r, 0.669; P = 0.02). In mice given cyclophosphamide, most of the circulating apoptotic cells were hematopoietic and not endothelial. Conversely, in mice given endostatin, all of the increase in apoptotic cells was in the endothelial cell compartment. CEC evaluation is promising as a noninvasive, surrogate angiogenesis marker.

Ringtail in suckling Munich Wistar Fromter rats: a histopathologic study.

Ringtail is a pathologic condition of the tail of rats and other rodents that is traditionally attributed to low environmental humidity, although dietary deficiencies, genetic susceptibility, environmental temperature, and degree of hydration of the animal also have been suggested as possible causes. To the authors' knowledge, a detailed histopathologic study that may serve to shed light on the etiopathogenesis of this disease has not yet been published. We describe the histologic findings of ringtail observed in 12 suckling Munich Wistar Fromter (MWF) rats from two litters. Epidermal hyperplasia characterized by orthokeratotic and parakeratotic hyperkeratosis and acanthosis was observed in all affected rats. Numerous often dilated vessels were present in the dermis of tails that appeared of red/brown color at gross examination. In severe cases, the dilated vascular structures were thrombotic and accompanied by dermal hemorrhages and focal coagulative necrosis of the overlying epidermis. These findings suggest that epidermal acanthosis and hyperkeratosis are the main and primary events in the development of ringtail. To clarify the cause of this disease, future studies should be focused on the numerous factors that can induce such epidermal changes.

Real-time quantitative PCR for human herpesvirus 6 DNA.

The diagnosis of human herpesvirus 6 (HHV-6) infection represents a complex issue because the most widely used diagnostic tools, such as immunoglobulin G antibody titer determination and qualitative DNA PCR with blood cells, are unable to distinguish between latent (clinically silent) and active (often clinically relevant) infection. We have developed a new, highly sensitive, quantitative PCR assay for the accurate measurement of HHV-6 DNA in tissue-derived cell suspensions and body fluids. The test uses a 5' nuclease, fluorogenic assay combined with real-time detection of PCR amplification products with the ABI PRISM 7700 sequence detector system. The sensitivity of this method is equal to the sensitivity of a nested PCR protocol (lower detection limit, 1 viral genome equivalent/test) for both the A and the B HHV-6 subgroups and shows a wider dynamic range of detection (from 1 to 10(6) viral genome equivalents/test) and a higher degree of accuracy, repeatability, and reproducibility compared to those of a standard quantitative-competitive PCR assay developed with the same reference DNA molecule. The novel technique is versatile, showing the same sensitivity and dynamic range with viral DNA extracted from different fluids (i.e., culture medium or plasma) or from tissue-derived cell suspensions. Furthermore, by virtue of its high-throughput format, this method is well suited for large epidemiological surveys.

Isospin tracing: A probe of nonequilibrium in central heavy-Ion collisions

Four different combinations of 9644Ru and 9640Zr nuclei, both as projectile and target, were investigated at the same bombarding energy of 400A MeV using a 4pi detector. The degree of isospin mixing between projectile and target nucleons is mapped across a large portion of the phase space using two different isospin-tracer observables, the number of measured protons and the tritium to 3He yield ratio. The experimental results show that the global equilibrium is not reached even in the most central collisions. Quantitative measures of stopping and mixing are extracted from the data. They are found to exhibit a quite strong sensitivity to the in-medium ( n,n) cross section used in microscopic transport calculations.

The thin red line: angiogenesis in normal and malignant hematopoiesis.

This review describes the current knowledge about cell subsets involved in vasculogenesis (i.e., differentiation of endothelial cells from mesodermal precursors) and angiogenesis (i.e., blood vessel generation from pre-existing vessels), together with recent findings about angiogenesis and antiangiogenic therapies in hematopoietic malignancies such as leukemia, lymphoma, myeloma, and myelodysplastic syndromes.

Coinfection of SCID-hu Thy/Liv mice with human herpesvirus 6 and human immunodeficiency virus type 1.

Human herpesvirus 6 (HHV-6) has been proposed as a potential cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We used the SCID-hu Thy/Liv mouse model to evaluate the in vivo interactions between HHV-6 and HIV-1. Our results demonstrate that HHV-6 and HIV-1 can simultaneously replicate in the human thymus in vivo. In this model, however, the presence of one virus appears not to modify the replication or cytopathicity of the other.