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During the filling phase of the injection molding process, the polymer in contact with the wall solidifies, developing the so-called skin layer. Although the no-flow temperature is often exploited in numerical simulations to model the skin layer formation mechanism, there is still an incomplete understanding of what happens for semi-crystalline PET. In fact, for this polymer, the high shear stresses near the cavity wall combined with the thermal gradient at the polymer-mold interface can cause the so-called flow-induced crystallization. This work aims to experimentally investigate the skin layer formation at different injection molding processing conditions. A full-factorial experimental plan was performed using a commercial PET injected into an open-cavity mold. The thermal and mechanical boundary conditions at the polymer-wall interface were varied using insulating coatings and different flow rates, respectively. The mold coatings were applied to different steel substrates to consider the substrate thermal conductivity contribution. Different flow rates were imposed, varying the cavity thickness and the injection speed. The in-line acquisition of the cavity pressure allows for assessing the contributions of the modified boundary conditions to the solidified skin layer formation. The results show that the insulating mold coating changes the thermal boundary conditions, leading to a maximum pressure decrease of 14 %. The cavity pressure vs. filling time curves for the uncoated inserts show an evident derivative discontinuity, suggesting the onset of flow-induced crystallization.

The demand for lighter and more performant aerospace and automotive components has resulted in a substantial surge in a recent interest in parts made of Fiber Metal Laminates (FMLs). For such components, drilling operations are crucial for permitting subsequent assembly. However, drillability of fiber metal laminates is critical due to the heterogeneous thermal and mechanical properties of the metal and composite that form the laminate. In this framework, the current research work aims at understanding how drilling operations can be affected by different surface treatments carried out on AZ31B magnesium alloy sheets joined with Glass Fiber Reinforced Polyamide 6 (PA6-GFRP) via hot metal pressing to form the FML. To this end, the Mg/PA6-GFRP/Mg composites were first fabricated using AZ31B surfaces that were previously treated through sandblasting, annealing, and their combination. Dry drilling was then performed using twist and spur drill bits. The feed was also varied, using two levels. The thrust force, hole quality, delamination and fiber pull-out were considered to evaluate the FMLs drillability. Results showed that the magnesium alloy sheet treatment influenced the drillability, and that the drill bit had an effect too. In particular, sheets that were both sandblasted and annealed allowed the highest drillability avoiding delamination. The use of spur drill bits improved the drillability too, reducing the FML inflection under the drill bit load.

To determine the accuracy of AlignRT surface deformation module in detecting and quantifying oedema in breast cancer radiotherapy.

Laser direct energy deposition is commonly used to improve the surface properties of poorly resistant materials, repair worn portions, or change the shape of a component. In this paper, C45 steel substrates were laser deposited with multiple layers of grade 300 maraging steel. Micromilling operations were then carried out on the laser depositions both in as-built and heat-treated conditions to improve the surface integrity. The cutting forces were measured at varying cutting directions. An in-depth characterization of the surface integrity induced by micromilling was conducted, considering microstructural features, microhardness, surface topography, and surface defects. The results proved that the laser deposition-induced anisotropy had a remarkable influence on the laser deposited material machinability and must be taken into account.

When dealing with post-processing steps of additively manufactured parts, the issue of the surface finishing of freeform surfaces has to be addressed. The flexibility of ball end milling makes this machining operation particularly suitable to finish such parts. However, literature records dealing with this kind of cutting operation on additively manufactured alloys are very scarce. The microstructural anisotropy induced by the additive manufacturing process may influence the machinability of a metal alloy such produced, distinguishing it from the same alloy conventionally fabricated. At present, there is no thorough understanding of the influence of additively built component anisotropy on ball end milling operations, resulting in the unpredictability of the part behavior once machined. In this work, ball end milling was carried out on both additively and conventionally manufactured Ti6Al4V alloy workpieces characterized by an inclination angle of 15°, 45°, and 75°. For the first time, the impact of the peculiar microstructural features induced by additive manufacturing was studied in ball end milling operations with different tool paths orientations. The interpretation of the results was helped by the comparison with the wrought alloy. The machinability was assessed in terms of cutting forces, surface topography, surface defects, and chip morphology. The results demonstrated that the additively manufactured alloy allowed for better machinability than the wrought one only when the cutting edge was parallel to the α phase colonies within the prior β grains, thus favoring the material removal by locally decreasing the material resistance to cutting.

When fabricating fiber metal laminates, the joining between the metal sheet and the composite is affected by the chemical and mechanical properties at the interface. To this end, this study investigated the influence of different induced-surface characteristics of AZ31B magnesium alloy sheets when joint with glass fiber reinforced polyamide 6. The treatments, carried out to modify the AZ31B surfaces, were annealing, sandblasting, and their combination. The mechanical and chemical interlocking at the metal-composite interface was assessed in terms of macroscopic and microscopic defects as well as lap shear strength. The obtained results indicated that the joint effectiveness was mainly affected by the annealing treatment, which induced both a chemical and morphological modification of the surface. The formed oxide layer at the interface, combined with surface topography modification, were capable to increase the lap shear strength up to 87%.

The ejection phase influences the quality and integrity of micro injection molded parts. The successful design of robust micro mold ejection systems requires studying the tribological interactions at the mold/polymer interface. At the micro-scale, the tooling topography can have a significant impact on the ejection friction. Here we propose a novel approach to the evaluation of ejection friction in micro injection molding. The two main contributors to the ejection force are the normal force due to shrinkage and the static friction coefficient. The former is addressed by developing a procedure for shrinkage characterization at the micro-scale. The latter is studied using experimental measurements of the ejection force in micro injection molding. Comparing the numerical and the experimental results allows identifying the friction coefficient as a function of polymer, process parameters, and mold surface roughness.

This work investigates the machinability characteristics of additively manufactured Ti6Al4V titanium alloy workpieces in finishing machining using ball end mills on 45° inclined surfaces. The surface finish results were compared with the ones from ball end milling trials on wrought Ti6Al4V samples using the same cutting conditions. Optical profilometry and scanning electron microscope imaging were used to compare the different surface texture and quality of the two alloys, as well as the chip morphology, with the aim of finding a correlation between the surface finish obtained at varying cutting parameters and the Ti6Al4V peculiar microstructure induced by the additive manufacturing process. The results showed that the additively manufactured alloy allowed for a better surface quality respect to the wrought one. This was attributed to the interactions of the ball mill cutting edge with the α phase colonies of such alloy, which may favor the material removal by locally lowering the material resistance to cutting.

Final machining steps are commonly requested on parts obtained via additive manufacturing to ensure the required surface finish and geometrical tolerances. When machining additive manufactured workpieces, their typical microstructural anisotropy is rarely taken into consideration. In this work, the influence of the build-up orientation of Ti6Al4V parts obtained via laser powder bed fusion on machinability is studied. Ti6Al4V blocks with horizontal and vertical development were additively manufactured and then milled. Tool wear progression was monitored and its effect on surface quality investigated. The cutting tool that machined the horizontally oriented sample showed a tool life 66% higher than the one that machined the vertically oriented one. This study demonstrates the strong correlation between the build-up orientation of additive manufactured components and their machining response.

So far, illumination optics design for extended sources (like LEDs) has been mainly treated as perturbations of ideal point sources without any extent. Such approaches work well provided that this ideal case is approximately met. However, the demand for very compact luminaires equipped with modern high-brightness LEDs results in configurations where the actual size of the sources cannot be ignored. Here, we develop a “wavefront tailoring” method producing prescribed illumination patterns while fully encompassing the extended source size. We combine this technique with a wavefront-coupling design scheme, obtaining a powerful tool for creating optics for large Lambertian emitters and prescribed intensity emissions. As an example, we design a highly compact and efficient freeform lens delivering a constant illuminance pattern. Importantly, the presented design strategy can work with various methods for calculating the optical surfaces, such as direct methods or optimization routines.

ABSTRACTCalcium (Ca2+) is an intracellular second messenger that ubiquitously masters remarkably diverse biological processes, including cell death. Growing evidence substantiates an involvement of the prion protein (PrPC) in regulating neuronal Ca2+homeostasis, which could rationalize most of the wide range of functions ascribed to the protein. We have recently demonstrated that PrPCcontrols extracellular Ca2+fluxes, and mitochondrial Ca2+uptake, in neurons stimulated with glutamate (De Mario et al., J Cell Sci 2017; 130:2736-46), suggesting that PrPCprotects neurons from threatening Ca2+overloads and excitotoxicity. In light of these results and of recent reports in the literature, here we review the connection of PrPCwith Ca2+metabolism and also provide some speculative hints on the physiologic outcomes of this link. In addition, because PrPCis implicated in neurodegenerative diseases, including prion disorders and Alzheimer's disease, we will also discuss possible ways by which disruption of PrPC-Ca2+association could be mechanistically connected with these pathologies.

An industrially feasible process for the fast mass-production of molded polymeric micro-patterned substrates is here presented. Microstructured polystyrene (PS) surfaces were obtained through micro injection molding (μIM) technique on directly patterned stamps realized with a new zirconia-based hybrid spin-on system able to withstand 300 cycles at 90 °C. The use of directly patterned stamps entails a great advantage on the overall manufacturing process as it allows a fast, flexible, and simple one-step process with respect to the use of milling, laser machining, electroforming techniques, or conventional lithographic processes for stamp fabrication. Among the different obtainable geometries, we focused our attention on PS replicas reporting 2, 3, and 4 μm diameter pillars with 8, 9, 10 μm center-to-center distance, respectively. This enabled us to study the effect of the substrate topography on human mesenchymal stem cells behavior without any osteogenic growth factors. Our data show that microtopography affected cell behavior. In particular, calcium deposition and osteocalcin expression enhanced as diameter and interpillar distance size increases, and the 4-10 surface was the most effective to induce osteogenic differentiation.

Micro injection moulding is a key technology for mass-production of micro structured surfaces, such as optical and microfluidic devices. The manufacturing of a microstructured master mould with traditional technologies poses challenges about durability, accuracy and high - volume production. This paper introduces a new approach to realize micro mould inserts in a fast and economical way. Suitable engineered materials as alternative inserts to the metallic one are proposed exploiting the following new strategy: a thermosetting epoxy resin from renewable sources was synthesized and used to realize the mould insert via casting. The initial low viscosity of the liquid epoxy resin precursors allows the achievement of a high fidelity replica of different micro structures and provides an inexpensive and convenient route for rapidly duplicate master mould. A staggered harringbone (SHM) micro-mixer geometry was replicated and the epoxy based resin insert withstood 900 moulding cycles showing good features replication and durability.

Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality. However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset.

Prion diseases are rare and fatal neurodegenerative disorders that occur when the cellular prion protein (PrPC) is converted into a conformationally modified isoform that originates the novel infectious agent, called prion. Although much information is now available on the different routes of prion infection, both the mechanisms underlying prion neurotoxicity and the physiologic role of PrPC remain unclear. By use of a novel paradigm, we have shown in a recent paper that - following a myotoxin-induced degenerative challenge - PrPC is implicated in the morphogenesis of the skeletal muscle of adult mice. PrPC accomplished this task by modulating signaling pathways central to the myogenic process, in particular the p38 kinase pathway. The possibility that PrPC acts in cell signaling has already been suggested after in vitro studies. Using our in vivo approach, we have instead provided proof of the physiologic relevance of PrPC commitment in signaling events, and that PrPC likely performed the task by controlling the activity of the enzyme (TACE) secreting the signaling TNF-α molecule. After a brief summary of our data, here we will discuss the suggestion, arising from our and other recent findings, implying that regulation of TACE, and of other members of the protease family TACE belongs to, may be exploited by PrPC in different cell contexts. Notably, this advancement of knowledge on PrPC physiology could also shed light on the defense mechanisms against the onset of a more common neurodegenerative disorder than prion disease, such as Alzheimer disease.

Tens of putative interacting partners of the cellular prion protein (PrPC) have been identified, yet the physiologic role of PrPCremains unclear. For the first time, however, a recent paper has demonstrated that the absence of PrPCproduces a lethal phenotype. Starting from this evidence, here we discuss the validity of past and more recent literature supporting that, as part of protein platforms at the cell surface, PrPCmay bridge extracellular matrix molecules and membrane proteins to intracellular signaling pathways.

The function of the prion protein (PrPc), implicated in transmissible spongiform encephalopathies (TSEs), is largely unknown. We examined the possible influence of PrPcon Ca2+homeostasis, by analyzing local Ca2+fluctuations in cells transfected with PrPcand Ca2+-sensitive aequorin chimeras targeted to defined subcellular compartments. In agonist-stimulated cells, the presence of PrPcsharply increases the Ca2+concentration of subplasma membrane Ca2+domains, a feature that may explain the impairment of Ca2+-dependent neuronal excitability observed in TSEs. PrPcalso limits Ca2+release from the endoplasmic reticulum and Ca2+uptake by mitochondria, thus rendering unlikely the triggering of cell death pathways. Instead, cells expressing Doppel, a PrPcparalogue, display opposite effects, which, however, are abolished by the coexpression of PrPc. These findings are consistent with the functional interplay and antagonistic role attributed to the proteins, whereby PrPcprotects, and Doppel sensitizes, cells toward stress conditions.

Prion diseases are probably caused by an abnormal form of a cellular glycoprotein, the prion protein. Recent evidence suggests that the prion strain causing BSE has been transmitted to humans, thereby provoking a variant form of Creutzfeldt–Jacob disease. In this work, we analyzed the behavior of normal and malformed isoforms of the bovine PrP in transfected mammalian cell lines. Biochemical and immunocytochemical assays were complimented with imaging of live cells expressing fusion constructs between PrP and GFP. Bovine homologues of human E200K and D178N (129M) mutations were used as models of pathogenic isoforms. We show that the GFP does not impair the metabolism of native and mutant bPrPs and is thus a valid marker of PrP cellular distribution. We also show that each amino acid replacement provokes alterations in the cell sorting and processing of bPrP. These are different from those ascribed to both murine mutant homologues. However, human and bovine PrPs carrying the D178N genotype had similar cellular behavior.

On the basis of far-Western blot and plasmon resonance (BIAcore) experiments, we show here that recombinant bovine prion protein (bPrP) (25–242) strongly interacts with the catalytic α/α´ subunits of protein kinase CK2 (also termed ‘casein kinase 2’). This association leads to increased phosphotransferase activity of CK2α, tested on calmodulin or specific peptides as substrate. We also show that bPrP counteracts the inhibition of calmodulin phosphorylation promoted by the regulatory β subunits of CK2. A truncated form of bPrP encompassing the C-terminal domain (residues 105–242) interacts with CK2 but does not affect its catalytic activity. The opposite is found with the N-terminal fragment of bPrP (residues 25–116), although the stimulation of catalysis is less efficient than with full-size bPrP. These results disclose the potential of the PrP to modulate the activity of CK2, a pleiotropic protein kinase that is particularly abundant in the brain.

Ten protein kinases have been assayed for their ability to phosphorylate in vitro the recombinant bovine PrP (25-242) (rbPrP). Substantial phosphorylation was observed with PKC, CK2, and two tyrosine kinases, Lyn and c-Fgr. With regard to CK2, phosphorylation occurs at Ser 154 with a stoichiometry of about 0.1 mol phosphate/mol rbPrP, which is doubled by mild heat treatment of rbPrP. Heat also reduces the overall protein ellipticity, suggesting that reversibly unfolded conformers are more susceptible to phosphorylation. Our data disclose the possibility that phosphorylation might modulate PrP biological activity.

Metal additive manufacturing (AM) technologies can produce complex components with unique and controlled lattice architectures and advantageous strength-to-weight properties, for which there is increasing interest by important industrial sectors, including aerospace, automotive and biomedical. One critical open issue of metal AM products is related to dimensional and geometrical verification, not only because the dimensional accuracy of products is often poor, but also because the typical geometrical complexity of such products can be difficult to evaluate via traditional measuring instruments (e.g. tactile and optical coordinate measuring systems), especially in the case of lattice structures. X-ray computed tomography (CT) can be used as a dimensional metrology tool enabling advanced control methods that are fundamental for improving the quality of complex metal AM products and processes. However, the quantification of uncertainty of CT dimensional measurements – fundamental to effectively improve the AM process based on CT metrology – is a very complex problem due to several error sources having complex nature, the lack of well accepted models of the full measurement process and consequently the current dearth of internationally standardized procedures. This work investigates a methodology for achieving metrological traceability in CT measurements of AM lattice structures. In particular, Ti6Al4V lattice structures produced by laser powder bed fusion were measured using a metrological X-ray CT system. A new reference object was designed, produced and calibrated to be similar to the investigated AM structures and to determine the task-specific uncertainty of CT-based dimensional measurements of lattice struts. In particular, the newly developed reference object enables the implementation of the substitution method, which – although being established for determining the uncertainty of CT dimensional measurements – has never been applied before to AM lattice structures. Two different approaches were investigated for the method implementation. Results and advantages were documented through dimensional verification of lattice structure features with respect to specified tolerances. Finally, limitations of the method and future perspectives are also discussed.

A patient with a severe amnesic syndrome following a glioma of the splenium of the corpus callosum is reported. The long-term memory deficit involved anterograde as well as retrograde events dating back to 40 years and causing topographical disorientation. Short-term memory test performance was in the normal range, with the exception of tactile memory which was severely impaired.The patient also showed disconnection symptoms, due to severing of occipito-parietal and parieto-temporal connections, while parieto-parietal connections were undamaged.

The inner membrane of mitochondria from various strains of Saccharomyces cerevisiae has been analyzed with the patch clamp technique for comparison with the better known homologous membrane in mammals (Sorgato, M. C., and Moran, O. (1993) CRC Crit. Rev. Biochem. Mol. Biol. 18, 127-171). Differently than in mammals, the yeast inner membrane was found to harbor essentially two channels with similar anionic selectivity but otherwise different functional behavior. One had a conductance of around 45 picosiemens (in symmetrical 150 mM KCl) and an activity only marginally sensitive to voltage. The other channel was prominent for the higher outwardly rectifying current and for the dependence upon voltage of the open probability that induced rapid closure at physiological (negative) membrane potentials. Particularly interesting was the effect of ATP (Mg2+ free) added on the matrix side of the membrane. In the case of the lower conducting channel, the nucleotide caused an immediate block of activity (IC50, 0.240 mM), whereas it locked the larger conductance in the open state at both positive and negative potentials. In proteoliposomes containing both mitochondrial membranes, the small conductance was clearly evident, whereas a larger channel, cationic and without the voltage dependence typical of that in the native inner membrane, was found.

In this report data are presented which firmly establish that by treating isolated F 0with the thiol reagent diamide, two 25 kDa F 0subunits react to form a dimer of 45 kDa apparent molecular mass. This dimerising effect is correlated to the impairment of the binding of F 1to F 0, both at μM and mM diamide concentrations. Under the latter condition, modification of other F 0subunits also occurs. Passive proton conductance through F 0, as well as its sensitivity to N, N′-dicyclohexylcarbodiimide, are affected at low diamide concentration. Thus perturbation of the cysteine residue of the 25 kDd F 0subunit is sufficient for altering the ATP synthase proton channel.

The rates of electron transport and of ATP synthesis have been measured in bovine heart Mg-ATP submito-chondrial particles oxidising succinate under conditions of partial attenuation of the proton-motive force by malonate or FCCP. This paper reports evidence that the relationship between the rate of ATP synthesis and the magnitude of the proton motive force is independent of the mode by which the decrease of the proton motive force is achieved.

We report the effects of treatment with plasma-exchange (PE) and intravenous immune globulins (IVIg) in 36 out of 50 patients with Guillain-Barré syndrome (GBS) recruited by an incidence study in the Emilia-Romagna region of Italy. Comparison of the patients treated with PE and IVIg showed no significant differences in terms of effectiveness in improving the clinical course of GBS: at one month, respectively 11.1% and 25% had recovered, and 55.5% and 58.3% had improved by at least one grade. These results are in agreement with those of the Dutch GBS trial. No relapses were observed in either group. Moreover, our results showed no difference in clinical outcome at 1 and 3 months between the patients receiving only one therapy and those receiving two; a second cycle of therapy did not seem to improve the clinical course of the disease significantly. We conclude that PE and IVIg are both safe and effective therapies for GBS.

We report the entire course of a case of thrombosis of the venous sinuses, very probably caused by contraceptive pill use, documented by MR imaging. MRI appears to be the examination of choice in such cases.

A rapid and simple method for ascites concentration and reinfusion was utilized to treat 103 episodes of tense ascites in 57 patients (38 men and 19 women, mean age 63±11 years). After a bedside total paracentesis, 6.06±2.87 liters of ascites were separately ultrafiltrated using a mechanical device during a mean interval of 134±88 min, and 430±368 ml of concentrate containing 39±42 g of albumin were restituted at bedside either intravenously (44 cases) or intraperitoneally (59 cases). Ultrafiltration was successfully and easily completed in all cases. Ascites concentration and reinfusion either intravenously or intraperitoneally did not adversely modify hemodynamic or renal parameters except for a transient decrease in mean arterial pressure (P<0.05). Transitory hyponatremia and renal failure occurred in two patients. A transient decrease in platelet count and serum fibrinogen levels (P<0.05) and pyrexia (12%) were observed only in patients reinfused intravenously. In conclusion, this new method for ascites concentration and reinfusion was effective, safe, and, with respect to traditional methods, simpler, faster and more comfortable. Therefore it is proposed for the routine management of tense ascites.

Liposome-bound haematoporphyrin or haematoporphyrin dimethylester, as well as haematoporphyrin dissolved in phosphate-buffered saline, were added to HeLa cell monolayers at a dose of 1 μg of porphyrin per 105 cells. After 2 min or 20 min incubation liposome-bound porphyrins were accumulated by cells in an about two-fold larger amount than the water-dissolved haematoporphyrin. This caused a more efficient photosensitization of HeLa cells by liposome-delivered porphyrins upon illumination with 366 nm light. Ultrastructural studies of HeLa cells, which had been incubated in a physiological medium for 24 h after the end of irradiation, showed that liposomal porphyrins induce an early and extensive endocytoplasmic damage, leading to swelling of the mitochondria and vesiculation; changes of the permeability of the cytoplasmic membrane are also evident, especially in the case of haematoporphyrin dimethylester. On the other hand, water-dissolved haematoporphyrin predominantly photosensitizes damage of the plasma membrane. The different pattern of cell photodamage probably reflects a different subcellular distribution of the photosensitizing drugs.

The problem of whether the rate of ATP synthesis is proportional to the magnitude of the protonmotive force has been studied in submitochondrial particles. It was found that the rate of ATP synthesis can decrease at constant protonmotive force and is more closely related to the rate of substrate oxidation.