Identification of spatial intensity profiles from femtosecond laser machined depth profiles via neural networks.

Laser machining involves many complex processes, especially when using femtosecond pulses due to the high peak intensities involved. Whilst conventional modelling, such as those based on photon-electron interactions, can be used to predict the appearance of the surface after machining, this generally becomes unfeasible for micron-scale features and larger. The authors have previously demonstrated that neural networks can simulate the appearance of a sample when machined using different spatial intensity profiles. However, using a neural network to model the reverse of this process is challenging, as diffractive effects mean that any particular sample appearance could have been produced by a large number of beam shape variations. Neural networks struggle with such one-to-many mappings, and hence a different approach is needed. Here, we demonstrate that this challenge can be solved by using a neural network loss function that is a separate neural network. Here, we therefore present a neural network that can identify the spatial intensity profiles needed, for multiple laser pulses, to produce a specific depth profile in 5 µm thick electroless nickel.

Modelling laser machining of nickel with spatially shaped three pulse sequences using deep learning.

Femtosecond laser machining is a complex process, owing to the high peak intensities involved. Modelling approaches for the prediction of final sample quality based on photon-atom interactions are therefore challenging to extrapolate up to the microscale and beyond. The problem is compounded when multiple exposures are used to produce a final structure, where surface modifications from previous exposures must be taken into consideration. Neural network approaches allow for the automatic creation of a model that accounts for these challenging processes, without any physical knowledge of the processes being programmed by a specialist. We present such a network for the prediction of surface quality for multi-exposure femtosecond machining on a 5µm electroless nickel layer deposited on copper, where each pulse is uniquely spatially shaped using a spatial light modulator. This neural network modelling method accurately predicts the surface profile after three, sequential, overlapping exposures of dissimilar intensity patterns. It successfully reproduces such effects as the sub-diffraction limit machining feasible with multiple exposures, and the smoothing effect on edge-burr from previous exposures expected in multi-exposure laser machining.

From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis.

Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.

Laser-Induced Forward Transfer-printing of focused ion beam pre-machined crystalline magneto-optic yttrium iron garnet micro-discs.

We present femtosecond laser-induced forward transfer of focused ion beam pre-machined discs of crystalline magneto-optic yttrium iron garnet (YIG) films. Debris-free circular micro-discs with smooth edges and surface uniformity have been successfully printed. The crystalline nature of the printed micro-discs has not been altered by the LIFT printing process, as was confirmed via micro-Raman measurements.

Laser-patterned paper-based flow-through filters and lateral flow immunoassays to enable the detection of C-reactive protein.

We report the use of a laser-based fabrication process in the creation of paper-based flow-through filters that when combined with a traditional lateral flow immunoassay provide an alternative pathway for the detection of a pre-determined analyte over a wide concentration range. The laser-patterned approach was used to create polymeric structures that alter the porosity of the paper to produce porous flow-through filters, with controllable levels of porosity. When located on the top of the front end of a lateral flow immunoassay the flow-through filters were shown to block particles (of known sizes of 200 nm, 500 nm, 1000 nm and 3000 nm) that exceed the effective pore size of the filter while allowing smaller particles to flow through onto a lateral flow immunoassay. The analyte detection is based on the use of a size-exclusive filter that retains a complex (∼3 µm in size) formed by the binding of the target analyte with two antibodies each of which is tagged with different-sized labels (40 nm Au-nanoparticles and 3 µm latex beads), and which is larger than the effective pore size of the filter. This method was tested for the detection of C-reactive protein in a broad concentration range from 10 ng/ml to 100,000 ng/ml with a limit-of-detection found at 13 ng/ml and unlike other reported methods used for analyte detection, with this technique we are able to counter the Hook effect which is a limiting factor in many lateral flow immunoassays.

Waveguide mode filters fabricated using laser-induced forward transfer.

Titanium (Ti)-in-diffused lithium niobate waveguide mode filters fabricated using laser-induced forward transfer followed by thermal diffusion are presented. The mode control was achieved by adjusting the separation between adjacent Ti segments thus varying the average value of the refractive index along the length of the in-diffused channel waveguides. The fabrication details, loss measurements and near-field optical characterization of the mode filters are presented. Modeling results regarding the device performance are also discussed.

Latent light-assisted poling of LiNbO3.

The observation of latent light-assisted poling (LAP) in lithium niobate single crystals is reported. More specifically, the nucleation field is reduced and remains reduced for an extended time period (up to several hours) after irradiation with ultrafast (approximately 150 fs) laser light at a wavelength of 400 nm. The maximum nucleation field reduction measured using latent-LAP (62%) was significantly higher in comparison with regular non-time-delayed LAP (41%) under identical irradiation conditions in undoped congruent lithium niobate crystals. No latent-LAP effect was observed in MgO-doped crystals for the experimental conditions used, despite the strong effect observed using regular LAP. The latent-LAP effect is attributed to the formation of a slowly decaying photo-induced space-charge distribution which assists local ferroelectric domain nucleation. The dynamics of latent-LAP are compared with the dynamics of photorefractive grating decay, recorded in lithium niobate crystals of different doping, confirming the space charge hypothesis.

Spectral and electro-optic response of UV-written waveguides in LiNbO3 single crystals.

An experimental study of the spectral and electro-optic response of direct UV-written waveguides in LiNbO3 is reported. The waveguides were written using c.w. laser radiation at 275, 300.3, 302, and 305 nm wavelengths with various writing powers (35-60 mW) and scan speeds (0.1-1.0 mm/sec). Spectral analysis was used to determine the multimode and single mode wavelength regions and, the cut-off point of the fabricated waveguides. Electro-optic characterization of these waveguides reveals that the electro-optic coefficient (r33) decreases for longer writing wavelengths, with a maximum of 31 pm/V for 275 nm and, is reduced to 14 pm/V for waveguides written with 305 nm.

Evoked cortical potentials: relation to visual field and handedness.

The amplitiude of evoked responses of occipital cortex in man depends on the visual field in which the stimulus appears. Greater responses occurred repeatedly for two of three subjects, both left-handed. when the stimululs appeared in the left field than in the right. Subsequent tests of 13 right- and 13 left-handed males indicted that the magnitude of the response of the right lobe, relative to that of the left, was greater for left-handed individuals. We conclude that the difference in amplitude between the two lobes is related to handedness.

Direct-writing of inverted domains in lithium niobate using a continuous wave ultra violet laser.

The inversion of ferroelectric domains in lithium niobate by a scanning focused ultra-violet laser beam (lambda = 244 nm) is demonstrated. The resulting domain patterns are interrogated using piezoresponse force microscopy and by chemical etching in hydrofluoric acid. Direct ultra-violet laser poling was observed in un-doped congruent, iron doped congruent and titanium in-diffused congruent lithium niobate single crystals. A model is proposed to explain the mechanism of domain inversion.

Dielectric binary oxide films as waveguide laser media: a review.

Sapphire (α-Al(2)O(3)), amorphous and polycrystalline Al(2)O(3), tantalum pentoxide Ta(2)O(5) and the sesquioxides Y(2)O(3), Sc(2)O(3), and Lu(2)O(3) are excellent laser hosts due to their very good thermomechanical properties, broad transparency range and ease of doping with active ions. This article reviews recent research towards the realization of active optical films and the demonstration of gain and laser operation in the waveguides produced from these materials. Compound structures in which laser operation has been demonstrated are highlighted together with the applied fabrication techniques, and details of the laser performance are presented.

Submicron patterning of DNA oligonucleotides on silicon.

The covalent attachment of DNA oligonucleotides onto crystalline silicon (100) surfaces, in patterns with submicron features, in a straightforward, two-step process is presented. UV light exposure of a hydrogen-terminated silicon (100) surface coated with alkenes functionalized with N-hydroxysuccinimide ester groups resulted in the covalent attachment of the alkene as a monolayer on the surface. Submicron-scale patterning of surfaces was achieved by illumination with an interference pattern obtained by the transmission of 248 nm excimer laser light through a phase mask. The N-hydroxysuccinimide ester surface acted as a template for the subsequent covalent attachment of aminohexyl-modified DNA oligonucleotides. Oligonucleotide patterns, with feature sizes of 500 nm, were reliably produced over large areas. The patterned surfaces were characterized with atomic force microscopy, scanning electron microscopy, epifluorescence microscopy and ellipsometry. Complementary oligonucleotides were hybridized to the surface-attached oligonucleotides with a density of 7 x 10(12) DNA oligonucleotides per square centimetre. The method will offer much potential for the creation of nano- and micro-scale DNA biosensor devices in silicon.

Laser direct-write for fabrication of three-dimensional paper-based devices.

We report the use of a laser-based direct-write (LDW) technique that allows the design and fabrication of three-dimensional (3D) structures within a paper substrate that enables implementation of multi-step analytical assays via a 3D protocol. The technique is based on laser-induced photo-polymerisation, and through adjustment of the laser writing parameters such as the laser power and scan speed we can control the depths of hydrophobic barriers that are formed within a substrate which, when carefully designed and integrated, produce 3D flow paths. So far, we have successfully used this depth-variable patterning protocol for stacking and sealing of multi-layer substrates, for assembly of backing layers for two-dimensional (2D) lateral flow devices and finally for fabrication of 3D devices. Since the 3D flow paths can also be formed via a single laser-writing process by controlling the patterning parameters, this is a distinct improvement over other methods that require multiple complicated and repetitive assembly procedures. This technique is therefore suitable for cheap, rapid and large-scale fabrication of 3D paper-based microfluidic devices.

The efficiency of folding of some proteins is increased by controlled rates of translation in vivo. A hypothesis.

We propose that the way in which some proteins fold is affected by the rates at which regions of their polypeptide chains are translated in vivo. Furthermore, we suggest that their gene sequences have evolved to control the rate of translational elongation such that the synthesis of defined portions of their polypeptide chains is separated temporally. We stress that many proteins are capable of folding efficiently into their native conformations without the help of differential translation rates. For these proteins the amino acid sequence does indeed contain all the information needed for the polypeptide chain to fold correctly (even in vitro, after denaturation). However, other proteins clearly do not fold efficiently into their native conformation in vitro. We argue that the efficiency of folding of these problematic proteins in vivo may be improved by controlled synthesis of the nascent polypeptide.

The secretory leukocyte protease inhibitor gene is a target of epidermal growth factor receptor action in endometrial epithelial cells.

The over-expression of epidermal growth factor receptor (EGFR) and its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha, is a common feature of epithelial carcinomas and correlates with neoplastic progression. Secretory leukocyte protease inhibitor (SLPI), a member of the Kazal superfamily of serine anti-proteases, induces proliferation and promotes malignancy of epithelial cells and is expressed at high levels in multiple tumor types. In the present study, we have demonstrated that EGF increases SLPI expression in the human endometrial epithelial cell line Ishikawa in a dose- and time-dependent manner. We have shown that this effect of EGF occurs, in part, at the level of the SLPI promoter and involves the MAP kinase signaling pathway. We have further shown that EGF promotion of cell proliferation, but not induction of cyclin D1 gene expression, involves SLPI. Our results suggest that the regulation of SLPI expression by EGFR ligand(s) may represent a 'feed-forward' mechanism by which the enhanced proliferative and migratory properties of EGFR over-expressing cancer cells are sustained. Increased SLPI expression is likely an important component of altered EGFR signaling in human tumors and may have significant therapeutic implications in cancer progression.

Single-transverse-mode Ti:sapphire rib waveguide laser.

Laser operation of Ti:sapphire rib waveguides fabricated using photolithography and ion beam etching in pulsed laser deposited layers is reported. Polarized laser emission was observed at 792.5 nm with an absorbed pump power threshold of 265 mW, which is more than a factor of 2 lower in comparison to their planar counterparts. Measured beam propagation factors M2x and M2y of 1.3 and 1.2, respectively, indicated single-transverse-mode emission. A quasi-cw output power of 27 mW for an absorbed pump power of 1W and a slope efficiency of 5.3% were obtained using an output coupler of 4.6% transmission with a pump duty cycle of 8%.

Engineering fluidic delays in paper-based devices using laser direct-writing.

We report the use of a new laser-based direct-write technique that allows programmable and timed fluid delivery in channels within a paper substrate which enables implementation of multi-step analytical assays. The technique is based on laser-induced photo-polymerisation, and through adjustment of the laser writing parameters such as the laser power and scan speed we can control the depth and/or the porosity of hydrophobic barriers which, when fabricated in the fluid path, produce controllable fluid delay. We have patterned these flow delaying barriers at pre-defined locations in the fluidic channels using either a continuous wave laser at 405 nm, or a pulsed laser operating at 266 nm. Using this delay patterning protocol we generated flow delays spanning from a few minutes to over half an hour. Since the channels and flow delay barriers can be written via a common laser-writing process, this is a distinct improvement over other methods that require specialist operating environments, or custom-designed equipment. This technique can therefore be used for rapid fabrication of paper-based microfluidic devices that can perform single or multistep analytical assays.

Genetic immunization of chimpanzees chronically infected with the hepatitis B virus, using a recombinant retroviral vector encoding the hepatitis B virus core antigen.

Cytotoxic T lymphocyte (CTL) activity and CD4+ helper T cell responses to the hepatitis B virus (HBV) core antigen (HBcAg) have been implicated in clearance of acute and chronic HBV infections. We showed that intramuscular injections of a novel recombinant retroviral vector expressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion protein induces HBc/eAg-specific antibodies and CD4+ and CD8+ T cell responses in mice and rhesus monkeys. We have now immunized three chronically infected chimpanzees, each with 10(10) CFU of nonreplicating retroviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg-specific CTLs and showed marginal, transient elevations of alanine aminotransferase (ALT) levels following injection. However, both chimpanzees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load throughout the study. In contrast, the third chimpanzee exhibited a traditional seroconversion evidenced by a loss of serum HBeAg and the subsequent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitations, the present study demonstrates (1) the safety of treatment with high titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immunization may be therapeutically beneficial in the treatment of chronic HBV infection.

The conjoint influence of spatial selective attention and motor set on very short latency VERs.

This study investigated whether motor set, in conjunction with spatial selective attention (sensory set), influences the transmission of incoming visual information at a precortical level in humans. Stimuli were presented concomitantly in both the right and left visual fields while subjects attended to the relevant visual field (either left or right) on a given trial, and was prepared to make one of three kinds of responses (an eye movement, foot-lift, or counting) to target stimuli appearing in that field. VERs were obtained from frontal and parietal sites. A deflection falling within a 40-70 msec range was more negative under the attend than under the unattend condition for the eye movement task, the opposite being the case for the counting task. No attention effect was found for the foot-lift task. The findings were interpreted as providing support for the precortical hypothesis.

Tropical pyomyositis in the Solomon Islands: clinical and aetiological features.

A prospective study of tropical pyomyositis (TP) in the Solomon Islands' Western Province followed 48 cases (mean age 10.6 years) from a population of 20,000 Melanesians over a two-year period. 32 patients were under 10 years and the male:female ratio was 1.7. Affected muscle was painful, swollen and often fluctuant but hard and indurated in presuppurative lesions. Abscesses, single in 40 and multiple in 8 subjects, were sited in the large muscles of the buttock, thigh, shoulder, arm and back on 52 occasions (90%). They contained 5-200 ml of pus which invariably grew penicillin-resistant Staphylococcus aureus sensitive to cloxacillin and erythromycin. All phage typable strains were identified as group 2 in contrast to the wider range of types found at carrier sites in otherwise healthy controls. TP was preceded by trauma in 30 cases (63%) and 26 (55%) of the patients had pre-existing pyoderma. Histological examination of clinically unaffected muscle biopsies from 10 subjects with solitary (7) or multiple (3) abscesses showed no abnormality. Serological evidence of previous infection with adenoviruses or myxoviruses was present in the same proportion (41-42%) of controls as of 22 patients tested. The results provide no evidence for antecedent diffuse myositis, viral or parasitic infections or nutritional deficiencies but support the role of trauma in localizing haematogenous skin staphylococci into damaged muscle.