White matter predicts functional connectivity in premanifest Huntington's disease.

OBJECTIVES: The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. METHODS: Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. RESULTS: We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. INTERPRETATION: Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero-posterior dissociation that is in keeping with the caudo-rostral gradient of striatal pathology in HD.

Mid-infrared nonlinear optical response of Si-Ge waveguides with ultra-short optical pulses.

We characterize the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared between 3.3 µm and 4 µm using femtosecond optical pulses. We estimate the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index from the experimental measurements. The effect of multiphoton absorption on the optical nonlinear Kerr response is evaluated and the nonlinear figure of merit estimated providing some guidelines for designing nonlinear optical devices in the mid-IR. Finally, we compare the impact of free-carrier absorption at mid-infrared wavelengths versus near-infrared wavelengths for these ultra-short pulses.

EBV-Specific Immune Response: Early Research and Personal Reminiscences.

Early research on Epstein-Barr virus (EBV) developed from serological observations that were made soon after the discovery of the virus. Indeed, the definition of the humoral response to a variety of EBV proteins dominated the early literature and was instrumental in providing the key evidence for the association of the virus with infectious mononucleosis (IM), Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC). Each of these disease associations involved a distinct pattern of serological reactivity to the EBV membrane antigens (MA), early antigens (EA), and the EBV nuclear antigen (EBNA). When it became generally accepted that the marked lymphocytosis , which is a hallmark of acute IM, was dominated by T cells, considerable effort was directed toward untangling the specificities that might be associated with restricting the proliferation of newly infected B cells. Early evidence was divided between support for both EBV non-specific and/or HLA non-restricted components. However, all results needed to be reassessed in light of the observation that T cells died by apoptosis within hours of separation from fresh blood from acute IM patients. The observation that EBV-infected cultures from immune (but not non-immune) individuals began to die (termed regression) about 10 days post-seeding, provided the first evidence of a specific memory response which was apparently capable of controlling the small pool of latently infected B cells which all immune individuals possess. In this early era, CD8(+) T cells were thought to be the effector population responsible for this phenomenon, but later studies suggested a role for CD4(+) cells. This historical review includes reference to key early observations in regard to both the specific humoral and cellular responses to EBV infection from the time of the discovery of the virus until 1990. As well, we have included personal recollections in regard to the events surrounding the discovery of the memory T cell response since we believe they add a human dimension to a chapter focussed on early history.

Nonlinear optical response of low loss silicon germanium waveguides in the mid-infrared.

We have investigated the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared wavelength range from 3.25- 4.75µm using picosecond optical pulses. We observed and measured the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index. The dynamics of the spectral broadening suggests that, in addition to multiphoton absorption, the corresponding higher order nonlinear refractive phenomena also needs to be included when high optical pulse intensities are used at mid-infrared wavelengths in this material.

Amorphous silicon nanowires combining high nonlinearity, FOM and optical stability.

We demonstrate optically stable amorphous silicon nanowires with both high nonlinear figure of merit (FOM) of ~5 and high nonlinearity Re(γ) = 1200W(-1)m(-1). We observe no degradation in these parameters over the entire course of our experiments including systematic study under operation at 2 W coupled peak power (i.e. ~2GW/cm(2)) over timescales of at least an hour.

Demonstration of a stable ultrafast laser based on a nonlinear microcavity.

Ultrashort pulsed lasers, operating through the phenomenon of mode-locking, have had a significant role in many facets of our society for 50 years, for example, in the way we exchange information, measure and diagnose diseases, process materials, and in many other applications. Recently, high-quality resonators have been exploited to demonstrate optical combs. The ability to phase-lock their modes would allow mode-locked lasers to benefit from their high optical spectral quality, helping to realize novel sources such as precision optical clocks for applications in metrology, telecommunication, microchip-computing, and many other areas. Here we demonstrate the first mode-locked laser based on a microcavity resonator. It operates via a new mode-locking method, which we term filter-driven four-wave mixing, and is based on a CMOS-compatible high quality factor microring resonator. It achieves stable self-starting oscillation with negligible amplitude noise at ultrahigh repetition rates, and spectral linewidths well below 130 kHz.

Exploitation of chick embryo environments to reprogram MYCN-amplified neuroblastoma cells to a benign phenotype, lacking detectable MYCN expression.

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia (SG) or adrenal gland. Tumours that occur in patients under 18 months of age have a particularly good prognosis and frequently undergo spontaneous regression. This led to the hypothesis that developmental cues in the youngest patients may prompt belated differentiation and/or apoptosis of the tumour cells. To test our hypothesis, we have injected MYCN-amplified neuroblastoma cells into the extra embryonic veins of chick embryos at embryonic day 3 (E3) and E6 and analysed the response of these Kelly cells at E10 and E14. Amplification of the MYCN gene occurs in up to 30% of tumours and is normally associated with a very poor prognosis. Kelly cells injected at E3 follow neural crest pathways and integrate into neural locations such as SG and the enteric nervous system although never into the adrenal gland. Additionally they migrate to non-neural locations such as the heart, meninges, jaw regions and tail. The cells respond to their respective microenvironments and in SG, some cells differentiate, they show reduced cell division and crucially all cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. We propose that the MYCN-amplicon in the Kelly cells retains the ability to correctly interpret the environmental cues leading to downregulation of MYCN.

All-optical wavelength conversion for 10 Gb/s DPSK signals in a silicon ring resonator.

We demonstrate all-optical wavelength conversion at 10 Gb/s for differential phase-shift keyed (DPSK) data signals in the C-band, based on four-wave mixing (FWM) in a silicon ring resonator. Error-free operation with a system penalty of ~4.1 dB at 10⁻9 BER is achieved.

All-optical XOR logic gate for 40Gb/s DPSK signals via FWM in a silicon nanowire.

We demonstrate an all-optical XOR logic function for 40Gb/s differential phase-shift keyed (DPSK) data signals in the C-band, based on four-wave mixing (FWM) in a silicon nanowire. Error-free operation with a system penalty of ~3.0dB and ~4.3dB at 10⁻9 BER is achieved.

On-chip CMOS-compatible all-optical integrator.

All-optical circuits for computing and information processing could overcome the speed limitations intrinsic to electronics. However, in photonics, very few fundamental 'building blocks' equivalent to those used in multi-functional electronic circuits exist. In this study, we report the first all-optical temporal integrator in a monolithic, integrated platform. Our device--a lightwave 'capacitor-like' element based on a passive micro-ring resonator--performs the time integral of the complex field of an arbitrary optical waveform with a time resolution of a few picoseconds, corresponding to a processing speed of ∼200 GHz, and a 'hold' time approaching a nanosecond. This device, compatible with electronic technology (complementary metal-oxide semiconductor), will be one of the building blocks of next-generation ultrafast data-processing technology, enabling optical memories and real-time differential equation computing units.

Optical signal processing on a silicon chip at 640Gb/s using slow-light.

We demonstrate optical performance monitoring of in-band optical signal to noise ratio (OSNR) and residual dispersion, at bit rates of 40Gb/s, 160Gb/s and 640Gb/s, using slow-light enhanced optical third harmonic generation (THG) in a compact (80microm) dispersion engineered 2D silicon photonic crystal waveguide. We show that there is no intrinsic degradation in the enhancement of the signal processing at 640Gb/s relative to that at 40Gb/s, and that this device should operate well above 1Tb/s. This work represents a record 16-fold increase in processing speed for a silicon device, and opens the door for slow light to play a key role in ultra-high bandwidth telecommunications systems.

Error-free all-optical demultiplexing at 160Gb/s via FWM in a silicon nanowire.

We demonstrate all-optical time division demultiplexing from 160Gb/s to 10Gb/s in the C-band, based on four-wave mixing (FWM) in a silicon nanowire. We achieve error-free operation with a system penalty of approximately 3.9dB at 10(-9) BER.

Low power four wave mixing in an integrated, micro-ring resonator with Q = 1.2 million.

We demonstrate efficient, low power, continuous-wave four-wave mixing in the C-band, using a high index doped silica glass micro ring resonator having a Q-factor of 1.2 million. A record high conversion efficiency for this kind of device is achieved over a bandwidth of 20 nm. We show theoretically that the characteristic low dispersion enables phase-matching over a tuning range > 160 nm.

Two-photon photodetector in a multiquantum well GaAs laser structure at 1.55 microm.

We report two-photon photocurrent in a GaAs/AlGaAs multiple quantum well laser at 1.55 microm. Using 1ps pulses, a purely quadratic photocurrent is observed. We measure the device efficiency, sensitivity, as well as the two-photon absorption coefficient. The results show that the device has potential for signal processing, autocorrelation and possibly two-photon source applications at sub-Watt power levels.

Two-photon absorption effects on Raman gain in single mode As2Se3 chalcogenide glass fiber.

We report approximately 22 dB of Raman gain in single mode As(2)Se(3) chalcogenide glass fiber using 15 ps optical pump pulses from 1470 nm to 1560 nm. We employ a novel technique of cross-phase modulation induced sideband amplification to map out the Raman gain spectrum of this glass, and investigate the role of both degenerate and non-degenerate (ND) two-photon absorption (TPA). We find that for materials such as As(2)Se(3) where the Raman gain coefficient (gR) and TPA are comparable, it is critical to know and account for the role of both of these in order to achieve appreciable Raman gain. This is highlighted by our results, where we achieve significantly higher Raman gain at the longest pump wavelength (1560 nm), despite the fact that the Raman gain coefficient itself (gR) is smallest at this wavelength. This occurs because the TPA is significantly larger for shorter wavelengths in As(2)Se(3). We conclude, therefore, that for Raman gain applications in As(2)Se(3), L-band operation is strongly favored over C-band operation.

High bit rate all-optical signal processing in a fiber photonic wire.

We report the first demonstration of high bit rate signal processing by a fiber-based photonic wire. We achieve 160 Gb/s demultiplexing via four wave mixing in a 1.9 microm diameter photonic wire tapered from As(2)S(3) chalcogenide glass single mode fibre, with very low pump power requirements ( < 20 mW average power, 0.45 W peak power), enabled by a very high nonlinearity (gamma approximately 7850 W(-1) km (-1) ) and greatly reduced dispersion.

The use of T-cell directed cellular therapies in Australia.

The use of cellular therapy in Australia has been limited by the number of facilities deemed acceptable for the preparation of T cells for immunotherapy. In spite of this, a number of trials using cellular immunotherapy have been conducted and a number are underway or are in the planning stage, and selected examples of these are summarized in this review.

Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours.

The four GPI-anchored cell adhesion molecules that exemplify the IgLON family are most highly expressed in the nervous system and associate to form up to six different heterodimeric 'Diglons' that can modify cell adhesion and inhibit axon migration. Recently, two members, OPCML and LSAMP, were identified as putative tumour suppressor genes in ovarian and renal carcinomas respectively. In this study, we investigated OPCML expression in nonneoplastic brain tissue and 35 brain tumours (18 glioblastoma multiformes, five anaplastic gliomas, five meningiomas, six metastases and one medulloblastoma) and four glioma cell lines using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). OPCML was highly expressed in cerebellum, less so in cerebral cortex, frontal lobe and meninges and was significantly reduced or absent in 83% of brain tumours and all cell lines compared with nonneoplastic whole brain. Two OPCML splice variants have been identified in humans, termed alpha1 and alpha2, but the latter has not been demonstrated in human neural tissues. Using PCR with specific primers, nonneoplastic brain and 3/6 of tested brain tumours expressed both splice variants, whereas the remaining brain tumours only expressed the alpha2 variant. Hypermethylation of the alpha1 OPCML promoter, associated with down-regulation of expression in ovarian tumours, did not correlate with expression levels in the subset of brain tumours tested, implying transcription of OPCML from an alternative promoter or a different mechanism of down-regulation. This study demonstrates that OPCML down-regulation occurs in the majority of brain tumours tested, warranting further investigation of OPCML and other IgLONs in the development and progression of brain tumours.

Treatment options for post-transplant lymphoproliferative disorder and other Epstein-Barr virus-associated malignancies.

Epstein-Barr virus (EBV) is associated with a range of malignancies that largely arise from a defect in EBV-specific cytotoxic T lymphocyte (CTL) immunity and function. Much work has focused on the reconstitution of CTL immunity to EBV in transplant patients, in whom immunosuppression modalities render them susceptible to post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of autologous CTLs is effective at both preventing and curing PTLD in solid organ transplant recipients and can produce a long-term memory response and protection against recurring disease. In this review, the benefits and restrictions of administering EBV-specific CTLs for the treatment of PTLD are discussed and compared with emerging therapies including the generation of allogeneic human leukocyte antigen-matched CTL banks and the anti-CD20 monoclonal antibody therapy, MabThera. Furthermore, studies involving other EBV-associated disorders have described the potential benefit of adoptive transfer of EBV-specific CTLs for Hodgkin's disease, nasopharyngeal carcinoma, chronic active EBV infection, and Burkitt's lymphoma. The challenges of tailor-making therapies for individual diseases and EBV antigen expression latencies are highlighted, in addition to considering vaccination strategies for optimal treatment.

No barrier to diffusion between cell soma and neurite membranes in sympathetic neurons for a GPI-anchored glycoprotein.

As neurons extend their axons, it is thought that newly synthesised membrane components travel in vesicles along the axon, fuse with the growth cone membrane, and diffuse back along the axonal membrane. However, it is difficult to explain how axons continue to be populated with membrane proteins as they extend in length. To investigate this problem, we have used a CEPU-green fluorescent protein (GFP) chimeric protein to study the site of insertion of new glycosyl phosphatidyl inositol (GPI)-anchored glycoproteins and their subsequent behaviour in chick dorsal root ganglia (DRG) neurons. Infection of cultures grown for 24 h revealed rapid expression of CEPU-GFP over the whole surface of the neuron, more rapidly than could be accounted for by diffusion from the growth cone, and fluorescence intensity was uniform along the length of the neurite. Photobleaching experiments of neurite membrane revealed that recovery of fluorescence was due to diffusion from adjacent membranes and there was no evidence for membrane flow in either direction. Photobleaching of membrane adjacent to the cell body also showed rapid recovery, with chimera diffusing both from cell body membrane and the distal neurite membrane into the bleached area. These results suggest there is no barrier to diffusion between the cell body and neurite membrane in DRG and sympathetic neurons cultured for 1 or 2 days in vitro. We propose that the neurite is populated by newly synthesised chimera by diffusion from both regions. This situation may also occur in neurons in the early stages of extending axons in vivo prior to polarisation and the development of the dendritic field.