Genetic characterization of the zoonotic parasite Ancylostoma caninum in the central and eastern United States.

Ancylostoma caninum is the most common nematode parasite of dogs in the United States. The present study aimed to describe the molecular epidemiology of A. caninum isolates from the central and eastern states of the United States using the partial mitochondrial cytochrome oxidase (cox1) gene and to compare them with those reported globally. We isolated eggs from faecal samples of dogs and characterized each isolate based on cox1 sequences. A total of 60 samples originating from Kansas, Iowa, New York, Florida and Massachusetts were included. 25 haplotypes were identified in the United States dataset with high haplotype diversity (0.904). Sequence data were compared to sequences from other world regions available in GenBank. Global haplotype analysis demonstrated 35 haplotypes with a haplotype diversity of 0.931. Phylogenetic and network analysis provide evidence for the existence of moderate geographical structuring of A. caninum haplotypes. Our results provide an updated summary of A. caninum haplotypes and data for neutral genetic markers with utility for tracking hookworm populations. Sequences have been deposited in GenBank (ON980650-ON980674). Further studies of isolates from other regions are essential to understand the genetic diversity of this parasite.

Electrically Controllable Kondo Correlation in Spin-Orbit-Coupled Quantum Point Contacts.

Integrating the Kondo correlation and spin-orbit interactions, each of which have individually offered unprecedented means to manipulate electron spins, in a controllable way can open up new possibilities for spintronics. We demonstrate electrical control of the Kondo correlation by coupling the bound spin to leads with tunable Rashba spin-orbit interactions, realized in semiconductor quantum point contacts. We observe a transition from single to double peak zero-bias anomalies in nonequilibrium transport-the manifestation of the Kondo effect-indicating a controlled Kondo spin reversal using only spin-orbit interactions. Universal scaling of the Kondo conductance is demonstrated, implying that the spin-orbit interactions could enhance the Kondo temperature. A theoretical model based on quantum master equations is also developed to calculate the nonequilibrium quantum transport.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study.

High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.

Analysing the impact of living in a rural setting on the presentation and outcome of colorectal cancer. A prospective single centre observational study.

INTRODUCTION: Approximately 17% of the Scottish population lives in a remote or rural location. Current research is contradictory as to whether living a rural location leads to poorer outcomes or affects survival from colorectal cancer (CRC). We aimed to assess if living in a rural location influences outcome of CRC patients in 21st century UK medicine. METHODS: A prospective single-centre observational study was conducted. All patients who underwent resection for colorectal cancer 2005-2016 in NHS Grampian were included. Patients were split into two groups for comparison (urban post-code vs rural) using the Scottish government two-tier classification system. Tumour location, one-year survival, lymph node involvement and extra-mural vascular invasion was recorded and compared between the groups. RESULTS: Of 2463 patients, 843 (34.2%) lived in a rural area. Rural patients were more likely to be detected through screening (17.4% versus 14.6%, p = 0.04). There were no differences in pathology between rural and urban groups if detected through screening. However, rural patients detected through symptomatic pathways were more likely to be node positive p = 0.015. On multivariable analysis, rurality did not independently predict for node positive presentation. Furthermore, there were no differences in cumulative survival between the two groups. CONCLUSION: Although there were some differences in pathological characteristics between rural and urban patients, place of residence did not independently predict for outcome in this cohort. Rurality had previously been shown to impact on outcome up to 20 years ago. Improvements in infrastructure and rural healthcare may have influenced this change.

Zero-Magnetic Field Fractional Quantum States.

Since the discovery of the fractional quantum Hall effect in 1982 there has been considerable theoretical discussion on the possibility of fractional quantization of conductance in the absence of Landau levels formed by a quantizing magnetic field. Although various situations have been theoretically envisaged, particularly lattice models in which band flattening resembles Landau levels, the predicted fractions have never been observed. In this Letter, we show that odd and even denominator fractions can be observed, and manipulated, in the absence of a quantizing magnetic field, when a low-density electron system in a GaAs based one-dimensional quantum wire is allowed to relax in the second dimension. It is suggested that such a relaxation results in formation of a zigzag array of electrons with ring paths which establish a cyclic current and a resultant lowering of energy. The behavior has been observed for both symmetric and asymmetric confinement but increasing the asymmetry of the confinement potential, to result in a flattening of confinement, enhances the appearance of new fractional states. We find that an in-plane magnetic field induces new even denominator fractions possibly indicative of electron pairing. The new quantum states described here have implications both for the physics of low dimensional electron systems and also for quantum technologies. This work will enable further development of structures which are designed to electrostatically manipulate the electrons for the formation of particular configurations. In turn, this could result in a designer tailoring of fractional states to amplify particular properties of importance in future quantum computation.

Experimental Realization of a Quantum Dot Energy Harvester.

We demonstrate experimentally an autonomous nanoscale energy harvester that utilizes the physics of resonant tunneling quantum dots. Gate-defined quantum dots on GaAs/AlGaAs high-electron-mobility transistors are placed on either side of a hot-electron reservoir. The discrete energy levels of the quantum dots are tuned to be aligned with low energy electrons on one side and high energy electrons on the other side of the hot reservoir. The quantum dots thus act as energy filters and allow for the conversion of heat from the cavity into electrical power. Our energy harvester, measured at an estimated base temperature of 75 mK in a He^{3}/He^{4} dilution refrigerator, can generate a thermal power of 0.13 fW for a temperature difference across each dot of about 67 mK.

Detection of alpha-synuclein conformational variants from gastro-intestinal biopsy tissue as a potential biomarker for Parkinson's disease.

AIMS: Gastrointestinal (GI) α-synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well-characterized cohort of PD patients and healthy controls (HC). METHODS: With immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS-PLA), we targeted oligomeric aSyn species specifically; and with paraffin-embedded tissue blot (AS-PET-blot) we aimed to detect fibrillary, synaptic aSyn. RESULTS: A total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS-PLA (cellular and diffuse signal) and with AS-PET-blot (aSyn-localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC. CONCLUSIONS: Our study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

Electrical Control of the Zeeman Spin Splitting in Two-Dimensional Hole Systems.

Semiconductor holes with strong spin-orbit coupling allow all-electrical spin control, with broad applications ranging from spintronics to quantum computation. Using a two-dimensional hole system in a gallium arsenide quantum well, we demonstrate a new mechanism of electrically controlling the Zeeman splitting, which is achieved through altering the hole wave vector k. We find a threefold enhancement of the in-plane g-factor g_{∥}(k). We introduce a new method for quantifying the Zeeman splitting from magnetoresistance measurements, since the conventional tilted field approach fails for two-dimensional systems with strong spin-orbit coupling. Finally, we show that the Rashba spin-orbit interaction suppresses the in-plane Zeeman interaction at low magnetic fields. The ability to control the Zeeman splitting with electric fields opens up new possibilities for future quantum spin-based devices, manipulating non-Abelian geometric phases, and realizing Majorana systems in p-type superconductor systems.

LO-Phonon Emission Rate of Hot Electrons from an On-Demand Single-Electron Source in a GaAs/AlGaAs Heterostructure.

Using a recent time-of-flight measurement technique with 1 ps time resolution and electron-energy spectroscopy, we develop a method to measure the longitudinal-optical-phonon emission rate of hot electrons traveling along a depleted edge of a quantum Hall bar. Comparison to a single-particle model implies the scattering mechanism involves a two-step process via an intra-Landau-level transition. We show that this can be suppressed by control of the edge potential profile, and a scattering length >1 mm can be achieved, allowing the use of this system for scalable single-electron device applications.

A hospital and home-based exercise program to address functional decline in people following allogeneic stem cell transplantation.

PURPOSE: The aims of this study are to investigate the feasibility of an exercise program commencing 60 days following allogeneic stem cell transplantation (alloSCT), to investigate changes in physical function and health-related quality of life (HRQoL) in patients from pre- to post-alloSCT and to explore changes in patient outcomes before and after the program. METHODS: This study is a single site, prospective case series including 43 adults undergoing alloSCT. The intervention was an 8-week outpatient and home-based exercise and education program. Outcomes included feasibility (consent, attendance, compliance and completion rates), functional exercise capacity (incremental shuttle walk test), muscle strength (hand-held dynamometry), self-efficacy for physical activity (Physical Activity Assessment Inventory) and HRQoL (Functional Assessment of Cancer Therapy-Bone Marrow Transplant). Outcomes were measured pre-alloSCT, 60 days post-alloSCT (pre-intervention) and 100 days post-alloSCT (post-intervention). RESULTS: The consent rate was 93%. From baseline to 60 days post-alloSCT, there was significant decline in functional exercise capacity (mean difference 224 m, 95% CI 153-295, p < 0.0005), self-efficacy for physical activity (294 points, 95% CI 136-452, p = 0.001) and HRQoL (15 points, 95% CI 8-21, p < 0.0005). Ten participants did not commence the exercise program due to death (n = 5), illness (n = 1) or cancellation of alloSCT (n = 4). The intervention was feasible in those not affected by major medical complications or death. No adverse events occurred. From pre- to post-intervention, there was significant improvement in functional exercise capacity (p = 0.001) and HRQoL (p = 0.001). CONCLUSIONS: AlloSCT results in significant decline in functional exercise capacity, self-efficacy for physical activity and HRQoL, which may be improved through an exercise program. This pilot demonstrated safety, feasibility and high patient interest. Further randomised research is required.

Mechanisms for Strong Anisotropy of In-Plane g-Factors in Hole Based Quantum Point Contacts.

In-plane hole g factors measured in quantum point contacts based on p-type heterostructures strongly depend on the orientation of the magnetic field with respect to the electric current. This effect, first reported a decade ago and confirmed in a number of publications, has remained an open problem. In this work, we present systematic experimental studies to disentangle different mechanisms contributing to the effect and develop the theory which describes it successfully. We show that there is a new mechanism for the anisotropy related to the existence of an additional B_{+}k_{-}^{4}σ_{+} effective Zeeman interaction for holes, which is kinematically different from the standard single Zeeman term B_{-}k_{-}^{2}σ_{+} considered until now.

Dark Solitons in High Velocity Waveguide Polariton Fluids.

We study exciton-polariton nonlinear optical fluids in the high momentum waveguide regime for the first time. We demonstrate the formation of dark solitons with the expected dependence of width on fluid density for both main classes of soliton-forming fluid defects. The results are well described by numerical modeling of the fluid propagation. We deduce a continuous wave nonlinearity more than ten times that on picosecond time scales, arising due to interaction with the exciton reservoir.

On-demand single-electron transfer between distant quantum dots.

Single-electron circuits of the future, consisting of a network of quantum dots, will require a mechanism to transport electrons from one functional part of the circuit to another. For example, in a quantum computer decoherence and circuit complexity can be reduced by separating quantum bit (qubit) manipulation from measurement and by providing a means of transporting electrons between the corresponding parts of the circuit. Highly controlled tunnelling between neighbouring dots has been demonstrated, and our ability to manipulate electrons in single- and double-dot systems is improving rapidly. For distances greater than a few hundred nanometres, neither free propagation nor tunnelling is viable while maintaining confinement of single electrons. Here we show how a single electron may be captured in a surface acoustic wave minimum and transferred from one quantum dot to a second, unoccupied, dot along a long, empty channel. The transfer direction may be reversed and the same electron moved back and forth more than sixty times-a cumulative distance of 0.25 mm-without error. Such on-chip transfer extends communication between quantum dots to a range that may allow the integration of discrete quantum information processing components and devices.

The impact of HLA class I and EBV latency-II antigen-specific CD8(+) T cells on the pathogenesis of EBV(+) Hodgkin lymphoma.

In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein-Barr virus (EBV) latency-II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV(+) cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA-A*02 is protective in EBV(+) cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA-A*02(-) versus HLA-A*02(+) EBV(+) cHL patients, suggesting that LMP2A-specific CD8(+) T cell anti-tumoral immunity may be relatively ineffective in HLA-A*02(-) EBV(+) cHL. To ascertain the impact of HLA class I on EBV latency antigen-specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV(+) cHL, the magnitude of ex-vivo LMP1/2A-specific CD8(+) T cell responses was elevated in HLA-A*02(+) patients. Furthermore, in a controlled in-vitro assay, LMP2A-specific CD8(+) T cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA class I-restricted immunity, immunodominant EBNA3A/3B/3C-specific CD8(+) T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A-specific responses were confined largely to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8(+) T cell response than non-HLA-A*02 alleles, an effect confined to EBV latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV(+) cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency-II antigen-specific CD8(+) T cell hierarchies.

Investigation of hollow cylindrical metal terahertz waveguides suitable for cryogenic environments.

The field of terahertz (THz) waveguides continues to grow rapidly, with many being tailored to suit the specific demands of a particular final application. Here, we explore waveguides capable of enabling efficient and accurate power delivery within cryogenic environments (< 4 K). The performance of extruded hollow cylindrical metal waveguides made of un-annealed and annealed copper, as well as stainless steel, have been investigated for bore diameters between 1.75 - 4.6 mm, and at frequencies of 2.0, 2.85 and 3.4 THz, provided by a suitable selection of THz quantum cascade lasers. The annealed copper resulted in the lowest transmission losses, < 3 dB/m for a 4.6 mm diameter waveguide, along with 90° bending losses as low as ~2 dB for a bend radius of 15.9 mm. The observed trends in losses were subsequently analyzed and related to measured inner surface roughness parameters. These results provide a foundation for the development of a wide array of demanding low-temperature THz applications, and enabling the study of fundamental physics.

Time-of-Flight Measurements of Single-Electron Wave Packets in Quantum Hall Edge States.

We report time-of-flight measurements on electrons traveling in quantum Hall edge states. Hot-electron wave packets are emitted one per cycle into edge states formed along a depleted sample boundary. The electron arrival time is detected by driving a detector barrier with a square wave that acts as a shutter. By adding an extra path using a deflection barrier, we measure a delay in the arrival time, from which the edge-state velocity v is deduced. We find that v follows 1/B dependence, in good agreement with the E[over →]×B[over →] drift. The edge potential is estimated from the energy dependence of v using a harmonic approximation.

Double-layer-gate architecture for few-hole GaAs quantum dots.

We report the fabrication of single and double hole quantum dots using a double-layer-gate design on an undoped accumulation mode [Formula: see text]/GaAs heterostructure. Electrical transport measurements of a single quantum dot show varying addition energies and clear excited states. In addition, the two-level-gate architecture can also be configured into a double quantum dot with tunable inter-dot coupling.

An entangled-light-emitting diode.

An optical quantum computer, powerful enough to solve problems so far intractable using conventional digital logic, requires a large number of entangled photons. At present, entangled-light sources are optically driven with lasers, which are impractical for quantum computing owing to the bulk and complexity of the optics required for large-scale applications. Parametric down-conversion is the most widely used source of entangled light, and has been used to implement non-destructive quantum logic gates. However, these sources are Poissonian and probabilistically emit zero or multiple entangled photon pairs in most cycles, fundamentally limiting the success probability of quantum computational operations. These complications can be overcome by using an electrically driven on-demand source of entangled photon pairs, but so far such a source has not been produced. Here we report the realization of an electrically driven source of entangled photon pairs, consisting of a quantum dot embedded in a semiconductor light-emitting diode (LED) structure. We show that the device emits entangled photon pairs under d.c. and a.c. injection, the latter achieving an entanglement fidelity of up to 0.82. Entangled light with such high fidelity is sufficient for application in quantum relays, in core components of quantum computing such as teleportation, and in entanglement swapping. The a.c. operation of the entangled-light-emitting diode (ELED) indicates its potential function as an on-demand source without the need for a complicated laser driving system; consequently, the ELED is at present the best source on which to base future scalable quantum information applications.

Nephrotic syndrome as a complication of chronic graft-versus-host disease after allogeneic haemopoietic stem cell transplantation.

Nephrotic syndrome (NS) is a rare complication following allogeneic haemopoietic stem cell transplantation (allo-HSCT), with limited current understanding of its pathogenesis. Here, we describe four cases of NS following allo-HSCT diagnosed at our institutions to identify key clinical and pathological features. In addition, a PubMed search was performed to identify existing reports that were pooled together with our cases for analysis. NS occurred as a late complication following allo-HSCT, with median onset 19.5 months after transplant (range: 3.9-84 months). The most common histopathology observed was membranous nephropathy; however, cases of minimal change disease have also been reported. There is a high incidence of prior extra-renal graft-versus-host disease (GvHD), with all four of our cases and 82% of published cases having prior GvHD. Glucocorticosteroids are the most common treatment, with variable degrees of response. Responses to immunosuppression with calcineurin inhibitors and rituximab have been described in steroid-refractory cases.