Electric Field Control of Spin Transport

Spintronics is an approach to electronics in which the spin of the electrons is exploited to control the electric resistance R of devices. One basic building block is the spin-valve, which is formed if two ferromagnetic electrodes are separated by a thin tunneling barrier. In such devices, R depends on the orientation of the magnetisation of the electrodes. It is usually larger in the antiparallel than in the parallel configuration. The relative difference of R, the so-called magneto-resistance (MR), is then positive. Common devices, such as the giant magneto-resistance sensor used in reading heads of hard disks, are based on this phenomenon. The MR may become anomalous (negative), if the transmission probability of electrons through the device is spin or energy dependent. This offers a route to the realisation of gate-tunable MR devices, because transmission probabilities can readily be tuned in many devices with an electrical gate signal. Such devices have, however, been elusive so far. We report here on a pronounced gate-field controlled MR in devices made from carbon nanotubes with ferromagnetic contacts. Both the amplitude and the sign of the MR are tunable with the gate voltage in a predictable manner. We emphasise that this spin-field effect is not restricted to carbon nanotubes but constitutes a generic effect which can in principle be exploited in all resonant tunneling devices.Comment: 22 pages, 5 figure

The connectome of the adult Drosophila mushroom body provides insights into function.

Making inferences about the computations performed by neuronal circuits from synapse-level connectivity maps is an emerging opportunity in neuroscience. The mushroom body (MB) is well positioned for developing and testing such an approach due to its conserved neuronal architecture, recently completed dense connectome, and extensive prior experimental studies of its roles in learning, memory, and activity regulation. Here, we identify new components of the MB circuit in Drosophila, including extensive visual input and MB output neurons (MBONs) with direct connections to descending neurons. We find unexpected structure in sensory inputs, in the transfer of information about different sensory modalities to MBONs, and in the modulation of that transfer by dopaminergic neurons (DANs). We provide insights into the circuitry used to integrate MB outputs, connectivity between the MB and the central complex and inputs to DANs, including feedback from MBONs. Our results provide a foundation for further theoretical and experimental work

Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Quality of dietary fat and genetic risk of type 2 diabetes: individual participant data meta-analysis.

OBJECTIVE: To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. REVIEW METHODS: Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. RESULTS: Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. CONCLUSIONS: These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.The EPIC-InterAct study received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). We thank all EPIC participants and staff for their contribution to the study. We thank Nicola Kerrison (MRC Epidemiology Unit, University of Cambridge, Cambridge, UK) for managing the data for the InterAct Project. In addition, InterAct investigators acknowledge funding from the following agencies: MT: Health Research Fund (FIS) of the Spanish Ministry of Health; the CIBER en Epidemiología y Salud Pública (CIBERESP), Spain; Murcia Regional Government (N° 6236); JS: JS was supported by a Heisenberg-Professorship (SP716/2-1), a Clinical Research Group (KFO218/1) and a research group (Molecular Nutrition to JS) of the Bundesministerium für Bildung und Forschung (BMBF); YTvdS, JWJB, PHP, IS: Verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; HBBdM: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); MDCL: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (N° 6236); FLC: Cancer Research UK; PD: Wellcome Trust; LG: Swedish Research Council; GH: The county of Västerbotten; RK: Deutsche Krebshilfe; TJK: Cancer Research UK; KK: Medical Research Council UK, Cancer Research UK; AK: Medical Research Council (Cambridge Lipidomics Biomarker Research Initiative); CN: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (N° 6236); KO: Danish Cancer Society; OP: Faculty of Health Science, 47 University of Aarhus, Denmark; JRQ: Asturias Regional Government; LRS: Asturias Regional Government; AT: Danish Cancer Society; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; DLvdA, WMMV: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); MMC: Wellcome Trust (083270/Z/07/Z), MRC (G0601261)

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Quantification of changes in brain morphology following posterior fossa decompression surgery in women treated for Chiari malformation type 1

Purpose While 84% of patients surgically treated for Chiari malformation type 1 (CM1) demonstrate improved quality of life after posterior fossa decompression surgery, there are many risks associated with this surgery. Surgical planning to identify candidates likely to improve postoperatively may benefit from an improved understanding of morphological changes after decompression surgery. To evaluate these changes, we quantified 59 morphological parameters on 42 CM1 adult female patients before and after CM1 decompression surgery. Methods Fifty-nine morphological parameters in the posterior cranial fossa, cranio-cervical, and intracranial regions in the midsagittal plane were evaluated using 42 T1-weighted magnetic resonance images of female CM1 patients before and after surgery, and 42 healthy female controls. Morphological differences before and after surgery were compared through the development of a technique to establish the opisthion location, a key reference point not present after surgery. Results In addition to the expected reduction of the cranio-caudal dimension of the cerebellum, objective analyses showed a significant increase in the area of the cerebrospinal fluid spaces, posterior (6x) and inferior (2.6x) to the cerebellum (+ 112 +/- 102 and + 140 +/- 127 mm(2), respectively). This increased area was primarily impacted by an average reduction in the occipital bone length of 24.5 +/- 7.3 mm following surgery. Based on multiple angles, results demonstrated a 2 degrees-4 degrees anterior rotation of the cerebellum after surgery. Conclusion Our results show that decompression surgery results in significant changes in the cerebellum and cerebrospinal fluid spaces. Further investigation should determine how these morphological changes impact clinical outcomes