Comparison of the intracellular trafficking itinerary of ctla-4 orthologues.

CTLA-4 is an essential inhibitor of T cell immune responses. At steady state, most CTLA-4 resides in intracellular compartments due to constitutive internalisation mediated via a tyrosine based endocytic motif (YVKM) within the cytoplasmic domain. This domain is highly conserved in mammals suggesting strong selective pressure. In contrast, the C-terminal domain varies considerably in non-mammals such as fish, xenopus and birds. We compared the ability of the C-terminus of these species to direct the trafficking of CTLA-4 with human CTLA-4. Using a chimeric approach, endocytosis was found to be conserved between human, xenopus and chicken CTLA-4 but was reduced substantially in trout CTLA-4, which lacks the conserved YXXM motif. Nevertheless, we identified an alternative YXXF motif in trout CTLA-4 that permitted limited endocytosis. Post-internalisation, CTLA-4 was either recycled or targeted for degradation. Human and chicken CTLA-4, which contain a YVKM motif, showed efficient recycling compared to xenopus CTLA-4 which contains a less efficient YEKM motif. Specific mutation of this motif in human CTLA-4 reduced receptor recycling. These findings suggest evolutionary development in the endocytic and recycling potential of CTLA-4, which may facilitate more refined functions of CTLA-4 within the mammalian immune system

Cancer mortality patterns in Ghana: a 10-year review of autopsies and hospital mortality

BACKGROUND: Cancer mortality pattern in Ghana has not been reviewed since 1953, and there are no population-based data available for cancer morbidity and mortality patterns in Ghana due to the absence of a population-based cancer registry anywhere in the country. METHODS: A retrospective review of autopsy records of Department of Pathology, and medical certificate of cause of death books from all the wards of the Korle-Bu Teaching Hospital (KBTH), Accra, Ghana during the 10-year period 1991–2000 was done. RESULTS: The present study reviews 3659 cancer deaths at the KBTH over the 10-year period. The male-to-female ratio was 1.2:1. The mean age for females was 46.5 [Standard Deviation (SD), 20.8] years, whilst that of males was 47.8 (SD, 22.2) years. The median age was 48 years for females and 50 years for males.Both sexes showed a first peak in childhood, a drop in adolescence and young adulthood, and a second peak in the middle ages followed by a fall in the elderly, with the second peak occurring a decade earlier in females than in males. The commonest cause of cancer death in females was malignancies of the breast [Age-Standardized Cancer Ratio (ASCAR), 17.24%], followed closely by haematopoietic organs (14.69%), liver (10.97%) and cervix (8.47%). Whilst in males, the highest mortality was from the liver (21.15%), followed by prostate (17.35%), haematopoietic organs (15.57%), and stomach (7.26%). CONCLUSION: Considering the little information available on cancer patterns in Ghana, this combined autopsy and death certification data from the largest tertiary hospital is of considerable value in providing reliable information on the cancer patterns in Ghana

Incorporating tumour pathology information into breast cancer risk prediction algorithms.

INTRODUCTION: Mutations in BRCA1 and BRCA2 confer high risks of breast cancer and ovarian cancer. The risk prediction algorithm BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) may be used to compute the probabilities of carrying mutations in BRCA1 and BRCA2 and help to target mutation screening. Tumours from BRCA1 and BRCA2 mutation carriers display distinctive pathological features that could be used to better discriminate between BRCA1 mutation carriers, BRCA2 mutation carriers and noncarriers. In particular, oestrogen receptor (ER)-negative status, triple-negative (TN) status, and expression of basal markers are predictive of BRCA1 mutation carrier status. METHODS: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees. RESULTS: The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history. CONCLUSIONS: This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

A monolithic integrated photonic microwave filter

[EN] Meeting the increasing demand for capacity in wireless networks requires the harnessing of higher regions in the radiofrequency spectrum, reducing cell size, as well as more compact, agile and power-efficient base stations that are capable of smoothly interfacing the radio and fibre segments. Fully functional microwave photonic chips are promising candidates in attempts to meet these goals. In recent years, many integrated microwave photonic chips have been reported in different technologies. To the best of our knowledge, none has monolithically integrated all the main active and passive optoelectronic components. Here, we report the first demonstration of a tunable microwave photonics filter that is monolithically integrated into an indium phosphide chip. The reconfigurable radiofrequency photonic filter includes all the necessary elements (for example, lasers, modulators and photodetectors), and its response can be tuned by means of control electric currents. This is an important step in demonstrating the feasibility of integrated and programmable microwave photonic processors.The authors acknowledge financial support from the Spanish Centro para el Desarrollo Tecnologico Industrial (CDTI) through the NEOTEC start-up programme, the European Commission through the 7th Research Framework Programme project, Photonic Advanced Research and Development for Integrated Generic Manufacturing (FP7-PARADIGM), the Generalitat Valenciana through the Programa para grupos de Investigacion de Excelencia (PROMETEO) project code 2013/012, the Spanish Ministerio de Economia y Comercio (MINECO) via project TEC2013-42332-P, PIF4ESP, and the Unwersitat Politecnica de Valencia (UPVOV) through projects 10-3E-492 and 08-3E-008 funded by the Fondos Europeos de Desarrollo Regional (FEDER). J.S. Fandino acknowledges financial support from Formacion de Profesorado Universitario (FPU) grant AP2010-1595.Sanchez Fandiño, JA.; Muñoz Muñoz, P.; Doménech Gómez, JD.; Capmany Francoy, J. (2017). A monolithic integrated photonic microwave filter. Nature Photonics. 11(2):124-129. https://doi.org/10.1038/NPHOTON.2016.233S124129112Novak, D. et al. Radio-over-fiber technologies for emerging wireless systems. IEEE J. Quantum Electron. 52, 1–11 (2016).Waterhouse, R. & Novak, D. Realizing 5G: microwave photonics for 5G mobile wireless systems. IEEE Microw. Mag. 16, 84–92 (2015).Won, R. Microwave photonics shines. Nat. Photon. 5, 736 (2011).Capmany, J. & Novak, D. Microwave photonics combines two worlds. Nat. Photon. 1, 319–330 (2007).Yao, J. Microwave photonics. J. Lightw. Technol. 27, 314–335 (2009).Andrews, J. G. et al. What will 5G be? IEEE J. Sel. Areas Commun. 32, 1065–1082 (2014).Gosh, A., et al. Millimetre-wave enhanced local area systems: a high-data-rate approach for future wireless networks. IEEE J. Sel. Areas Commun. 32, 1152–1163 (2014).Marpaung, D. et al. Integrated microwave photonics. Laser Photon. Rev. 7, 506–538 (2013).Iezekiel, S., Burla, M., Klamkin, J., Marpaung, D. & Capmany, J. RF engineering meets optoelectronics: progress in integrated microwave photonics. IEEE Microw. Mag. 16, 28–45 (2015).Mitchell, J. E. Integrated wireless backhaul over optical access networks. J. Lightw. Technol. 32, 3373–3382 (2014).Liu, C., Wang, J., Cheng, L., Zhu, M. & Chang, G.-K. Key microwave-photonics technologies for next-generation cloud-based radio access networks. J. Lightw. Technol. 32, 3452–3460 (2014).Norberg, E. J., Guzzon, R. S., Parker, J. S., Johansson, L. A. & Coldren, L. A. Programmable photonic microwave filters monolithically integrated in InP/InGaAsP. J. Lightw. Technol. 29, 1611–1619 (2011).Guzzon, R., Norberg, E., Parker, J., Johansson, L. & Coldren, L. Integrated InP–InGaAsP tuneable coupled ring optical bandpass filters with zero insertion loss. Opt. Express 19, 7816–7826 (2011).Fandiño, J. S. & Muñoz, P. Photonics-based microwave frequency measurement using a double-sideband suppressed-carrier modulation and an InP integrated ring-assisted Mach–Zehnder interferometer filter. Opt. Lett. 38, 4316–4319 (2013).Burla, M. et al. On-chip ultra-wideband microwave photonic phase shifter and true time delay line based on a single phase-shifted waveguide Bragg grating. In IEEE International Topical Meeting on Microwave Photonics 92–95 (IEEE, 2013).Shi, W., Veerasubramanian, V., Patel, D. & Plant, D. Tuneable nanophotonic delay lines using linearly chirped contradirectioinal couplers with uniform Bragg gratings. Opt. Lett. 39, 701–703 (2014).Guan, B. et al. CMOS compatible reconfigurable silicon photonic lattice filters using cascaded unit cells for RF-photonic processing. IEEE J. Sel. Top. Quantum Electron. 20, 359–368 (2014).Khan, M. H. et al. Ultrabroad-bandwidth arbitrary radiofrequency waveform generation with a silicon photonic chip-based spectral shaper. Nat. Photon. 4, 117–122 (2010).Pagani, M. et al. Instantaneous frequency measurement system using four-wave mixing in an ultra-compact long silicon waveguide. In Proc. 41st European Conf. on Optical Communication (ECOC) 1–3 (IEEE, 2015).Khilo, A. et al. Photonic ADC: overcoming the bottleneck of electronic jitter. Opt. Express 20, 4454–4469 (2012).Wang, J. et al. Reconfigurable radio-frequency arbitrary waveforms synthesized in a silicon photonic chip. Nat. Commun. 6, 5957 (2015).Marpaung, D. et al. Si3N4 ring resonator-based microwave photonic notch filter with an ultrahigh peak rejection. Opt. Express 21, 23286–23294 (2013).Zhuang, L. et al. Ring resonator-based on-chip modulation transformer for high-performance phase-modulated microwave photonic links. Opt. Express 21, 25999–26013 (2013).Marpaung, D., Chevalier, L., Burla, M. & Roeloffzen, C. Impulse radio ultrawideband pulse shaper based on a programmable photonic chip frequency discriminator. Opt. Express 19, 24838–24848 (2011).Marpaung, D. On-chip photonic-assisted instantaneous microwave frequency measurement system. IEEE Photon. Technol. Lett. 25, 837–840 (2013).Burla, M. et al. On-chip CMOS compatible reconfigurable optical delay line with separate carrier tuning for microwave photonic signal processing. Opt. Express 19, 21475–21484 (2011).Tan, K. et al. Photonic-chip-based all-optical ultra-wideband pulse generation via XPM and birefringence in a chalcogenide waveguide. Opt. Express 21, 2003–2011 (2013).Pagani, M. et al. Tuneable wideband microwave photonic phase shifter using on-chip stimulated Brillouin scattering. Opt. Express 22, 28810–28818 (2014).Pérez, D., Gasulla, I. & Capmany, J. Software-defined reconfigurable microwave photonics processor. Opt. Express 23, 14640–14654 (2015).Capmany, J., Gasulla, I. & Pérez, D. 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High-normal blood glucose levels may be associated with decreased spatial perception in young healthy adults.

The negative effects of high normal glucose on cognitive function were previously reported in euglycemic individuals of middle age and the elderly population. This study aimed at examining the effect of baseline blood glucose levels on spatial ability, specifically verticality perception on the computerized rod and frame test (CRFT) in young healthy adults. 63 healthy male medical students (age range from 18-23 years), of whom 30 were non-fasting outside the month of Ramadan and 33 fasting during Ramadan of the year 2016, were recruited in order to create varying degrees of glycemia during which verticality perception was carried out. Baseline blood glucose reading was obtained prior to commencing the CRFT test. Blood glucose levels at the time of testing decreased as the duration between the last meal and testing increased. A blood glucose range of 62-117 mg/dl was achieved among participants for this study. Linear regression analysis showed that blood glucose level at testing correlated positively with all alignment spatial error parameters, indicating a probable reduction of spatial perception ability with higher blood glucose levels. These results are consistent with other cognitive studies in older healthy humans and emphasize the critical impact of early glucose dys-homeostasis on cognitive function. They also indicate that elevated blood glucose may affect cognitive functioning outside of the usual complications of diabetes

Bioinformatics and Structural Characterization of a Hypothetical Protein from Streptococcus mutans: Implication of Antibiotic Resistance

As an oral bacterial pathogen, Streptococcus mutans has been known as the aetiologic agent of human dental caries. Among a total of 1960 identified proteins within the genome of this organism, there are about 500 without any known functions. One of these proteins, SMU.440, has very few homologs in the current protein databases and it does not fall into any protein functional families. Phylogenetic studies showed that SMU.440 is related to a particular ecological niche and conserved specifically in some oral pathogens, due to lateral gene transfer. The co-occurrence of a MarR protein within the same operon among these oral pathogens suggests that SMU.440 may be associated with antibiotic resistance. The structure determination of SMU.440 revealed that it shares the same fold and a similar pocket as polyketide cyclases, which indicated that it is very likely to bind some polyketide-like molecules. From the interlinking structural and bioinformatics studies, we have concluded that SMU.440 could be involved in polyketide-like antibiotic resistance, providing a better understanding of this hypothetical protein. Besides, the combination of multiple methods in this study can be used as a general approach for functional studies of a protein with unknown function

Multipurpose silicon photonics signal processor core

[EN] Integrated photonics changes the scaling laws of information and communication systems offering architectural choices that combine photonics with electronics to optimize performance, power, footprint, and cost. Application-specific photonic integrated circuits, where particular circuits/chips are designed to optimally perform particular functionalities, require a considerable number of design and fabrication iterations leading to long development times. A different approach inspired by electronic Field Programmable Gate Arrays is the programmable photonic processor, where a common hardware implemented by a two-dimensional photonic waveguide mesh realizes different functionalities through programming. Here, we report the demonstration of such reconfigurable waveguide mesh in silicon. We demonstrate over 20 different functionalities with a simple seven hexagonal cell structure, which can be applied to different fields including communications, chemical and biomedical sensing, signal processing, multiprocessor networks, and quantum information systems. Our work is an important step toward this paradigm.J.C. acknowledges funding from the ERC Advanced Grant ERC-ADG-2016-741415 UMWP-Chip, I.G. acknowledges the funding through the Spanish MINECO Ramon y Cajal program. D.P. acknowledges financial support from the UPV through the FPI predoctoral funding scheme. D.J.T. acknowledges funding from the Royal Society for his University Research Fellowship.Pérez-López, D.; Gasulla Mestre, I.; Crudgington, L.; Thomson, DJ.; Khokhar, AZ.; Li, K.; Cao, W.... (2017). Multipurpose silicon photonics signal processor core. Nature Communications. 8(1925):1-9. https://doi.org/10.1038/s41467-017-00714-1S1981925Doerr, C. R. & Okamoto, K. Advances in silica planar lightwave circuits. J. 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Quantum Electron. 19, 6100117 (2013).Sacher, W. et al. Multilayer silicon nitride-on-silicon integrated photonic platforms and devices. J. Lightw. Technol. 33, 901–910 (2015).Asghari, M. Silicon photonics: A low cost integration platform for datacom and telecom applications. In OFC/NFOEC 2008 – 2008 Conference on Optical Fiber Communication/National Fiber Optic Engineers Conference 1–10 (San Diego, USA, 2008).Melati, D. et al. Integrated all-optical MIMO demultiplexer for mode- and wavelength-division-multiplexed transmission. Opt. Lett. 42, 342–345 (2017).Waterhouse, R. & Novak, D. Realizing 5G: microwave photonics for 5G mobile wireless systems. IEEE Microw. Mag. 16, 84–92 (2015).Marpaung, D. et al. Integrated microwave photonics. Laser Photon. Rev. 7, 506–538 (2013).Iezekiel, S., Burla, M., Klamkin, J., Marpaung, D. & Capmany, J. RF engineering meets optoelectronics: Progress in integrated microwave photonics. IEEE Microw. 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Microviridae Goes Temperate: Microvirus-Related Proviruses Reside in the Genomes of Bacteroidetes

The Microviridae comprises icosahedral lytic viruses with circular single-stranded DNA genomes. The family is divided into two distinct groups based on genome characteristics and virion structure. Viruses infecting enterobacteria belong to the genus Microvirus, whereas those infecting obligate parasitic bacteria, such as Chlamydia, Spiroplasma and Bdellovibrio, are classified into a subfamily, the Gokushovirinae. Recent metagenomic studies suggest that members of the Microviridae might also play an important role in marine environments. In this study we present the identification and characterization of Microviridae-related prophages integrated in the genomes of species of the Bacteroidetes, a phylum not previously known to be associated with microviruses. Searches against metagenomic databases revealed the presence of highly similar sequences in the human gut. This is the first report indicating that viruses of the Microviridae lysogenize their hosts. Absence of associated integrase-coding genes and apparent recombination with dif-like sequences suggests that Bacteroidetes-associated microviruses are likely to rely on the cellular chromosome dimer resolution machinery. Phylogenetic analysis of the putative major capsid proteins places the identified proviruses into a group separate from the previously characterized microviruses and gokushoviruses, suggesting that the genetic diversity and host range of bacteriophages in the family Microviridae is wider than currently appreciated

A systematic review of the health, social and financial impacts of welfare rights advice delivered in healthcare settings

BACKGROUND: Socio-economic variations in health, including variations in health according to wealth and income, have been widely reported. A potential method of improving the health of the most deprived groups is to increase their income. State funded welfare programmes of financial benefits and benefits in kind are common in developed countries. However, there is evidence of widespread under claiming of welfare benefits by those eligible for them. One method of exploring the health effects of income supplementation is, therefore, to measure the health effects of welfare benefit maximisation programmes. We conducted a systematic review of the health, social and financial impacts of welfare rights advice delivered in healthcare settings. METHODS: Published and unpublished literature was accessed through searches of electronic databases, websites and an internet search engine; hand searches of journals; suggestions from experts; and reference lists of relevant publications. Data on the intervention delivered, evaluation performed, and outcome data on health, social and economic measures were abstracted and assessed by pairs of independent reviewers. Results are reported in narrative form. RESULTS: 55 studies were included in the review. Only seven studies included a comparison or control group. There was evidence that welfare rights advice delivered in healthcare settings results in financial benefits. There was little evidence that the advice resulted in measurable health or social benefits. This is primarily due to lack of good quality evidence, rather than evidence of an absence of effect. CONCLUSION: There are good theoretical reasons why income supplementation should improve health, but currently little evidence of adequate robustness and quality to indicate that the impact goes beyond increasing income