A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Richer than Gold: the fungal biodiversity of Reserva Los Cedros, a threatened Andean cloud forest.

BACKGROUND: Globally, many undescribed fungal taxa reside in the hyperdiverse, yet undersampled, tropics. These species are under increasing threat from habitat destruction by expanding extractive industry, in addition to global climate change and other threats. Reserva Los Cedros is a primary cloud forest reserve of ~ 5256 ha, and is among the last unlogged watersheds on the western slope of the Ecuadorian Andes. No major fungal survey has been done there, presenting an opportunity to document fungi in primary forest in an underrepresented habitat and location. Above-ground surveys from 2008 to 2019 resulted in 1760 vouchered collections, cataloged and deposited at QCNE in Ecuador, mostly Agaricales sensu lato and Xylariales. We document diversity using a combination of ITS barcode sequencing and digital photography, and share the information via public repositories (GenBank & iNaturalist). RESULTS: Preliminary identifications indicate the presence of at least 727 unique fungal species within the Reserve, representing 4 phyla, 17 classes, 40 orders, 101 families, and 229 genera. Two taxa at Los Cedros have recently been recommended to the IUCN Fungal Red List Initiative (Thamnomyces chocöensis Læssøe and "Lactocollybia" aurantiaca Singer), and we add occurrence data for two others already under consideration (Hygrocybe aphylla Læssøe & Boertm. and Lamelloporus americanus Ryvarden). CONCLUSIONS: Plants and animals are known to exhibit exceptionally high diversity and endemism in the Chocó bioregion, as the fungi do as well. Our collections contribute to understanding this important driver of biodiversity in the Neotropics, as well as illustrating the importance and utility of such data to conservation efforts. RESUMEN: Antecedentes: A nivel mundial muchos taxones fúngicos no descritos residen en los trópicos hiper diversos aunque continúan submuestreados. Estas especies están cada vez más amenazadas por la destrucción del hábitat debido a la expansión de la industria extractivista además del cambio climático global y otras amenazas. Los Cedros es una reserva de bosque nublado primario de ~ 5256 ha y se encuentra entre las últimas cuencas hidrográficas no explotadas en la vertiente occidental de los Andes ecuatorianos. Nunca antes se ha realizado un estudio de diversidad micológica en el sitio, lo que significa una oportunidad para documentar hongos en el bosque primario, en hábitat y ubicación subrepresentatadas. El presente estudio recopila información entre el 2008 y 2019 muestreando material sobre todos los sustratos, reportando 1760 colecciones catalogadas y depositadas en el Fungario del QCNE de Ecuador, en su mayoría Agaricales sensu lato y Xylariales; además se documenta la diversidad mediante secuenciación de códigos de barras ITS y fotografía digital, la información está disponible en repositorios públicos digitales (GenBank e iNaturalist). RESULTADOS: La identificación preliminar indica la presencia de al menos 727 especies únicas de hongos dentro de la Reserva, que representan 4 filos, 17 clases, 40 órdenes, 101 familias y 229 géneros. Recientemente dos taxones en Los Cedros se recomendaron a la Iniciativa de Lista Roja de Hongos de la UICN (Thamnomyces chocöensis Læssøe y "Lactocollybia" aurantiaca Singer) y agregamos datos de presencia de otros dos que ya estaban bajo consideración (Hygrocybe aphylla Læssøe & Boertm. y Lamelloporus americanus Ryvarden). CONCLUSIONES: Se sabe que plantas y animales exhiben una diversidad y endemismo excepcionalmente altos en la bioregión del Chocó y los hongos no son la excepción. Nuestras colecciones contribuyen a comprender este importante promotor de la biodiversidad en el Neotrópico además de ilustrar la importancia y utilidad de dichos datos para los esfuerzos de conservación.

Interference in multi-user optical wireless communications systems.

Visible light communications (VLC) (including LiFi) represent a subset of the broader field of optical wireless communications. Where narrow beams, typical of free space optical communications are largely free from interference. VLC encompasses use cases involving combined illumination and data access and supporting a wireless access point (AP) model. The use of many units provides scaling of spatial coverage for both lighting and data access. However, AP replication in close proximity creates many interference challenges that motivate the investigation embodied in this paper. In particular, we frame the interference challenge in the context of existing strategies for driving improvements in link performance and consider the impacts of multiple users, multiple sources and multiple cells. Lastly, we review the state of existing research in this area and recommend areas for further study. This article is part of the theme issue 'Optical wireless communication'.

Analysis of the B cell receptor repertoire in six immune-mediated diseases.

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

Expression, purification and metal utilization of recombinant SodA from Borrelia burgdorferi.

Borrelia are microaerophilic spirochetes capable of causing multisystemic diseases such as Lyme disease and Relapsing Fever. The ubiquitous Fe/Mn-dependent superoxide dismutase (SOD) provides essential protection from oxidative damage by the superoxide anion. Borrelia possess a single SOD enzyme - SodA that is essential for virulence, providing protection against host-derived reactive oxygen species (ROS). Here we present a method for recombinant expression and purification of Borrelia burgdorferi SodA in E. coli. Metal exchange or insertion into the Fe/Mn-SOD is inhibited in the folded state. We therefore present a method whereby the recombinant Borrelia SodA binds to Mn under denaturing conditions and is subsequently refolded by a reduction in denaturant. SodA purified by metal affinity chromatography and size exclusion chromatography reveals a single band on SDS-PAGE. Protein folding is confirmed by circular dichroism. A coupled enzyme assay demonstrates SOD activity in the presence of Mn, but not Fe. The apparent molecular weight determined by size exclusion corresponds to a dimer of SodA; a homology model of dimeric SodA is presented revealing a surface Cys distal to the dimer interface. The method presented of acquiring a target metal under denaturing conditions may be applicable to the refolding of other metal-binding proteins.

Global patterns and drivers of ecosystem functioning in rivers and riparian zones.

River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth's biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented "next-generation biomonitoring" by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.

Benefits of a Physician-Scientist-Tailored Curriculum at a Medical Student-Run Free Clinic.

We designed a curriculum to help sustain pre-clinical knowledge for MD/PhD trainees in their graduate training phase while securing regular providers for our student-run free clinic. MD/PhD involvement increased from 1.91 to 2.45 students-per-clinic-day following implementation, and participants affirmed increased preparedness and comfort entering medical school clinical clerkships.

A potential biotechnological process for the sustainable production of vitamin K1.

The primary objective of this review is to propose an approach for the biosynthesis of phylloquinone (vitamin K1) based upon its known sources, its role in photosynthesis and its biosynthetic pathway. The chemistry, health benefits, market, and industrial production of vitamin K are also summarized. Vitamin K compounds (K vitamers) are required for the normal function of at least 15 proteins involved in diverse physiological processes such as coagulation, tissue mineralization, inflammation, and neuroprotection. Vitamin K is essential for the prevention of Vitamin K Deficiency Bleeding (VKDB), especially in neonates. Increased vitamin K intake may also reduce the severity and/or risk of bone fracture, arterial calcification, inflammatory diseases, and cognitive decline. Consumers are increasingly favoring natural food and therapeutic products. However, the bulk of vitamin K products employed for both human and animal use are chemically synthesized. Biosynthesis of the menaquinones (vitamin K2) has been extensively researched. However, published research on the biotechnological production of phylloquinone is restricted to a handful of available articles and patents. We have found that microalgae are more suitable than plant cell cultures for the biosynthesis of phylloquinone. Many algae are richer in vitamin K1 than terrestrial plants, and algal cells are easier to manipulate. Vitamin K1 can be efficiently recovered from the biomass using supercritical carbon dioxide extraction.

Two-Phase Framework for Indoor Positioning Systems Using Visible Light.

Recently with the advancement of solid state lighting and the application thereof to Visible Light Communications (VLC), the concept of Visible Light Positioning (VLP) has been targeted as a very attractive indoor positioning system (IPS) due to its ubiquity, directionality, spatial reuse, and relatively high modulation bandwidth. IPSs, in general, have four major components: (1) a modulation, (2) a multiple access scheme, (3) a channel measurement, and (4) a positioning algorithm. A number of VLP approaches have been proposed in the literature and primarily focus on a fixed combination of these elements and moreover evaluate the quality of the contribution often by accuracy or precision alone. In this article, we provide a novel two-phase indoor positioning algorithmic framework that is able to increase robustness when subject to insufficient anchor luminaries and also incorporate any combination of the four major IPS components.

Beam shaping with tip-tilt varifocal mirror for indoor optical wireless communication.

MEMS mirrors are currently used in many applications to steer beams of light. An area of continued research is developing mirrors with varifocal capability that allows the beam to be shaped and focused. In this work, we study the varifocal capability of a 380 µm diameter, thermally actuated MEMS mirror with a ± 40° tip-tilt angle and a radius of curvature between -0.48 mm to 20.5 mm. Light is coupled to the mirror via a single mode optical fiber, similar to an indoor optical wireless communication architecture. The performance of the mirror is characterized with respect to (1) the profile of the reflected beam as the mirror deforms and (2) the mirror's impact when integrated into an optical communication system. We found that the mirror can focus light to a beam with a 0.18° half-angle divergence. Additionally, the ability to change the shape of fiberized light from a wide to narrow beam provides an unmatched level of dynamic control and significantly improves the bit error rate in an optical communication system.

Electrothermally actuated tip-tilt-piston micromirror with integrated varifocal capability.

MEMS micromirrors have proven to be very important optical devices with applications ranging from steerable mirrors for switches and cross-connects to spatial light modulators for correcting optical distortions. Usually beam steering and focusing are done with different MEMS devices and tilt angles in excess of 10 degrees are seldom obtained. Here we describe a single MEMS device that combines tip/tilt, piston mode and varifocal capability into a single, low cost device with very large tilt angles. Our device consists of a 400 micron diameter mirror driven with thermal bimorphs. We have demonstrated deflection angles of ± 40 degrees along both axes, a tunable focal length which varies between -0.48 mm to + 20.5 mm and a piston mode range of 300 microns - four separately controllable degrees of freedom in a single device. Potential applications range from smart lighting to optical switches and devices for telecom systems.

Reverse polarity optical-OFDM (RPO-OFDM): dimming compatible OFDM for gigabit VLC links.

Visible light communications (VLC) technology permits the exploitation of light-emitting diode (LED) luminaries for simultaneous illumination and broadband wireless communication. Optical orthogonal frequency-division multiplexing (O-OFDM) is a promising modulation technique for VLC systems, in which the real-valued O-OFDM baseband signal is used to modulate the instantaneous power of the optical carrier to achieve gigabit data rates. However, a major design challenge that limits the commercialization of VLC is how to incorporate the industry-preferred pulse-width modulation (PWM) light dimming technique while maintaining a broadband and reliable communication link. In this work, a novel signal format, reverse polarity O-OFDM (RPO-OFDM), is proposed to combine the fast O-OFDM communication signal with the relatively slow PWM dimming signal, where both signals contribute to the effective LED brightness. The advantages of using RPO-OFDM include, (1) the data rate is not limited by the frequency of the PWM signal, (2) the LED dynamic range is fully utilized to minimize the nonlinear distortion of the O-OFDM communication signal, and (3) the bit-error performance is sustained over a large fraction of the luminaire dimming range. In addition, RPO-OFDM offers a practical approach to utilize off-the-shelf LED drivers. We show results of numerical simulations to study the trade-offs between the PWM duty cycle, average electrical O-OFDM signal power, radiated optical flux as well as human perceived light.

Monitoring walking and cycling of middle-aged to older community dwellers using wireless wearable accelerometers.

Changes in gait parameters have been shown to be an important indicator of several age-related cognitive and physical declines of older adults. In this paper we propose a method to monitor and analyze walking and cycling activities based on a triaxial accelerometer worn on one ankle. We use an algorithm that can (1) distinguish between static and dynamic functional activities, (2) detect walking and cycling events, (3) identify gait parameters, including step frequency, number of steps, number of walking periods, and total walking duration per day, and (4) evaluate cycling parameters, including cycling frequency, number of cycling periods, and total cycling duration. Our algorithm is evaluated against the triaxial accelerometer data obtained from a group of 297 middle-aged to older adults wearing an activity monitor on the right ankle for approximately one week while performing unconstrained daily activities in the home and community setting. The correlation coefficients between each of detected gait and cycling parameters on two weekdays are all statistically significant, ranging from 0.668 to 0.873. These results demonstrate good test-retest reliability of our method in monitoring walking and cycling activities and analyzing gait and cycling parameters. This algorithm is efficient and causal in time and thus implementable for real-time monitoring and feedback.

A non-coding plastid DNA phylogeny of Asian Begonia (Begoniaceae): evidence for morphological homoplasy and sectional polyphyly.

Maximum likelihood and Bayesian analyses of non-coding plastid DNA sequence data based on a broad sampling of all major Asian Begonia sections (ndhA intron, ndhF-rpl32 spacer, rpl32-trnL spacer, 3977 aligned characters, 84 species) were used to reconstruct the phylogeny of Asian Begonia and to test the monophyly of major Asian Begonia sections. Ovary and fruit characters which are crucial in current sectional circumscriptions were mapped on the phylogeny to assess their utility in infrageneric classifications. The results indicate that the strong systematic emphasis placed on single, homoplasious characters such as undivided placenta lamellae (section Reichenheimia) and fleshy pericarps (section Sphenanthera), and the recognition of sections primarily based on a suite of plesiomorphic characters including three-locular ovaries with axillary, bilamellate placentae and dry, dehiscent pericarps (section Diploclinium), has resulted in the circumscription of several polyphyletic sections. Moreover, sections Platycentrum and Petermannia were recovered as paraphyletic. Because of the homoplasy of systematically important characters, current classifications have a certain diagnostic, but only poor predictive value. The presented phylogeny provides for the first time a reasonably resolved and supported phylogenetic framework for Asian Begonia which has the power to inform future taxonomic, biogeographic and evolutionary studies.

Diagnostic radiography and adult acute myeloid leukaemia: an interview and medical chart review study.

BACKGROUND: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. METHODS: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. RESULTS: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. CONCLUSION: The association between diagnostic radiography and AML risk remains uncertain.

Continuous monitoring of functional activities using wearable, wireless gyroscope and accelerometer technology.

The development of functional activity monitors (FAMs) will allow rehabilitation researchers and clinicians to evaluate treatment efficacy, to monitor compliance to exercise instructions, and to provide real time feedback in the treatment of movement disorders during the performance of daily activities. The purpose of the present study was to develop and test a small sized wearable FAM system comprised of three sensors positioned on the sternum and both thighs, wireless Bluetooth transmission capability to a smartphone, and computationally efficient activity detection algorithms for the accurate detection of functional activities. Each sensor was composed of a tri-axial accelerometer and a tri-axial gyroscope. Computationally efficient activity recognition algorithms were developed, using a sliding window of 1 second, the variability of the tilt angle time series and power spectral analysis. In addition, it includes a decision tree that identifies postures such as sitting, standing and lying, walking at comfortable, slow and fast speeds, transitions between these functional activities (e.g, sit-to-stand and stand-to-sit), activity duration and step frequency. In a research lab setting the output of the FAM system, video recordings and a 3D motion analysis system were compared in 10 healthy young adults. The results show that the agreement between the FAM system and the video recordings ranged from 98.10% to 100% for all postures, transfers and walking periods. There were no significant differences in activity durations and step frequency between measurement instruments.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Systems biological and mechanistic modelling of radiation-induced cancer.

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy.

Haplotype sharing analysis using mantel statistics.

OBJECTIVE: The potential value of haplotypes has attracted widespread interest in the mapping of complex traits. Haplotype sharing methods take the linkage disequilibrium information between multiple markers into account, and may have good power to detect predisposing genes. We present a new approach based on Mantel statistics for spacetime clustering, which is developed in order to improve the power of haplotype sharing analysis for gene mapping in complex disease. METHODS: The new statistic correlates genetic similarity and phenotypic similarity across pairs of haplotypes for case-only and case-control studies. The genetic similarity is measured as the shared length between haplotypes around a putative disease locus. The phenotypic similarity is measured as the mean-corrected cross-product based on the respective phenotypes. We analyzed two tests for statistical significance with respect to type I error: (1) assuming asymptotic normality, and (2) using a Monte Carlo permutation procedure. The results were compared to the chi(2) test for association based on 3-marker haplotypes. RESULTS: The results of the type I error rates for the Mantel statistics using the permutational procedure yielded pointwise valid tests. The approach based on the assumption of asymptotic normality was seriously liberal. CONCLUSION: Power comparisons showed that the Mantel statistics were better than or equal to the chi(2) test for all simulated disease models.