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The Earth's Magnetospheric System is the complex and highly dynamic environment in near-Earth space where plasma gets actively energized and transport of large amounts of energy occurs, due to the interaction of the solar wind with the Earth's magnetic field. Understanding plasma energization and energy transport is an open challenge of space plasma physics, with important implications for space weather science as well as for the understanding of distant astrophysical plasmas. Plasma energization and energy transport are related to fundamental processes such as shocks, magnetic reconnection, turbulence and waves, plasma jets and instabilities, which are at the core of the current space plasma physics research. ESA/Cluster and NASA/MMS four-point constellations, as well as the large-scale multipoint mission NASA/THEMIS, have greatly improved over the last two decades our understanding of plasma processes at individual scales compared to earlier single-point measurements. Despite the large amount of available observations, we still do not fully understand the physical mechanisms which give rise to plasma energization and energy transport. The reason is that the fundamental physical processes governing plasma energization and energy transport operate across multiple scales ranging from the large fluid to the smaller kinetic scales. Here we present the Plasma Observatory (PO) multiscale mission concept which is tailored to study plasma energization and energy transport within the Earth's Magnetospheric System. PO baseline is comprised of one mothercraft (MSC) and six identical smallsat daughtercraft (DSC) in an HEO 8 RE X 18 RE orbit, covering all the key regions of the Magnetospheric System where strong energization and transport occur: the foreshock, bow shock, magnetosheath, magnetopause, magnetotail current sheet, and the transition region. MSC payload provides a complete characterization of electromagnetic fields and plasma particles in a single point with time resolution sufficient to resolve kinetic physics at sub-ion scales. The DSCs have identical payload which is much simpler than on the MSC, yet giving a full characterization of the plasma at the ion and fluid scales. Going beyond Cluster, THEMIS and MMS, PO will permit us to resolve for the first time the coupling between ion and fluid scales as well as the non-planarity and non-stationarity of plasma structures at those scales. PO is one of the five ESA M7 candidates to be launched around 2037 and is currently undergoing a competitive Phase 0 at ESA for further downselection to Phase A at the end of 2023.

The majority of the atmospheres of solar system bodies are composed of neutral gas, and hence their upper atmosphere are always partially ionized by the solar UV and collisions, allowing a complex nonlinear interaction with interplanetary plasma. Thus, ion-neutral and electron-neutral interaction plays a key role in this transition regions (ionosphere for planets and moons). However, our current understanding of plasma-neutral gas interactions is very limited due to lack of observations with proper instrumentation and to the difficulty in making laboratory experiments (almost impossible to reproduce the ionosphere with low energy plasma). Particularly the effect of small amount of neutral species in space above the exobase and the effects of electric charges on neutrals have been underestimated. To advance our knowledge of these basic but still poorly understood interactions between plasma and neutral gas at key regions of energy, momentum, and mass exchange between the space and the atmosphere, we evaluate what kind of measurement package is needed for different solar system objects in a cost-effective manner. We particularly focus on understanding the re-distribution of externally provided energy to the composing species through this interaction. The presentation is based on a white paper submitted to ESA's Voyage 2050 (Experimental Astronomy, 2022), and related mission proposals to space agencies. Here we skip the chemical aspect that is also mentioned in the white paper.Reference: https://doi.org/10.1007/s10686-022-09846-9

We review a number of studies, undertaken during the 10 years of Swarm, using distributed, multi-scale measurements arising from the combination with Cluster, MMS and ground based arrays. The scaling, coherence and correlation of field-aligned current sheets (FACs) connecting different regions of the magnetosphere have been explored with associated analysis techniques using these multi-point measurements at both low (LEO) and high altitudes, and in relation to (R1/R2) auroral boundaries. Individual events can map to conjugate current density distributions at the magnetopause and ring current and regions in between; as well as to associated ground signatures, driven by the external conditions. Large and small-scale (MLT) trends in FAC orientation can be inferred from dual-spacecraft (e.g. the Swarm A&C spacecraft). Conjugate effects seen in ground (dH/dt), ionospheric and magnetospheric magnetic signals show that intense, coherent FA currents can take place in the polar cusp during the main phase of a geomagnetic storm and at near tail local times during substorm activity, at different altitudes. In the former event the mesoscale FACs show vertical scaling and a corresponding geomagnetic disturbance, driven by unsteady magnetic reconnection at the magnetopause. In the latter event, the most intense dH/dt is shown to be associated with FACs driven into the ionosphere by the arrival of bursty bulk flows BBFs at geosynchronous orbit (linked via a modified sub-storm current wedge, SCW). In situ ring current morphology can also be investigated by MMS, THEMIS and Cluster during the Swarm era, and can be compared to distributions of R2-FACs.

We review the range of applications and use of the curlometer, initially developed to analyze electric current density using Cluster multi-spacecraft magnetic field data; but more recently adapted to other arrays of spacecraft flying in formation, such as MMS small-scale, 4-spacecraft configurations; THEMIS close constellations of 3-5 spacecraft, and Swarm 2-3 spacecraft configurations. The method (and associated methods based on spatial gradients) has been shown to be easily adaptable to other multi-point and multi-scale arrays. Although magnetic gradients require knowledge of spacecraft separations and the magnetic field, the structure of the electric current density (for example, its relative spatial scale), and any temporal evolution, limits measurement accuracy. Nevertheless, in many magnetospheric regions the curlometer is reliable (within certain limits), particularly under conditions of time stationarity, or with supporting information on morphology (for example, when the geometry of the large scale structure is expected). A number of large-scale regions have been investigated directly, such as: the cross-tail current sheet, ring current, the current layer at the magnetopause and field-aligned currents. In addition, the analysis can support investigations of transient and smaller scale current structures (e.g. reconnected flux tubes, boundary layer sub-structure, or dipolarisation fronts) and energy transfer processes. The method is able to provide estimates of single components of the vector current density, even if there are only two or three satellites flying in formation, within the current region, as can be the case when there is a highly irregular spacecraft configuration. The computation of magnetic field gradients and topology in general includes magnetic rotation analysis and various least squares approaches, as well as the curlometer, and indeed the combination with plasma measurements and the extension to larger arrays of spacecraft have recently been considered. We touch on these extensions and on new methodology accessing the properties of the underlying formulism.

The Earth’s ring current forms a complex current system at the boundary of the inner magnetosphere. It is highly dynamic because of the interaction between the solar wind with the Earth's magnetosphere (the influence of space weather), while its morphology depends on the nature of the magnetospheric-ionospheric (M-I) coupling, generating field-aligned currents (FACs). Its behaviour can therefore have a huge impact on the terrestrial environment. According to Ampere's law, these currents can be directly measured by perturbations in the magnetic field using multi-spacecraft observation techniques. We have analyzed the magnetic field data from the four MMS spacecraft in their small-sale configuration to obtain the in-situ current density and have carried out statistical analysis from several years of data. The form of the current density distribution and its changing nature has been investigated. Our results show that the current density exhibits a three-dimensional layered structure in the ring current region. The significant westward current on the day side flows to higher magnetic latitudes and complete closure there rather than to the magnetic equator. There are some differences between geomagnetic quiet period and storm period on current density, but the basic spatial structure remains similar and compares well with previous space mission data. Comparison with Swarm data at low Earth altitudes, we found that the stratification is consistent with the distribution of the R2 field-aligned currents seen both adjacent to the ring current and at ionospheric altitudes (at Swarm). In addition, significant continuous eastward currents exist in some latitudes and some regions, indicating the complexity of the ring current. Some of them can be explained by the formation of banana currents.

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Purpose: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas.Experimental Design: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10−7. Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58].Results: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10−7 level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r2 = 0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50–2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211).Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance. Clin Cancer Res; 19(23); 6430–7. ©2013 AACR.

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N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79–0.91), 0.84 (95%CI: 0.79–0.90) and 0.80 (95%CI: 0.71–0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.

Background Substantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance. Methods A comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed. Results Forty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9–485 cases) and lack of independent external validation (76.7%). Conclusions This review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.

SummaryObjectiveThere are few prospective data exploring the combined effect of genetic and lifestyle factors on the incidence of inflammatory bowel disease (IBD), and whether genetic risk of IBD may be mitigated by lifestyle remains unclear.DesignWe conducted a prospective cohort study based on the UK Biobank to examine the associations across genetic risk, modifiable lifestyle factors, and risk of Crohn’s disease (CD) and ulcerative colitis (UC). Genetic susceptibility to CD and UC was estimated by polygenic risk scores using common genetic variants identified by genome-wide association studies and was further categorized into high, intermediate, and low genetic risk categories. Weighted unhealthy lifestyle scores were constructed based on disease-related lifestyle factors, including ever smoking, unhealthy diet, physical inactivity, obesity, and abnormal sleep duration, and were categorized into ‘favorable’, ‘intermediate’, and ‘unfavorable’ categories. The Cox proportional hazard regression model was used to estimate the HRs and 95% CIs for their associations and accumulative risk for developing CD and UC were estimated for each risk group.ResultsDuring a median follow-up of 12.0 years, 707 CD and 1576 UC cases were diagnosed. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk and there was no multiplicative interaction between them. Compared with participants with low genetic risk, the hazard ratios (HRs) of CD and UC were 2.24 (95% confidence interval [CI] 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with high genetic risk, respectively. The HRs of CD and UC for individuals in unfavorable lifestyle category were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively, compared with those in favorable category. When considering genetic risk and lifestyle jointly, the HRs of individuals with high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI, 1.58-2.66 for UC) were reduced nearly by half comparing to those with high genetic risk but an unfavorable lifestyle (4.40, 95% CI, 2.91-6.66 for CD and 4.44, 95% CI, 3.34-5.91 for UC).ConclusionGenetic and lifestyle factors were independently associated with susceptibility to CD and UC. Participants at high genetic risk could reduce nearly 50% risk of CD and UC by adherence to a favorable lifestyle.FundingXL: the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001). XYW: National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province(2019SK2041); SCL: the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden); ET: CRUK Career Development Fellowship (C31250/A22804); KFD: Project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903).What is already known on this topicPrevious studies have identified a number of genetic variants and several modifiable risk factors for IBD. However, there is a lack of studies on the combined effects of genetic and lifestyle factors on IBD risk.What this study addsIn this prospective cohort study, genetic risk and modifiable lifestyle factors were independently associated with the risk of incident Crohn’s disease and ulcerative colitis. Participants at high genetic risk could reduce nearly 50% of their genetic susceptibility to Crohn’s disease and ulcerative colitis by adherence to a favorable lifestyle.How this study might affect research, practice or policyPromoting a healthy lifestyle is an effective strategy to lower the incidence of these diseases, especially among those with high-risk genetic background.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions, and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Cross-tissue analyses indicated that over a third of effector genes most likely act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis, and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Background:Proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). Methods: Protein quantitative trait loci (pQTL) were derived from seven published genome-wide association studies (GWAS) on plasma proteosome, and summary-level data were extracted for 4,853 circulating protein markers. Genetic associations with CRC were obtained from a large-scaled GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4,957 cases and 304,197 controls) and the UK Biobank (9,276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. Results: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which six (CLSTN3, POLR2F, ADPGK, CSAG1, STXBP6, FUT3) were novel protein markers. These protein-coding genes mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. Conclusion: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.

The ring current and field-aligned currents have a dominant effect in the inner magnetospheric current system, where the coupling mechanism to the ionosphere has a significant impact on space weather and magnetic activity on the ground. We use FGM data from the four spacecraft MMS mission to estimate in situ current density and study the distribution of the ring current, by statistically analyzing the azimuth component of current density. We also compare the statistical results of field-aligned component of current density from MMS with the statistical results of dual-FAC data of Swarm in the same time range to explore the large-scale coupling of the ring current and field-aligned currents. The joint observational results show that: on the one hand (on the dawn side), due to the injection of Region 2 field-aligned currents, the westward ring current increases continuously from noon to midnight; while (on the dusk side, from midnight to noon), due to the injection of Region 1 field-aligned current near midnight and the outflow of Region 2 field-aligned currents, the westward ring current increases, then decreases until it turns eastward and increases in magnitude. On the other hand, due to the existence of a mesoscale, clockwise banana current centered at about 4.8Re (Earth Radii) between noon and dusk, the eastward ring current is significantly enhanced in the inner ring and enhanced westward in the outer ring. Similarly, due to the existence of a mesoscale counterclockwise current centered at about 4.8Re between midnight and dawn, the westward ring current is slightly enhanced in the inner ring and enhanced eastward in the outer ring. The influence of these two factors on the distribution of the ring current is of the same order of magnitude. Work to clarify the operation of these effects relative to activity levels is in progress.

The interaction of the solar wind with the Earth’s magnetosphere can result in various disturbance phenomena inside the magnetosphere, such as the density, occurrence, and distribution of the field-aligned currents (FACs) in the magnetosphere-ionosphere system. The FACs take an important role in the magnetosphere - ionosphere coupling and have been investigated for many decades. However, it’s response to the solar wind and IMF still needs to be further studied. In this study, we statistically investigate the influence of the solar wind dynamic pressure (SW Pdyn) on the FACs in the magnetotail based on 1492 FAC cases occurring from July to October in 2001 and 2004, which covers 117 Cluster spacecraft crossings of plasma sheet boundary layer (PSBL). The FAC density in the magnetotail is derived from the magnetic field data with the four-point measurement of Cluster and the SW Pdyn is derived from ACE data. It was confirmed that the magnetotail FAC density depended on the solar wind dynamic pressure during both magnetic storm and non-storm time, and the FAC density was much stronger with intense SW Pdyn during storm time. The statistical results show that the FAC occurrence increases monotonically with SW Pdyn in the three levels (weak: SW Pdyndyn>5 nPa). The FAC density increases with increasing SW Pdyn, while its footprint (invariant latitude, ILAT) in the polar region decreases with increasing SW Pdyn. Also, the FAC in the magnetotail response to SW Pdyn has a north-south hemispheric asymmetry. The correlation of FAC density with SW Pdyn is better in the Northern Hemisphere, while the correlation of the footprint position with SW Pdyn is better in the Southern Hemisphere. Furthermore, the influences of the solar wind core angle and clock angle on the FAC density, occurrence, and distribution are also shown in this presentation. The concerned mechanisms for our results are analyzed and discussed.

In the White Paper, submitted in response to the European Space Agency (ESA) Voyage 2050 Call, we present the importance of advancing our knowledge of plasma-neutral gas interactions, and of deepening our understanding of the partially ionized environments that are ubiquitous in the upper atmospheres of planets and moons, and elsewhere in space. In future space missions, the above task requires addressing the following fundamental questions: (A) How and by how much do plasma-neutral gas interactions influence the re-distribution of externally provided energy to the composing species? (B) How and by how much do plasma-neutral gas interactions contribute toward the growth of heavy complex molecules and biomolecules? Answering these questions is an absolute prerequisite for addressing the long-standing questions of atmospheric escape, the origin of biomolecules, and their role in the evolution of planets, moons, or comets, under the influence of energy sources in the form of electromagnetic and corpuscular radiation, because low-energy ion-neutral cross-sections in space cannot be reproduced quantitatively in laboratories for conditions of satisfying, particularly, (1) low-temperatures, (2) tenuous or strong gradients or layered media, and (3) in low-gravity plasma. Measurements with a minimum core instrument package (

International audience; We review the range of applications and use of the curlometer, initially developed to analyze Cluster multi-spacecraft magnetic field data; but more recently adapted to other arrays of spacecraft flying in formation, such as MMS small-scale, 4-spacecraft configurations; THEMIS close constellations of 3–5 spacecraft, and Swarm 2–3 spacecraft configurations. Although magnetic gradients require knowledge of spacecraft separations and the magnetic field, the structure of the electric current density (for example, its relative spatial scale), and any temporal evolution, limits measurement accuracy. Nevertheless, in many magnetospheric regions the curlometer is reliable (within certain limits), particularly under conditions of time stationarity, or with supporting information on morphology (for example, when the geometry of the large scale structure is expected). A number of large-scale regions have been covered, such as: the cross-tail current sheet, ring current, the current layer at the magnetopause and field-aligned currents. Transient and smaller scale current structures (e.g., reconnected flux tube or dipolarisation fronts) and energy transfer processes. The method is able to provide estimates of single components of the vector current density, even if there are only two or three satellites flying in formation, within the current region, as can be the case when there is a highly irregular spacecraft configuration. The computation of magnetic field gradients and topology in general includes magnetic rotation analysis and various least squares approaches, as well as the curlometer, and indeed the added inclusion of plasma measurements and the extension to larger arrays of spacecraft have recently been considered.

Objective To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer. Design Population based cohort study. Setting Data from the UK Biobank study, collected between March 2006 and July 2010. Participants 434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts. Main outcome measures Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. Results Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone. Conclusions Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population.

In this study, a novel algorithm for jointly estimating the linear and quadratic gradients of physical quantities with multiple spacecraft observations based on the least square method has been put...

While subauroral polarization streams (SAPS) are well recognized as representatively one of the most important features of magnetosphere-ionosphere (M-I) coupling processes in the subauroral region, the double-peak subauroral ion drifts (DSAIDs) is a newly recognized ionospheric phenomenon, categorized as a subset of subauroral ion drifts (SAIDs). In this study, we investigate both SAPS and DSAIDs that appear during the storm main phase of the 17 March 2015 event through a combination of multi-point observations and numerical simulations. We find that when SAPS/DSAIDs are observed by the DMSP spacecraft near the dusk subauroral region, strong electric fields are detected minutes later by the Van Allen Probes almost in the same conjugate region near the equatorial plane. Numerical simulations are carried out not only to reveal the global context and dynamic evolution of the SAPS in both the magnetospheric and ionospheric systems, but also to aid the understanding of the effect of conductance on the DSAIDs. Our results confirm that SAPS are indeed associated with Region 2 field-aligned currents (FACs) flowing into the low conductance region. On the other hand, the DSAIDs may be related to the double-conductance-trough in the subauroral region.

The energy distribution at wave number space is known to be anisotropic in space plasmas. At kinetic scales, the standard Kinetic Alfven Wave model predicts anisotropy scaling of kpar ∝ kperp(1/3), whereas the latest models considering the intermittency, or tearing instabilities, predict scalings such as kpar ∝ kperp(2/3) and kpar ∝ kperp(3/3). Recent numerical simulations also payed considerable attention to this issue. Based on a unified analysis of five-point structure functions of the turbulence in three kinetic simulations, Cerri et al. 2019 obtained a converging result of lpar ∝ lperp(3/3). To enrich our knowledge of the anisotropic scaling relation from an observational point of view, we conducted a statistical survey for the turbulence measured by MMS in the magnetosheath. For the 349 intervals with burst mode data, abundant evidence of 3D anisotropy at the sub-proton scale (1-100 km) is revealed by five-point second order structure functions. In particular, the eddies are mostly elongated along background magnetic field B0 and shortened in the two perpendicular directions. The ratio between eddies’ parallel and perpendicular lengths features a trend of rise then fall toward small scales, whereas the anisotropy in the perpendicular plane appears scale invariant. Moreover, over 30% of the events exhibit scaling relations close to lpar ∝ lperp(2/3). In order to explain such signature, additional factors such as intermittency caused by different coherent structures may be required in addition to the critical balance premise.

During geomagnetically disturbed times the surface geomagnetic field often changes abruptly, producing geomagnetically induced currents (GICs) in a number of ground based systems. There are, however, few studies reporting GIC effects which are driven directly by bursty bulk flows (BBFs) in the inner magnetosphere. In this study, we investigate the characteristics and responses of the magnetosphere-ionosphere-ground system during the 7 January 2015 storm by using a multi-point approach which combines space-borne measurements and ground magnetic observations. During the event, multiple BBFs are detected in the inner magnetosphere while the magnetic footprints of both magnetospheric and ionospheric satellites map to the same conjugate region surrounded by a group of magnetometer ground stations. It is suggested that the observed, localized substorm currents are caused by the observed magnetospheric BBFs, giving rise to intense geomagnetic perturbations. Our results provide direct evidence that the wide-range of intense dB/dt (and dH/dt) variations are associated with a large-scale, substorm current system, driven by multiple BBFs.

Magnetospheric Multiscale (MMS) data are used to investigate the energy dissipation in a reconnection diffusion region at the magnetopause. The four MMS spacecraft were separated by about 10 km such that comparative study between each spacecraft within the diffusion region can be implemented. Similar magnetic field and electric current behavior between each spacecraft indicates the formation of a quasi-homogeneous diffusion region structure. However, we find that the energy dissipation results between each spacecraft are different due to the temporal or spatial effect of the out-of-plane merging electric field (EM) during the dissipation region. Our study suggests that the intermittent energy dissipation in the reconnection dissipation region can be a common phenomenon, even under a stable diffusion region structure.

The ring current is an important part of the large-scale magnetosphere-ionosphere current system; mainly concentrated in the equatorial plane, between 2-7 RE, and strongly ordered between ± 30 ° latitude. The morphology of ring current directly affects the geomagnetic field at low to middle latitudes. Rapid changes in ring current densities can occur during magnetic storms/sub-storms. Traditionally, the Dst index is used to characterize the intensity of magnetic storms and to reflect the variation of ring current intensity, but this index does not reflect the MLT distribution of ring current. In fact, the ring current has significant variations with MLT, depending on geomagnetic activity, due to the influence of multiple factors; such as, the partial ring current, region 1/region 2 field-aligned currents, the magnetopause current and sub-storm cycle (magnetotail current). The form of the ring current has been inferred from the three-dimensional distribution of ion differential fluxes from neutral atom imaging; however, this technique can not directly obtain the current density distribution (as can be obtained using multi-spacecraft in situ data). Previous in situ estimates of current density have used: Cluster, THEMIS and other spacecraft groups to study the distribution of the ring current for limited ranges of either radial profile, or MLT and MLAT variations. Here, we report on an extension to these studies using FGM data from MMS obtained during the period September 1, 2015 to December 31, 2016, when the MMS orbit and configuration provided good coverage. We employ the curlometer method to calculate the current density, statistically, to analysis the MLT distribution according to different geomagnetic conditions. Our results show the clear asymmetry of the ring current and its different characteristics under different geomagnetic conditions.

A statistical survey of spectral anisotropy of space plasma turbulence is performed using five years measurements from MMS in the magnetosheath. By measuring the five-point second-order structure functions of the magnetic field, we have for the first time quantified the three-dimensional anisotropies and scalings at sub-ion-scales ($, Comment: Accepted

Magnetic reconnection is a universal physical process during which energy can be transferred from the electromagnetic field to the plasma. Energy dissipation in the diffusion region has always been a significant issue for understanding this energy transport. Using the four MMS spacecraft data, we investigate a magnetic reconnection diffusion region event at the magnetopause. Similar magnetic field and electric current behavior between each spacecraft indicates the formation of a quasi 2D structure. However, we find that the energy dissipation results of each spacecraft are different. Further analysis indicates that the reconnection electric field, EM, plays a key role in this process. Thus, we suggest that the energy dissipation of magnetic reconnection is unsteady on this spatial or temporal scale, even under stable diffusion conditions.

During geomagnetically disturbed times, geomagnetically induced currents (GICs) flow in power systems potentially causing damage to the system. The largest GICs are often produced when the surface geomagnetic field abruptly changes (for example, an induced rate of change of the horizontal magnetic field component, dH/dt). It is well established that intense dB/dt variations take place in the main phase of a geomagnetic storm, particularly while magnetic substorms occur during the active period. However, there are currently few studies that report intense dB/dt variations which are directly driven by bursty bulk flows (BBFs) at geosynchronous orbit. In this study, we investigate the characteristics and response in the magnetosphere-ionosphere system during the recovery phase of a geomagnetic storm that occurred on 7 January 2015 by using a multi-point approach combining space-borne Cluster and SWARM measurements, and a group of ground-based magnetometer observations. The locations of Cluster and SWARM map to the same conjugate region as the magnetometer ground stations at the time of the BBF. The measurements show that corresponding signals in all measurements occur simultaneously in this region. Our results suggest that the most intense dB/dt (dH/dt) variations are associated with R1-type FACs that are driven by BBFs at geosynchronous orbit around substorm onset.

The orientation of field-aligned current sheets (FACs) can be inferred from dual-spacecraft correlations of the FAC signatures between two Swarm spacecraft (A and C), using the maximum correlations obtained from sliding data segments. Statistical analysis of both the correlations and the inferred orientations shows clear trends in magnetic local time (MLT) which reveal behaviour of both large and small scale currents. The maximum correlation coefficients show distinct behaviour in terms of either the time shift, or the shift in longitude between Swarm A and C for various filtering levels. The lower-latitude FACs show the strongest correlations for a broad range of MLT centred on dawn and dusk, with a higher correlation coefficient on the dusk-side and lower correlations near noon and midnight, and broadly follow the mean shape of the auroral boundary for the lower latitudes corresponding to Region 2 FACs (and are most well-ordered on the dusk side). Individual events sampled by higher altitude spacecraft (e.g. the 4 Cluster spacecraft), in conjunction with Swarm (mapping both to region 1 and 2), also show two different domains of FACs: time variable, small-scale (10s km), and more stationary large-scale (>100 km) FACs. We investigate further how these FAC regimes are dependent on geomagnetic activity, focusing on high activity events. Both the statistical trends, and individual conjugate events, show comparable effects seen in the ground magnetometer signals (dH/dt) during storm/substorm activity and show distributions that are similar.

The Earth’s magnetopause is highly variable in location and shape, and is modulated by solar wind conditions. On 8 March 2012, the ARTEMIS probes were located near the tail current sheet when an interplanetary shock arrived under northward interplanetary magnetic field (IMF) conditions, and recorded an abrupt tail compression at ~(-60, 0, -5) RE in Geocentric Solar Ecliptic (GSE) coordinate in the deep magnetotail. Approximately 10 minutes later, the probes crossed the magnetopause many times within an hour after the oblique interplanetary shock passed by. The solar wind velocity vector downstream from the shock was not directed along the Sun-Earth line, but had a significant Y component. We propose that the compressed tail was pushed aside by the appreciable solar wind flow in the Y direction. Using a virtual spacecraft in a global magnetohydrodynamic (MHD) simulation, we reproduce the sequence of magnetopause crossings in the X-Y plane observed by ARTEMIS probes under oblique shock conditions, demonstrating that the compressed magnetopause is sharply deflected at lunar distances in response to the shock and solar wind VY effects. The results of the two different global MHD simulations show that the shocked magnetotail at lunar distances is mainly controlled by the solar wind direction with a timescale of about a quarter hour, which appears to be consistent with the windsock effect. The results also provide some references for investigating interactions between the solar wind/magnetosheath and lunar nearside surface during full moon time intervals, which should not happen in general.