The importance of lake breach floods for valley incision on early Mars.

The surface environment of early Mars had an active hydrologic cycle, including flowing liquid water that carved river valleys1-3 and filled lake basins4-6. Over 200 of these lake basins filled with sufficient water to breach the confining topography4,6, causing catastrophic flooding and incision of outlet canyons7-10. Much past work has recognized the local importance of lake breach floods on Mars for rapidly incising large valleys7-12; however, on a global scale, valley systems have often been interpreted as recording more persistent fluvial erosion linked to a distributed Martian hydrologic cycle1-3,13-16. Here, we demonstrate the global importance of lake breach flooding, and find that it was responsible for eroding at least 24% of the volume of incised valleys on early Mars, despite representing only approximately 3% of total valley length. We conclude that lake breach floods were a major geomorphic process responsible for valley incision on early Mars, which in turn influenced the topographic form of many Martian valley systems and the broader landscape evolution of the cratered highlands. Our results indicate that the importance of lake breach floods should be considered when reconstructing the formative conditions for Martian valley systems.

The genomic landscape of breast cancer brain metastases: a systematic review.

Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.

Beta-blocker therapy in patients with COPD: a systematic literature review and meta-analysis with multiple treatment comparison.

BACKGROUND: Beta-blockers are associated with reduced mortality in patients with cardiovascular disease but are often under prescribed in those with concomitant COPD, due to concerns regarding respiratory side-effects. We investigated the effects of beta-blockers on outcomes in patients with COPD and explored within-class differences between different agents. METHODS: We searched the Cochrane Central Register of Controlled Trials, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Medline for observational studies and randomized controlled trials (RCTs) investigating the effects of beta-blocker exposure versus no exposure or placebo, in patients with COPD, with and without cardiovascular indications. A meta-analysis was performed to assess the association of beta-blocker therapy with acute exacerbations of COPD (AECOPD), and a network meta-analysis was conducted to investigate the effects of individual beta-blockers on FEV1. Mortality, all-cause hospitalization, and quality of life outcomes were narratively synthesized. RESULTS: We included 23 observational studies and 14 RCTs. In pooled observational data, beta-blocker therapy was associated with an overall reduced risk of AECOPD versus no therapy (HR 0.77, 95%CI 0.70 to 0.85). Among individual beta-blockers, only propranolol was associated with a relative reduction in FEV1 versus placebo, among 199 patients evaluated in RCTs. Narrative syntheses on mortality, all-cause hospitalization and quality of life outcomes indicated a high degree of heterogeneity in study design and patient characteristics but suggested no detrimental effects of beta-blocker therapy on these outcomes. CONCLUSION: The class effect of beta-blockers remains generally positive in patients with COPD. Reduced rates of AECOPD, mortality, and improved quality of life were identified in observational studies, while propranolol was the only agent associated with a deterioration of lung function in RCTs.

FoxO6 regulates memory consolidation and synaptic function.

The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

Decision Making Influences Tibial Impact Accelerations During Lateral Cutting.

Lower-extremity musculoskeletal injuries are common in sports such as basketball and soccer. Athletes competing in sports of this nature must maneuver in response to the actions of their teammates, opponents, etc. This limits their ability to preplan movements. The purpose of this study was to compare impact accelerations during preplanned versus unplanned lateral cutting. A total of 30 subjects (15 males and 15 females) performed preplanned and unplanned cuts while the authors analyzed impact accelerations using an accelerometer secured to their tibia. For the preplanned condition, subjects were aware of the movement to perform before initiating a trial. For the unplanned condition, subjects initiated their movement and then reacted to the illumination of one of 3 visual stimuli which dictated whether they would cut, land, or land-and-jump. A mixed-model analysis of variance with a between factor of sex (male and female) and a within factor of condition (preplanned and unplanned) was used to analyze the magnitude and variability of the impact accelerations for the cutting trials. Both males and females demonstrated higher impact accelerations (P = .01) and a trend toward greater intertrial variability (P = .07) for the unplanned cutting trials (vs preplanned cuts). Unplanned cutting may place greater demands on the musculoskeletal system.

Analysis of the genetic basis of disease in the context of worldwide human relationships and migration.

Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation.

Hip External Rotator Strength Is Associated With Better Dynamic Control of the Lower Extremity During Landing Tasks.

The purpose of this study was to determine the association between hip strength and lower extremity kinematics and kinetics during unanticipated single-leg landing and cutting tasks in collegiate female soccer players. Twenty-three National Collegiate Athletic Association division I female soccer players were recruited for strength testing and biomechanical analysis. Maximal isometric hip abduction and external rotation strength were measured using a hand-held dynamometer and expressed as muscle torque (force × femoral length) and normalized to body weight. Three-dimensional lower extremity kinematics and kinetics were assessed with motion analysis and force plates, and an inverse dynamics approach was used to calculate net internal joint moments that were normalized to body weight. Greater hip external rotator strength was significantly associated with greater peak hip external rotation moments (r = 0.47; p = 0.021), greater peak knee internal rotation moments (r = 0.41; p = 0.048), greater hip frontal plane excursion (r = 0.49; p = 0.017), and less knee transverse plane excursion (r = -0.56; p = 0.004) during unanticipated single-leg landing and cutting tasks. In addition, a statistical trend was detected between hip external rotator strength and peak hip frontal plane moments (r = 0.39; p = 0.06). The results suggest that females with greater hip external rotator strength demonstrate better dynamic control of the lower extremity during unanticipated single-leg landing and cutting tasks and provide further support for the link between hip strength and lower extremity landing mechanics.

Aging-like changes in the transcriptome of irradiated microglia.

Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767.

Prediction of multiple infections after severe burn trauma: a prospective cohort study.

OBJECTIVE: To develop predictive models for early triage of burn patients based on hypersusceptibility to repeated infections. BACKGROUND: Infection remains a major cause of mortality and morbidity after severe trauma, demanding new strategies to combat infections. Models for infection prediction are lacking. METHODS: Secondary analysis of 459 burn patients (≥16 years old) with 20% or more total body surface area burns recruited from 6 US burn centers. We compared blood transcriptomes with a 180-hour cutoff on the injury-to-transcriptome interval of 47 patients (≤1 infection episode) to those of 66 hypersusceptible patients [multiple (≥2) infection episodes (MIE)]. We used LASSO regression to select biomarkers and multivariate logistic regression to built models, accuracy of which were assessed by area under receiver operating characteristic curve (AUROC) and cross-validation. RESULTS: Three predictive models were developed using covariates of (1) clinical characteristics; (2) expression profiles of 14 genomic probes; (3) combining (1) and (2). The genomic and clinical models were highly predictive of MIE status [AUROCGenomic = 0.946 (95% CI: 0.906-0.986); AUROCClinical = 0.864 (CI: 0.794-0.933); AUROCGenomic/AUROCClinical P = 0.044]. Combined model has an increased AUROCCombined of 0.967 (CI: 0.940-0.993) compared with the individual models (AUROCCombined/AUROCClinical P = 0.0069). Hypersusceptible patients show early alterations in immune-related signaling pathways, epigenetic modulation, and chromatin remodeling. CONCLUSIONS: Early triage of burn patients more susceptible to infections can be made using clinical characteristics and/or genomic signatures. Genomic signature suggests new insights into the pathophysiology of hypersusceptibility to infection may lead to novel potential therapeutic or prophylactic targets.

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes.

Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10(-20)). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.

The association of dorsiflexion flexibility on knee kinematics and kinetics during a drop vertical jump in healthy female athletes.

PURPOSE: While previous studies have examined the association between ankle dorsiflexion flexibility and deleterious landing postures, it is not currently known how landing kinetics are influenced by ankle dorsiflexion flexibility. The purpose of this study was to examine whether ankle dorsiflexion flexibility was associated with landing kinematics and kinetics that have been shown to increase the risk of anterior cruciate ligament (ACL) injury in female athletes. METHODS: Twenty-three female collegiate soccer players participated in a preseason screening that included the assessment of ankle dorsiflexion flexibility and lower-body kinematics and kinetics during a drop vertical jump task. RESULTS: The results demonstrated that females with less ankle dorsiflexion flexibility exhibited greater peak knee abduction moments (r = -.442), greater peak knee abduction angles (r = .355), and less peak knee flexion angles (r = .385) during landing. The range of dorsiflexion flexibility for the current study was between 9° and 23° (mean = 15.0°; SD 3.9°). CONCLUSION: Dorsiflexion flexibility may serve as a useful clinical measure to predict poor landing postures and external forces that have been associated with increased knee injury risk. Rehabilitation specialists can provide interventions aimed at improving dorsiflexion flexibility in order to ameliorate the impact of this modifiable factor on deleterious landing kinematics and kinetics in female athletes. LEVEL OF EVIDENCE: II.

Phosphoryl-rich flame-retardant ions (FRIONs): towards safer lithium-ion batteries.

The functionalized catecholate, tetraethyl (2,3-dihydroxy-1,4-phenylene)bis(phosphonate) (H2 -DPC), has been used to prepare a series of lithium salts Li[B(DPC)(oxalato)], Li[B(DPC)2], Li[B(DPC)F2], and Li[P(DPC)3]. The phosphoryl-rich character of these anions was designed to impart flame-retardant properties for their use as potential flame-retardant ions (FRIONs), additives, or replacements for other lithium salts for safer lithium-ion batteries. The new materials were fully characterized, and the single-crystal structures of Li[B(DPC)(oxalato)] and Li[P(DPC)3] have been determined. Thermogravimetric analysis of the four lithium salts show that they are thermally stable up to around 200 °C. Pyrolysis combustion flow calorimetry reveals that these salts produce high char yields upon combustion.

Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells.

STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4(+) T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.

Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia.

BACKGROUND: Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach. METHODS: Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment. RESULTS: In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively. CONCLUSIONS: Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

Comparison of Impact Accelerations During Performance of Common Ballet Maneuvers: A Pilot Study.

INTRODUCTION: Ballet landings produce accelerations that are transmitted proximally up the kinetic chain. If overly excessive/repetitive, these "shocks" to the lower body may contribute to overuse injury. The shocks imposed by different ballet maneuvers are largely unknown at this time, making it difficult to appreciate the physical stresses associated with different maneuvers. Therefore, the purpose of this study was to compare the impact accelerations associated with different common ballet maneuvers. METHODS: As part of this study, 11 adolescent ballet dancers performed 9 different common ballet maneuvers: (1) glissade, (2) pas de chat, (3) petit jeté, (4) petit assemblé, (5) grand assemblé, (6) grand jeté, (7) saut de chat, (8) changement, and (9) entrechat quatre. An inertial sensor secured to the pelvis was used to record the peak resultant acceleration during landings ("impact acceleration"). A Friedman test was conducted to compare impact accelerations across the maneuvers and Wilcoxon signed-rank tests were conducted as pairwise comparisons. RESULTS: The omnibus test indicated that there were differences in impact accelerations among the maneuvers (P < .001). In general, the glissade (2.08 ± 0.47g), pes de chat (2.33 ± 0.23g), petit jeté (2.42 ± 0.29g), and petite assemblé (2.54 ± 0.47g) tended to be the lower impact maneuvers; the grand assemblé (2.90 ± 0.41g), grand jeté (2.99 ± 0.33g), and saut de chat (3.13 ± 0.54g) tended to be the more moderate impact maneuvers; and the changement (4.10 ± 0.48g) and entrechat quatre (4.32 ± 0.52g) tended to be higher impact maneuvers. CONCLUSION: These findings may provide clinicians and dance instructors with greater insight regarding the physical stresses imposed by different ballet maneuvers.

ProfileChaser: searching microarray repositories based on genome-wide patterns of differential expression.

SUMMARY: We introduce ProfileChaser, a web server that allows for querying the Gene Expression Omnibus based on genome-wide patterns of differential expression. Using a novel, content-based approach, ProfileChaser retrieves expression profiles that match the differentially regulated transcriptional programs in a user-supplied experiment. This analysis identifies statistical links to similar expression experiments from the vast array of publicly available data on diseases, drugs, phenotypes and other experimental conditions. AVAILABILITY: http://profilechaser.stanford.edu CONTACT: abutte@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Intumescent multilayer nanocoating, made with renewable polyelectrolytes, for flame-retardant cotton.

Thin films of fully renewable and environmentally benign electrolytes, cationic chitosan (CH) and anionic phytic acid (PA), were deposited on cotton fabric via layer-by-layer (LbL) assembly in an effort to reduce flammability. Altering the pH of aqueous deposition solutions modifies the composition of the final nanocoating. CH-PA films created at pH 6 were thicker and had 48 wt % PA in the coating, while the thinnest films (with a PA content of 66 wt %) were created at pH 4. Each coating was evaluated at both 30 bilayers (BL) and at the same coating weight added to the fabric. In a vertical flame test, fabrics coated with high PA content multilayers completely extinguished the flame, while uncoated cotton was completely consumed. Microcombustion calorimetry confirmed that all coated fabric reduces peak heat release rate (pkHRR) by at least 50% relative to the uncoated control. Fabric coated with pH 4 solutions shows the greatest reduction in pkHRR and total heat release of 60% and 76%, respectively. This superior performance is believed to be due to high phosphorus content that enhances the intumescent behavior of these nanocoatings. These results demonstrate the first completely renewable intumescent LbL assembly, which conformally coats every fiber in cotton fabric and provides an effective alternative to current flame retardant treatments.

Geospatial data from a global survey of martian fan-shaped sedimentary landforms.

Data in this article are related to the research article "The global distribution and morphologic characteristics of fan-shaped sedimentary landforms on Mars". We used globally available image and topographic data to document the location of every fan-shaped sedimentary landform on the surface of Mars. We mapped fan outlines and associated drainage basins and collected a number of morphologic metrics. These data can be used as a boundary condition for studies of global scale studies of Mars, including climate and hydrologic modeling. Data files publicly available on Figshare include point shapefile of fan apices, and polygon shapefiles of fan outlines and drainage basins.