Borrelia recurrentis employs a novel multifunctional surface protein with anti-complement, anti-opsonic and invasive potential to escape innate immunity

Borrelia recurrentis, the etiologic agent of louse-borne relapsing fever in humans, has evolved strategies, including antigenic variation, to evade immune defence, thereby causing severe diseases with high mortality rates. Here we identify for the first time a multifunctional surface lipoprotein of B. recurrentis, termed HcpA, and demonstrate that it binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. Cell surface bound factor H was found to retain its activity and to confer resistance to complement attack. Moreover, ectopic expression of HcpA in a B. burgdorferi B313 strain, deficient in Factor H binding proteins, protected the transformed spirochetes from complement-mediated killing. Furthermore, HcpA-bound plasminogen/plasmin endows B. recurrentis with the potential to resist opsonization and to degrade extracellular matrix components. Together, the present study underscores the high virulence potential of B. recurrentis. The elucidation of the molecular basis underlying the versatile strategies of B. recurrentis to escape innate immunity and to persist in human tissues, including the brain, may help to understand the pathological processes underlying louse-borne relapsing fever

Recognising and reacting to angry and happy facial expressions: a diffusion model analysis.

Researchers have reported two biases in how people recognise and respond to angry and happy facial expressions: (1) a gender-expression bias (Becker et al. in J Pers Soc Psychol, 92(2):179-190, https://doi.org/10.1037/0022-3514.92.2.179 , 2007)-faster identification of male faces as angry and female faces as happy and (2) an approach-avoidance bias-faster avoidance of people who appear angry and faster approach responses people who appear happy (Heuer et al. in Behav Res The, 45(12):2990-3001, https://doi.org/10.1016/j.brat.2007.08.010 2007; Marsh et al. in Emotion, 5(1), 119-124, https://doi.org/10.1037/1528-3542.5.1.119 , 2005; Rotteveel and Phaf in Emotion 4(2):156-172, https://doi.org/10.1037/1528-3542.4.2.156 , 2004). The aim of the current research is to gain insight into the nature of such biases by applying the drift diffusion model to the results of an approach-avoidance task. Sixty-five participants (33 female) identified faces as either happy or angry by pushing and pulling a joystick. In agreement with the original study of this effect (Solarz 1960) there were clear participant gender differences-both the approach avoidance and gender-expression biases were larger in magnitude for female compared to male participants. The diffusion model results extend recent research (Krypotos et al. in Cogn Emot 29(8):1424-1444, https://doi.org/10.1080/02699931.2014.985635 , 2015) by indicating that the gender-expression and approach-avoidance biases are mediated by separate cognitive processes

Body Composition, Symptoms, and Survival in Advanced Cancer Patients Referred to a Phase I Service

Background: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. Methods: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)$25 kg/m 2 was considered overweight. Sarcopenia, severe muscle depletion, was assessed using CT-based criteria. Results: Most patients were overweight (n = 65, 63$25 kg/m 2. Sarcopenic patients were older and less frequently African-American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71–358) (BMI,25 kg/m 2; sarcopenic), 271 (99–443) (BMI,25 kg/m 2; non-sarcopenic), 484 (286–681) (BMI$25 kg/m 2; sarcopenic); 501 d (309–693) (BMI$25 kg/m 2; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. Conclusions: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI$25 kg/m 2, independent o

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Automated Transmission-Mode Scanning Electron Microscopy (tSEM) for Large Volume Analysis at Nanoscale Resolution

Transmission-mode scanning electron microscopy (tSEM) on a field emission SEM platform was developed for efficient and cost-effective imaging of circuit-scale volumes from brain at nanoscale resolution. Image area was maximized while optimizing the resolution and dynamic range necessary for discriminating key subcellular structures, such as small axonal, dendritic and glial processes, synapses, smooth endoplasmic reticulum, vesicles, microtubules, polyribosomes, and endosomes which are critical for neuronal function. Individual image fields from the tSEM system were up to 4,295 µm2 (65.54 µm per side) at 2 nm pixel size, contrasting with image fields from a modern transmission electron microscope (TEM) system, which were only 66.59 µm2 (8.160 µm per side) at the same pixel size. The tSEM produced outstanding images and had reduced distortion and drift relative to TEM. Automated stage and scan control in tSEM easily provided unattended serial section imaging and montaging. Lens and scan properties on both TEM and SEM platforms revealed no significant nonlinear distortions within a central field of ~100 µm2 and produced near-perfect image registration across serial sections using the computational elastic alignment tool in Fiji/TrakEM2 software, and reliable geometric measurements from RECONSTRUCT™ or Fiji/TrakEM2 software. Axial resolution limits the analysis of small structures contained within a section (~45 nm). Since this new tSEM is non-destructive, objects within a section can be explored at finer axial resolution in TEM tomography with current methods. Future development of tSEM tomography promises thinner axial resolution producing nearly isotropic voxels and should provide within-section analyses of structures without changing platforms. Brain was the test system given our interest in synaptic connectivity and plasticity; however, the new tSEM system is readily applicable to other biological systems.This study was funded by United States National Institutes of Health (http://www.nih.gov; grant numbers NS021184, NS074644, and MH095980 to KMH) and Texas Emerging Technologies Fund (http://governor.state.tx.us/ecodev/etf/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.Matthew T. Witkowski, Yifang Hu, Kathryn G. Roberts, Judith M. Boer, Mark D. McKenzie, Grace J. Liu, Oliver D. Le Grice, Cedric S. Tremblay, Margherita Ghisi, Tracy A. Willson, Martin A. Horstmann, Iannis Aifantis, Luisa Cimmino, Seth Frietze, Monique L. den Boer, Charles G. Mullighan, Gordon K. Smyth, and Ross A. Dickin