ZASC1 knockout mice exhibit an early bone marrow-specific defect in murine leukemia virus replication

Abstract Background ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010). Methods To determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies. Results Mice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection. Conclusions These studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection

Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

[EN] Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte-fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+-Ca2+ exchange and SR Ca2+ leak. Changes required to normalize action potentials in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in heart failure and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart.This work was partially supported by the National Science Foundation (MCB 1615677), the American Heart Association (15GRNT25490006), the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 from the Ministerio de Economia, Industria y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) DPI2016-75799-R (AEI/FEDER, UE)", and the "Programa de Ayudas de Investigacion y Desarrollo (PAID-01-17)" from the Universitat Politecnica de Valencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Mora-Fenoll, MT.; Ferrero De Loma-Osorio, JM.; Gómez García, JF.; Sobie, EA.; Trenor Gomis, BA. (2018). Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01194S9Aguilar, M., Qi, X. Y., Huang, H., Comtois, P., & Nattel, S. (2014). Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation. Biophysical Journal, 107(10), 2444-2455. doi:10.1016/j.bpj.2014.10.014R. ALPERT, N., HASENFUSS, G., J. LEAVITT, B., P. ITTLEMAN, F., PIESKE, B., & A. MULIERI, L. (2000). A Mechanistic Analysis of Reduced Mechanical Performance in Human Heart Failure. Japanese Heart Journal, 41(2), 103-116. doi:10.1536/jhj.41.103Bers, D. M. (2000). Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction. 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Proceedings of the National Academy of Sciences, 106(16), 6854-6859. doi:10.1073/pnas.0809777106Andrew MacCannell, K., Bazzazi, H., Chilton, L., Shibukawa, Y., Clark, R. B., & Giles, W. R. (2007). A Mathematical Model of Electrotonic Interactions between Ventricular Myocytes and Fibroblasts. Biophysical Journal, 92(11), 4121-4132. doi:10.1529/biophysj.106.101410Majumder, R., Nayak, A. R., & Pandit, R. (2012). Nonequilibrium Arrhythmic States and Transitions in a Mathematical Model for Diffuse Fibrosis in Human Cardiac Tissue. PLoS ONE, 7(10), e45040. doi:10.1371/journal.pone.0045040Mayourian, J., Savizky, R. M., Sobie, E. A., & Costa, K. D. (2016). Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes. PLOS Computational Biology, 12(7), e1005014. doi:10.1371/journal.pcbi.1005014Miragoli, M., Gaudesius, G., & Rohr, S. (2006). Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts. Circulation Research, 98(6), 801-810. doi:10.1161/01.res.0000214537.44195.a3Mora, M. T., Ferrero, J. M., Romero, L., & Trenor, B. (2017). Sensitivity analysis revealing the effect of modulating ionic mechanisms on calcium dynamics in simulated human heart failure. PLOS ONE, 12(11), e0187739. doi:10.1371/journal.pone.0187739Morotti, S., Nieves-Cintrón, M., Nystoriak, M. A., Navedo, M. F., & Grandi, E. (2017). Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia. Channels, 11(4), 340-346. doi:10.1080/19336950.2017.1293220Muszkiewicz, A., Britton, O. J., Gemmell, P., Passini, E., Sánchez, C., Zhou, X., … Rodriguez, B. (2016). Variability in cardiac electrophysiology: Using experimentally-calibrated populations of models to move beyond the single virtual physiological human paradigm. 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Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+Load Attributable to the Predominance of Forward Mode Block. Circulation Research, 102(11), 1398-1405. doi:10.1161/circresaha.108.173922Péréon, Y., Demolombe, S., Baró, I., Drouin, E., Charpentier, F., & Escande, D. (2000). Differential expression of KvLQT1 isoforms across the human ventricular wall. American Journal of Physiology-Heart and Circulatory Physiology, 278(6), H1908-H1915. doi:10.1152/ajpheart.2000.278.6.h1908Piacentino, V., Weber, C. R., Chen, X., Weisser-Thomas, J., Margulies, K. B., Bers, D. M., & Houser, S. R. (2003). Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes. Circulation Research, 92(6), 651-658. doi:10.1161/01.res.0000062469.83985.9bRocchetti, M., Alemanni, M., Mostacciuolo, G., Barassi, P., Altomare, C., Chisci, R., … Zaza, A. (2008). Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model. Journal of Pharmacology and Experimental Therapeutics, 326(3), 957-965. doi:10.1124/jpet.108.138701Romero, L., Carbonell, B., Trenor, B., Rodríguez, B., Saiz, J., & Ferrero, J. M. (2011). Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models. Progress in Biophysics and Molecular Biology, 107(1), 60-73. doi:10.1016/j.pbiomolbio.2011.06.012Romero, L., Pueyo, E., Fink, M., & Rodríguez, B. (2009). Impact of ionic current variability on human ventricular cellular electrophysiology. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1436-H1445. doi:10.1152/ajpheart.00263.2009Rook, M. B., van Ginneken, A. C., de Jonge, B., el Aoumari, A., Gros, D., & Jongsma, H. J. (1992). 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Broadening Participation in Biology Education Research: Engaging Community College Students and Faculty

Nearly half of all undergraduates are enrolled at community colleges (CCs), including the majority of U.S. students who represent groups underserved in the sciences. Yet only a small minority of studies published in discipline-based education research journals address CC biology students, faculty, courses, or authors. This marked underrepresentation of CC biology education research (BER) limits the availability of evidence that could be used to increase CC student success in biology programs. To address this issue, a diverse group of stakeholders convened at the Building Capacity for Biology Education Research at Community Colleges meeting to discuss how to increase the prevalence of CC BER and foster participation of CC faculty as BER collaborators and authors. The group identified characteristics of CCs that make them excellent environments for studying biology teaching and learning, including student diversity and institutional cultures that prioritize teaching, learning, and assessment. The group also identified constraints likely to impede BER at CCs: limited time, resources, support, and incentives, as well as misalignment between doing research and CC faculty identities as teachers. The meeting culminated with proposing strategies for faculty, administrators, journal editors, scientific societies, and funding agencies to better support CC BER

Physiological Stress and Refuge Behavior by African Elephants

Physiological stress responses allow individuals to adapt to changes in their status or surroundings, but chronic exposure to stressors could have detrimental effects. Increased stress hormone secretion leads to short-term escape behavior; however, no studies have assessed the potential of longer-term escape behavior, when individuals are in a chronic physiological state. Such refuge behavior is likely to take two forms, where an individual or population restricts its space use patterns spatially (spatial refuge hypothesis), or alters its use of space temporally (temporal refuge hypothesis). We tested the spatial and temporal refuge hypotheses by comparing space use patterns among three African elephant populations maintaining different fecal glucocorticoid metabolite (FGM) concentrations. In support of the spatial refuge hypothesis, the elephant population that maintained elevated FGM concentrations (iSimangaliso) used 20% less of its reserve than did an elephant population with lower FGM concentrations (Pilanesberg) in a reserve of similar size, and 43% less than elephants in the smaller Phinda reserve. We found mixed support for the temporal refuge hypothesis; home range sizes in the iSimangaliso population did not differ by day compared to nighttime, but elephants used areas within their home ranges differently between day and night. Elephants in all three reserves generally selected forest and woodland habitats over grasslands, but elephants in iSimangaliso selected exotic forest plantations over native habitat types. Our findings suggest that chronic stress is associated with restricted space use and altered habitat preferences that resemble a facultative refuge behavioral response. Elephants can maintain elevated FGM levels for ≥6 years following translocation, during which they exhibit refuge behavior that is likely a result of human disturbance and habitat conditions. Wildlife managers planning to translocate animals, or to initiate other management activities that could result in chronic stress responses, should consider the potential for, and consequences of, refuge behavior

Investigating Instructor Talk in Novel Contexts: Widespread Use, Unexpected Categories, and an Emergent Sampling Strategy.

Instructor Talk-noncontent language used by instructors in classrooms-is a recently defined and promising variable for better understanding classroom dynamics. Having previously characterized the Instructor Talk framework within the context of a single course, we present here our results surrounding the applicability of the Instructor Talk framework to noncontent language used by instructors in novel course contexts. We analyzed Instructor Talk in eight additional biology courses in their entirety and in 61 biology courses using an emergent sampling strategy. We observed widespread use of Instructor Talk with variation in the amount and category type used. The vast majority of Instructor Talk could be characterized using the originally published Instructor Talk framework, suggesting the robustness of this framework. Additionally, a new form of Instructor Talk-Negatively Phrased Instructor Talk, language that may discourage students or distract from the learning process-was detected in these novel course contexts. Finally, the emergent sampling strategy described here may allow investigation of Instructor Talk in even larger numbers of courses across institutions and disciplines. Given its widespread use, potential influence on students in learning environments, and ability to be sampled, Instructor Talk may be a key variable to consider in future research on teaching and learning in higher education

Collectively Improving Our Teaching: Attempting Biology Department–wide Professional Development in Scientific Teaching

Many efforts to improve science teaching in higher education focus on a few faculty members at an institution at a time, with limited published evidence on attempts to engage faculty across entire departments. We created a long-term, department-wide collaborative professional development program, Biology Faculty Explorations in Scientific Teaching (Biology FEST). Across 3 years of Biology FEST, 89% of the department's faculty completed a weeklong scientific teaching institute, and 83% of eligible instructors participated in additional semester-long follow-up programs. A semester after institute completion, the majority of Biology FEST alumni reported adding active learning to their courses. These instructor self-reports were corroborated by audio analysis of classroom noise and surveys of students in biology courses on the frequency of active-learning techniques used in classes taught by Biology FEST alumni and nonalumni. Three years after Biology FEST launched, faculty participants overwhelmingly reported that their teaching was positively affected. Unexpectedly, most respondents also believed that they had improved relationships with departmental colleagues and felt a greater sense of belonging to the department. Overall, our results indicate that biology department-wide collaborative efforts to develop scientific teaching skills can indeed attract large numbers of faculty, spark widespread change in teaching practices, and improve departmental relations

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV