Cortical Tension Allocates the First Inner Cells of the Mammalian Embryo

Every cell in our body originates from the pluripotent inner mass of the embryo, yet it is unknown how biomechanical forces allocate inner cells in vivo. Here we discover subcellular heterogeneities in tensile forces, generated by actomyosin cortical networks, which drive apical constriction to position the first inner cells of living mouse embryos. Myosin II accumulates specifically around constricting cells, and its disruption dysregulates constriction and cell fate. Laser ablations of actomyosin networks reveal that constricting cells have higher cortical tension, generate tension anisotropies and morphological changes in adjacent regions of neighboring cells, and require their neighbors to coordinate their own changes in shape. Thus, tensile forces determine the first spatial segregation of cells during mammalian development. We propose that, unlike more cohesive tissues, the early embryo dissipates tensile forces required by constricting cells via their neighbors, thereby allowing confined cell repositioning without jeopardizing global architecture.Fil: Samarage, Chaminda R.. Monash University; AustraliaFil: White, Melanie D.. Monash University; AustraliaFil: Alvarez, Yanina Daniela. Monash University; Australia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fierro González, Juan Carlos. Monash University; AustraliaFil: Henon, Yann. Monash University; AustraliaFil: Jesudason, Edwin C.. National Health Service Scotland; Reino UnidoFil: Bissiere, Stephanie. Monash University; Australia. Institute of Molecular and Cell Biology; SingapurFil: Fouras, Andreas. Monash University; AustraliaFil: Plachta, Nicolas. Monash University; Australia. Institute of Molecular and Cell Biology; Singapu

CMMSE2017: On two classes of fourth- and seventh-order vectorial methods with stable behavior

[EN] A family of fourth-order iterative methods without memory, for solving nonlinear systems, and its seventh-order extension, are analyzed. By using complex dynamics tools, their stability and reliability are studied by means of the properties of the rational function obtained when they are applied on quadratic polynomials. The stability of their fixed points, in terms of the value of the parameter, its critical points and their associated parameter planes, etc. give us important information about which members of the family have good properties of stability and whether in any of them appear chaos in the iterative process. The conclusions obtained in this dynamical analysis are used in the numerical section, where an academical problem and also the chemical problem of predicting the diffusion and reaction in a porous catalyst pellet are solved.This research was partially supported by Ministerio de Economia y Competitividad MTM2014-52016-C02-2-P and Generalitat Valenciana PROMETEO/2016/089.Cordero Barbero, A.; Guasp, L.; Torregrosa Sánchez, JR. (2018). CMMSE2017: On two classes of fourth- and seventh-order vectorial methods with stable behavior. Journal of Mathematical Chemistry. 56(7):1902-1923. https://doi.org/10.1007/s10910-017-0814-0S19021923567S. Amat, S. Busquier, Advances in Iterative Methods for Nonlinear Equations (Springer, Berlin, 2016)S. Amat, S. Busquier, S. Plaza, Review of some iterative root-finding methods from a dynamical point of view. Sci. Ser. A Math. Sci. 10, 3–35 (2004)S. Amat, S. Busquier, S. Plaza, A construction of attracting periodic orbits for some classical third-order iterative methods. Comput. Appl. Math. 189, 22–33 (2006)I.K. Argyros, Á.A. Magreñn, On the convergence of an optimal fourth-order family of methods and its dynamics. Appl. Math. Comput. 252, 336–346 (2015)D.K.R. Babajee, A. Cordero, J.R. Torregrosa, Study of multipoint iterative methods through the Cayley quadratic test. Comput. Appl. Math. 291, 358–369 (2016). doi: 10.1016/J.CAM.2014.09.020P. Blanchard, The dynamics of Newton’s method. Proc. Symp. Appl. Math. 49, 139–154 (1994)F.I. Chicharro, A. Cordero, J.R. Torregrosa, Drawing dynamical and parameters planes of iterative families and methods. Sci. World J. 2013, Article ID 780153 (2013)C. Chun, M.Y. Lee, B. Neta, J. Džunić, On optimal fourth-order iterative methods free from second derivative and their dynamics. Appl. Math. Comput. 218, 6427–6438 (2012)A. Cordero, E. Gómez, J.R. Torregrosa, Efficient high-order iterative methods for solving nonlinear systems and their application on heat conduction problems. Complexity 2017, Article ID 6457532 (2017)A. Cordero, J.R. Torregrosa, Variants of Newton’s method using fifth-order quadrature formulas. Appl. Math. Comput. 190, 686–698 (2007)R.L. Devaney, An Introduction to Chaotic Dynamical Systems (Addison-Wesley Publishing Company, Reading, 1989)P.G. Logrado, J.D.M. Vianna, Partitioning technique procedure revisited: formalism and first application to atomic problems. Math. Chem. 22, 107–116 (1997)C.G. Jesudason, I. Numerical nonlinear analysis: differential methods and optimization applied to chemical reaction rate determination. Math. Chem. 49, 1384–1415 (2011)Á.A. Magreñán, Different anomalies in a Jarratt family of iterative root-finding methods. Appl. Math. Comput. 233, 29–38 (2014)M. Mahalakshmi, G. Hariharan, K. Kannan, The wavelet methods to linear and nonlinear reaction-diffusion model arising in mathematical chemistry. Math. Chem. 51(9), 2361–2385 (2013)K. Maleknejad, M. Alizadeh, An efficient numerical scheme for solving Hammerstein integral equation arisen in chemical phenomenon. Proc. Comput. Sci. 3, 361–364 (2011)B. Neta, C. Chun, M. Scott, Basins of attraction for optimal eighth-order methods to find simple roots of nonlinear equations. Appl. Math. Comput. 227, 567–592 (2014)M.S. Petković, B. Neta, L.D. Petković, J. Džunić, Multipoint Methods for Solving Nonlinear Equations (Elsevier, Amsterdam, 2013)R.C. Rach, J.S. Duan, A.M. Wazwaz, Solving coupled Lane–Emden boundary value problems in catalytic diffusion reactions by the Adomian decomposition method. Math. Chem. 52(1), 255–267 (2014)R. Singh, G. Nelakanti, J. Kumar, A new effcient technique for solving two-point boundary value problems for integro-differential equations. Math. Chem. 52, 2030–2051 (2014

SERCA directs cell migration and branching across species and germ layers

Branching morphogenesis underlies organogenesis in vertebrates and invertebrates, yet is incompletely understood. Here, we show that the sarco-endoplasmic reticulum Ca2+ reuptake pump (SERCA) directs budding across germ layers and species. Clonal knockdown demonstrated a cell-autonomous role for SERCA in Drosophila air sac budding. Live imaging of Drosophila tracheogenesis revealed elevated Ca2+ levels in migratory tip cells as they form branches. SERCA blockade abolished this Ca2+ differential, aborting both cell migration and new branching. Activating protein kinase C (PKC) rescued Ca2+ in tip cells and restored cell migration and branching. Likewise, inhibiting SERCA abolished mammalian epithelial budding, PKC activation rescued budding, while morphogens did not. Mesoderm (zebrafish angiogenesis) and ectoderm (Drosophila nervous system) behaved similarly, suggesting a conserved requirement for cell-autonomous Ca2+ signaling, established by SERCA, in iterative budding

Recruitment of men to a multi-centre diabetes prevention trial: an evaluation of traditional and online promotional strategies

Background: Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial. Methods: An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50–74 years at high risk of developing diabetes. Study participation was promoted via mainstream media—television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff. Results: Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941). Conclusion: Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT.Karen Bracken, Wendy Hague, Anthony Keech, Ann Conway, David J. Handelsman, Mathis Grossmann, David Jesudason, Bronwyn Stuckey, Bu B. Yeap, Warrick Inder, Carolyn Allan, Robert McLachlan, Kristy P. Robledo and Gary Witter

Contrasting Expression of Canonical Wnt Signaling Reporters TOPGAL, BATGAL and Axin2LacZ during Murine Lung Development and Repair

Canonical Wnt signaling plays multiple roles in lung organogenesis and repair by regulating early progenitor cell fates: investigation has been enhanced by canonical Wnt reporter mice, TOPGAL, BATGAL and Axin2LacZ. Although widely used, it remains unclear whether these reporters convey the same information about canonical Wnt signaling. We therefore compared beta-galactosidase expression patterns in canonical Wnt signaling of these reporter mice in whole embryo versus isolated prenatal lungs. To determine if expression varied further during repair, we analyzed comparative pulmonary expression of beta-galactosidase after naphthalene injury. Our data show important differences between reporter mice. While TOPGAL and BATGAL lines demonstrate Wnt signaling well in early lung epithelium, BATGAL expression is markedly reduced in late embryonic and adult lungs. By contrast, Axin2LacZ expression is sustained in embryonic lung mesenchyme as well as epithelium. Three days into repair after naphthalene, BATGAL expression is induced in bronchial epithelium as well as TOPGAL expression (already strongly expressed without injury). Axin2LacZ expression is increased in bronchial epithelium of injured lungs. Interestingly, both TOPGAL and Axin2LacZ are up regulated in parabronchial smooth muscle cells during repair. Therefore the optimal choice of Wnt reporter line depends on whether up- or down-regulation of canonical Wnt signal reporting in either lung epithelium or mesenchyme is being compared

Genetic epidemiology of SARS-CoV-2 transmission in renal dialysis units - a high risk community-hospital interface

OBJECTIVES: Patients requiring haemodialysis are at increased risk of serious illness with SARS-CoV-2 infection. To improve the understanding of transmission risks in six Scottish renal dialysis units, we utilised the rapid whole-genome sequencing data generated by the COG-UK consortium. METHODS: We combined geographical, temporal and genomic sequence data from the community and hospital to estimate the probability of infection originating from within the dialysis unit, the hospital or the community using Bayesian statistical modelling and compared these results to the details of epidemiological investigations. RESULTS: Of 671 patients, 60 (8.9%) became infected with SARS-CoV-2, of whom 16 (27%) died. Within-unit and community transmission were both evident and an instance of transmission from the wider hospital setting was also demonstrated. CONCLUSIONS: Near-real-time SARS-CoV-2 sequencing data can facilitate tailored infection prevention and control measures, which can be targeted at reducing risk in these settings

Clinical outcomes in typhoid fever: adverse impact of infection with nalidixic acid-resistant Salmonella typhi

BACKGROUND: Widespread use of fluoroquinolones has resulted in emergence of Salmonella typhi strains with decreased susceptibility to fluoroquinolones. These strains are identifiable by their nalidixic acid-resistance. We studied the impact of infection with nalidixic acid-resistant S. typhi (NARST) on clinical outcomes in patients with bacteriologically-confirmed typhoid fever. METHODS: Clinical and laboratory features, fever clearance time and complications were prospectively studied in patients with blood culture-proven typhoid fever, treated at a tertiary care hospital in north India, during the period from November 2001 to October 2003. Susceptibility to amoxycillin, co-trimoxazole, chloramphenicol, ciprofloxacin and ceftriaxone were tested by disc diffusion method. Minimum inhibitory concentrations (MIC) of ciprofloxacin and ceftriaxone were determined by E-test method. RESULTS: During a two-year period, 60 patients (age [mean ± SD]: 15 ± 9 years; males: 40 [67%]) were studied. All isolates were sensitive to ciprofloxacin and ceftriaxone by disc diffusion and MIC breakpoints. However, 11 patients had clinical failure of fluoroquinolone therapy. Infections with NARST isolates (47 [78%]) were significantly associated with longer duration of fever at presentation (median [IQR] 10 [7-15] vs. 4 [3-6] days; P = 0.000), higher frequency of hepatomegaly (57% vs. 15%; P = 0.021), higher levels of aspartate aminotransferase (121 [66–235] vs. 73 [44–119] IU/L; P = 0.033), and increased MIC of ciprofloxacin (0.37 ± 0.21 vs. 0.17 ± 0.14 μg/mL; P = 0.005), as compared to infections with nalidixic acid-susceptible isolates. All 11 patients with complications were infected with NARST isolates. Total duration of illness was significantly longer in patients who developed complications than in patients who did not (22 [14.8–32] vs. 12 [9.3–20.3] days; P = 0.011). Duration of prior antibiotic intake had a strong positive correlation with the duration of fever at presentation (r = 0.61; P = 0.000) as well as the total duration of illness (r = 0.53; P = 0.000). CONCLUSION: Typhoid fever caused by NARST infection is associated with poor clinical outcomes, probably due to delay in initiating appropriate antibiotic therapy. Fluoroquinolone breakpoints for S. typhi need to be redefined and fluoroquinolones should no longer be used as first-line therapy, if the prevalence of NARST is high

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

SummaryGlobal dispersal and increasing frequency of the SARS-CoV-2 Spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of Spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.</jats:p

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant