Juvenile Myelomonocytic Leukemia: Molecular Pathogenesis Informs Current Approaches to Therapy and Hematopoietic Cell Transplantation

Juvenile myelomonocytic leukemia (JMML) is a rare childhood leukemia that has historically been very difficult to confidently diagnose and treat. The majority of patients ultimately require allogeneic hematopoietic cell transplantation (HCT) for cure. Recent advances in the understanding of the pathogenesis of the disease now permit over 90% of patients to be molecularly characterized. Pre-HCT management of patients with JMML is currently symptom-driven. However, evaluation of potential high-risk clinical and molecular features will determine which patients could benefit from pre-HCT chemotherapy and/or local control of splenic disease. Furthermore, new techniques to quantify minimal residual disease burden will determine whether pre-HCT response to chemotherapy is beneficial for long-term disease-free survival. The optimal approach to HCT for JMML is unclear, with high relapse rates regardless of conditioning intensity. An ongoing clinical trial in the Children’s Oncology Group will test if less toxic approaches can be equally effective, thereby shifting the focus to post-HCT immunomanipulation strategies to achieve long-term disease control. Finally, our unraveling of the molecular basis of JMML is beginning to identify possible targets for selective therapeutic interventions, either pre- or post-HCT, an approach which may ultimately provide the best opportunity to improve outcomes for this aggressive disease

Semidefinite Representation of the kk-Ellipse

The $k$-ellipse is the plane algebraic curve consisting of all points whose sum of distances from $k$ given points is a fixed number. The polynomial equation defining the $k$-ellipse has degree $2^k$ if $k$ is odd and degree $2^k{-}\binom{k}{k/2}$ if $k$ is even. We express this polynomial equation as the determinant of a symmetric matrix of linear polynomials. Our representation extends to weighted $k$-ellipses and $k$-ellipsoids in arbitrary dimensions, and it leads to new geometric applications of semidefinite programming.Comment: 16 pages, 5 figure

CRL1-FBXO11 Promotes Cdt2 Ubiquitylation and Degradation and Regulates Pr-Set7/Set8-Mediated Cellular Migration

The Cul4-Cdt2 (CRL4(Cdt2)) E3 ubiquitin ligase is a master regulator of cell-cycle progression and genome stability. Despite its central role in the degradation of many cell-cycle regulators, e.g., Cdt1, p21, and Pr-Set7/Set8, little is known about the regulation of its activity. We report that Cdt2 is autoubiquitylated by the CRL4A E3 ubiquitin ligase. Cdt2 is additionally polyubiquitylated and degraded by Cul1-FBXO11 (CRL1(FBXO11)). CRL1(FBXO11)-mediated degradation of Cdt2 stabilizes p21 and Set8, and this is important during the response to TGF-β, with the Set8 induction being important for turning off the activation of Smad2. The migration of epithelial cells is also stimulated by CRL1(FBXO11)-mediated downregulation of Cdt2 and the consequent stabilization of Set8. This is an interesting example of cross-regulation between specific Cullin 4 and Cullin 1 E3 ubiquitin ligases and highlights the role of ubiquitylation in regulating cellular responses to TGF-β and the migration of epithelial cells.Fil: Abbas, Tarek. University of Virginia; Estados UnidosFil: Mueller, Adam C.. University of Virginia; Estados UnidosFil: Shibata, Etsuko. University of Virginia; Estados UnidosFil: Keaton, Mignon. University of Virginia; Estados UnidosFil: Rossi, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; ArgentinaFil: Dutta, Anindya. University of Virginia; Estados Unido

Review: Towards the agroecological management of ruminants, pigs and poultry through the development of sustainable breeding programmes. II. Breeding strategies

Agroecology uses ecological processes and local resources rather than chemical inputs to develop productive and resilient livestock and crop production systems. In this context, breeding innovations are necessary to obtain animals that are both productive and adapted to a broad range of local contexts and diversity of systems. Breeding strategies to promote agroecological systems are similar for different animal species. However, current practices differ regarding the breeding of ruminants, pigs and poultry. Ruminant breeding is still an open system where farmers continue to choose their own breeds and strategies. Conversely, pig and poultry breeding is more or less the exclusive domain of international breeding companies which supply farmers with hybrid animals. Innovations in breeding strategies must therefore be adapted to the different species. In developed countries, reorienting current breeding programmes seems to be more effective than developing programmes dedicated to agroecological systems that will struggle to be really effective because of the small size of the populations currently concerned by such systems. Particular attention needs to be paid to determining the respective usefulness of cross-breeding v. straight breeding strategies of well-adapted local breeds. While cross-breeding may offer some immediate benefits in terms of improving certain traits that enable the animals to adapt well to local environmental conditions, it may be difficult to sustain these benefits in the longer term and could also induce an important loss of genetic diversity if the initial pure-bred populations are no longer produced. As well as supporting the value of within-breed diversity, we must preserve between-breed diversity in order to maintain numerous options for adaptation to a variety of production environments and contexts. This may involve specific public policies to maintain and characterize local breeds (in terms of both phenotypes and genotypes), which could be used more effectively if they benefited from the scientific and technical resources currently available for more common breeds. Last but not least, public policies need to enable improved information concerning the genetic resources and breeding tools available for the agroecological management of livestock production systems, and facilitate its assimilation by farmers and farm technicians

Characterisation of stellar activity of M dwarfs. I. Long-timescale variability in a large sample and detection of new cycles

M dwarfs are active stars that exhibit variability in chromospheric emission and photometry at short and long timescales, including long cycles that are related to dynamo processes. This activity also impacts the search for exoplanets because it affects the radial velocities. We analysed a large sample of 177 M dwarfs observed with HARPS (2003-2020) in order to characterise the long-term variability of these stars. We compared the variability obtained in three chromospheric activity indices (Ca II H & K, the Na D doublet, and Halpha) and with ASAS photometry. We focused on the detailed analysis of the chromospheric emission based on linear, quadratic, and sinusoidal models. We used various tools to estimate the significance of the variability and to quantify the improvement brought by the models. In addition, we analysed complementary photometric time series for the most variable stars to be able to provide a broader view of the long-term variability in M dwarfs. We find that most stars are significantly variable, even the quietest stars. Most stars in our sample (75%) exhibit a long-term variability, which manifests itself mostly through linear or quadratic variability, although the true behaviour may be more complex. We found significant variability with estimated timescales for 24 stars, and estimated the lower limit for a possible cycle period for an additional 9 stars that were not previously published. We found evidence of complex variability because more than one long-term timescale may be present for at least 12 stars, together with significant differences between the behaviour of the three activity indices. This complexity may also be the source of the discrepancies observed between previous publications. We conclude that long-term variability is present for all spectral types and activity level in M dwarfs, without a significant trend with spectral type or mean activity level.Comment: article accepted in Astronomy and Astrophysics, February 2023, 31 page

Fast, broad-band magnetic resonance spectroscopy with diamond widefield relaxometry

We present an alternative to conventional Electron Paramagnetic Resonance spectroscopy equipment. Avoiding the use of bulky magnets and magnetron equipment, we use the photoluminescence of an ensemble of Nitrogen-Vacancy centers at the surface of a diamond. Monitoring their relaxation time (or T1), we detected their cross-relaxation with the compound of interest. In addition, the EPR spectra is encoded through a localized magnetic field gradient. While 12 minutes was necessary to record each data point of the spectrum with previous individual NV center's technics, we are able to reconstruct a full spectrum at once in 3 seconds, over a range from 3 to 11 gauss. In term of sensitivity, only 0.5 microliter of a hexaaquacopper (II) ion solution with 1 micromole per liter concentration was necessary.Comment: Main text (15 pages, 6 Figures) + Supplementary (6 Pages, 7 Figures

Negotiations of minority ethnic rugby league players in the Cathar country of France

This article is based on new empirical, qualitative research with minority ethnic rugby league players in the southwest of France. Drawing on similar research on rugby league in the north and the south of England, the article examines how rugby league, traditionally viewed as a white, working-class male game (Collins, 2006; Denham, 2004; Spracklen, 1995, 2001) has had to re-imagine its symbolic boundaries as they are constituted globally and locally to accommodate the needs of players from minority ethnic backgrounds. In particular, the article examines the sense in which experiences of minority ethnic rugby league players in France compare with those of their counterparts in England (Spracklen, 2001, 2007), how rugby league is used in France to construct identity, and in what sense the norms associated with the imaginary community of rugby league are replicated or challenged by the involvement of minority ethnic rugby league players in France. Questions about what it means to be (provincial, national) French (Kumar, 2006) are posed, questions that relate to the role of sport in the construction of Frenchness, and in particular the role of rugby league (and union). © Copyright ISSA and SAGE Publications

Second-order shaped pulses for solid-state quantum computation

We present the constructon and detailed analysis of highly-optimized self-refocusing pulse shapes for several rotation angles. We characterize the constructed pulses by the coefficients appearing in the Magnus expansion up to second order. This allows a semi-analytical analysis of the performance of the constructed shapes in sequences and composite pulses by computing the corresponding leading-order error operators. Higher orders can be analyzed with the numerical technique suggested by us previously. We illustrate the technique by analysing several composite pulses designed to protect against pulse amplitude errors, and on decoupling sequences for potentially long chains of qubits with on-site and nearest-neighbor couplings.Comment: 16 pages, 29 figure