MFV SUSY: A Natural Theory for R-Parity Violation

We present an alternative approach to low-energy supersymmetry. Instead of imposing R-parity we apply the minimal flavor violation (MFV) hypothesis to the R-parity violating MSSM. In this framework, which we call MFV SUSY, squarks can be light and the proton long lived without producing missing energy signals at the LHC. Our approach differs from that of Nikolidakis and Smith in that we impose holomorphy on the MFV spurions. The resulting model is highly constrained and R-parity emerges as an accidental approximate symmetry of the low-energy Lagrangian. The size of the small R-parity violating terms is determined by the flavor parameters, and in the absence of neutrino masses there is only one renormalizable R-parity violating interaction: the baryon-number violating $\bar{u}\bar{d}\bar{d}$ superpotential term. Low energy observables (proton decay, dinucleon decay and $n-\bar{n}$ oscillation) pose only mild constraints on the parameter space. LHC phenomenology will depend on whether the LSP is a squark, neutralino, chargino or slepton. If the LSP is a squark it will have prompt decays, explaining the non-observation of events with missing transverse energy at the LHC.Comment: 41 pages, 14 figures; v3: minor corrections, matches published versio

Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia

High frequencies of blasts in primary acute lymphoblastic leukaemia (ALL) samples have the potential to induce leukaemia and to engraft mice. However, it is unclear how individual ALL cells each contribute to drive leukaemic development in a bulk transplant and the extent to which these blasts vary functionally. We used cellular barcoding as a fate mapping tool to track primograft ALL blasts in vivo. Our results show that high numbers of ALL founder cells contribute at similar frequencies to leukaemic propagation over serial transplants, without any clear evidence of clonal succession. These founder cells also exhibit equal capacity to home and engraft to different organs, although stochastic processes may alter the composition in restrictive niches. Our findings enhance the stochastic stem cell model of ALL by demonstrating equal functional abilities of singular ALL blasts and show that successful treatment strategies must eradicate the entire leukaemic cell population

The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Measurement of the electron electric dipole moment using GdIG

A new method for the detection of the electron edm using a solid is described. The method involves the measurement of a voltage induced across the solid by the alignment of the samples magnetic dipoles in an applied magnetic field, H. A first application of the method to GdIG has resulted in a limit on the electron edm of 5E-24 e-cm, which is a factor of 40 below the limit obtained from the only previous solid-state edm experiment. The result is limited by the imperfect discrimination of an unexpectedly large voltage that is even upon the reversal of the sample magnetization.Comment: 10 pages, 5 figures, v2:references corrected, submitted to PRL, v3:added labels to figure

Asymptomatic cardiac disease following mediastinal irradiation

AbstractObjectivesThis study was designed to evaluate the potential benefit of screening previously irradiated patients with echocardiography.BackgroundMediastinal irradiation is known to cause cardiac disease. However, the prevalence of asymptomatic cardiac disease and the potential for intervention before symptom development are unknown.MethodsWe recruited 294 asymptomatic patients (mean age 42 ± 9 years, 49% men, mean mantle irradiation dose 43 ± 0.3 Gy) treated with at least 35 Gy to the mediastinum for Hodgkin's disease. After providing written consent, each patient underwent electrocardiography and transthoracic echocardiography.ResultsValvular disease was common and increased with time following irradiation. Patients who had received irradiation more than 20 years before evaluation had significantly more mild or greater aortic regurgitation (60% vs. 4%, p < 0.0001), moderate or greater tricuspid regurgitation (4% vs. 0%, p = 0.06), and aortic stenosis (16% vs. 0%, p = 0.0008) than those who had received irradiation within 10 years. The number needed to screen to detect one candidate for endocarditis prophylaxis was 13 (95% confidence interval [CI] 7 to 44) for patients treated within 10 years and 1.6 (95% CI 1.3 to 1.9) for those treated at least 20 years ago. Compared with the Framingham Heart Study population, mildly reduced left ventricular fractional shortening (<30%) was more common (36% vs. 3%), and age- and gender-adjusted left ventricular mass was lower (90 ± 27 g/m vs. 117 g/m) in irradiated patients.ConclusionsThere is a high prevalence of asymptomatic heart disease in general, and aortic valvular disease in particular, following mediastinal irradiation. Screening echocardiography should be considered for patients with a history of mediastinal irradiation

Critical and Non-Critical Einstein-Weyl Supergravity

We construct N=1 supersymmetrisations of some recently-proposed theories of critical gravity, conformal gravity, and extensions of critical gravity in four dimensions. The total action consists of the sum of three separately off-shell supersymmetric actions containing Einstein gravity, a cosmological term and the square of the Weyl tensor. For generic choices of the coefficients for these terms, the excitations of the resulting theory around an AdS_4 background describe massive spin-2 and massless spin-2 modes coming from the metric; massive spin-1 modes coming from a vector field in the theory; and massless and massive spin-3/2 modes (with two unequal masses) coming from the gravitino. These assemble into a massless and a massive N=1 spin-2 multiplet. In critical supergravity, the coefficients are tuned so that the spin-2 mode in the massive multiplet becomes massless. In the supersymmetrised extensions of critical gravity, the coefficients are chosen so that the massive modes lie in a "window" of lowest energies E_0 such that these ghostlike fields can be truncated by imposing appropriate boundary conditions at infinity, thus leaving just positive-norm massless supergravity modes.Comment: 29 page

Susceptibility of rhabdomyosarcoma cells to macrophage-mediated cytotoxicity

The prognosis of advanced stage rhabdomyosarcoma (RMS) is still sobering. In recent years, outcome has not been further improved by conventional therapy. Therefore, novel treatment options such as macrophage-directed immunotherapy have to be investigated. The aim of this study was to analyze the phagocytosis of RMS cells by macrophages and to modulate the susceptibility using monoclonal antibodies and cytotoxic drugs

Staphylococcus aureus pathogenicity in cystic fibrosis patients-results from an observational prospective multicenter study concerning virulence genes, phylogeny, and gene plasticity

Staphylococcus aureus and cystic fibrosis (CF) are closely interlinked. To date, however, the impact of S. aureus culture in CF airways on lung function and disease progression has only been elucidated to a limited degree. This analysis aims to identify bacterial factors associated to clinical deterioration. Data were collected during an observational prospective multi-center study following 195 patients from 17 centers. The average follow-up time was 80 weeks. S. aureus isolates (n = 3180) were scanned for the presence of 25 virulence genes and agr-types using single and multiplex PCR. The presence of specific virulence genes was not associated to clinical deterioration. For the agr-types 1 and 4, however, a link to the subjects' clinical status became evident. Furthermore, a significant longitudinal decrease in the virulence gene quantity was observed. Analyses of the plasticity of the virulence genes revealed significantly increased plasticity rates in the presence of environmental stress. The results suggest that the phylogenetic background defines S. aureus pathogenicity rather than specific virulence genes. The longitudinal loss of virulence genes most likely reflects the adaptation process directed towards a persistent and colonizing rather than infecting lifestyle