Mixed Gauge and Anomaly Mediation From New Physics at 10 TeV

In the context of anomaly-mediated supersymmetry breaking, it is natural for vectorlike fields and singlets to have supersymmetry breaking masses of order 10 TeV, and therefore act as messengers of supersymmetry breaking. We show that this can give rise to phenomenologically viable spectra compatible with perturbative gauge coupling unification. The minimal model interpolates continuously between pure anomaly mediation and gauge mediation with a messenger scale of order 10 TeV. It is also possible to have non-minimal models with more degenerate specta, with some squarks lighter than sleptons. These models reduce to the MSSM at low energies and incorporate a natural solution of the mu problem. The minimal model has four continuous parameters and one discrete parameter (the number of messengers). The LEP Higgs mass bound can be satisfied in the minimal model by tuning parameters at the GUT scale to one part in 50.Comment: 17 pages, 4 figure

To divide or not to divide: A key role of Rim15 in calorie-restricted yeast cultures

AbstractThe PAS kinase Rim15 is proposed to integrate signals from different nutrient-sensing pathways and to control transcriptional reprogramming of Saccharomyces cerevisiae upon nutrient depletion. Despite this proposed role, previous transcriptome analyses of rim15 mutants solely focused on growing cultures. In the present work, retentostat cultivation enabled analysis of the role of Rim15 under severely calorie-restricted, virtually non-growing conditions. Under these conditions, deletion of RIM15 affected transcription of over 10-fold more genes than in growing cultures. Transcriptional responses, metabolic rates and cellular morphology indicated a key role of Rim15 in controlled cell-cycle arrest upon nutrient depletion. Moreover, deletion of rim15 reduced heat-shock tolerance in non-growing, but not in growing cultures. The failure of rim15 cells to adapt to calorie restriction by entering a robust post-mitotic state resembles cancer cell physiology and shows that retentostat cultivation of yeast strains can provide relevant models for healthy post-mitotic and transformed human cells

Realistic Anomaly Mediation with Bulk Gauge Fields

We present a simple general framework for realistic models of supersymmetry breaking driven by anomaly mediation. We consider a 5-dimensional "brane universe" where the visible and hidden sectors are localized on different branes, and the standard model gauge bosons propagate in the bulk. In this framework there can be charged scalar messengers that have contact interactions with the hidden sector, either localized in the hidden sector or in the bulk. These scalars obtain soft masses that feed into visible sector scalar masses at two loop order via bulk gauge interactions. This contribution is automatically flavor-blind, and can be naturally positive. If the messengers are in the bulk this contribution is automatically the same order of magnitude as the anomaly mediated contribution, independent of the brane spacing. If the messengers are localized to a brane the two effects are of the same order for relatively small brane spacings. The gaugino masses and A terms are determined completely by anomaly mediation. In order for anomaly mediation to dominate over radion mediation the radion must be is stabilized in a manner that preserves supersymmetry, with supergravity effects included. We show that this occurs in simple models. We also show that the mu problem can be solved by the vacuum expectation value of a singlet in this framework.Comment: 16 pages, LaTeX2e, no figure

The GUT Scale and Superpartner Masses from Anomaly Mediated Supersymmetry Breaking

We consider models of anomaly-mediated supersymmetry breaking (AMSB) in which the grand unification (GUT) scale is determined by the vacuum expectation value of a chiral superfield. If the anomaly-mediated contributions to the potential are balanced by gravitational-strength interactions, we find a model-independent prediction for the GUT scale of order $M_{\rm Planck} / (16\pi^2)$. The GUT threshold also affects superpartner masses, and can easily give rise to realistic predictions if the GUT gauge group is asymptotically free. We give an explicit example of a model with these features, in which the doublet-triplet splitting problem is solved. The resulting superpartner spectrum is very different from that of previously considered AMSB models, with gaugino masses typically unifying at the GUT scale.Comment: 17 page

Muscle wasting as an independent predictor of survival in patients with chronic heart failure

Background: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. Methods: Two hundred sixty‐eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co‐morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual‐energy X‐ray absorptiometry was present in 47 patients (17.5%). Results During a mean follow‐up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N‐terminal pro‐B‐type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01–3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. Conclusions: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co‐morbidity

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer

Background Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. Objectives We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. Methods We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50–61, > 61 g/m2; men, < 60, 60–74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3–6 months for 85 patients. Results Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9–4.2), 0.8 (0.2–2.2), 0.5 (0.3–1.6) ng/mL, p = 0.029; men, 2.1 (0.8–3.2), 0.6 (0.1–1.7), 0.7 (0.2–1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48–116), 72 (48–95), 49 (35–76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r =  − 0.591, p < 0.001; men, r =  − 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r =  − 0.318, p = 0.003). Conclusion In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up

The genomics of heart failure: design and rationale of the HERMES consortium

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction

The genomics of heart failure: design and rationale of the HERMES consortium

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.</p