Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth

Target of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not

Degradation dynamics and dissipation kinetics of an imidazole fungicide (Prochloraz) in aqueous medium of varying pH

Laboratory degradation studies were performed in water at pH 4.0, 7.0 and 9.2 using Prochloraz (450 EC) formulation at the concentration of 1.0 (T1) and 2.0 (T2) µg/mL. Water samples collected on 0 (2 h), 3, 7, 15, 30, 45, 60 and 90 days after treatments were processed for residue analysis of Prochloraz by HPLC-UV detector. In 60 days, dissipation was 89.1–90.5% at pH 4.0, 84.1–88.2% at pH 7.0, and 92.4–93.8% at pH 9.2 in both treatments. The results indicate that at pH 7.0 the degradation of Prochloraz was much slower as compared to other two. Between pH 4.0 and 9.2 the degradation of compound is little faster at pH 9.2. The half-life periods observed were 18.35 and 19.17 days at pH 4.0, 22.6 and 25.1 days at pH 7.0 and 15.8 and 16.6 days at pH 9.2 at T1 and T2 doses respectively

Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker

Background: The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor alpha beta-positive CD8(+) memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. Results: We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. Conclusions: DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed

Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.

To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic

TERAVOLT: Thoracic Cancers International COVID-19 Collaboration.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies

Search for antihelium in cosmic rays

The Alpha Magnetic Spectrometer (AMS) was flown on the space shuttle Discovery during flight STS-91 in a 51.7 degree orbit at altitudes between 320 and 390 km. A total of 2.86 * 10^6 helium nuclei were observed in the rigidity range 1 to 140 GV. No antihelium nuclei were detected at any rigidity. An upper limit on the flux ratio of antihelium to helium of < 1.1 * 10^-6 is obtained.Comment: 18 pages, Latex, 9 .eps figure

Protons in near earth orbit

The proton spectrum in the kinetic energy range 0.1 to 200 GeV was measured by the Alpha Magnetic Spectrometer (AMS) during space shuttle flight STS-91 at an altitude of 380 km. Above the geomagnetic cutoff the observed spectrum is parameterized by a power law. Below the geomagnetic cutoff a substantial second spectrum was observed concentrated at equatorial latitudes with a flux ~ 70 m^-2 sec^-1 sr^-1. Most of these second spectrum protons follow a complicated trajectory and originate from a restricted geographic region.Comment: 19 pages, Latex, 7 .eps figure

High-resolution ptychographic imaging at a seeded free-electron laser source using OAM beams

Electromagnetic waves possessing orbital angular momentum (OAM) are powerful tools for applications in optical communications, new quantum technologies and optical tweezers. Recently, they have attracted growing interest since they can be harnessed to detect peculiar helical dichroic effects in chiral molecular media and in magnetic nanostructures. In this work, we perform single-shot per position ptychography on a nanostructured object at a seeded free-electron laser, using extreme ultraviolet OAM beams of different topological charge order $\ell$ generated with spiral zone plates. By controlling $\ell$, we demonstrate how the structural features of OAM beam profile determine an improvement of about 30% in image resolution with respect to conventional Gaussian beam illumination. This result extends the capabilities of coherent diffraction imaging techniques, and paves the way for achieving time-resolved high-resolution (below 100 nm) microscopy on large area samples.Comment: M. Pancaldi and F. Guzzi contributed equally to this wor

CUORE-0 detector: design, construction and operation

The CUORE experiment will search for neutrinoless double-beta decay of$^{130}$Te with an array of 988 TeO$_2$ bolometers arranged in 19 towers.CUORE-0, the first tower assembled according to the CUORE procedures, was builtand commissioned at Laboratori Nazionali del Gran Sasso, and took data fromMarch 2013 to March 2015. In this paper we describe the design, constructionand operation of the CUORE-0 experiment, with an emphasis on the improvementsmade over a predecessor experiment, Cuoricino. In particular, we demonstratewith CUORE-0 data that the design goals of CUORE are within reach