Plasma next generation sequencing and droplet digital-qPCR-based quantification of circulating cell-free RNA for noninvasive early detection of cancer

Early detection of cancer holds high promise for reducing cancer-related mortality. Detection of circulating tumor-specific nucleic acids holds promise, but sensitivity and specificity issues remain with current technology. We studied cell-free RNA (cfRNA) in patients with non-small cell lung cancer (NSCLC; n = 56 stage IV, n = 39 stages I-III), pancreatic cancer (PDAC, n = 20 stage III), malignant melanoma (MM, n = 12 stage III-IV), urothelial bladder cancer (UBC, n = 22 stage II and IV), and 65 healthy controls by means of next generation sequencing (NGS) and real-time droplet digital PCR (RT-ddPCR). We identified 192 overlapping upregulated transcripts in NSCLC and PDAC by NGS, more than 90% of which were noncoding. Previously reported transcripts (e.g., HOTAIRM1) were identified. Plasma cfRNA transcript levels of POU6F2-AS2 discriminated NSCLC from healthy donors (AUC = 0.82 and 0.76 for stages IV and I-III, respectively) and significantly associated (p = 0.017) with the established tumor marker Cyfra 21-1. cfRNA yield and POU6F2-AS transcript abundance discriminated PDAC patients from healthy donors (AUC = 1.0). POU6F2-AS2 transcript was significantly higher in MM (p = 0.044). In summary, our findings support further validation of cfRNA detection by RT-ddPCR as a biomarker for early detection of solid cancers

Roots of Ehrhart Polynomials of Smooth Fano Polytopes

V. Golyshev conjectured that for any smooth polytope P of dimension at most five, the roots z\in\C of the Ehrhart polynomial for P have real part equal to -1/2. An elementary proof is given, and in each dimension the roots are described explicitly. We also present examples which demonstrate that this result cannot be extended to dimension six.Comment: 10 page

The contact binary VW Cephei revisited: surface activity and period variation

Context. Despite the fact that VW Cephei is one of the well-studied contact binaries in the literature, there is no fully consistent model available that can explain every observed property of this system. Aims. Our motivation is to obtain new spectra along with photometric measurements, to analyze what kind of changes may have happened in the system in the past two decades, and to propose new ideas for explaining them. Methods. For the period analysis we determined 10 new times of minima from our light curves, and constructed a new O$-$C diagram of the system. Radial velocities of the components were determined using the cross-correlation technique. The light curves and radial velocities were modelled simultaneously with the PHOEBE code. All observed spectra were compared to synthetic spectra and equivalent widths of the H$\alpha$ line were measured on their differences. Results. We have re-determined the physical parameters of the system according to our new light curve and spectral models. We confirm that the primary component is more active than the secondary, and there is a correlation between spottedness and the chromospheric activity. We propose that flip-flop phenomenon occurring on the primary component could be a possible explanation of the observed nature of the activity. To explain the period variation of VW Cep, we test two previously suggested scenarios: presence of a fourth body in the system, and the Applegate-mechanism caused by periodic magnetic activity. We conclude that although none of these mechanisms can be ruled out entirely, the available data suggest that mass transfer with a slowly decreasing rate gives the most likely explanation for the period variation of VW Cep.Comment: 13 pages, 18 figures, 9 tables, accepted for publication in Astronomy and Astrophysic

Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment

Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment

Testing SNe Ia distance measurement methods with SN 2011fe

The nearby, bright, almost completely unreddened Type Ia supernova 2011fe in M101 provides a unique opportunity to test both the precision and the accuracy of the extragalactic distances derived from SNe Ia light curve fitters. We apply the current, public versions of the independent light curve fitting codes MLCS2k2 and SALT2 to compute the distance modulus of SN 2011fe from high-precision, multi-color (BVRI) light curves. The results from the two fitting codes confirm that 2011fe is a "normal" (not peculiar) and only slightly reddened SN Ia. New unreddened distance moduli are derived as 29.21 +/- 0.07 mag (D ~ 6.95 +/- 0.23$ Mpc, MLCS2k2), and 29.05 +/- 0.07 mag (6.46 +/- 0.21 Mpc, SALT2). Despite the very good fitting quality achieved with both light curve fitters, the resulting distance moduli are inconsistent by 2 sigma. Both are marginally consistent (at ~1 sigma) with the HST Key Project distance modulus for M101. The SALT2 distance is in good agreement with the recently revised Cepheid- and TRGB-distance to M101. Averaging all SN- and Cepheid-based estimates, the absolute distance to M101 is ~6.6 +/- 0.5 Mpc.Comment: 8 pages, 7 figures, accepted for publication in A&

LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations

Aims To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. Methods: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥20 ng/l. Results: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m2. The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m2 decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. Conclusions: In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations

Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes.

Fruiting bodies (sporocarps, sporophores or basidiomata) of mushroom-forming fungi ( Agaricomycetes) are among the most complex structures produced by fungi. Unlike vegetative hyphae, fruiting bodies grow determinately and follow a genetically encoded developmental program that orchestrates their growth, tissue differentiation and sexual sporulation. In spite of more than a century of research, our understanding of the molecular details of fruiting body morphogenesis is still limited and a general synthesis on the genetics of this complex process is lacking. In this paper, we aim at a comprehensive identification of conserved genes related to fruiting body morphogenesis and distil novel functional hypotheses for functionally poorly characterised ones. As a result of this analysis, we report 921 conserved developmentally expressed gene families, only a few dozens of which have previously been reported to be involved in fruiting body development. Based on literature data, conserved expression patterns and functional annotations, we provide hypotheses on the potential role of these gene families in fruiting body development, yielding the most complete description of molecular processes in fruiting body morphogenesis to date. We discuss genes related to the initiation of fruiting, differentiation, growth, cell surface and cell wall, defence, transcriptional regulation as well as signal transduction. Based on these data we derive a general model of fruiting body development, which includes an early, proliferative phase that is mostly concerned with laying out the mushroom body plan (via cell division and differentiation), and a second phase of growth via cell expansion as well as meiotic events and sporulation. Altogether, our discussions cover 1 480 genes of Coprinopsis cinerea, and their orthologs in Agaricus bisporus, Cyclocybe aegerita, Armillaria ostoyae, Auriculariopsis ampla, Laccaria bicolor, Lentinula edodes, Lentinus tigrinus, Mycena kentingensis, Phanerochaete chrysosporium, Pleurotus ostreatus, and Schizophyllum commune, providing functional hypotheses for ~10 % of genes in the genomes of these species. Although experimental evidence for the role of these genes will need to be established in the future, our data provide a roadmap for guiding functional analyses of fruiting related genes in the Agaricomycetes. We anticipate that the gene compendium presented here, combined with developments in functional genomics approaches will contribute to uncovering the genetic bases of one of the most spectacular multicellular developmental processes in fungi. Citation: Nagy LG, Vonk PJ, Künzler M, Földi C, Virágh M, Ohm RA, Hennicke F, Bálint B, Csernetics Á, Hegedüs B, Hou Z, Liu XB, Nan S, M. Pareek M, Sahu N, Szathmári B, Varga T, Wu W, Yang X, Merényi Z (2023). Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes. Studies in Mycology 104: 1-85. doi: 10.3114/sim.2022.104.01