Compiler fuzzing: how much does it matter?

Despite much recent interest in randomised testing (fuzzing) of compilers, the practical impact of fuzzer-found compiler bugs on real-world applications has barely been assessed. We present the first quantitative and qualitative study of the tangible impact of miscompilation bugs in a mature compiler. We follow a rigorous methodology where the bug impact over the compiled application is evaluated based on (1) whether the bug appears to trigger during compilation; (2) the extent to which generated assembly code changes syntactically due to triggering of the bug; and (3) whether such changes cause regression test suite failures, or whether we can manually find application inputs that trigger execution divergence due to such changes. The study is conducted with respect to the compilation of more than 10 million lines of C/C++ code from 309 Debian packages, using 12% of the historical and now fixed miscompilation bugs found by four state-of-the-art fuzzers in the Clang/LLVM compiler, as well as 18 bugs found by human users compiling real code or as a by-product of formal verification efforts. The results show that almost half of the fuzzer-found bugs propagate to the generated binaries for at least one package, in which case only a very small part of the binary is typically affected, yet causing two failures when running the test suites of all the impacted packages. User-reported and formal verification bugs do not exhibit a higher impact, with a lower rate of triggered bugs and one test failure. The manual analysis of a selection of the syntactic changes caused by some of our bugs (fuzzer-found and non fuzzer-found) in package assembly code, shows that either these changes have no semantic impact or that they would require very specific runtime circumstances to trigger execution divergence

Spontaneous activity in peripheral diaphragmatic lymphatic loops.

The spontaneous contractility of FITC-dextran-filled lymphatics at the periphery of the pleural diaphragm was documented for the first time “in vivo” in anesthetized Wistar rats. We found that lymphatic segments could be divided into four phenotypes: 1) active, displaying rhythmic spontaneous contractions (51.8% of 197 analyzed sites); 2) stretch-activated, whose contraction was triggered by passive distension of the vessel lumen (4.1%); 3) passive, which displayed a completely passive distension (4.5%); and 4) inert, whose diameter never changed over time (39.6%). Smooth muscle actin was detected by immunofluorescence and confocal microscopy in the vessel walls of active but also of inert sites, albeit with a very different structure within the vessel wall. Indeed, while in active segments, actin was arranged in a dense mesh completely surrounding the lumen, in inert segments actin decorated the vessels wall in sparse longitudinal strips. When located nearby along the same lymphatic loop, active, stretch-activated, and passive sites were always recruited in temporal sequence starting from the active contraction. The time delay was ∼0.35 s between active and stretch-activated and 0.54 s between stretch-activated and passive segments, promoting a uniform lymph flux of ∼150/200 pl/min. We conclude that, unlike more central diaphragmatic lymphatic vessels, loops located at the extreme diaphragmatic periphery do require an intrinsic pumping mechanism to propel lymph centripetally, and that such an active lymph propulsion is attained by means of a complex interplay among sites whose properties differ but are indeed able to organize lymph flux in an ordered fashion. </jats:p

Interplay between gut lymphatic vessels and microbiota

Lymphatic vessels play a distinctive role in draining fluid, molecules and even cells from interstitial and serosal spaces back to the blood circulation. Lymph vessels of the gut, and especially those located in the villi (called lacteals), not only serve this primary function, but are also responsible for the transport of lipid moieties absorbed by the intestinal mucosa and serve as a second line of defence against possible bacterial infections. Here, we briefly review the current knowledge of the general mechanisms allowing lymph drainage and propulsion and will focus on the most recent findings on the mutual relationship between lacteals and intestinal microbiota

Characterization and control of oocyte large-scale chromatin configuration in different cattle breeds.

Made available in DSpace on 2020-12-11T01:57:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Differences in reproductive physiology between cattle breeds may help to explain distinct responses to assisted reproductive techniques and to define breed-specific protocols with improved efficiency. Germinal vesicle (GV) stage oocytes are characterized by increasing levels of chromatin compaction enclosed within the nucleus (graded from GV0 to GV3), associated with different developmental competence. The first objective of this study was to characterize chromatin configuration of GV stage oocytes recovered by OPU at random days of the estrous cycle from Nelore (Bos indices) and Holstein (Bos taurus) cows. In Nelore 90% of the oocytes presented advanced stages of chromatin compaction associated with higher developmental competence (GV2 and GV3), while in Holstein, only 65% of the oocytes were at these stages. Then, aiming to obtain a more homogeneous population of oocytes in Holstein, we tested two synchronization protocols combining aspiration of all visible follicles at a random day (day 0), two IM injections of FSH 12 h apart on day 2, and OPU on day 4 (OPU/D4) or 5 (OPU/D5). The protocol OPU/D4 provided around 45% of the oocytes with low chromatin compaction (GV1), while the protocol OPU/D5 provided 70% of the oocytes at GV2 and 20% at GV3. Finally, we assessed the effects of a culture system known to prevent meiotic resumption on chromatin configuration of the GV2 enriched oocyte population obtained with the protocol OPU/D5. After 9 h of culture most oocytes transited from GV2 to GV3, with 90% of the oocytes at GV3 stage. This study demonstrates differences between Nelore and Holstein cows regarding patterns of chromatin configuration that may account for their different performance in IVM/IVF. In addition, it provides novel references for the design of protocols aiming to regulate oocyte quality before IVM for the optimization of IVF outcomes. (C) 2019 Elsevier Inc. All rights reserved. Sao Paulo State Univ, Inst Biosci, Dept Physiol, Ovarian Mol Physiol Lab, Sao Paulo, Brazil Univ Sao Paulo, Dept Anim Reprod, Sao Paulo, Brazil Univ Milan, Dept Hlth Anim Sci & Food Safety, Reprod & Dev Biol Lab, Milan, Italy Sao Paulo State Univ, Inst Biosci, Dept Physiol, Ovarian Mol Physiol Lab, Sao Paulo, Brazil CAPES: 001 FAPESP: 2017/07588-4 FAPESP: 2016/21671-

Crowd and environmental management during mass gatherings.

Crowds are a feature of large cities, occurring not only at mass gatherings but also at routine events such as the journey to work. To address extreme crowding, various computer models for crowd movement have been developed in the past decade, and we review these and show how they can be used to identify health and safety issues. State-of-the-art models that simulate the spread of epidemics operate on a population level, but the collection of fine-scale data might enable the development of models for epidemics that operate on a microscopic scale, similar to models for crowd movement. We provide an example of such simulations, showing how an individual-based crowd model can mirror aggregate susceptible-infected-recovered models that have been the main models for epidemics so far

Comprehensive longitudinal non-invasive quantification of healthspan and frailty in a large cohort (n = 546) of geriatric C57BL/6 J mice

Frailty is an age-related condition characterized by a multisystem functional decline, increased vulnerability to stressors, and adverse health outcomes. Quantifying the degree of frailty in humans and animals is a health measure useful for translational geroscience research. Two frailty measurements, namely the frailty phenotype (FP) and the clinical frailty index (CFI), have been validated in mice and are frequently applied in preclinical research. However, these two tools are based on different concepts and do not necessarily identify the same mice as frail. In particular, the FP is based on a dichotomous classification that suffers from high sample size requirements and misclassification problems. Based on the monthly longitudinal non-invasive assessment of frailty in a large cohort of mice, here we develop an alternative scoring method, which we called physical function score (PFS), proposed as a continuous variable that resumes into a unique function, the five criteria included in the FP. This score would not only reduce misclassification of frailty but it also makes the two tools, PFS and CFI, integrable to provide an overall measurement of health, named vitality score (VS) in aging mice. VS displays a higher association with mortality than PFS or CFI and correlates with biomarkers related to the accumulation of senescent cells and the epigenetic clock. This longitudinal non-invasive assessment strategy and the VS may help to overcome the different sensitivity in frailty identification, reduce the sample size in longitudinal experiments, and establish the effectiveness of therapeutic/preventive interventions for frailty or other age-related diseases in geriatric animals

Author Correction: Accurate detection of circulating tumor DNA using nanopore consensus sequencing

The Data Availability statement in the original version of the paper reads: “The sequencing datasets generated during the current study are available upon request at EGA, under accession number EGAS00001003759”. However, as this data upload was not successful, the authors reuploaded the data under a different accession number and have amended the Data Availability statement to read “The sequencing datasets generated during the current study are available upon request at EGA, under accession number EGAS00001007090”. The original article has been corrected.</p

Accurate detection of circulating tumor DNA using nanopore consensus sequencing

Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows

Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential

The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with <1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression