Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

Eumelanin-based coloration and fitness parameters in birds: a meta-analysis

Although melanin is the most common pigment in animal integuments, the adaptive function of variation in melanin-based coloration remains poorly understood. The individual fitness returns associated with melanin pigments can be variable across species as these pigments can have physical and biological protective properties and genes involved in melanogenesis may vary in the intensity of pleiotropic effects. Moreover, dark and pale coloration can also enhance camouflage in alternative habitats and melanin-based coloration can be involved in social interactions. We investigated whether darker or paler individuals achieve a higher fitness in birds, a taxon wherein associations between melanin-based coloration and fitness parameters have been studied in a large number of species. A meta-analysis showed that the degree of melanin-based coloration was not significantly associated with laying date, clutch size, brood size, and survival across 26 species. Similar results were found when restricting the analyses to non-sexually dimorphic birds, colour polymorphic and monomorphic species, in passerines and non-passerines and in species for which inter-individual variation in melanism is due to colour intensity. However, eumelanic coloration was positively associated with clutch and brood size in sexually dimorphic species and those that vary in the size of black patches, respectively. Given that greater extent of melanin-based coloration was positively associated with reproductive parameters and survival in some species but negatively in other species, we conclude that in birds the sign and magnitude of selection exerted on melanin-based coloration is species- or trait-specific

Quantification of mechanical forces and physiological processes involved in pollen tube growth using microfluidics and microrobotics

Pollen tubes face many obstacles on their way to the ovule. They have to decide whether to navigate around cells or penetrate the cell wall and grow through it or even within it. Besides chemical sensing, which directs the pollen tubes on their path to the ovule, this involves mechanosensing to determine the optimal strategy in specific situations. Mechanical cues then need to be translated into physiological signals, which eventually lead to changes in the growth behavior of the pollen tube. To study these events, we have developed a system to directly quantify the forces involved in pollen tube navigation. We combined a lab-on-a-chip device with a microelectromechanical systems-based force sensor to mimic the pollen tube's journey from stigma to ovary in vitro. A force-sensing plate creates a mechanical obstacle for the pollen tube to either circumvent or attempt to penetrate while measuring the involved forces in real time. The change of growth behavior and intracellular signaling activities can be observed with a fluorescence microscope

Genomic detection of a secondary family burial in a single jar coffin in early Medieval Korea

Abstract Objectives Family relationship is a key to understand the structure of past societies but its archeological reconstruction mostly stays circumstantial. Archaeogenetic information, especially genome-wide data, provide an objective approach to accurately reconstruct the familial relationship of ancient individuals, thus allowing a robust test of an archaeology-driven hypothesis of kinship. In this study, we applied this approach to disentangle the genetic relationship of early Medieval individuals from Korea, who were secondarily co-buried in a single jar coffin. Materials and Methods We obtained genome-wide data of six early Medieval Korean individuals from a jar coffin. We inferred the genetic relatedness between these individuals and characterized their genetic profiles using well-established population genetics methods. Results Congruent with the unusual pattern of multiple individuals in a single jar coffin, genome-wide analysis of these individuals shows that they form an extended family, including a couple, their two children and both paternal and maternal relatives. We show that these early Medieval Koreans have a genetic profile similar to present-day Koreans. Discussion We show that an unusual case of the secondary multiple burial in a single jar coffin reflects family relationship among the co-buried individuals. We find both paternal and maternal relatives co-buried with the nuclear family, which may suggest a family structure with limited gender bias. We find the genetic profile of early Medieval Koreans similar to that of present-day Koreans, showing that the genetic root of the present-day Koreans goes back at least 1500?years in the Korean peninsula.1 Introduction 2 Materials and methods 2.1 Archeological context of the Gunsan jar coffin 2.2 Permission for destructive analyses of skeletal elements 2.3 Skeletal analysis 2.4 Sampling of skeletal materials 2.5 Ancient DNA laboratory work and sequencing 2.6 Ancient DNA sequencing data processing and authentication 2.7 Reprocessing of whole genome sequences of present-day Koreans 2.8 Data set compilation 2.9 Principal component analysis 2.10 Genetic kinship analysis 2.11 Runs of homozygosity analysis 2.12 F-statistics and qpWave/qpAdm analysis 3 Results 3.1 | Ancient genome-wide data production 3.2 | A familial relationship of individuals from a single jar coffin 3.3 | The genetic profile of early medieval Koreans 4 Discussio

Self-Calibration of Cameras with Euclidean Image Plane in Case of Two Views and Known Relative Rotation Angle

The internal calibration of a pinhole camera is given by five parameters that are combined into an upper-triangular $3\times 3$ calibration matrix. If the skew parameter is zero and the aspect ratio is equal to one, then the camera is said to have Euclidean image plane. In this paper, we propose a non-iterative self-calibration algorithm for a camera with Euclidean image plane in case the remaining three internal parameters --- the focal length and the principal point coordinates --- are fixed but unknown. The algorithm requires a set of $N \geq 7$ point correspondences in two views and also the measured relative rotation angle between the views. We show that the problem generically has six solutions (including complex ones). The algorithm has been implemented and tested both on synthetic data and on publicly available real dataset. The experiments demonstrate that the method is correct, numerically stable and robust.Comment: 13 pages, 7 eps-figure

Sleeping hearts: 12 years after a follow up study on cardiac findings due to sleeping sickness

Both American Trypanosomiasis (Chagas disease) and Human African Trypanosomiasis (HAT) are diseases caused by single-celled flagellate protozoan parasites. While cardiac complications such as conduction problems and heart failure are very common in Chagas disease there is little known about the long-term effects of Human African Trypanosomiasis (HAT) on cardiac sequelae in Sub-Saharan Africa, where heart failure has become an increasing problem and growing burden. In the context of clinical trials conducted between 2004 and 2005 in the Democratic Republic of the Congo (DRC), the prevalence of HAT related signs and symptoms and an ECG were evaluated prior to the initiation of treatment. The object of this follow-up study in 2017 was to assess the prevalence of cardiac sequelae in the same 51 first stage and 18 second stage HAT patients 12-13 years after their treatment by conducting a clinical examination and an ECG. A control group matched by age (± 5 years), sex and whenever possible form the same village was enrolled. There were no significant differences in the prevalence of cardiac symptoms and in ECG findings between patients and their controls at the time of the follow-up evaluation. Repolarization changes disappeared or improved in 24.7% of HAT patients and were even less frequent than in the control group. Peripheral low voltage was the only parameter that increased over time in HAT patients and in three patients, new conduction problems in the ECG (ventricular bigeminy, RBBB, and bifascicular block) could be found, although none of these findings was clinically significant. However, the appearance of these conduction problems might represent an early indication of a HAT related cardiomyopathy or ongoing subclinical infection. This hypothesis would be supported by the findings of an older study in which antibodies (IFAT) against trypanosomiasis in 27% of Cameroonian patients with dilated cardiomyopathy compared to 2% in normal controls had been observed

Clinical study on the melarsoprol-related encephalopathic syndrome: risk factors and HLA association

Melarsoprol administration for the treatment of late-stage human African trypanosomiasis (HAT) is associated with the development of an unpredictable and badly characterized encephalopathic syndrome (ES), probably of immune origin, that kills approximately 50% of those affected. We investigated the characteristics and clinical risk factors for ES, as well as the association between the Human Leukocyte Antigen (HLA) complex and the risk for ES in a case-control study. Late-stage Gambiense HAT patients treated with melarsoprol and developing ES (69 cases) were compared to patients not suffering from the syndrome (207 controls). Patients were enrolled in six HAT treatment centres in Angola and in the Democratic Republic of Congo. Standardized clinical data was obtained from all participants before melarsoprol was initiated. Class I (HLA-A, HLA-B, HLA-Cw) and II (HLA-DR) alleles were determined by PCR-SSOP methods in 62 ES cases and 189 controls. The principal ES pattern consisted in convulsions followed by a coma, whereas ES with exclusively mental changes was not observed. Oedema, bone pain, apathy, and a depressed humour were associated with a higher risk of ES, while abdominal pain, coma, respiratory distress, and a Babinski sign were associated with higher ES-associated mortality. Haplotype C*14/B*15 was associated with an elevated risk for ES (OR: 6.64; p-value: 0.008). Haplotypes A*23/C*14, A*23/B*15 and DR*07/B*58 also showed a weaker association with ES. This result supports the hypothesis that a genetically determined peculiar type of immune response confers susceptibility for ES

Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

A Molecular Sensor To Characterize Arenavirus Envelope Glycoprotein Cleavage by Subtilisin Kexin Isozyme 1/Site 1 Protease.

UNLABELLED: Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses, only genetic information is available, and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears, therefore, to be a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate the efficiency and subcellular location of arenavirus GPC processing. In a proof of concept, our sensor correctly predicts efficient processing of the GPC of the newly emergent pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and nonpathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system for assessment of the processing of putative cleavage sites derived from the GPCs of newly discovered arenavirus by the SKI-1/S1P of humans or any other species, based solely on sequence information. IMPORTANCE: Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive arenavirus infection of human cells is the processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). In order to break the species barrier during zoonotic transmission and cause severe disease in humans, newly emerging arenaviruses must be able to hijack human SKI-1/S1P efficiently. Here we implement a newly developed cell-based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emergent pathogenic Lujo virus by human SKI-1/S1P. Our sensor thus represents a rapid and robust test system with which to assess whether the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information