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Chromosome organization is crucial for genome function. Here, we present a method for visualizing chromosomal DNA at super-resolution and then integrating Hi-C data to produce three-dimensional models of chromosome organization. Using the super-resolution microscopy methods of OligoSTORM and OligoDNA-PAINT, we trace 8 megabases of human chromosome 19, visualizing structures ranging in size from a few kilobases to over a megabase. Focusing on chromosomal regions that contribute to compartments, we discover distinct structures that, in spite of considerable variability, can predict whether such regions correspond to active (A-type) or inactive (B-type) compartments. Imaging through the depths of entire nuclei, we capture pairs of homologous regions in diploid cells, obtaining evidence that maternal and paternal homologous regions can be differentially organized. Finally, using restraint-based modeling to integrate imaging and Hi-C data, we implement a method-integrative modeling of genomic regions (IMGR)-to increase the genomic resolution of our traces to 10 kb.

The connection between chromatin nuclear organization and gene activity is vividly illustrated by the observation that transcriptional coregulation of certain genes appears to be directly influenced by their spatial proximity. This fact poses the more general question of whether it is at all feasible that the numerous genes that are coregulated on a given chromosome, especially those at large genomic distances, might become proximate inside the nucleus. This problem is studied here using steered molecular dynamics simulations in order to enforce the colocalization of thousands of knowledge-based gene sequences on a model for the gene-rich human chromosome 19. Remarkably, it is found that most (≈ 88%) gene pairs can be brought simultaneously into contact. This is made possible by the low degree of intra-chromosome entanglement and the large number of cliques in the gene coregulatory network. A clique is a set of genes coregulated all together as a group. The constrained conformations for the model chromosome 19 are further shown to be organized in spatial macrodomains that are similar to those inferred from recent HiC measurements. The findings indicate that gene coregulation and colocalization are largely compatible and that this relationship can be exploited to draft the overall spatial organization of the chromosome in vivo. The more general validity and implications of these findings could be investigated by applying to other eukaryotic chromosomes the general and transferable computational strategy introduced here.

Type I and III interferons share similar antiviral properties, but there are some important distinctions. Hartmann and colleagues review the specialized functions of type III interferons, including their ability to mediate antiviral functions at barrier surfaces. Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain healthy mucosal surfaces through immune protection, without the significant immune-related pathogenic risk associated with type I IFN responses. Type III IFNs also target the human liver, with dual effects: they induce an antiviral state in hepatocytes, but specific IFN-λ4 action impairs the clearance of hepatitis C virus and could influence inflammatory responses. This constitutes a paradox that has yet to be resolved.

The protozoan Leishmania chagasi can cause disseminated, fatal visceral leishmaniasis (VL) or asymptomatic infection in humans. We hypothesized that host genetic factors contribute to this variable response to infection. A family study was performed in neighborhoods of endemicity for L. chagasi near Natal in northeastern Brazil. Study subjects were assessed for the presence of VL or asymptomatic infection, which was defined by a positive delayed-type hypersensitivity (DTH) skin test response to Leishmania antigen without disease symptoms. A genomewide panel of 385 autosomal microsatellite markers in 1254 subjects from 191 families was analyzed to identify regions of linkage. Regions with potential linkage to the DTH response on chromosomes 15 and 19, as well as a novel region on chromosome 9 with potential linkage to VL, were identified. Understanding the genetic factors that determine whether an individual will develop symptomatic or asymptomatic infection with L. chagasi may identify proteins essential for immune protection against this parasitic disease and reveal strategies for immunotherapy or prevention.

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality worldwide. Defects in trophoblast invasion, differentiation of extravillous trophoblasts and spiral artery remodeling are key factors in PE development. Currently there are no predictive biomarkers clinically available for PE. Recent technological advancements empowered transcriptome exploration and led to the discovery of numerous non-coding RNA species of which microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most investigated. They are implicated in the regulation of numerous cellular functions, and as such are being extensively explored as potential biomarkers for various diseases. Altered expression of numerous lncRNAs and miRNAs in placenta has been related to pathophysiological processes that occur in preeclampsia. In the following text we offer summary of the latest knowledge of the molecular mechanism by which lnRNAs and miRNAs (focusing on the chromosome 19 miRNA cluster (C19MC)) contribute to pathophysiology of PE development and their potential utility as biomarkers of PE, with special focus on sample selection and techniques for the quantification of lncRNAs and miRNAs in maternal circulation.

Several placental microRNAs (miRNAs) have been identified as pregnancy-associated molecules with the potential for use in estimating the condition of the placenta. Our understanding of these novel molecules is still limited, however. The aim of this study was to isolate and characterize pregnancy-associated miRNAs in maternal plasma. By microarray-based screening of 723 human miRNAs, we selected miRNAs that exhibited signal intensities >100 times higher in placental tissues than in the corresponding whole blood samples. Subsequent quantitative real-time reverse-transcription PCR revealed miRNAs produced predominantly in the placenta that showed significantly decreased concentrations in maternal plasma after delivery. These miRNAs were identified as pregnancy-associated miRNAs. We selected 82 miRNAs produced predominantly in the placenta and identified 24 as pregnancy-associated miRNAs. The genes encoding these miRNAs included 16 that are clustered on 19q13.42 and 5 clustered on 14q32. As the pregnancy progressed into the third trimester, the plasma concentrations of cell-free chromosome 19-derived miRNAs (has-miR-515-3p, has-miR-517a, has-miR-517c, has-miR-518b, and has-miR-526b) increased significantly (P = 0.0284, 0.0069, 0.0125, 0.0284, and 0.0093, respectively, Wilcoxon signed rank test), whereas that of cell-free has-miR-323-3p on chromosome 14q32.31 showed no change (P = 0.2026). In addition to the known pregnancy-associated miRNAs, we identified new pregnancy-associated miRNAs with our microarray-based approach. Most of the genes encoding these miRNAs were clustered on 19q13.42 or 14q32, which are critical regions for placental and embryonic development. These new pregnancy-associated miRNAs may be useful molecular markers for monitoring pregnancy-associated diseases.

Adult-type diffuse gliomas are divided into Astrocytoma, IDH-mutant, Oligodendroglioma, IDH-mutant and 1p/19q-codeleted and Glioblastoma, IDH-wildtype based on the IDH mutation, and 1p/19q codeletion status. To determine the treatment strategy for these tumors, pre-operative prediction of IDH mutation and 1p/19q codeletion status might be effective. Computer-aided diagnosis (CADx) systems using machine learning have been noted as innovative diagnostic methods. However, it is difficult to promote the clinical application of machine learning systems at each institute because the support of various specialists is essential. In this study, we established an easy-to-use computer-aided diagnosis system using Microsoft Azure Machine Learning Studio (MAMLS) to predict these statuses. We constructed an analysis model using 258 adult-type diffuse glioma cases from The Cancer Genome Atlas (TCGA) cohort. Using MRI T2-weighted images, the overall accuracy, sensitivity, and specificity for the prediction of IDH mutation and 1p/19q codeletion were 86.9%, 80.9%, and 92.0%, and 94.7%, 94.1%, and 95.1%, respectively. We also constructed an reliable analysis model for the prediction of IDH mutation and 1p/19q codeletion using an independent Nagoya cohort including 202 cases. These analysis models were established within 30 min. This easy-to-use CADx system might be useful for the clinical application of CADx in various institutes.

Background Breast cancer (BC) is the most prevalent cancer among females worldwide. Numerous studies suggest that specific RNAs play a crucial role in carcinogenesis. The primate-specific microRNA gene cluster located on the 19q27.3 region of chromosome 19 (C19MC) could potentially regulate tumor cell proliferation, migration, and invasion. Objective The objective of this study was to compare the expression of miRNAs from the C19MC cluster in breast cancer tumor and non-tumor samples, as well as in the serum of individuals affected by BC and healthy individuals. Methods Peripheral blood was collected from 100 BC patients and 100 healthy individuals, and breast cancer samples including tumor and margin tissues were obtained. After RNA extraction, Real-time PCR was employed to investigate the expression of C19MC, specifically mir-515–1, mir-515–2, mir-516-A1, mir-516-A2, mir-516-B1, mir-516-B2, mir-517-A, mir-517-B, mir-517-C, and mir-518-A1, in the serum and tissue of BC patients and tumor margins. Statistical analyses and ROC curves were generated using GraphPad Prism software (v8.04), with a significance level set at p  < 0.05. Results Our findings demonstrate a strong correlation between high expression of all C19MC miRNAs mentioned, except for mir-517-B, mir-517-C and mir- 518 in BC. These miRNAs show potential as notable non-invasive tumor markers. Conclusion The data obtained from our study support the overall impact of C19MC miRNAs in BC detection and emphasize the potential role of several C19MC members in this process.

Prader-Willi syndrome (PWS) is a well-known imprinting disorder arising from a loss of paternally imprinted gene(s) at 15q11.2-q13. We report a typical PWS patient with a balanced reciprocal translocation, 46, XY, t(15;19)(q11.2;q13.3). After Illumina whole-genome sequencing, we used BreakDancer-1.45 software to predict candidate breakpoints and manually investigated via the Integrated Genome Viewer. Breakpoint PCR followed by Sanger sequencing determined the t(15;19) breakpoints. We investigated the expression of upstream/centromeric and downstream/telomeric genes of the 15q11.2 breakpoint by reverse transcriptase PCR, using total RNA extracted from the patient's lymphoblasts. Of note, the expression of paternally expressed genes PWAR6, SNORD109A/B, SNORD116, IPW, and PWAR1, downstream of the breakpoint, was abolished. Interestingly, the breakpoint did not destroy protein coding genes or individual snoRNAs. These results indicate that these genes may play a major role in the PWS phenotype.