Abstract
Motivation
Eukaryotic chromosomes adapt a complex and highly dynamic three-dimensional (3D) structure, which profoundly affects different cellular functions and outcomes including changes in ...epigenetic landscape and in gene expression. Making the scenario even more complex, cancer cells harbor chromosomal abnormalities e.g. copy number variations (CNVs) and translocations altering their genomes both at the sequence level and at the level of 3D organization. High-throughput chromosome conformation capture techniques (e.g. Hi-C), which are originally developed for decoding the 3D structure of the chromatin, provide a great opportunity to simultaneously identify the locations of genomic rearrangements and to investigate the 3D genome organization in cancer cells. Even though Hi-C data has been used for validating known rearrangements, computational methods that can distinguish rearrangement signals from the inherent biases of Hi-C data and from the actual 3D conformation of chromatin, and can precisely detect rearrangement locations de novo have been missing.
Results
In this work, we characterize how intra and inter-chromosomal Hi-C contacts are distributed for normal and rearranged chromosomes to devise a new set of algorithms (i) to identify genomic segments that correspond to CNV regions such as amplifications and deletions (HiCnv), (ii) to call inter-chromosomal translocations and their boundaries (HiCtrans) from Hi-C experiments and (iii) to simulate Hi-C data from genomes with desired rearrangements and abnormalities (AveSim) in order to select optimal parameters for and to benchmark the accuracy of our methods. Our results on 10 different cancer cell lines with Hi-C data show that we identify a total number of 105 amplifications and 45 deletions together with 90 translocations, whereas we identify virtually no such events for two karyotypically normal cell lines. Our CNV predictions correlate very well with whole genome sequencing data among chromosomes with CNV events for a breast cancer cell line (r = 0.89) and capture most of the CNVs we simulate using Avesim. For HiCtrans predictions, we report evidence from the literature for 30 out of 90 translocations for eight of our cancer cell lines. Furthermore, we show that our tools identify and correctly classify relatively understudied rearrangements such as double minutes and homogeneously staining regions. Considering the inherent limitations of existing techniques for karyotyping (i.e. missing balanced rearrangements and those near repetitive regions), the accurate identification of CNVs and translocations in a cost-effective and high-throughput setting is still a challenge. Our results show that the set of tools we develop effectively utilize moderately sequenced Hi-C libraries (100-300 million reads) to identify known and de novo chromosomal rearrangements/abnormalities in well-established cancer cell lines. With the decrease in required number of cells and the increase in attainable resolution, we believe that our framework will pave the way towards comprehensive mapping of genomic rearrangements in primary cells from cancer patients using Hi-C.
Availability and implementation
CNV calling: https://github.com/ay-lab/HiCnv, Translocation calling: https://github.com/ay-lab/HiCtrans and Hi-C simulation: https://github.com/ay-lab/AveSim.
Supplementary information
Supplementary data are available at Bioinformatics online.
The global pandemic caused by the newly described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused worldwide suffering and death of unimaginable magnitude from coronavirus ...disease 2019 (COVID-19). The virus is transmitted through aerosol droplets, and causes severe acute respiratory syndrome. SARS-CoV-2 uses the receptor-binding domain of its spike protein S1 to attach to the host angiotensin-converting enzyme 2 receptor in lung and airway cells. Binding requires the help of another host protein, transmembrane protease serine S1 member 2. Several factors likely contribute to the efficient transmission of SARS-CoV-2. The receptor-binding domain of SARS-CoV-2 has a 10- to 20-fold higher receptor-binding capacity compared with previous pandemic coronaviruses. In addition, because asymptomatic persons infected with SARS-CoV-2 have high viral loads in their nasal secretions, they can silently and efficiently spread the disease. PCR-based tests have emerged as the criterion standard for the diagnosis of infection. Caution must be exercised in interpreting antibody-based tests because they have not yet been validated, and may give a false sense of security of being “immune” to SARS-CoV-2. We discuss how the development of some symptoms in allergic rhinitis can serve as clues for new-onset COVID-19. There are mixed reports that asthma is a risk factor for severe COVID-19, possibly due to differences in asthma endotypes. The rapid spread of COVID-19 has focused the efforts of scientists on repurposing existing Food and Drug Administration–approved drugs that inhibit viral entry, endocytosis, genome assembly, translation, and replication. Numerous clinical trials have been launched to identify effective treatments for COVID-19. Initial data from a placebo-controlled study suggest faster time to recovery in patients on remdesivir; it is now being evaluated in additional controlled studies. As discussed in this review, till effective vaccines and treatments emerge, it is important to understand the scientific rationale of pandemic-mitigation strategies such as wearing facemasks and social distancing, and implement them.
In this paper, we study the topological properties of the global supply chain network in terms of its degree distribution, clustering coefficient, degree-degree correlation, bow-tie structure, and ...community structure to test the efficient supply chain propositions proposed by E. J.S. Hearnshaw et al. The global supply chain data in the year 2017 are constructed by collecting various company data from the web site of Standard Poors Capital IQ platform. The in- and out-degree distributions are characterized by a power law of the form of gamma.sub.in = 2.42 and gamma.sub.out = 2.11. The clustering coefficient decays ( C ( k) ) ~ k - beta k with an exponent beta.sub.k = 0.46. The nodal degree-degree correlations (k.sub.nn (k)) indicates the absence of assortativity. The bow-tie structure of giant weakly connected component (GWCC) reveals that the OUT component is the largest and consists 41.1% of all firms. The giant strong connected component (GSCC) is comprised of 16.4% of all firms. We observe that upstream or downstream firms are located a few steps away from the GSCC. Furthermore, we uncover the community structures of the network and characterize them according to their location and industry classification. We observe that the largest community consists of the consumer discretionary sector based mainly in the United States (US). These firms belong to the OUT component in the bow-tie structure of the global supply chain network. Finally, we confirm the validity of Hearnshaw et al.s efficient supply chain propositions, namely Proposition S1 (short path length), Proposition S2 (power-law degree distribution), Proposition S3 (high clustering coefficient), Proposition S4 (fit-gets-richer growth mechanism), Proposition S5 (truncation of power-law degree distribution), and Proposition S7 (community structure with overlapping boundaries) regarding the global supply chain network. While the original propositions S1 just mentioned a short path length, we found the short path from the GSCC to IN and OUT by analyzing the bow-tie structure. Therefore, the short path length in the bow-tie structure is a conceptual addition to the original propositions of Hearnshaw.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the advent of the chromosome conformation capture technology, our understanding of the human genome 3D organization has grown rapidly and we now know that human interphase chromosomes are ...folded into multiple layers of hierarchical structures and each layer can play a critical role in transcriptional regulation. Alterations in any one of these finely-tuned layers can lead to unwanted cascade of molecular events and ultimately drive the manifestation of diseases and phenotypes. Here we discuss, starting from chromosome level organization going down to single nucleotide changes, recent studies linking diseases or phenotypes to changes in the 3D genome architecture.
Handwashing is now considered as one of the best safety measures to prevent COVID-19 infection. The effect of excessive handwashing for health on obsessive compulsive disorder (OCD) patients who are ...already having washing compulsion is not known. Furthermore, the fear of contamination of COVID-19 in patients who already have obsession of contamination is not known. This study aims to evaluate the effect of COVID-19 on OCD patients.
Phone interviews were done with 84 patients previously diagnosed with obsession of contamination and compulsive washing. Yale Brown Obsessive Compulsive Scale was used and the scores of the participants were compared to their prepandemic scores.
Only 5 patients (6%) had exacerbation of symptoms after the COVID-19 pandemic. Most of the patients did not report any deterioration of symptoms due to the pandemic.
Handwashing protocol does not aggravate the washing compulsion of patients. Similarly, the fear of infection with COVID-19 does not increase their fear of contamination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The compartmental organization of mammalian genomes and its changes play important roles in distinct biological processes. Here, we introduce dcHiC, which utilizes a multivariate distance measure to ...identify significant changes in compartmentalization among multiple contact maps. Evaluating dcHiC on four collections of bulk and single-cell contact maps from in vitro mouse neural differentiation (n = 3), mouse hematopoiesis (n = 10), human LCLs (n = 20) and post-natal mouse brain development (n = 3 stages), we show its effectiveness and sensitivity in detecting biologically relevant changes, including those orthogonally validated. dcHiC reported regions with dynamically regulated genes associated with cell identity, along with correlated changes in chromatin states, subcompartments, replication timing and lamin association. With its efficient implementation, dcHiC enables high-resolution compartment analysis as well as standalone browser visualization, differential interaction identification and time-series clustering. dcHiC is an essential addition to the Hi-C analysis toolbox for the ever-growing number of bulk and single-cell contact maps. Available at: https://github.com/ay-lab/dcHiC .
The eleven monohydrates of 1, 2, 3, 4-tetrahydroisoquinoline (THIQ) are analyzed through natural bond orbital (NBO) analysis and QTAIM methods employing M06-2X functional in DFT and MP2 methods. ...Here, the role of OH bonds as an acceptor and donor is critically analyzed. The role of lone pairs of O is critically monitored in two of the complexes, where N–H···O hydrogen bonds are present. The relative contributions of rehybridisation and hyperconjugation are compared in detail. Popelier criteria are satisfied in all the complexes barring a few exceptions involving weak hydrogen bonds. At the bond critical points (BCP), four monohydrates show higher values of electron density (ρ
C
) and negative values of total electron energy density (H
C
), while Laplacian
(
∇
2
ρ
C
)
remains positive. These complexes satisfy the criteria of partial covalency. All these are O–H⋅⋅⋅N-type bonds. Remaining h-bonds are weaker in nature. These are also confirmed by the smaller values of ρ
C
at the respective BCP. The variation of potential energy density (V
C
) among the complexes seems to be the most important factor in determining the nature of non-covalent interactions.
Every nation prioritizes the inclusive economic growth and development of all regions. However, we observe that economic activities are clustered in space, which results in a disparity in per-capita ...income among different regions. A complexity-based method was proposed by Hidalgo and Hausmann PNAS 106, 10570-10575 (2009) to explain the large gaps in per-capita income across countries. Although there have been extensive studies on countries' economic complexity using international export data, studies on economic complexity at the regional level are relatively less studied. Here, we study the industrial sector complexity of prefectures in Japan based on the basic information of more than one million firms. We aggregate the data as a bipartite network of prefectures and industrial sectors. We decompose the bipartite network as a prefecture-prefecture network and sector-sector network, which reveals the relationships among them. Similarities among the prefectures and among the sectors are measured using a metric. From these similarity matrices, we cluster the prefectures and sectors using the minimal spanning tree technique. The computed economic complexity index from the structure of the bipartite network shows a high correlation with macroeconomic indicators, such as per-capita gross prefectural product and prefectural income per person. We argue that this index reflects the present economic performance and hidden potential of the prefectures for future growth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate ...CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.
•Tisagenlecleucel (CTL019) has demonstrated clinical efficacy in relapsed/refractory B-cell ALL and CLL.•The cellular kinetic profile of tisagenlecleucel was consistent across the 2 diseases, with higher exposure in responding vs nonresponding patients.
Economies are frequently affected by natural disasters and both domestic and overseas financial crises. These events disrupt production and cause multiple other types of economic losses, including ...negative impacts on the banking system. Understanding the transmission mechanism that causes various negative second-order post-catastrophe effects is crucial if policymakers are to develop more efficient recovery strategies. In this work, we introduce a credit-based adaptive regional input-output (ARIO) model to analyse the effects of disasters and crises on the supply chain and bank-firm credit networks. Using real Japanese networks and the exogenous shocks of the 2008 Lehman Brothers bankruptcy and the Great East Japan Earthquake (March 11, 2011), this paper aims to depict how these negative shocks propagate through the supply chain and affect the banking system. The credit-based ARIO model is calibrated using Latin hypercube sampling and the design of experiments procedure to reproduce the short-term (one-year) dynamics of the Japanese industrial production index after the 2008 Lehman Brothers bankruptcy and the 2011 Great East Japan earthquake. Then, through simulation experiments, we identify the chemical and petroleum manufacturing and transport sectors as the most vulnerable Japanese industrial sectors. Finally, the case of the 2011 Great East Japan Earthquake is simulated for Japanese prefectures to understand differences among regions in terms of globally engendered indirect economic losses. Tokyo and Osaka prefectures are the most vulnerable locations because they hold greater concentrations of the above-mentioned vulnerable industrial sectors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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