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Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies1–8. However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer.

Motivated by increased interest in experiments in which light appears to propagate by tunnelling at superluminal velocity, the Lorentz invariant theory proposed by Partha Ghose to explain these surprising effects is revisited. This theory is based on the Harish-Chandra formalism, which describes the relativistic dynamics of a massless spin-1 boson, like a photon. Via this formalism, the Bohmian average transport velocity of the electromagnetic energy is formulated. It is proved that, if the dielectric making the waveguide is nonabsorptive and nondispersive, this velocity can be superluminal. This result is validated in the framework of quantum electrodynamics, demonstrating that the average velocity of the photon inside the waveguide is given by the contribution of instantaneous superluminal velocities. This theory, therefore, suggests the optimal conditions for designing optical devices capable of locally transporting electromagnetic energy at superluminal velocities mitigating the signal attenuation., 19 pages

Formulating a relativistic equation for particles with arbitrary spin remains an open challenge in theoretical physics. In this study, the main algebraic approaches used to generalize the Dirac and Kemmer Duffin equations for particles of arbitrary spin are investigated. It is proved that an irreducible relativistic equation formulated using spin matrices satisfying the commutation relations of the anti-de Sitter group leads to inconsistent results, mainly as a consequence of violation of unitarity and the appearance of a mass spectrum that does not reflect the physical reality of elementary particles. However, the introduction of subsidiary conditions resolves the problem of unitarity and restores the physical meaning of the mass spectrum. The equations obtained by these approaches are solved and the physical nature of the solutions is discussed., 26 pages, 1 figure

Формулировка релятивистского уравнения в случае частиц с произвольным спином остается открытой задачей в теоретической физике. Исследованы основные алгебраические подходы, позволяющие обобщить уравнения Дирака и Кеммера-Дэффина для произвольного спина частиц. Доказано, что неприводимое релятивистское уравнение, сформулированное с использованием матриц спина, удовлетворяющих коммутационным соотношениям группы анти-де Ситтера, приводит к противоречивым результатам, главным образом вследствие нарушения унитарности и появления спектра масс, который не отражает физическую природу элементарных частиц. Однако введение дополнительных условий решает проблему унитарности и восстанавливает физический смысл спектра масс. Найдены решения уравнений, полученных с помощью этих подходов, и обсуждается физическая природа решений.

In this study, the N-dimensional radial Schrodinger equation with an anharmonic sextic potential is solved by the extended Nikirov-Uranov method. We prove that the radial function can be factorised as the product between an exponential function and a polynomial function solution of the biconfluent Heun equation. The approach investigated in this article aims to be an alternative to other known methods of solving, as it has the advantage of dealing with simple, first-order differential and algebraic equations and avoiding numerous and laborious coordinate transformations and series expansions.

In this paper, the tunnelling of a particle through a potential barrier is investigated in the presence of a time-dependent perturbation. The latter is attributed to the process of the energy measurement of the scattered particle. The time-dependent Schrodinger equation of the model is exactly solved. The calculation of the probability density inside the barrier proves that the tunnelling dynamics is determined not only by the transmitted and reflected waves but also by their interference. Furthermore, the interference term is time-dependent and contribute to the scattering process duration. The tunnelling time is calculated as the time to stop the flow of probability density inside the barrier. This is the minimum duration of the measurement process before detecting the particle beyond the barrier. Based on this, a new method of estimating the tunnelling time by energy experimental measuring is proposed., 8 pages

Whole genome doubling promotes tumorigenesis through loss of chromatin segregation and compartment repositioning PART 2 hic_maps_K562.zip:Hi-C maps (.hic format) of K562 samples hic_features.zip hic_features/compartment_domains:contains, for each of the hic matrices, the compartmentdomains imputed by Calder in BED format hic_features/compartment_domain_boundaries:boundaries between adjacent compartment domains in Control andWGD samples from RPE TP53-/- cell line hic_features/compartment_scores:for each compartment domain in Control and WGD samples fromRPE TP53-/- cell line it reports its C-score hic_features/insulation_scores:for each of the Hi-C matrices, the insulation scores computed at50 Kb resolution, in bigwig format ihic_features/nsulation_boundaries:TAD boundaries detected using the insulation score, for each Hi-Csample chipseq.zip chipseq/input_normalized: contains bigwig files of ChIP-seq experiments generatedin this study. Files are log2 input normalized tracks. The "bw_signals_attributes.txt" file can be used to addmetadata to the tracks for visualization in IGV scRNAseq.zip differential_expression: contains the output of the differential expression analysis. A README file is present explaining the meaning of each column in the table expression: gene expression matrix (cell x gene) containing normalized expression value. A table containing metadata of each cell (like sample of origin, uuid) is also available infercnv: copy numbers inferred by INFERCNV. Linkage matrix providing the clustering output of the infercnv data is also provided. copy_numbers.zip ControlFREEC_log2_coverage_ratio_10Kb.seg: .seg file (to be loaded in IGV) containing coverage log2 fold-change between samples and control as computed by ControlFREEC for the detection of CNVs filtered_cnvs.seg: significant CNVs detected by ControlFREEC RPE_cnvs_20wTumors_merged.bed: consensus set of CNVs in RPE TP53-/- 20w post-WGD tumors mutations.zip RPE_somatic_all.maf:MAF file of mutations detected by Mutect2 on RPE TP53-/- sample RPE_somatic_all_FILTER_PASS.tsv: mutations passing the quality filters &nbsp

DNA is the molecular basis of life and would total about three meters if linearly untangled. To fit in the cell nucleus at the micrometer scale, DNA has, therefore, to fold itself into several layers of hierarchical structures, which are thought to be associated with functional compartmentalization of genomic features like genes and their regulatory elements. For this reason, understanding the mechanisms of genome folding is a major biological research problem. Studying chromatin conformation requires high computational resources and complex data analyses pipelines. In this chapter, we first present the PyGMQL software for interactive and scalable data exploration for genomic data. PyGMQL allows the user to inspect genomic datasets and design complex analysis pipelines. The software presents itself as a easy-to-use Python library and interacts seamlessly with other data analysis packages. We then use the software for the study of chromatin conformation data. We focus on the epigenetic determinants of Topologically Associating Domains (TADs), which are region of high self chromatin interaction. The results of this study highlight the existence of a “grammar of genome folding” which dictates the formation of TADs and boundaries, which is based on the CTCF insulator protein. Finally we focus on the relationship between chromatin conformation and gene expression, designing a graph representation learning model for the prediction of gene co-expression from gene topological features obtained from chromatin conformation data. We demonstrate a correlation between chromatin topology and co-expression, shedding a new light on this debated topic and providing a novel computational framework for the study of co-expression networks.

In this study the data of the OPERA and MINOS experiments, together with those related to the SN1987A supernova, are discussed in the context of the recent theories proposed for the superluminal muon neutrino. It is proved that for the models in which the Lorentz symmetry is violated, the decay mechanism leading to neutrino oscillation becomes possible. Within this framework, a new model based on the Hartman effect is proposed, according to which the neutrino becomes superluminal by quantum tunnelling, crossing a potential barrier generated by its interaction with the earth's crust matter. This model does not violate the Lorentz symmetry since the tachyonic state is generated by the quantum fluctuation of the neutrino initial energy, even if it requires to conjecture the presence of a quantum field that we ascribe to be that due to dark matter. In this model all superluminal neutrino decay mechanisms proposed in other studies are allowed. The hypothetical boson mediating the interaction between neutrino and dark matter is also discussed.

In this study, the Majorana equation for particles with arbitrary spin is solved for a half-integer spin free particle. The solution for the fundamental state, corresponding to the reference frame in which the particle is at rest, is compared with that obtained using the Dirac equation, especially as regards the approximation in the relativistic limit, in which the speed of the particle is close to that of light. Furthermore, the solutions that Majorana defines unphysical, proving that their occupation probability increases with the particle velocity, are taken into consideration. The anomalous behavior exhibited by these states also shows that for high-energy particles with small mass, transitions from a bradyonic state to a tachyonic state become possible., Comment: 17 pages, 2 figures

In this study, the Schrodinger equation of a valence electron in a periodic crystal potential is formulated and solved using the elliptic function formalism. The method allows double periodic lattice planes to be represented in the Gauss plane. The reality of the obtained eigenfunctions and the structure of the valence and conduction bands are also investigated., 11 pages, this is the preprint of the accepted manuscript

Background Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by specific vascular and obstetric manifestations and by antiphospholipid antibodies (aPL) positivity. Microvascular damage in the course of APS and “aPL carrier” patients without symptoms is poorly investigated. Objectives This study aims to compare nailfold videocapillaroscopy (NVC) microvascular parameters in APS patients and non-symptomatic "aPL carriers" and to investigate their possible correlations with different aPL subtypes. Methods NVC was performed during standard evaluations in 18 APS patients (mean age 50 ± 13.8 years), 24 "aPL carriers" without symptoms (mean age 46.4 ± 16.4 years), and 18 control patients (CTR) (mean age 74 ± 12.5 years) taking oral anticoagulants for non-immunological indications (i.e., cardiovascular accidents). All patients were investigated for the presence of dilated capillaries, giant capillaries, microhemorrhages, capillary loss, and further non-specific/specific abnormalities (i.e., branched “bushy” capillaries, sign of neoangiogenesis) by NVC. Every alteration was also classified according to a semi-quantitative score. Lupus anticoagulant, anticardiolipin antibodies, and antibeta2 glycoprotein I antibodies were tested in each patient. Results APS patients showed at NVC increased frequency of microhemorrhages (p = 0.039)—particularly a “comb-like” pattern (parallel hemorrhages) (p = 0.002)—than "aPL carriers". Of note, there were no significant differences concerning the isolated number of microhemorrhages between APS and the CTR group (p = 0.314), but “comb-like” hemorrhages were significantly more frequent in the APS group (p = 0.034). Not any significant correlation was found between the aPL subtypes and NVC parameters. Conclusions APS patients showed significantly a greater number of non-specific NVC abnormalities than "aPL carriers", particularly the “comb-like” NVC pattern. Oral anticoagulants may represent a confounding factor for isolated microhemorrhages. Not any correlation was found between aPL subtypes and NVC parameters. Further investigations are needed to better characterize the microvascular endothelium damage induced by aPL.

Breast Cancer comprises multiple subtypes implicated in prognosis. Existing stratification methods rely on the expression quantification of small gene sets. Next Generation Sequencing promises large amounts of omic data in the next years. In this scenario, we explore the potential of machine learning and, particularly, deep learning for breast cancer subtyping. Due to the paucity of publicly available data, we leverage on pan-cancer and non-cancer data to design semi-supervised settings. We make use of multi-omic data, including microRNA expressions and copy number alterations, and we provide an in-depth investigation of several supervised and semi-supervised architectures. Obtained accuracy results show simpler models to perform at least as well as the deep semi-supervised approaches on our task over gene expression data. When multi-omic data types are combined together, performance of deep models shows little (if any) improvement in accuracy, indicating the need for further analysis on larger datasets of multi-omic data as and when they become available. From a biological perspective, our linear model mostly confirms known gene-subtype annotations. Conversely, deep approaches model non-linear relationships, which is reflected in a more varied and still unexplored set of representative omic features that may prove useful for breast cancer subtyping.

In this study the tachyon-like Dirac equation, formulated by Chodos to describe superluminal neutrino, is solved. The analytical solutions are Gaussian wave packets obtained using the envelope method. It is shown that the superluminal neutrino behaves like a pseudo-tachyon, namely a particle with subluminal velocity and pure imaginary mass that fulfils the energy-momentum relation typical of classical tachyons. The obtained results are used to prove that the trembling motion of the particle position around the median, known as Zitterbewegung, also takes place for the superluminal neutrino, even if the oscillation velocity is always lower than the speed of light. Finally, the pseudo-tachyon wave packet is used to calculate the probability of oscillation between mass states, obtaining a formula analogous to the one obtained for the ordinary neutrino. This suggest that in the experiments concerning neutrino oscillation is not possible to distinguish tachyonic neutrinos from ordinary ones., 11 pages, 2 figures

In this paper, we revisit the two theoretical approaches for the formulation of the tachyonic Dirac equation. The first approach works within the theory of restricted relativity, starting from a Lorentz invariant Lagrangian consistent with a spacelike four-momentum. The second approach uses the theory of relativity extended to superluminal motions and works directly on the ordinary Dirac equation through superluminal Lorentz transformations. The equations resulting from the two approaches show mostly different, if not opposite, properties. In particular, the first equation violates the invariance under the action of the parity and charge conjugation operations. Although it is a good mathematical tool to describe the dynamics of a space-like particle, it also shows that the mean particle velocity is subluminal. In contrast, the second equation is invariant under the action of parity and charge conjugation symmetries, but the particle it describes is consistent with the classical dynamics of a tachyon. This study shows that it is not possible with the currently available theories to formulate a covariant equation that coherently describes the neutrino in the framework of the physics of tachyons, and depending on the experiment, one equation rather than the other should be used., Comment: 14 pages

This study reconsiders the decay of an ordinary particle in bradyons, tachyons and luxons in the field of the relativistic quantum mechanics. Lemke already investigated this from the perspective of covariant kinematics. Since the decay involves both spacelike and timelike particles, the study uses the Majorana equation for particles with an arbitrary spin. The equation describes the tachyonic and bradyonic realms of massive particles, and approaches the problem of how spacelike particles might develop. This method confirms the kinematic constraints that Lemke theory provided and proves that some possible decays are more favourable than others are., 9 pages

A broad class of physical processes is described by second-order differential equations. The equation of waves, the diffusion equation and the stationary equation, which are found both in classical and quantum physics, belong to this class. In this article, these equations are reformulated under the assumption that the source determining the physical phenomenon acts instantaneously, using the formalism of generalised functions. Some particular cases of these equations are precisely solved by applying the Fourier transform. The obtained solutions form a subspace of the singular generalised functions’ space and are mentioned by the product between a step function and a function with at most a finite number of discontinuity points.

Motivation With the spreading of biological and clinical uses of next-generation sequencing (NGS) data, many laboratories and health organizations are facing the need of sharing NGS data resources and easily accessing and processing comprehensively shared genomic data; in most cases, primary and secondary data management of NGS data is done at sequencing stations, and sharing applies to processed data. Based on the previous single-instance GMQL system architecture, here we review the model, language and architectural extensions that make the GMQL centralized system innovatively open to federated computing. Results A well-designed extension of a centralized system architecture to support federated data sharing and query processing. Data is federated thanks to simple data sharing instructions. Queries are assigned to execution nodes; they are translated into an intermediate representation, whose computation drives data and processing distributions. The approach allows writing federated applications according to classical styles: centralized, distributed or externalized. Availability The federated genomic data management system is freely available for non-commercial use as an open source project at http://www.bioinformatics.deib.polimi.it/FederatedGMQLsystem/ Contact {arif.canakoglu, pietro.pinoli}@polimi.it Summary

We investigate the important clinical problem of predicting prognosis-related breast cancer molecular subtypes using whole-transcriptome information present in The Cancer Genome Atlas Project (TCGA) dataset. From a Machine Learning perspective, the data is both high-dimensional with over nineteen thousand features, and extremely small with only about one thousand labeled instances in total. To deal with the dearth of information we compare classical, deep and semi-supervised learning approaches on the subtyping task. Specifically, we compare a L\(_1\)-regularized Logistic Regression, a 2-hidden layer Feed Forward Neural Network and a Variational Autoencoder based semi-supervised learner that makes use of pan-cancer TCGA data as well as normal breast tissue data from a second source. We find that the classical supervised technique performs at least as well as the deep and semi-supervised learning approaches, although learning curve analysis suggests that insufficient unlabeled data may be being provided for the chosen semi-supervised learning technique to be effective.

Recently, a new theory based on superluminal tunnelling has been proposed to explain the transition of highly energetic neutrinos propagating in matter to tachyonic states. In this work, we determine the possible mechanisms that lead neutrinos into a superluminal realm based on the assumption that ultrarelativistic neutrinos travelling in matter lose part of their energy with the emission of Bremsstrahlung radiation. The obtained photons, in turn, can create neutrino antineutrino pairs, one or both of which can be superluminal. We also prove that pair creation may occur with neutrino flavour oscillation provided that only one of them is a space-like particle. This suggests that mass oscillation and superluminal behaviour could be related phenomena. Finally, using the generalised Lorentz transformations, we formulate the Lagrangian of the kinematically allowed scattering processes. The structure of this Lagrangian is consistent with the formalism of the Standard Model. Based on this Lagrangian, at least one of the particles forming the pair must always be subluminal. The possibility that the pair creation process is mediated by a dark photon is also discussed., Comment: 13 pages

Topologically associated domains (TADs) are defined as regions of self-interaction. To date, it is unclear how to reconcile TAD structure with CTCF site orientation, which is known to coordinate chromatin loops anchored by Cohesin rings at convergent CTCF site pairs. We first approached this problem by 4C analysis of the FKBP5 locus. This uncovered a CTCF loop encompassing FKBP5 but not its entire TAD. However, adjacent CTCF sites were able to form ‘back-up’ loops and these were located at TAD boundaries. We then analysed the spatial distribution of CTCF patterns along the genome together with a boundary identity conservation ‘gradient’ obtained from primary blood cells. This revealed that divergent CTCF sites are enriched at boundaries and that convergent CTCF sites mark the interior of TADs. This conciliation of CTCF site orientation and TAD structure has deep implications for the further study and engineering of TADs and their boundaries.

An evanescent wave is a non-propagating wave with an imaginary wave vector. In this study, we prove that these are solutions of the tachyon-like Klein Gordon equation, and that in the tunneling of ultrarelativistic half integer spin particles they describe superluminal states arising from interactions between a particle and barrier. These states decay as a particle emerges from the opposite side of a potential barrier, conserving the same initial energy but not necessarily the same mass. The obtained theory is applied to the neutrino, to explain flavor oscillations during free flight and determine the conditions that maximize the probability of their occurrence., Comment: 9 pages, 1 figure

In this study, a novel theory to investigate the mass oscillation of particles is proposed. It has been proven that, at high-energy conditions, the fermion field described by Dirac Lagrangian interacts with the half-integer spin tachyon field with negative energy, causing the formation of composite particles whose mass depends on the total angular momentum. The proposed theory is based on a new interpretation of the Majorana equation for particles with arbitrary spin and shows that mass oscillation is a phenomenon in which the component of particle decay prevails over that of mixing mass states. Using the kinematic of Lemke for spacelike particle decay, we propose a mechanism able to explain the neutrino flavour change. The proposed mechanism is also investigated concerning the shape of its spectrum. Finally, the Lagrangian field of composite particles is formulated., Comment: 18 pages, 1 figure

Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.